Pediatric HIV Infection

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Practice Essentials

Since the first cases of human immunodeficiency virus (HIV) infection were identified, the number of children infected with HIV has risen dramatically in developing countries, the result of an increased number of HIV-infected women of childbearing age in these areas. HIV is a retrovirus and can be transmitted vertically, sexually, or via contaminated blood products or IV drug abuse. Vertical HIV infection occurs before birth, during delivery, or after birth.

The genome layouts of HIV-1 and HIV type 2 (HIV-2) are shown in the image below.



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Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

Essential update: Study suggests benefits to starting HAART earlier in HIV-infected children

In a study of HIV-1-infected, highly active antiretroviral therapy (HAART)-naive children, Yin et al found that beginning HAART at younger ages and healthier CD4 levels results in better immune recovery.[1, 2] In all, 72% of children who were immunosuppressed at baseline recovered to normal within 4 years after initiating HAART therapy. Compared with children with severe immunosuppression, more children with mild immunosuppression (+36%) or advanced immunosuppression (+20.8%) recovered a normal CD4 percentage.

For every 5-year increase in baseline age, the proportion of children who achieved a normal CD4 percentage fell by 19%.[2] Combining age effects and baseline CD4 percentage resulted in more than 90% recovery when HAART was initiated in children with mild immunosuppression at any age or advanced immunosuppression at an age younger than 3 years. Most of the immunologic benefits of HAART remained significant at 4 years.

Signs and symptoms

History

Signs and symptoms of pediatric HIV infection include the following:

Physical examination

Signs and symptoms of pediatric HIV infection found during physical examination include the following:

See Clinical Presentation for more detail.

Diagnosis

Detection of antibody to HIV is the usual first step in diagnosing HIV infection. The 2010 Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children[3] recommendations for diagnosing infants include the following:

An antibody test to document seroreversion to HIV antibody–negative status in uninfected infants is no longer recommended.

In older children and adults, an enzyme-linked immunosorbent assay (ELISA) to detect HIV antibody, followed by a confirmatory Western blot (which has increased specificity), should be used to diagnose HIV infection.

Rapid HIV tests, which provide results in minutes, simplify and expand the availability of HIV testing. Their sensitivity is as high as 100%, but they must be followed with confirmatory Western blotting or immunofluorescence antibody testing, as with conventional HIV antibody tests.

See Workup for more detail.

Management

Appropriate ART and therapy for specific infections and malignancies are critical in treating patients who are HIV positive. Classes of antiretroviral agents include the following:

Combination ART with at least 3 drugs from at least 2 classes of drugs is recommended for initial treatment of infected infants, children, and adolescents because it provides the best opportunity to preserve immune function and delay disease progression. Drug combinations for initial therapy in ART-naive children include a backbone of 2 NRTIs plus 1 NNRTI or 1 PI.

Pediatric HIV experts agree that infected infants who have clinical symptoms of HIV disease or evidence of immune compromise should be treated.[3] Patients aged 1 year or older with acquired immunodeficiency syndrome (AIDS) or significant symptoms should be aggressively treated regardless of CD4+ percentage and count or plasma HIV RNA level.

In addition to antiretroviral drugs (ARDs), other types of medication are required as appropriate for specific infections or malignancies. For example, P jiroveci pneumonia prophylaxis is recommended in patients who are HIV positive and younger than 1 year and in older children based on CD4+ counts.

See Treatment and Medication for more detail.

Background

Over the past 30 years, since the first cases of what is now recognized as human immunodeficiency virus (HIV) infection were identified in 1981, the number of children infected with HIV has increased dramatically in developing countries because the number of HIV-infected women of childbearing age has risen. However, great advances have been made in the United States and in other industrialized nations to control transmission of the virus from mother to infant.

In the United States, universal prenatal HIV testing has been recommended to obstetricians since 1995. However, this testing was not mandatory in all states. Before prenatal testing was common, diagnosing HIV infections in a woman after diagnosing it in her child was not unusual, and the diagnosis of acquired immunodeficiency syndrome (AIDS) in a previously healthy child was not rare.

Before 1985, one way in which children were infected was the transfusion of blood-products. Improved screening tests have essentially eliminated such transmission. A common way adolescents become infected is by engaging in high-risk behaviors such as unprotected sexual intercourse and injection drug abuse.

Surveillance data now show that the only group with increasing HIV incidence is men who have sex with men. The proportion of this population who are unaware of their infection is high, with unawareness among young men (18-29 y) reaching 63%.[4]

In the United States, youths aged 13-24 years accounted for 25.7% of new HIV infections in 2010.[5]

In pediatric patients, HIV infection progresses as it does in adults, although surveillance data from the Centers for Disease Control and Prevention (CDC) suggest that patients who are aged 13-24 years when diagnosed with AIDS survive longer than older individuals do. Vertically transmitted HIV can cause rapidly progressive, chronically progressive, or adultlike disease in which a significant clinical latency period occurs before symptoms appear.

The World Health Organization (WHO)[6] estimates that approximately 2.5 million children were living with HIV infection as of 2009. In 2009 alone, 370,000 children were newly infected.[7] This is a drop of 24% from 5 years earlier.[8]

Not only are the children themselves ravaged by disease, but their primary caregivers have also often succumbed to AIDS. This is most prevalent in sub-Saharan Africa, where an estimated 11.6 million children had been orphaned by AIDS as of 2007.

Although 2 strains of HIV have currently been identified, most patients who have AIDS are positive for HIV type 1 (HIV-1) or are positive for both HIV-1 and HIV type 2 (HIV-2). HIV-2 infection is most commonly observed in West Africa.

Vertical transmission of HIV from mother to child is the main route by which childhood HIV infection is acquired; the risk of perinatal acquisition is 25-40% without intervention.[9] Perinatal transmission of infection by the mother accounts for 80% of pediatric HIV disease cases in the United States. Perinatal transmission can occur in utero, during the peripartum period, and from breastfeeding.

Other routes of transmission, such as transfusion of blood and blood components, are rare in the United States but still exist in developing countries. Sexual abuse of children and high-risk behaviors in adolescents also contribute to youth HIV infection.

A variety of signs and symptoms should alert the clinician to the possibility of HIV infection in a child. The presentations include recurrent bacterial infections, unrelenting fever, unrelenting diarrhea, unrelenting thrush, recurrent pneumonia, chronic parotitis, generalized lymphadenopathy, delay in development with failure to thrive, and significant pruritic dermatoses. Mucocutaneous eruptions may be the first sign of HIV infection and may vary in presentation, depending on the child's immune status.

For information on HIV infection in adults and adolescents, see HIV Disease.

Pathophysiology

HIV can be transmitted vertically, sexually, or via contaminated blood products or IV drug abuse. Vertical HIV infection occurs before birth, during delivery, or after birth. With infection before birth (period 1), the fetus can be hematologically infected by means of transmission across the placenta or across the amniotic membranes, especially if the membranes are inflamed or infected.

Most vertical infections occur during delivery (period 2), and many factors affect the risk of infection during this period (see Deterrence/Prevention). In general, the longer and the greater amount of contact the neonate has with infected maternal blood and cervicovaginal secretions, the greater the risk of vertical transmission. Premature and low-birthweight neonates appear to have an increased risk of infection during delivery because of their reduced skin barrier and immunologic defenses.

Postnatal vertical transmission (period 3) occurs with the ingestion of HIV in the breast milk.

HIV virology

HIV is a retrovirus. Structurally, a lipid bilayer envelope surrounds the cylindrical core of HIV, which contains the RNA genetic information and the machinery that promotes viral replication and integration during initial cellular infection. From the outside, the virion appears spherical, with a diameter of 110 nm.

HIV has a variety of structural and nonstructural proteins that determine the interaction of the virus with the host's immune system and cellular components. The genome layouts of HIV-1 and HIV type 2 (HIV-2) are shown in the image below.



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Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

The HIV virus attaches to the host cell by the association of a surface glycoprotein to the CD4 molecule; therefore, it primarily infects CD4+ lymphocytes and macrophages.

After HIV enters a host, trimeric gp120 glycoproteins that protrude from its lipoprotein bilayer envelope bind to CD4 cell-surface receptors and CCR5 or CXCR4 chemokine co-receptors. Juxtapositioned co-receptors are needed for viral infection. The V3 region of the gp120 glycoprotein determines cellular tropism, and tropism is involved in syncytial formation. M-tropic (nonsyncytial) strains prefer the CCR5 co-receptor and are the primary causes of infection.

Deficiency of CCR5 chemokine co-receptors is present in as many as 10% of Europeans and 20% of Ashkenazi Jews, and it appears to confer some protection against infection. After gp120 binds to the receptors, an associated gp41 transmembrane glycoprotein is inserted into the cell membrane and initiates cell-membrane fusion.

Upon entering the cell, the protease enzyme produces the reverse transcriptase and ribonuclease (RNAse) H enzymes responsible for synthesizing the single-stranded DNA (ssDNA) molecules and primers necessary to produce the complementary DNA strand. Because reverse transcriptase lacks proofreading capacity, considerable base-to-base variability results. The high mutation rate, combined with the high reproductive rate, results in substantial evolution and subsequent resistance to treatment.

Once the virus core enters the cell cytoplasm of the host, viral reverse transcriptase copies viral RNA to the DNA of the host. The viral DNA is then transported into the nucleus and incorporated into the DNA of that cell. If activated, viral expression can result in new viral RNA and proteins. New viral core proteins, enzymes, and viral RNA molecules can induce budding, with additional cell infection.

Immune response

Acute infection rapidly increases the viral load and causes a mild-to-moderate viremia. Although viral loads tend to diminish rapidly after acute infection in adults, they decrease slowly in vertically infected children and may not reach baseline levels until age 4-5 years. Although infants possess numerous antigen-presenting and effector cells compared with adults, their cytokine production, proliferation, and cytotoxicity are reduced.

Envelope-specific cytotoxic T-lymphocytes are less common in children who vertically acquire the disease than in children who acquire HIV by means of blood transfusion. Among those with vertically acquired disease, such lymphocytes are least common in those with rapidly progressing disease. Precursors of cytotoxic T-lymphocyte that are specific to HIV type 1 (HIV-1) do not develop in significant number until the child is aged 1 year.

In adults, antibodies to gp120 develop several months after the initial viremia occurs. The development of broadly neutralizing antibodies is associated with slowed disease progression in adults, children, and infants.

The reduction in cell-mediated immunity and secondary B-cell dysfunction result in the immunocompromised state and in the proliferation of opportunistic infections and malignancies. An elevated level of activation-induced cell death resulting from apoptosis of T cells occurs in patients who are HIV positive.

The CD95/Fas receptor/ligand system is necessary for the apoptosis of T cells, and abnormalities in this system are linked with increased T-cell death in patients who are HIV positive. As the immune status deteriorates, an increase in CD95+ T cells is found; conversely, a low CD95+ T-cell count is found in asymptomatic patients who are HIV positive.

Hematopoietic effects

Although HIV infects hematopoietic stem cells, the importance is minor. Hematopoietic disturbances are believed to occur as a consequence of changes in the microenvironment of the marrow and of deficiencies in local and systemic growth factors.

In typical conditions, the stroma of the marrow promotes stem cell proliferation and differentiation by producing granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-3. HIV-infected stroma produces less G-CSF and IL-3 than normal and produces excessive tumor necrosis factor (TNF)-alpha and IFN-gamma. This cytokine dysregulation halts the production of badly needed hematopoietic cell lines and causes apoptosis of committed progenitor cells.

HIV also appears to retard the production of thrombopoietin in the liver and erythropoietin in the kidney. In addition to a low serum erythropoietin level, HIV-induced anemia is also a result of a blunted response to erythropoietin.

Thrombocytopenia occurs in 40% of patients with HIV infection during the course of the disease. It is most common in people with advanced disease, those who use IV drugs, African Americans, and those with a history of anemia or lymphoma. The presence of thrombocytopenia suggests a shortened survival time.

Immune thrombocytopenia may occur in half of the cases and appears to be the result of molecular mimicry of the platelet glycoprotein (GP)-IIb/IIIa receptor by the HIV-GP 160/120 antigen. Decreased platelet production is common in HIV infection regardless of the platelet count, and it may be associated with the ultrastructural damage in HIV-infected megakaryocytes.

Anemia may be present in as many as 20% of patients at the time of diagnosis, and it occurs in as many as 80% of patients at some point. Patients with clinical AIDS are more likely than others to have anemia, as are patients with low CD4+ counts.

The etiology is probably multifactorial in most patients. Common contributing factors are bone marrow suppression, iatrogenic causes, vitamin deficiencies, suppressed erythropoietin production, and a blunted erythropoietin response. Bone marrow infiltration with lymphoma or Kaposi sarcoma may be noted. Bone marrow suppression may be due to pathogens such as MAC, parvovirus B19, or CMV. Disseminated fungemia can cause anemia.

Neutropenia is observed in 10% of patients with early asymptomatic HIV infections and in 50% of patients with AIDS. Neutropenia results from the aforementioned mechanisms, as well as from medication. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF deficiencies not only reduce neutrophil production but also reduce granulocytic and monocytic function. GM-CSF and G-CSF promote increased neutrophilic function, including superoxide production, phagocytosis, intracellular killing, and antibody-dependent cellular cytotoxicity.

Neurologic effects

HIV exhibits tropism for the CNS, especially the microglia. As many as 10% of children with AIDS have progressive encephalopathy. Progressive white matter degeneration and brain atrophy may develop. Neurologic symptoms develop along with developmental delay.

Viral resistance

In terms of the mechanisms of resistance development, the rapid turnover rate and high error rate of reverse transcriptase induces 3300 new single mutations per day. When a mutation improves the survival of the virus in an existing drug environment, that quasispecies is selected to reproduce. The higher the viral load and the higher the rate of replication, the greater the number of resistant quasispecies. Quasispecies can be transmitted to a fetus or neonate.

HIV resistance develops because of low antiretroviral drug (ARD) levels due to several factors including variations in drug absorption and metabolism and noncompliance because of adverse effects or a poor understanding of the importance of the medication. Viral sanctuary sites may be exposed to low levels of ARDs, and resistant quasispecies may develop.

Etiology

Infection is due to HIV, a complex member of the Lentivirus genus of the Retroviridae family. HIV-1 is the most common cause of HIV infection in the Americas, in Europe, in Asia, and in Africa. HIV-2 has caused epidemics in West Africa, although this virus is also found in European countries. HIV-2 disease progresses more slowly than HIV-1 disease, and HIV-2 is less transmissible than HIV-1.

HIV-1 subtypes differ by geographic region. HIV-1 subtype B is predominant in the United States. Non-B subtypes are particularly prevalent in Africa and Asia. The high transmission rate from Africa to Europe has increased the diversity of subtypes in Europe. Non-B subtype HIV-1 infections are increasing in the United States.

Vertical transmission of HIV from mother to child is the main route by which childhood HIV infection is acquired; the risk of perinatal acquisition is 25%. African epidemiologic data of almost 2000 infants indicate that female infants may be more susceptible to HIV infection before birth and continuing after birth compared with male infants.

Epidemiology

United States statistics

The HIV seroprevalence rate in pregnant women is as high as 0.3%. The seroprevalence of women infected with HIV is highest in the Northeast, followed by the South. Perinatal HIV transmission rates are 25% but as low as 2% in untreated women with viral loads of less than 100 copies/mL.

Although prophylactic interventions have reduced vertical transmissions, cases of perinatal HIV transmission continue to occur.[10] This is largely because of missed opportunities for prevention, particularly among women who lack prenatal care or who are not being offered voluntary HIV counseling and testing during pregnancy. In many as 40% of the mothers of infants with perinatally acquired HIV infection, the HIV infection was not known before delivery.

The CDC estimates that in 2009, in the 40 states with confidential name-based HIV infection reporting, an estimated 131 infants acquired HIV infection by means of vertical transmission.[11] Estimates place the peak of perinatally-transmitted HIV in the US at 1651 cases in 1991.

The CDC estimates that in 2009, in those 40 states, the number of pediatric HIV infections diagnosed was as follows[12] :

In 2009, 12 cases of perinatally transmitted late HIV disease (AIDS) were diagnosed. The estimated cumulative number of perinatally transmitted AIDS cases diagnosed through 2009 is 8640.

At the end of 2008, 3022 children younger than 13 years were living with HIV infection in the 40 states with confidential name-based HIV infection reporting.

In the entire United States in 2009, an estimated 13 cases of AIDS were diagnosed in children younger than 13 years. The cumulative estimated number of diagnoses of AIDS in children younger than 13 years through 2009 in the United States is 9448.

In the United States, the number of new cases of pediatric AIDS is decreasing, mostly because of public health initiatives regarding universal HIV testing for pregnant women and use of zidovudine and other antiretroviral therapies in infected pregnant women and their newborn infants.

In 2007, 19 US children younger than 15 years died of HIV disease.[12] These numbers are in stark contrast to what is occurring internationally.

Adolescents and young adults

CDC HIV surveillance statistics from 2010 report that 25.7% (approximately 12,200 individuals) of new cases of HIV infection in the United States are in adolescents and young adults aged 13-24 years. Males accounted for 82.8% of new cases of HIV infection among this age group. Of these, 7,000 (57.4%) were African Americans, 2,390 (19.6%) were Latino, and 2,380 (19.5%) were white. Male-to-male sexual contact accounted for 72.1% (8,800 individuals). The percentage of youths tested for HIV infection was 12.9% in high-school students and 34.5% in individuals aged 18-24 years. Testing rates were lower in males than in females. More than half (59.5%) of youths with HIV infection are unaware of their infection.[5]

International statistics

The WHO estimates that over 33 million individuals are infected with HIV worldwide, and 90% of them are in developing countries. HIV has infected 4.4 million children and has resulted in the deaths of 3.2 million. Each day, 1800 children—the vast majority newborns—are infected with HIV. Approximately 7% of the population in sub-Saharan Africa is infected with HIV; these individuals represent 64% of the world's HIV-infected population. Furthermore, 76% of all women infected with HIV live in this region.

HIV-1 is the most common cause of HIV infection in the Americas, in Europe, in Asia, and in Africa. HIV-1 subtypes differ by geographic region. HIV-1 subtype B is predominant in the United States, though non-B subtype HIV-1 infections are increasing.

The HIV seroprevalence rate among pregnant women in South America is 0.3-5%; in sub-Saharan Africa, the range is 13-45%. In Europe, the HIV seroprevalence is greatest in western countries; France, Spain, and Italy have the highest incidences. Pregnant women in urban areas of these countries have a seroprevalence rate as high as 1%.

Although the annual number of new HIV infections has been steadily declining since the late 1990s, the epidemics in Eastern Europe and in Central Asia continue to grow; the number of people living with HIV in these regions reached an estimated 1.6 million in 2005—an increase of almost 20-fold in less than 10 years.[8] The overwhelming majority of these people living with HIV are young; 75% of infections reported between 2000 and 2004 were in people younger than 30 years. In Western Europe, the corresponding percentage was 33%.

The magnitude of the AIDS epidemic in Asia is significant. Although national HIV infection prevalence rates are low in Asia compared with other continents (notably Africa), the populations of many Asian nations are so large that even low prevalence rates reflect large numbers of people are living with HIV. The seroprevalence rate in pregnant women is already 2%, and the vertical transmission rate is 24% without breastfeeding. Indian mothers infected with HIV routinely breastfeed and have transmission rates as high as 48%.

Perinatal transmission rates are relatively low in Europe and high in Africa, independent of treatment. Untreated women infect 13% and 40% of children in Europe and Africa, respectively. The rate of postnatal transmission in Africa and other developing countries is elevated because of the need for breastfeeding.

HIV-1 is the most common cause of HIV infection in the Americas, Europe, Asia, and Africa. HIV type 2 (HIV-2) has caused epidemics in West Africa, though this virus is also found in European countries. HIV-1 subtypes differ by geographic region. Non-B subtypes are particularly prevalent in Africa and in Asia. The high transmission rate from Africa to Europe has increased the diversity of subtypes in Europe.

Globally, children outside the United States are not faring as well. Every day, 1400 children become HIV positive and 1000 children die of HIV-related causes. An estimated 2.5 million children worldwide younger than 15 years are living with HIV/AIDS. In sub-Saharan Africa alone, 1.9 million children are living with HIV/AIDS and more than 60% of all new HIV infections occur in women, infants, or young children. As of 2007, 90% of the newly infected children are infants who acquire HIV from their infected mothers. Alarmingly, 90% of babies who acquire the disease from infected mothers are found in sub-Saharan Africa. The prevalence of HIV infection among undernourished children has been estimated to be as high as 25%.

The prevalence of HIV infection in Asia and Europe varies considerably because of varied cultural practices and lack of a national reporting system in many areas. The commercial sex worker industry in countries such as Thailand and in the Caribbean Islands is responsible for increased HIV transmission to young girls and, vertically, to infants.

In 2004, more than half a million children younger than 15 years died from HIV/AIDS. In 2006, this number decreased to 380,000. In 2002, HIV/AIDS was the seventh leading cause of mortality in children in developing countries. The disease progresses rapidly in approximately 10-20% of children who are infected, and they die of AIDS by age 4 years, whereas 80-90% survive to a mean age of 9-10 years.

In affected regions of sub-Saharan Africa, the infant mortality rate has increased by 75% due, in part, to the orphaned status of most children. In contrast to much of the developed world, the mortality rates for children younger than 5 years are higher today than in 1990 in many African countries, mostly because of the devastating effects of HIV/AIDS.

A 2006 South African study estimated that HIV/AIDS is the single largest cause of infant and childhood deaths in rural South Africa.[13] HIV/AIDS is now responsible for 332,000 child deaths in sub-Saharan Africa, almost 8% of all child deaths in the region.

The results of one study noted that pneumonia and malnutrition are highly prevalent and are significantly associated with high rates of mortality among hospitalized, HIV-infected or HIV-exposed children in sub-Saharan Africa. Other independent predictors of death were septicemia, Kaposi sarcoma, meningitis, and esophageal candidiasis for HIV-infected children; and meningitis and severe anemia for inpatients exposed to HIV. These results stress the importance of expediently establishing therapeutic strategies in African pediatric hospitals.[14]

Racial differences in incidence

Black and Hispanic children are disproportionately infected in the United States. As of 2002, HIV infection was the 7th and 10th leading cause of death in black children and in Hispanic teens, respectively.[15] Approximately 62% of children with AIDS are black.

In the United States, children from minority communities have been most affected by AIDS. More than 50% of infected children are black, and slightly less than 25% are Hispanic. Of the new childhood HIV cases in 2003, 68% occurred in African Americans. The number of pediatric AIDS cases reported in black non-Hispanic children is 3.4 times higher than in white non-Hispanic children and is 2.6 times higher than that of Hispanic children.

Sexual differences in incidence

Women of childbearing age are one of the fastest growing groups with AIDS; 20% of AIDS cases in adults in the United States occur in this group.

Young people (aged 15-44 y) account for one of the fastest growing infected groups and account for almost half of all infections. Among young people, young women are more likely to become infected. In sub-Saharan Africa, more than two thirds of all youth infected are young girls. Variations in frequencies in the sexes in other regions of the world depend on the predominance of commercial sex workers and the proportion of a transient and mobile workforce more likely to be separated from family.

Age-related differences in incidence

Because vertical transmission from mother to child is the main route by which pediatric HIV infection is acquired, most children who are HIV positive should be identified in infancy. Although current treatment strategies can prevent vertical transmission, the drugs are simply not available in many places, especially in Africa.

Nevertheless, the age of presentation can be highly variable in a high-risk child who was previously unidentified. Children can be asymptomatic for many years, and the appearance of an opportunistic infection in a 10-year-old child or in an adolescent in whom AIDS is subsequently diagnosed is not rare. Children who acquire HIV by means of nonvertical transmission may have an illness during the acute phase of the retroviral syndrome, or they may present many years later with opportunistic or recurrent infections.

The CDC estimates that 50% of all new HIV infections in the United States occur among individuals aged 13-24 years. This is an important statistic that influences the mortality rates in young adults. For example, HIV is the 5th leading cause of death among black women aged 20-24 years, and it is the principal cause of mortality in black women aged 25-34 years.

Prognosis

Although HIV infection is usually deadly in children, especially in developing countries, the development of new antiretroviral drugs is promising. The lack of access to antiretroviral agents by children in developing countries is of particular concern.

The nutritional status of the child and the diligence with which viral replication is controlled are paramount in determining the outcome of most children with HIV disease.

Aggressive treatment of opportunistic infections prevents the more deleterious effects of secondary disease from progressing and further weakening the patient. The social setting and the stressors to which children are exposed have also been linked to the progression of the disease.

Hematologic disturbances, such as anemia, thrombocytopenia, and neutropenia, increase the risk of complications and death. Resolution of anemia improves the prognosis, and treatment of anemia with erythropoietin improves survival. Neutropenia significantly increases the risk of bacterial infection, and treatment of neutropenia with granulocyte colony-stimulating factor substantially decreases the risk of bacteremia and death.

Infection with Mycobacteriumavium complex (MAC) hastens death, especially in patients with coexisting anemia (defined as a hematocrit < 25%).

The following factors are associated with rapidly progressive disease in infants:

Each logarithmic decrease in the viral load after the start of therapy decreases the risk of progression by 54%.

Baseline CD4+ T-lymphocyte percentage and associated intermediate-term risk of death in HIV-infected children is as follows[16] :

Baseline HIV RNA copy number (copies/mL) and associated intermediate-term risk for death in HIV-infected children is as follows[16] :

The natural progression of vertically acquired HIV infection appears to have a trimodal distribution. Approximately 15% of children have rapidly progressive disease, and the remainder has either a chronic progressive course or an infection pattern typical of that observed in adults. Mean survival is about 10 years.

In resource-poor nations, the progression to death is accelerated. In some instances, close to 45-90% of HIV-infected children died by the age of 3 years. However, among children and adolescents, the start of combination therapy including protease inhibitors reduces the intermediate-term risk of death by an estimated 67%. Also, host genetics play an important role in HIV-1–related disease progression and neurologic impairment

The patient's overall progression and prognosis is followed up by using the CDC classification system for children infected with HIV (see Staging).

Patient Education

Educating parents regarding the importance of compliance with prescribed medications and health care visits is a major challenge because of many factors. See Deterrence/Prevention for further discussion about this topic.

Patients should be educated regarding the transmission of HIV. Increasing their awareness of the mechanism and consequences of HIV transmission is important. Safe social interactions that do not expose people to an increased risk for HIV transmission should also be emphasized.

A single-blinded, randomized controlled trial reported that adolescent family-centered pediatric advance care planning on HIV-specific symptoms was worthwhile in increasing and maintaining agreement about goals and length of care which resulted in lowering physical symptoms and pain.[17]

For patient education information, see the Immune System Center and Sexually Transmitted Diseases Center, as well as HIV/AIDS and Rapid Oral HIV Test.

History

Ideally, the diagnosis of HIV in a child is made through perinatal testing. The Centers for Disease Control and Prevention (CDC) has issued guidelines for recommended testing and counseling for all pregnant women; however, many women, especially in developing countries and in poorer areas of the developed world, do not have access to or do not avail themselves of the resources available. Thus, for example, the diagnosis of HIV infection may follow an investigation of a prolonged or unusual presentation of an infection or a malignancy.

Some studies suggest that children vertically infected with HIV become symptomatic from the neonatal period up to age 8 years and that 57% of this group have associated disease within the first year.

Children infected as a result of sexual abuse or drug use may not present with known HIV infection.

Immunodeficiency should be suspected in individuals with recurrent bacterial infections (especially invasive infections, eg, bacteremia, meningitis, and pneumonia) and in those with unusual infections, such as those caused by the Mycobacterium avium-intracellulare complex (MAC).

Children with HIV infection often present with the common bacterial infections of childhood (eg, otitis media, sinusitis, pneumonia). These can be more frequent and more severe than similar infections in immunologically healthy children. Recurrent fungal infections, such as candidiasis (thrush), that do not respond to standard antifungal agents suggest lymphocytic dysfunction.

Recurrent or unusually severe viral infections, such as recurrent or disseminated herpes simplex or zoster infection or cytomegalovirus (CMV) retinitis, are seen with moderate-to-severe cellular immune deficiency.

Growth

Growth failure, failure to thrive, or wasting in a child may indicate HIV infection if other common metabolic and endocrine disorders do not appear to be the etiologies. Growth failure, failure to thrive, or wasting in a patient with HIV infection may signify disease progression or underlying malnutrition.

Development

Failure to attain typical milestones suggests a developmental delay. Such delays, particularly impairment in the development of expressive language, may indicate HIV encephalopathy. The loss of previously attained milestones may signify a CNS insult due to progressive HIV encephalopathy or opportunistic infection.

In older children, behavioral abnormalities (eg, loss of concentration and memory) may indicate HIV encephalopathy.

Physical Examination

A high percentage of oral disease has been seen in children infected with HIV, and oral manifestations are often early indicators of infection. Numerous mucocutaneous disorders have been reported in children infected with HIV. As the CD4+ count decreases, an increase in the number and severity of skin manifestations can be expected. Dermatologic manifestations occur more frequently in children with advanced HIV disease; many tend to improve after antiretroviral therapy is initiated.

The most common oral disease and mucocutaneous presentation of HIV infection is candidiasis caused by Candida albicans. Both the pseudomembranous variant and the atrophic oral variant are most common.

Pseudomembranous candidiasis manifests as creamy white-to-yellow oral plaques, commonly referred to as thrush. Atrophic candidiasis manifests as distinct areas of erythema with the loss of tongue papillae if the tongue is affected. Hyperplastic candidiasis (with both erythematous and white mucosal coloration symmetrically distributed) and angular cheilitis are 2 additional clinical variants of candidiasis.

The usual symptoms in children with candidal esophagitis are odynophagia, dysphagia, and retrosternal pain.[18] These symptoms may contribute to the already-compromised nutritional status of the child.

An inflammatory, destructive, and necrotic process characterizes candidal periodontal disease in the gingival mucosa and the underlying connective tissue.

Although C albicans is the most commonly identified Candida species, C dubliniensis has garnered notice as a cause of oral infection that is seen, for the most part, only in patients who are HIV positive.[19] Other Candida species implicated in HIV-related candidiasis are C glabrata and C tropicalis.

Candidiasis may manifest as an unresponsive or recurrent diaper rash or as a chronic paronychia and onychomycosis. In Candida -associated diaper dermatitis, the area covered by the diaper is usually inflamed and erythematous, with satellite lesions extending beyond the central area of involvement. Involvement of other intertriginous areas, including neck folds and axillary regions, has also been reported.

Candidal involvement of the proximal nailfolds causes severe paronychia and nail dystrophy. Candidal onychomycosis results in yellow-brown thickened nail plates.

Linear gingival erythema and median rhomboid glossitis have also been found, especially in children with a low CD4+ cell count.

Children infected with HIV have a higher rate of dental caries in the primary teeth but a diminished prevalence in the permanent teeth, a finding attributed to the greater number of primary teeth and the delayed eruption of the permanent teeth in these patients. HIV-infected children should be screened and considered at high risk for dental caries, usually secondary to chronic medication use.[20, 21]

Oral hairy leukoplakia, which is associated with Epstein-Barr virus, is usually rare in US children, but it has been reported in children as the second most common oral presentation after candidiasis in some Asian countries. Results from a 2006 Brazilian study suggest that oral hairy leukoplakia may be more common than previously believed; 16.7% of patients demonstrated subclinical, cytological disease, although only 1.7% of children had clinically visible disease.[22]

Herpes simplex virus infections, parotid enlargement, and recurrent aphthous ulcers are also common oral manifestations.

Dermatophytosis manifesting as an aggressive tinea capitis, corporis, versicolor, or onychomycosis may be challenging to treat. As in adults, Trichophyton rubrum infection in the form of proximal, white, subungual onychomycosis is categorized as a typical nail manifestation of HIV disease.

Deep fungal infections are not commonly seen in children who are HIV positive. Cryptococcosis, sporotrichosis, and histoplasmosis have been reported as either localized or disseminated variants. Molluscumlike Cryptococcus papules have been identified in some patients.

Herpetic infection with herpes simplex virus (HSV) may take the form of herpes labialis; gingivostomatitis; esophagitis; or as chronic erosive, vesicular, and vegetating skin lesions. The involved areas of the lips, mouth, tongue, and esophagus are ulcerated, which may result in difficulty with oral nutritional intake.

Skin lesions usually manifest as chronic erosions, which may have grouped vesicles. The fingers are a frequent site of infection. Pyoderma gangrenosum and ecthyma gangrenosum may be in the differential diagnosis of cutaneous herpetic infections.

Recurrent or persistent varicella-zoster infection is strongly linked with the CD4+ count. Scarring can occur from a severe outbreak, in which lesions may be hyperkeratotic and/or hemorrhagic and involve more than 1 dermatome.

Because herpes zoster is usually not seen in children who are immunocompetent, an evaluation for HIV infection should be undertaken in a child with this diagnosis. Children should be evaluated for evidence of dissemination because disastrous sequelae, such as encephalitis, intracranial thrombosis, fulminant hepatitis, disseminated intravascular coagulation, pneumonitis, and retinal necrosis, have been reported in patients with dissemination.

Human papillomavirus infection, which may mimic the tinea versicolor–like rash in epidermodysplasia verruciformis, is noted. Large areas of flat warts most commonly occur on the forehead, the temples, the neck, and the upper body. Unusually large treatment-resistant condylomata are reported in children who are HIV positive.

Widespread molluscum contagiosum can occur in pediatric AIDS patients. Molluscum contagiosum may manifest as a diffuse eruption of umbilicated papules involving areas (eg, face) usually not affected in patients who are immunocompetent. Molluscum lesions tend to be more persistent in patients with HIV infection. Some lesions are large and may be confused with Cryptococcus neoformans lesions. Molluscum tends to improve with antiretroviral therapy.

Recurrent bacterial infections are seen in children who are HIV positive because of the abnormal B-cell response and consequent defective humoral immunity. A variety of bacterial infections occurs, the most common of which is caused by Staphylococcus aureus. As the CD4+ count decreases, invasive bacterial infections, including sepsis and pneumonia, may occur.

Sepsis, otitis media, impetigo, cellulitis, and furunculosis have been reported. Although the infections may initially manifest in a manner similar to that in a child who is not immunocompromised, widespread and persistent infection should prompt consideration of HIV status. Acral lesions should be sought if sepsis is a concern because a pustule on the sole may be the first sign of sepsis.

Atypical presentations, such as plaquelike staphylococcal folliculitis, are also reported.

Rare conditions, such as ecthyma gangrenosum as a result of infection by Pseudomonas aeruginosa, are also noted. In this disorder, hemorrhagic necrotic bullae that eventually form a black eschar manifest primarily on the extremities and the gluteal and perineal regions.

Bacillary angiomatosis caused by Bartonella henselae and Bartonella quintana is rare in children but has been reported.[23] Bacillary angiomatosis is considered by some to be an AIDS-defining opportunistic infection, typically seen with a CD4+ count less than 200 cells/μL. Clinically and histologically, the lesions often resemble pyogenic granulomas and Kaposi sarcoma. They often begin as pinpoint papules, which enlarge to become red nodules and usually involve the face or the upper torso. In addition to the cutaneous findings, these patients may have lymphadenopathy, abdominal symptoms, anemia, and an elevated alkaline phosphatase level.

Mycobacterial infections caused by Mycobacterium tuberculosis and M avium complex are increasing in incidence in children who are HIV positive. These children are usually extremely sick. Usually, pulmonary disease is present, but extrapulmonary findings can also occur. Acute pustular eruptions, widespread keratotic papules with hyperkeratotic palms and soles, tuberculous lymphadenitis, purple necrotic lesions, and ulcerations have been reported in HIV-associated mycobacterial infections.

M haemophilum often causes disseminated infection in patients with AIDS. Diffuse swelling and induration of the periarticular soft tissue and nodular formation are reported in patients infected with M haemophilum.

Pneumocystis jiroveci (formerly P carinii) pneumonia (PCP) is the primary AIDS-defining illness and occurs in 7-20% of patients who have not been administered prophylaxis and are younger than 1 year. Most commonly, PCP manifests as cough, dyspnea, tachypnea, and fever. The incidence of PCP is declining in areas where AIDS medications are available, but it continues to shorten life expectancy in areas in which access to antiretrovirals is limited.

Scabies in children infected with HIV may progress from a widespread pruritic papular eruption to a crusted variant as the CD4+ count decreases. This crusted (Norwegian) variant is characterized by an extremely high mite count and thus is very contagious. Secondary bacterial infection may complicate crusted scabies.

In regions of the world where measles vaccination is not routinely administered and where HIV is endemic, the potential for serious measles infection exists.[7, 24] Measles typically manifests with an erythematous macular eruption of the trunk with caudal spread. Koplik spots (small blue-white dots surrounded by erythematous rings on the buccal mucosa) are the most common oral manifestation. In children who are immunocompromised, measles may manifest without skin involvement but with more severe complications.

Death from pneumonitis and encephalitis has been reported in African children with both HIV infection and measles.

Noma (cancrum oris) is a necrotic disease of tissues of the mouth.[25] This disease quickly spreads to surrounding bone and soft tissue and is often associated with immunodeficient states, such as AIDS. Noma predominately occurs in young children from sub-Saharan Africa and is often associated with measles.

Seborrheic dermatitis may be a manifestation of HIV in children who present outside of the usual neonatal and adolescent timeframes or who present with generalized disease. An association between Pityrosporum orbiculare growth in the presence of waning CD4+ cells and Langerhans cells has been postulated.

The eczematous periorofacial eruption of acrodermatitis enteropathica caused by nutritional deficiency of zinc, secondary to diarrhea-induced malabsorption, has been reported. Other vitamin deficiencies can also be expected because of poor oral intake or diarrhea.

Metabolic abnormalities have been reported in association with pediatric HIV disease. Lipodystrophy associated with insulin resistance and dyslipidemia occurs in children who are HIV positive (similar to adults who are HIV positive) and may be attributed to highly active antiretroviral therapy, although individual variations may make certain children more susceptible.[26] See also HIV Lipodystrophy.

Variations in presentation include peripheral lipoatrophy, truncal lipohypertrophy, and combined versions of these presentations. A more severe presentation occurs at puberty. Thyroid abnormalities with hypothyroidism have also occurred in children infected perinatally.[27]

A variety of skin conditions, including exaggerated eczema, psoriasis, drug eruptions (including morbilliform eruptions and Stevens-Johnson syndrome), intense reactions to arthropod bites,[28] alopecia, and trichomegaly, have been reported in children who are HIV positive.

Children with HIV infection are at risk for child abuse because of family stressors; therefore, unusual skin lesions should be evaluated for potential signs of exogenous injury.

A higher incidence of neoplasia is noted in children with HIV infection than in noninfected children.[29] B-cell lymphoproliferative diseases, including non-Hodgkin lymphoma, Burkitt lymphoma, and smooth muscle tumors, have been identified.

The prevalence of HIV-associated malignancies has been reported to be as high as 2%. A 2005 evaluation of 2969 pediatric patients with AIDS in the United States from 1993-2003 revealed that the incidence of malignancy is 1.56 cases per 1000 person-years, a number lower than in European counterparts but significantly higher than in noninfected children.[30]

Kaposi sarcoma is unusual in children; however, an African study has shown the childhood incidence of Kaposi sarcoma has risen more than 40-fold since the advent of the AIDS epidemic.[31] Previously thought to only occur in males, it has been reported in both males and females born to mothers who are infected with HIV in high-risk groups for Kaposi sarcoma or in children infected postnatally by blood products. The most common sites of AIDS-related Kaposi sarcoma in children are the orofacial and the inguinal or genital regions.[32]

Few physical findings are specific to HIV infection, and many physical findings are caused by opportunistic infections. Lymphadenopathy, hepatomegaly, and splenomegaly are fairly common in HIV infection. Other findings may include those discussed below.

Anthropometric findings

Monitoring the patient's growth is one of the most important parts of the pediatric physical examination. Anthropometric measurements should be obtained at each visit.

Delayed growth in the head circumference is correlated with the development of underlying encephalopathy. However, normal head growth does not help in ruling out encephalopathy, and many patients with a normal head circumference may have radiographic or psychometric findings consistent with encephalopathy.

Fat redistribution syndrome in association with lipid abnormalities and insulin resistance is being described in HIV-infected children and adults. Presentations vary (eg, central adiposity vs peripheral fat wasting) and depend on factors such as race and age. Body habitus is altered because of lipoatrophy, lipohypertrophy, or both.

Diverse diagnostic criteria have been used. Anthropometric measurements, such as skin-fold thickness and the waist-to-hip ratio, are useful to monitor the progression of changes. Technically sophisticated tools include bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), CT, and MRI.

Head, eyes, ears, nose, and throat (HEENT) findings

Parotid enlargement is observed in 30% of children with category C disease (see Staging) and in 15% of children with disease in other categories.

Tonsillar hypertrophy may be observed. Aphthous ulcers may be observed.

Thrush in the oral cavity and posterior pharynx is observed in approximately 30% of HIV-infected children. In children with AIDS, the prevalence of thrush is correlated with a low CD4+ count. Thrush in the posterior pharynx may signify candidal esophagitis, especially in patients with feeding difficulties or retrosternal pain.

CMV retinitis occurs in 3.4% of children with CD4+ counts of less than 50/mL.

Cardiac, pulmonary, and abdominal findings

Cardiomyopathy may be present. Congestive heart failure may be present.

Lung examination is important, and good documentation of findings is required at each visit. Chronic lung disease may produce baseline findings of crackles and decreased regional breath sounds.

Changes in the lung findings are important to note because pneumonia is common in children with HIV infection. Pneumonia may not be obvious during the examination, and many children have few symptoms. For example, Mycoplasma infection may not cause a high temperature, and Pneumocystis jiroveci infection may cause only tachypnea, fever, and hypoxemia.

Changing findings at lung examination may also signify worsening of chronic lung disease, lymphoid interstitial pneumonitis, or tuberculosis.

Hepatomegaly is observed in 45% of HIV-infected children without AIDS and in 70% of those with AIDS. Splenomegaly is observed in about 35% of children with HIV infection.

Lymphatic findings

Generalized cervical, axillary, or inguinal lymphadenopathy is common and may be the first sign of initial infection during the asymptomatic phase of the disease. Generalized lymphadenopathy may not be present with well-controlled disease or end-stage AIDS. New shotty nodes may indicate that the disease has again progressed and that treatment failure has occurred.

A single large node may indicate lymphoma, and it may need to be examined with biopsy.

Neurologic findings

Motor delay, hypotonia, hypertonia, and/or pyramidal-tract signs may indicate progressive HIV encephalopathy or opportunistic infection of the CNS.

Spastic diplegia and oral motor dysfunction are early signs of encephalopathy.

Acquired microcephaly with accompanying cerebral atrophy is a poor prognostic sign.

Subacute combined degeneration of the spinal cord with higher cortical dysfunction occurs in vitamin B-12 deficiency.

Ischemic and hemorrhagic strokes can occur in children with AIDS, but they seem to be related to infection or other mechanisms other than atherosclerosis or hypercoagulable states, as in the adult HIV-infected population.

Skin findings

HIV dermatitis causes an erythematous papular rash and is observed in about 25% of children with HIV infection.

Vesicular lesions in a unilateral dermatomal distribution or in the oral, genital, or anal area may represent reactivation of herpes zoster.

Erythematous candidal dermatitis that does not respond to standard therapy may be present.

Bleeding or bruising of the mucous membranes and skin may be observed in children with HIV and immune thrombocytopenic purpura, although this is uncommon.

Extremity findings

Digital clubbing may be observed as a result of chronic lung disease.

Nonpitting edema may result from hypoalbuminemia caused by HIV nephropathy or malnutrition. Pitting edema may develop as a result of congestive heart failure.

Opportunistic infections

PCP is the most common opportunistic infection in children with vertically transmitted HIV infection unless antibiotic prophylaxis is used. Without prophylaxis, PCP commonly occurs in infants aged 3 months. Without prophylactic suppression, infection may develop in infants younger than 1 year regardless of their baseline CD4+ count because the rapid progression of immunosuppression may precipitate a sharp decrease in their CD4+ counts.

PCP typically occurs in children with moderate immune suppression; this warrants category C classification.

Upon examination, fever and tachypnea are usually the presenting symptoms. Chest radiographs may or may not show diffuse interstitial pulmonary infiltrates. Lung examination may or may not reveal rales. The diagnosis is confirmed by detecting PCP antigen in a sputum or, preferably, in a specimen obtained during bronchoscopic lavage.

Systemic complications

Dysrhythmias, hemodynamic abnormalities, and cardiomyopathy develop in about 20% and 5% of HIV-infected children with AIDS and those without AIDS, respectively. Congestive heart failure is a late manifestation of HIV infection. Children must be treated symptomatically with sodium restriction, diuretics, digitalis glycosides, and angiotensin converting–enzyme inhibitor (ACEI) therapy. Progressive changes in cardiac structure are correlated with disease progression.

Chronic diarrhea develops in approximately 15% of children with HIV infection. Infectious agents may cause diarrhea. MAC and Cryptosporidium species are not uncommon causes of diarrhea in children with low CD4+ counts.

Stool examination and cultures for bacteria, fungi, viruses, parasites, and acid-fast organisms should be performed every day for at least 3 days, with special instructions for detecting Cryptosporidium,Isospora, and microsporidia organisms. Clostridium difficile tests should be requested if patients currently or recently received antimicrobial therapy.

Bile-acid malabsorption, but not bacterial overgrowth, appears to contribute to chronic diarrhea of HIV. Cholestyramine 4-8 g given 3 times a day may substantially slow diarrhea in some patients.

Pancreatitis can develop from medication, ascending infection, or the HIV infection itself. Amylase and lipase levels should be monitored in patients at risk for pancreatitis with abdominal complaints.

Abdominal pain with associated diarrhea, hepatosplenomegaly, intestinal lymphadenopathy, fever, or anemia is common in disseminated MAC infection.

In adults, wasting syndrome is common with advanced disease. Although older children with advanced disease may have wasting syndrome, young children have growth failure even without advanced disease. Undiagnosed HIV infection may present in patients with a diagnosis of failure to thrive.

Nephropathy

In approximately 15% and 5% of HIV-infected children with AIDS and those without AIDS, respectively, the disease progresses to HIV nephropathy. HIV nephropathy is more common in African American children than in others.

Proteinuria and hyponatremia with elevation in BUN and creatinine levels and a slight increase in blood pressure develop early and are not uncommon.

Renal biopsy most often reveals focal segmental glomerulosclerosis or, sometimes, mesangial hyperplasia. Necrotizing glomerulonephritis and minimal histologic changes also are observed.

Angiotensin-converting enzyme inhibitors appear to have kidney-sparing effects and are being studied.

Symptomatic treatment with fluid restriction, a low-salt diet, and diuretics may be needed in cases of frank nephrosis.

Non-HIV nephropathy may develop, especially in children who are treated with repeat courses of nephrotoxic medications. Some children have chronic renal failure with electrolyte wasting. Electrolyte levels should be monitored closely, and patients should receive appropriate supplementation.

Approach Considerations

Prompt diagnosis of human immunodeficiency virus (HIV) infection is critical. As such, the Centers for Disease Control and Prevention (CDC) recommends routine prenatal HIV testing as the standard of care for all pregnant women in the United States, with repeat screening in the third trimester recommended in certain jurisdictions with elevated rates of HIV infection among pregnant women.[33] However, routine late pregnancy testing at 36-37 weeks' gestation in all women is recommended by many experts because infection during pregnancy now makes up a significant percentage of children with AIDS.

The American College of Obstetricians and Gynecologists updated their guidelines on HIV testing during pregnancy.[34, 35] The new guidelines include the following:

Diagnosis of HIV infection in infants is aided by HIV culture or DNA/RNA polymerase chain reaction (PCR); positive results are confirmed by repeating the test. In suspected cases, HIV testing should occur in the newborn period (ie, before the infant is 48 h old), at age 1-2 months, and again at age 3-6 months. Testing at age 14 days may allow for earlier detection of HIV in infants who had negative test results within the first 48 hours of life. By approximately age 1 month, PCR testing has a 96% sensitivity and 99% specificity to identify HIV.

The 2010 Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children[3] recommendations for diagnosing infants are as follows:

The Panel does not recommend use of the currently approved HIV p24 antigen assay for infant diagnosis in the United States because the sensitivity and specificity of the assay in the first months of life is less than that of other HIV virologic tests.

Within the first 48 hours, 14 days, and 4 weeks of life, 38%, 93%, and 96% of infected children, respectively, have positive HIV DNA PCR results. Any positive HIV DNA PCR finding should be confirmed with follow-up HIV DNA PCR before infection is diagnosed.

HIV infection can be ruled out if one of the following is true:

Monitor CD4+ levels or percentages in infants or patients newly diagnosed with HIV at 3- to 4-month intervals to assess patients' immune status. In children younger than 5 years, the 2010 Panel recommends using CD4 percentages over absolute CD4 counts for monitoring disease progression because of inherent age-related changes in absolute CD4 counts.

Monitor for opportunistic infections. Perform a CBC count with differential and a urinalysis every 1-3 months in infants. Older children can be screened every 3-6 months (CBC count) or yearly (urinalysis). Culture urine samples monthly for the presence of cytomegalovirus (CMV) until age 2 months and then at 2-month intervals until age 12 months.

Assess HIV RNA levels twice at baseline and then every 3-4 months. (Consistently use the same HIV RNA assay method to monitor a particular patient.) More frequent testing of HIV RNA levels and CD4 counts may be necessary for children who have virologic or clinical deterioration or when initiating or changing antiretroviral therapy or in children under 12 months of age.

If the mother is HIV positive, use serologic tests to screen the infant for hepatitis B, hepatitis C, syphilis, and toxoplasmosis.

Decreased levels of albumin, serum immunoglobulin G, and CD8+ T cells are linked with fatality in children.

Monitor laboratory studies in accordance with drug therapy protocols and clinical status (eg, lipid profile in a patient with lipodystrophy).

Perform chest radiography, CT scanning, MRI, echocardiography, and electrocardiography for baseline determinations and subsequently as clinically indicated. For example, brain imaging is indicated in patients with suspected HIV encephalopathy. Imaging may demonstrate degeneration of the white matter, atrophy, and/or calcifications of the basal ganglia with progressive HIV encephalopathy.

Detection of HIV

HIV detection is the first step in the laboratory workup. In September 2006, the CDC released its Revised Recommendations for HIV Testing of Adults Adolescents, and Pregnant Women in Health-Care Settings.[33] These new recommendations, which replaced the CDC’s 1993 Recommendations for HIV Testing Services for Inpatients and Outpatients in Acute Care Hospital Settings, advise routine HIV screening for adults, adolescents, and pregnant women in healthcare settings in the United States. They also recommend reducing barriers to HIV testing.

A 2011 revision to the American Academy of Pediatrics (AAP) policy statement recommends that routine screening be offered to all adolescents at least once by 16 to 18 years of age in communities with high HIV prevalence. In areas of lower prevalence, routine testing is encouraged for all sexually active adolescents and those with other risk factors for HIV.[36]

Detection of antibody to HIV is the usual first step in diagnosing HIV infection. In adults and older children, enzyme-linked immunosorbent assay (ELISA) and Western blotting are used to initially detect HIV-specific antibodies. However, because maternal antibodies are present in neonatal blood, these tests are not used for diagnosis in patients younger than 2 years. A nucleic acid PCR assay is the standard detection method in infants and young children.

HIV DNA PCR is used to detect HIV-1 provirus in mononuclear cells by using oligonucleotides directed at highly conserved regions of the viral genome. This test can be performed within 24 hours of infection and has a sensitivity and a specificity of 95% and 97%, respectively. Although it is more sensitive than viral culturing, the diagnostic performances of the 2 methods are equivalent.

Viral cultures are obtained by co-cultivating potentially infected and uninfected mononuclear cells together to promote viral replication. Every few days, the culture is assayed for HIV p24 antigen. Positive results on 2 sequential p24 antigen detection assays indicate infection. This technique requires a mean of 7-14 days to perform, but it may require as long as 28 days.

A positive virologic result should be confirmed with repeat virologic testing with a second specimen as soon as possible after the first result is available.

ELISA for HIV antibody, followed by a confirmatory Western blot (which has increased specificity), should be used to diagnose HIV infection in older children and adults.

Rapid HIV tests, which provide results in minutes, simplify and expand the availability of HIV testing. Their sensitivity is as high as 100%, but they must be followed with confirmatory Western blotting or immunofluorescence antibody testing, as with conventional HIV antibody tests.

The US Food and Drug Administration (FDA) has approved 4 rapid HIV screening tests that are available commercially in the United States, as listed below. Before the FDA approved these tests, the most commonly used rapid HIV test was the Single-Use Diagnostic System (Murex SUDS; Abbott Diagnostics, Abbott Park, IL), which is no longer available.

HIV RNA assays are used to detect extracellular viral RNA in the plasma and are as sensitive as HIV DNA PCR for early diagnosis of HIV infection in exposed infants. However, nucleic acid amplification tests are not the preferred methods of diagnosis in infants perinatally exposed because they may falsely indicate low viral loads in individuals who are HIV negative. Also, whether antenatal treatment of the mother with combination antiretrovirals and/or antiretroviral prophylaxis in the infant affects the sensitivity of RNA assays is unknown.

The FDA has approved the APTIMA HIV-1 RNA Qualitative Assay (Gen-Probe Incorporated, San Diego, CA). This assay enables people to learn with certainty whether they are infected within a few days rather than up to 6 months, as with an HIV antibody test. Unlike some approved antibody tests, the APTIMA assay is intended to detect only HIV-1 and not HIV-2.

The test could become a potential alternative to traditional Western blotting now used to confirm HIV-1 infection when screening results for HIV antibodies are positive. The APTIMA assay is approved for the diagnosis of primary HIV-1 infection for confirming HIV-1 infection when antibody results are positive.

Viral Load Testing

The viral load can be quantified by using several HIV assays. The number of virions in the peripheral blood is an important indicator of disease activity and of the effectiveness of antiretroviral therapy (ART). A 5- or 3-fold change in the viral load is needed to reliably indicate a clinically significant change in children younger than 2 years or older than 2 years, respectively.

Certain viral-load tests are not sensitive to non-B subtypes of HIV-1. Therefore, viral loads can seem to be considerably reduced if these tests are used to process samples of non-B subtypes.

Reverse-transcription PCR (RT-PCR) and nucleic acid sequence—based amplification (NASBA) of plasma RNA reveal a viral load 2 times that obtained with the branched-chain DNA (bDNA) method. The former methods are sensitive to only HIV-1 subtype B viruses, whereas the bDNA method is sensitive to other HIV-1 subtypes. Switching test methods during treatment is not advised because their molecular technologies differ.

Initial infection is associated with high viral loads, especially in the neonate. In adults and adolescents with nonvertically acquired infections, the viral load rapidly decreases 6-12 months after the primary viremia. Neonates have high viral loads that persist throughout infancy; therefore, these values are hard to interpret in the first year of life. In children with vertically acquired infections, the load slowly declines after 1 year of age. The predictive value of specific HIV RNA concentrations for disease progression and death for an individual child in the first year of life is moderate.

Viral Resistance Assays

Viral resistance to ART may be present. Both primary and secondary mutations can develop. Primary mutations alter the effectiveness of ART. Secondary mutations improve viral survival.

Both genotypic and phenotypic assays can be performed. Genotypic assays are fast and available, but they reveal only known mutations, and they cannot be used to predict complex interactions when several antiretroviral drugs (ARDs) are used together.

Automated recombinant phenotypic assays are commercially available, but the results require additional time to be ready, and the tests are expensive. However, these assays can be used to detect complex interactions between ARDs and quasispecies, to perform in vitro drug trials, and to measure ART inhibitory concentrations.

Resistance testing is recommended before the initiation of ART in all treatment-naïve children, with the results used to refine selection of drugs for initial combination therapy. Resistance testing is also recommended before changing therapy for treatment failure.[3]

Genotype and phenotype assays may not be useful for detecting minor quasispecies, and treatment failure occurs despite the use of these techniques.

Development of resistance to 1 or more of the drugs in a combination regimen is often the cause for viral rebound. Numerous clinical trials have demonstrated the clinical use of ARD-resistance testing in selecting an alternate effective combination and in improving clinical outcomes.

Hematology Studies

The CD4+ lymphocyte count is a surrogate marker for disease progression and should be monitored closely. The CD4+ count should be obtained before therapy. A rapid decrease in the count, especially in infants younger than 1 year, is a poor prognostic sign and should prompt the start or alteration of therapy.

Consumptive thrombocytopenia is a common finding in children with HIV infection and may be observed in 10% of patients at initial diagnosis.

Anemia occurs in as many as 20% of patients at diagnosis and occurs in as many as 80% of patients at some time. Anemia can have many etiologies in HIV infected individuals and requires a workup as described in Medical Care.

A high mean corpuscular volume (MCV) is most commonly caused by zidovudine and can be used to verify compliance. Other medications also cause a high MCV, as well as vitamin B-12 and folate deficiencies.

Anemia continues to predict decreased survival even with highly active ART (HAART).

Pancytopenia results from folate deficiency, use of pharmaceutical agents, and infections with viruses such as parvovirus B19.

Neutropenia is observed in 10% of patients with early asymptomatic HIV infections and in 50% of patients with AIDS.

Blood smears may reveal large ovalocytes and hypersegmented polymorphonucleocytes in cases of folate deficiency.

Other Clinical Laboratory Tests

Serum electrolytes should be monitored on a regular basis because medications or HIV infection may induce nephrotoxicity.

Liver function can be impaired as a result of medication, HIV, co-infection with hepatitis viruses, or opportunistic infections, so transaminase levels should be monitored. Pancreatitis can be the result of medication, HIV or opportunistic infections, so amylase and lipase levels should be monitored in patients with abdominal symptoms. Parotiditis (parotitis) is not uncommon, and amylase levels should be followed up if parotiditis is suspected or if the patient has a history of the condition.

Quantitative immunoglobulin levels should be followed up periodically. Hyperimmunoglobulinemia is associated with disease progression. Hypoimmunoglobulinemia is observed in end-stage disease and is associated with a poor prognosis.

Renal Imaging Studies

Patients with HIV nephropathy demonstrate increased size and echogenicity of the kidneys on renal ultrasonography, with a loss of cortical medullary differentiation. Renal cysts are observed with an increased incidence.

On renal CT scanning, stasis of urine in the pyramids is observed in patients with HIV nephropathy. This finding, combined with characteristic renal ultrasound findings, is specific for HIV nephropathy.

Renal scintigraphy with technetium-99m mercaptoacetyltriglycine (99m Tc MAG3) demonstrates delayed elimination of the tracer and increased residual activity consistent with tubular dysfunction in HIV nephropathy. These abnormalities correlated with creatinine clearance.

On renal gallium scanning, increased signal indicates inflammation in patients with HIV nephropathy and is correlated with proteinuria.

Biopsy

A biopsy sample should be taken from enlarged lymph nodes of undetermined cause, especially if they are single, hard, nonmotile, or unaccompanied by generalized lymphadenopathy.

Biopsy may also be considered to clearly determine the identity of an apparently infectious or malignant cutaneous lesion. Maintain a high index of suspicion for a wide array of infections and malignancies, and request the appropriate staining and tissue preparation.

Diagnosis of Lymphoid Interstitial Pneumonitis

Lymphoid interstitial pneumonitis (LIP) is the second most common AIDS-defining illness in children. LIP most commonly occurs in children with a relatively high CD4+ count. Chest radiography demonstrates a reticulonodular pattern with or without hilar adenopathy that persists for more than 2 months despite treatment.

Patients are usually asymptomatic at first, but cough and shortness of breath develop as lymphoid interstitial pneumonitis progresses. Hypoxia typically responds to a 2-week course of steroids, but oxygen dependence develops if an underlying chronic lung disease exists. Lymphoid interstitial pneumonitis increases the risk of bacterial pneumonia, especially with Haemophilus influenzae and pneumococcus.

Recurrent pneumonia destroys lung tissue and leads to chronic lung disease. Chest radiographs demonstrate chronic changes, including areas of chronic atelectasis. This condition requires management by a pulmonologist. Chronic respiratory therapy may be required, including home oxygen therapy.

Staging

Clinical categories are based on the 2010 CDC guidelines[3] for antiretroviral treatment of pediatric AIDS (review and modification of the 1994 CDC HIV pediatric classification system for clinical categories in children younger than 13 y). This system uses a clinical-category letter and an immunologic number to note each stage of disease progression. The clinical categories are based on clinic manifestations. The immunologic category is based on the age-dependent CD4+ count (see Table 1, below).

Clinical categories include the following:

Category N includes children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in category A.

Category A includes children with 2 or more of the following conditions but none of the conditions listed in categories B and C:

Lymphadenopathy (≥0.5 cm at more than 2 sites; bilateral = one site)

Category B includes children who have symptomatic conditions, other than those listed for category A or category C, that are attributed to HIV infection. Examples of conditions in clinical category B include, but are not limited to, the following:

Category C includes children who have any condition listed in the 1987 surveillance case definition for AIDS, with the exception of LIP (which is a category B condition). These conditions are as follows:

Once an advanced class is assigned, the disease cannot be reassigned to a lesser class, even if the clinical or immunologic manifestations resolve. Category C and clinical manifestations of advanced disease are synonymous with AIDS.

Table 1. CDC Immunologic Categories for HIV-Infection in Children Based on Absolute CD4+ Counts



View Table

See Table

Approach Considerations

ART is the mainstay in human immunodeficiency virus (HIV) treatment. Appropriate antiretroviral therapy (ART) and treatment of specific infections and malignancies are critical in treating patients who are HIV positive. Intervening early may prevent damage to the immune system and potentially retard dissemination of infection. Combination ART is recommended for all infants, children, and adolescents who meet treatment criteria.

Reduction in the mortality rate associated with perinatally acquired HIV-1 over the past 10 years is a result of improved ART. However, only triple combination ART appears to significantly reduce the relative hazard ratio of death, as compared with no treatment.

The inadequacy of merely reducing the viral load has been realized in recent years. Quick suppression of the viral load with highly active ART (HAART) substantially slows viral replication and prevents resistant mutations.

Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children

The following include goals for treating pediatric patients with HIV infection, from the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children[3] :

The following are several important factors to consider in making treatment decisions about when to initiate antiretroviral therapy:

Opportunistic infections

A high prevalence of infections, such as candidiasis and varicella-zoster virus infection, must also be anticipated, and appropriate prevention and treatment strategies must be initiated.

An expert panel issued updated guidelines in December 2013 for the prevention and treatment of opportunistic infections in HIV-exposed and infected children. The panel represents the National Institutes of Health, the Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics.[37]

Key updates in the guidelines cover the following topics[37] :

Other considerations

As the disease progresses, wasting is noted, with weight loss and growth retardation in children. Low protein stores can be countered by increasing the intake of amino acids, specifically threonine and methionine.

Address abnormalities in psychological and neurologic development, due, in part, to the tropism of the virus for CNS tissue in children who are HIV positive.

Social, economic, and psychological factors impair the ability of many HIV-infected children and their parents to attend regular clinic appointments. This problem can be challenging and may require substantial use of social and child protective services on a regular basis.

Psychosocial support is extremely important. Failure to provide such services can result in a lack of compliance with medications and appointments.

Treatment guidelines for HIV disease change constantly. The most current guidelines may be viewed at the AIDS Info Web site, a service of the US Department of Health and Human Services.

Although current HAART regimens have substantially and dramatically decreased AIDS-related opportunistic infections (OIs) and deaths, prevention and management of OIs remain critical components of care for HIV-infected children.[38] The Centers for Disease Control and Prevention (CDC), the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics release periodic updated Guide lines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children.

Overview of Antiretroviral Therapy

Advances in medical management have dramatically reduced morbidity and mortality in children with in HIV in the United States.[39]  Many antiretroviral drugs are approved for children and some are approved for infants and neonates. There are also varying formulations (eg, oral liquids) or capsule sizes that accommodate pediatric dosing. Classes of antiretroviral agents include the following:

The reverse transcriptase inhibitors (NRTIs, NNRTIs) suppress HIV replication by competitive inhibition of viral reverse transcriptase. PIs prevent the late stages of viral replication by interfering with the formation of structural proteins of the virion core.

Treatment Guidelines

Recommended treatment regimens are constantly modified and changed; any publication like this article may become quickly outdated. Therefore, this article is intended to be a primer, and all children should be referred to a pediatric infectious specialist for management.

Most patients with vertically acquired HIV are treated regardless of their immune status. Most infants younger than 1 year should be aggressively treated. Pediatric HIV experts agree that infected infants who have clinical symptoms of HIV disease or evidence of immune compromise should be treated.[3] Patients aged 1 year or older with AIDS or significant symptoms should be aggressively treated regardless of CD4 percentage and count or plasma HIV RNA level.

The importance of early treatment of HIV in children younger than 12 months was illustrated in the Children with HIV Early Antiretroviral Therapy trial, which showed a 76% reduction in infant mortality and a 75% reduction in HIV progression with the early initiation of treatment.[40]  The case of a 9-year-old South African girl from this trial by Violari et al[40] was presented at the International AIDS Society 2017 Conference as the third case of long-term pediatric HIV remission after short antiretroviral treatment  At HIV diagnosis when she was 32 days old, a viral load of 750,000 copies/mL was reported. The viral load dropped to 151,000 copies/mL at initiation of antiretroviral therapy and soon after dropped to 915 copies/mL. At 40 weeks old the viral load was below 20 copies/mL and remains undetectable to date.[41]

A study by Cotton et al found that fosamprenavir/ritonavir–containing regimens in HIV-infected children aged 4 weeks to 2 years achieved plasma amprenavir exposures comparable to those of regimens approved in adults (except for trough exposures in infants under age 6 months). Viral suppression was achieved in 61% of patients, and the regimens were generally well tolerated, with the most common adverse events being diarrhea, upper respiratory tract infection, gastroenteritis, and otitis media.[42]

For patients aged 1 year or older, the age-related CD4 thresholds for initiating treatment are less than 25% for children aged 1-4 years and less than 350 cells/μL for children aged 5 years or older, regardless of symptoms or plasma HIV RNA level.

Initiate treatment in children aged 1 year or older who are asymptomatic or have mild symptoms and have a CD4 of 25% or more in children aged 1-4 years or 350 cells/μL or more in children aged 5 years or older who have plasma HIV RNA of 100,000 copies/mL or more.

ART may be considered or deferred in children aged 1 year or older who are asymptomatic or have mild symptoms and who have a CD4 of 25% or more in children aged 1-4 years and 350 cell/μL or more for children aged 5 years or older who have plasma HIV RNA or less than 100,000 copies/mL.

When treating older children, some advocate considering a child's Tanner stage when determining dosing regimens. Adolescents in early puberty (Tanner stages I and II) should be treated according to pediatric dosing guidelines. Adolescents in late puberty (Tanner stage IV) and postpubertal adolescents should follow adult dosing guidelines.

Initial combination therapy for ART-naive children

Combination ART with at least 3 drugs from at least 2 classes of drugs is recommended for initial treatment of infected infants, children, and adolescents because it provides the best opportunity to preserve immune function and delay disease progression.

The use of zidovudine as a single agent is appropriate only when used in infants of indeterminate HIV status during the first 6 weeks of life to prevent perinatal HIV transmission. Infants confirmed as HIV infected while receiving chemoprophylaxis should have prophylactic antiretroviral drugs discontinued and treatment initiated, with a combination regimen of at least 3 drugs.

Infants exposed to nevirapine in the peripartum period as part of a preventing-mother-to-child-transmission (PMTCT) strategy should not be treated with nevirapine-based combination therapy because of the established higher risk of treatment failure due to nevirapine resistance. Lopinavir/ritonavir-based combination therapy would be the only recommended, preferred initial regimen.

One study evaluated the use of lopinavir/ritonavir combination therapy in children younger than 6 years with HIV type 1 infection who have not undergone highly active antiretroviral therapy (HAART). Seventy percent of the 43 children in the study realized a virologic success at month 12. Overall, 20 children experienced virologic failure; risk factors for virologic failure were determined to be young age and low socioeconomic status.[43]

The integrase strand transfer inhibitor dolutegravir is indicated as an adjunct agent for patients with HIV-1 infection. Dolutegravir, which interferes with an enzyme needed for HIV to multiply, is a once-daily pill used in combination with other antiretroviral drugs. Pediatric indications are for children who weigh at least 30 kg and are treatment-naïve or, if they are treatment-experienced, have not previously taken other integrase strand transfer inhibitors.[44, 45]

An oral suspension formulation and chewable tablet of the integrase strand transfer inhibitor raltegravir are also available for pediatric patients aged 4 weeks and older who weigh at least 3 kg and less than 20 kg.[46, 47, 48] It may be taken with or without food. This agent is used in combination with other HIV-1 antiretroviral agents.

Drug combinations for initial therapy in treatment-naive children include 3 drugs, including either a boosted protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or integrase strand inhibitor plus a dual-nucleoside/nucleotide reverse transcriptase inhibitor.[3]

Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir AF) was approved in 2015 as a complete treatment regimen for HIV-1 infection in adults and children aged ≥12 years (weight, ≥35 kg) who are ART-naive or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA, < 50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components.[49]

In February 2016, emtricitabine/rilpivirine/tenofovir DF (Complera) was approved as a complete regimen for treatment of HIV-1 infection in treatment-naive adults and adolescents aged 12 years or older (weight, ≥35 kg) with HIV-1 RNA levels of >100,000 copies/mL, and in certain virologically suppressed (HIV-1 RNA, < 50 copies/mL) patients on a stable ART regimen at the start of therapy in order to replace their current ART regimen.[50]

In June 2019, the FDA approved the 3-drug combination of bictegravir (BIC), an HIV-1 integrase strand transfer inhibitor (INSTI), and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs). The 3-drug combination is indicated as a complete regimen for treatment of HIV-1 infection in adults and pediatric patients weighing ≥25 kg who are ART-naive or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA, < 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components.[51]

Another complete regimen approved by the FDA was Symtuza (darunavir/cobicistat/emtricitabine/tenofovir AF) in March 2020. It is indicated for HIV-1 infection in adults weighing at least 40 kg who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA, < 50 copies/mL) on a stable ART regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.[52]

Preferred regimens are as follows:

See the full Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection for additional information including alternant ART regimens

Monitoring therapy

Close monitoring to determine whether the child is tolerating ART and to answer any questions the caregiver may have are essential to the success of these therapies. At 4-8 weeks after the start of therapy, the CD4+ count and/or percentage and HIV RNA levels should be reassessed, and laboratory evaluations for toxicity should be done.

The main goal of therapy is to lower HIV RNA to undetectable levels, although not all infants achieve this. Some have a 10-fold or 5-fold decrease in the viral load.

Treatment failure

Treatment failure is defined as virologic, immunologic, or clinical.[3]

Virologic failure includes incomplete response and viral rebound. Incomplete virologic response to therapy is defined for all children with any of the following:

Viral rebound is repeated detection of HIV RNA despite previously achieved undetectable viral load levels

Immunologic failure includes incomplete response and immunologic decline. Incomplete response is defined as a failure by a child younger than 5 years with severe immune suppression (CD4+< 15%) to improve CD4+ values by 5 or more percentage points, or as a failure by a child aged 5 years or older with severe immunosuppression (CD4+< 200 cells/µL) to improve CD4+ values by 50 cells/µL or greater above baseline within the first year of therapy

Immunologic decline includes a sustained decline of 5 percentage points in CD4+ percentage below pretherapy baseline at any age, or decline to below pretherapy baseline in absolute CD4+ cell count in children who are aged 5 years and older.

Clinical failure includes all of the following:

Breastfeeding

In the United States and other parts of the world where replacement feeding is affordable, feasible, acceptable, sustainable, and safe, breastfeeding by HIV-infected women (including those receiving antiretroviral drugs) is not recommended.[3]

Observational data and randomized clinical trials have demonstrated that infant prophylaxis (primarily using daily infant nevirapine) during breastfeeding significantly decreases the risk of postnatal transmission in breast milk and that maternal triple-drug prophylaxis during breastfeeding may likewise decrease postnatal infection.[20, 53] The results from a randomized, double-blind, placebo-controlled trial confirm that nevirapine prophylaxis via breastfeeding infants up to age 6 months provides protection from transmission of HIV-1 from mother to child.[54]

Both infant nevirapine prophylaxis and maternal triple-drug prophylaxis during breastfeeding may be associated with the development of antiretroviral drug resistance in infants who become infected despite prophylaxis.[3]

Drug interactions with antiretroviral drugs

Antiretroviral drug (ARD) regimens often contain 3 or more agents. In addition, other drugs are typically required to manage the numerous infectious and systemic consequences of AIDS.

Therefore, the likelihood of drug interactions increases. The outcome of the drug interactions may reduce or eliminate the efficacy or increase the toxicity of 1 or both drugs. A thorough understanding of the mechanisms of interactions is essential to minimize or prevent adverse effects and to prevent inadequate treatment.

Regarding the mechanisms, drug interactions are classified as pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions alter drug absorption, distribution, or elimination (metabolism, excretion). Pharmacodynamic alterations manifest as additive, synergistic, or antagonistic drug effects.

Several ARDs may affect or be affected by absorption kinetics. Didanosine contains an aluminum and magnesium buffer that may affect the absorption of other drugs (eg, ciprofloxacin). Delavirdine, atazanavir, and rilpivirine are poorly absorbed when the pH of the GI tract increases.

Many ARD pharmacokinetic interactions alter the cytochrome P450 (CYP) metabolic enzyme system. Cytochromes are metabolic enzymes in the liver, and CYP denotes the specific enzyme.

The CYP system is classified into families, 3 of which are important in humans: CYP1, CYP2, and CYP3. Further delineation into subfamilies is denoted with a capital letter (eg, CYP3A). The nomenclature is completed with the description of individual proteins called isoenzymes, which are delineated with a second number (eg, CYP3A4).

Drugs may be substrates, inhibitors, and/or inducers of particular isoenzymes. Substrates are metabolized by means of the CYP system. They may also be classified as inhibitors (ie, those with reversible and competitive action that decreases metabolism) and/or inducers (ie, those with reversible and competitive action that increases metabolism). Inhibitors decrease hepatic metabolism of isoenzyme substrates (ie, increase serum concentrations), whereas inducers increase this metabolism (ie, decrease serum levels).

All currently approved protease inhibitors and NNRTIs are metabolized in the CYP system, principally by the 3A4 isoenzyme. Some also induce or inhibit CYP3A4, respectively decreasing or increasing serum levels of the 3A4 substrate. Strong inhibitors (eg, ritonavir) have been used in small doses to increase drug levels (eg, of the lopinavir-ritonavir combination), enhancing the efficacy of those drugs with a low enough dose to limit the risk of adverse effects.

Drug interactions among antiretroviral agents may be used to increase and sustain serum levels of one another, enhancing efficacy and decreasing adverse effects (eg, Kaletra, which is a fixed-dose combination product of lopinavir and ritonavir). Other interactions may decrease levels, causing concern about sufficient efficacy. Discussion of drug interactions can be found in Antiretroviral Therapy for HIV Infection.

Treatment for patients at risk for vertical acquisition

Within 6-12 hours of the delivery of a neonate at risk, zidovudine therapy should be started after a baseline CBC count is obtained. Zidovudine should be continued until the infant is 6 weeks of age, when it may be discontinued if all DNA HIV PCR results are negative. If HIV infection is confirmed in the infant, zidovudine monotherapy must be stopped immediately.

Prophylaxis and Treatment of Opportunistic Infections

Although current HAART regimens have substantially and dramatically decreased AIDS-related OIs and deaths, prevention and management of OIs remain critical components of care for HIV-infected children.[38]

OIs are typically an indication of severe immune suppression. However, an increased capacity to mount inflammatory reactions as a result of successful HAART may result in the development of immune reconstitution inflammatory syndrome (IRIS), which manifests as worsening of an existing active, latent, or occult OI. Although IRIS has primarily been reported in adults after initiation of HAART, it also has been reported in children .

IRIS may unmask viable pathogens. Alternatively, in so-called paradoxical IRIS, symptomatic relapse reflects reconstitution of specific T-cell–mediated immunity against persisting antigens from dead organisms; cultures in these cases are sterile.[38]

Selected opportunistic pathogens and common sources are as follows:

Antibiotic therapy

Tables 2 and 3 below summarize the antibiotics used for primary and secondary prophylaxis of opportunistic infections and their appropriate dosages.

Antibiotic prophylaxis does not guarantee protection, and opportunistic infections should be appropriately included in the differential diagnosis for all HIV-infected patients.

Several antibiotics used for prophylaxis have clinically significant adverse interactions with antiretroviral agents. For example, rifampin and rifabutin reduce the effectiveness and increase the toxicity of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Also, isoniazid is hepatotoxic and may interact poorly with protease inhibitors that are hepatotoxic.

Table 2. Antibiotics for Primary and Secondary Prophylaxis of Opportunistic Infections



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Table 3. Drugs and Doses for Prophylaxis of Opportunistic Infections



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Pneumocystis pneumonia

Prophylaxis is the most important measure for decreasing the incidence of PCP, it but does not guarantee protection. Table 4 below delineates the CD4+ indications for starting prophylaxis with regard to the patient's age or status.

Table 4. CD4+ -Based Indications for Starting PCP Prophylaxis



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PCP prophylaxis should be started in all infants aged 6 weeks who were born to HIV-infected mothers. It should be continued until HIV infection has been ruled out.

Viral infection

Previous CMV infection or CMV retinitis requires secondary prophylaxis with ganciclovir 5 mg/kg/day IV, or valganciclovir, or an implant delivering sustained-release ganciclovir or cidofovir.

Severe or frequent recurrences of herpes simplex require prophylaxis with acyclovir 80 mg/kg/d given by mouth 2 or 4 times day.

Varicella or herpes zoster should be treated with IV acyclovir 500 mg/m2/dose 3 times a day for 7 days.

Fungal infection

Candida

Thrush occurs in a third of patients with non–category C disease and in one half of patients with category C disease. Candidal esophagitis is an AIDS-defining condition and can result in severe dysphagia and anorexia; the diagnosis can be confirmed with endoscopy. Disseminated systemic fungemia is rare, but indwelling catheters and neutropenia increase a patient's susceptibility.

Primary prophylaxis is not generally recommended, but prophylaxis after repeated infections may be helpful. Prophylactic treatment is used in severe recurrent cases, but prolonged prophylaxis can lead to resistance.

Nystatin may not be helpful in managing repeated thrush or cutaneous infections, and topical clotrimazole or miconazole may be needed. Fluconazole, itraconazole, or ketoconazole may be needed if topical treatments fail or if candidal esophagitis develops. Candidal esophagitis recalcitrant to treatment with azole compounds and disseminated disease should be treated with amphotericin.

Cryptosporidium

Cryptosporidium infections cause chronic, secretory, watery diarrhea that may be large in volume. Maintaining an adequate fluid balance is most important and may be challenging.

A unique parasitophorous vacuole in the host cell shelters the parasite from antimicrobial drugs. Control of the infection can be difficult because no curative therapy exists. The best treatment is prevention and good immunity. Avoidance of unfiltered tap water may have some value in prevention.

Cryptococcus

Cryptococcal meningitis is uncommon in children, though it should be ruled out when symptoms and/or signs of meningitis are observed or when fever without a clear source causes severe headache. CSF samples should be examined with India ink stain, and the presence of cryptococcal antigen in serum and CSF should be determined. Treatment with amphotericin and flucytosine is necessary, followed by maintenance therapy with fluconazole or itraconazole.

Mycobacterial infection

M tuberculosis causes primary pulmonary disease in children and is most likely to affect children with existing lung disease. Extrapulmonary disease can occur, especially when immune function is decreased, and it may be present with or without pulmonary disease. Fever, cough, and tachypnea are common presenting symptoms.

PPD testing is useful only if the findings are positive, and it should not be used as a diagnostic method. Gastric aspirates, induced sputum samples, and bronchoalveolar lavage specimens are necessary, and susceptibility testing should be performed.

Initial therapy should involve 4 drugs: isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol or streptomycin. Therapy should continue for 1 year if the isolate is drug susceptible or more than 1 year if the isolate is multidrug resistant. Rifampin and rifabutin interact with protease inhibitors, requiring an alteration in HAART. Children younger than 4 years should not be treated with ethambutol because of possible optic neuritis.

Multidrug-resistant TB is highly prevalent among HIV-infected individuals. It is associated with a poor prognosis.

Efavirenz is effective against HIV in children who are also being treated for TB, according to a study by van Dijk et al. The study population consisted of 114 HIV-infected children younger than 3 years of age or weighing less than 10 kg: 45 children who were also being treated for TB received an efavirenz-based ART regimen; a second group of 69 children, including 7 who were being treated for TB, received an ART regimen using nevirapine.

At the initiation of ART, the children treated with efavirenz had a lower CD4+ percentage and weight-for-age z-score than did the nevirapine group. Nevertheless, improvement with the efavirenz-based regimen was such that the CD4+ percentage and z-score for both groups were comparable at 2-year follow-up.[55]

MAC infection

Disseminated M avium-intracellulare complex (MAC) infection is not uncommon in children with clinically significant disease progression, and a low CD4+ count is a major risk factor for MAC disease. MAC infection is second only to PCP among the most common opportunistic infections in children with AIDS, occurring in 6-15% of children with HIV infection. This percentage increases to 24% in children with CD4+ counts of less than 100 cells/mL. In the United States, MAC infection may be more common in the South than elsewhere.

MAC is ubiquitous, commonly existing in water, soil, and household environments. In some individuals, colonization may occur before infection. Person-to-person transmission has not been documented.

Although localized pulmonary disease is the common form of infection in hosts not infected with HIV, localized disease is uncommon in HIV-infected individuals, and disseminated disease is typical. Disseminated MAC infections commonly cause fever, night sweats, malaise, anorexia, and weight loss. Anemia and elevated alkaline phosphatase levels are also common. Involvement of the bone marrow may produce neutropenia.

GI symptoms are common in some presentations. Abdominal pain, hepatosplenomegaly, and diarrhea with associated malabsorption may be common, but elevated transaminase levels are not common. CT or MRI may reveal general intestinal lymphadenopathy.

Sputum, stool, and blood acid-fast cultures should be obtained when the presence of MAC is suspected. The reticuloendothelial system is a common reservoir for mycobacteria, though the bone marrow, GI tract, lungs, adrenals, and kidneys may also be affected.

Control of a MAC infection requires at least 2 or 3 antibiotics, but more may be necessary if clinical symptoms do not resolve. Early detection and treatment is most effective.

Exposure to antibiotics before treatment suggests that other agents may be more effective than those previously used. In addition, a lack of a response to a regimen may indicate the need to empirically change antibiotics instead of simply adding antibiotics, as drug resistance can develop rapidly. Although polyantimicrobial therapy may be useful, toxicity is more common with this approach.

Initial regimens may include macrolides, rifabutin, and ethambutol. Rifabutin interacts with several protease inhibitors, and ethambutol is not generally used in children younger than 4 years because of the possible development of optic neuritis. However, ethambutol is the only choice in many situations, and it is used when indicated. Amikacin, cefoxitin, ciprofloxacin, ofloxacin, doxycycline, rifampin, and streptomycin may also be used for treatment. The best treatment is effective HAART with immune reconstitution, which increases the CD4+ count.

Blood cultures should be obtained at regular intervals until the results are negative and the susceptibilities of identified organisms are determined. Treatment must be continued indefinitely.

Prophylaxis is extremely important. Table 5 indicates the CD4+ count at which prophylaxis should be started with regard to the patient's age.

Table 5. CD4+ -Based Indications for MAC Prophylaxis



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Clarithromycin administered for MAC prophylaxis may also protect the patient against Cryptosporidium infection. Nitazoxanide is being investigated for treatment of cryptosporidiosis in patients with AIDS. Other drugs, such as paromomycin, azithromycin, and hyperimmune bovine colostrum have been used with suboptimal results. Octreotide must be used with caution because it can slow diarrhea but not clear the infection.

Pancreatitis and/or bowel infarction may develop.

Toxoplasmosis

Toxoplasmosis is a rare CNS infection in children. When it occurs, it is usually acquired congenitally.

Specific immunoglobulin G and immunoglobulin M titers, as well as head ultrasonography to detect CNS lesions, should be performed in neonates with risk of congenital infection or in whom it is suspected. Treatment with pyrimethamine, folinic acid, and sulfadiazine or clindamycin is required when infection occurs.

Screening for opportunistic infections

All HIV-infected children should be screened for certain opportunistic infections. The patient and all family members should undergo yearly TB screening.

CMV infection accelerates HIV progression in infants. At birth, positive findings on urine culture can help guide later management. Cultures not obtained immediately after birth may imply colonization and not congenital infection. CMV infection should be treated only if it is symptomatic.

Toxoplasmosis, syphilis, rubella, CMV, and herpes simplex (TORCH syndrome) are not common during gestation in women with well-controlled HIV infection. However, women with poorly controlled HIV infection or neonates who have growth retardation at birth should be screened for TORCH infections. Patients with AIDS not uncommonly carry toxoplasmosis, and this infection may be transmitted in utero if the mother is severely immunosuppressed during pregnancy.

Assessment of immunologic function

Immunologic function should be assessed in high-risk patients. Immunoglobulin levels should be checked every 3-6 months. Hypogammaglobulinemia is defined as an immunoglobulin G level of less than 2.5 g/L.

Humoral immune function can be checked by measuring specific antibody titers after immunization. Cellular immune function is checked by using a subcutaneous candidal control.

Children with hypogammaglobulinemia, humoral immune dysfunction, or more than 2 serious bacterial infections in a year should be given intravenous immunoglobulin (IVIG) 400 mg/kg every 4 weeks.

Treatment for Hematopoietic Disturbances

Thrombocytopenia is common in HIV infection, and platelet production generally decreases regardless of the platelet count. Anemia can result from HIV infection or its treatment. Neutropenia is relatively common in advanced disease and creates a clinically significant risk for infection.

Thrombocytopenia

Immune-mediated platelet destruction develops in approximately 20% of children with HIV infection. In children with advanced disease, severe thrombocytopenia may need to be managed.

The platelet count may transiently increase with IV immunoglobulin (IVIG), interferon (IFN)-alfa, corticosteroids, or anti-Rh immunoglobulin. IVIG is the treatment of choice. Regimens include IVIG 1-2 g/kg/day for 2-5 days. Three million units of IFN-alfa administered 3 times per week increases the platelet count in 50% of adults after 3 weeks. A 4-week course of prednisone 1-2 mg/kg followed by a 2- to 4-week taper is an alternative, but the immunosuppressive adverse effects must be considered carefully.

Anti-Rh immunoglobulin is useful in Rh-positive patients who have not undergone splenectomy, and it is relatively inexpensive. A 1- to 2-g decrease in the hemoglobin level occurs, which limits use of this therapy in patients with anemia. In most patients, 25 mcg/kg administered IV on 2 consecutive days with repeated doses of IV anti-Rh or intramuscular (IM) anti-D every 2-4 weeks increases the platelet count. As an alternative, 6-13 mcg/kg IM administered every week also produces a reasonable increase in the platelet count.

More long-lasting responses can be achieved with zidovudine or danazol treatment or splenectomy. In most adults, high-dose zidovudine can reverse HIV-related idiopathic thrombocytopenia purpura (HIV-ITP). Treatment of HIV infection, especially with zidovudine, appears to improve the platelet count and platelet production. In adults, danazol 400-800 mg daily increases the platelet count in 1-2 months.

Splenectomy is an effective long-term treatment. Although splenectomy is not associated with an increased mortality rate, the risk of fulminant infections with encapsulated bacteria increases.

Anemia

Iatrogenic anemia is not uncommon, and HIV infection often suppresses bone marrow, serum erythropoietin levels, and responses of the bone marrow to erythropoietin. An infectious or neoplastic agent may cause new-onset anemia. A standard workup for anemia should be performed along with a determination of the erythropoietin level, reticulocyte count, and indirect bilirubin level.

A high reticulocyte count indicates a good bone marrow response. When accompanied by a high indirect bilirubin level, hemolytic anemia should be suspected. In the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, the use of sulfonamides, dapsone, or oxidant drugs can cause iatrogenic erythrocyte hemolysis. A low indirect bilirubin level indicates a response to acute blood loss or recent replacement of a necessary cofactor.

Disseminated intravascular coagulation and thrombotic thrombocytopenic purpura can cause hemolytic anemia and are associated with thrombocytopenia and fragmented RBCs on smears.

Although the prevalence of erythrocyte autoantibodies is high in HIV-infected patients, especially those with hypergammaglobulinemia, the rate of hemolysis by this mechanism is low.

Hemophagocytic syndrome occurs when macrophages in the bone marrow phagocytose erythrocytes.

A low reticulocyte count indicates bone marrow suppression, ineffective erythropoiesis, or a myelophthisic process. Vitamin B-12 or folic acid deficiency produces a high mean corpuscular volume (MCV) and indirect bilirubin level. Patients with HIV are especially at risk for these deficiencies because of poor nutrition and poor small-bowel function. As many as 33% of patients with HIV have a negative vitamin B-12 balance.

Folic acid deficiency causes the production of large oval erythrocytes, hypersegmented polymorphonucleocytes, and pancytopenia. Vitamin B-12 deficiency causes subacute combined degeneration of the spinal cord with high cortical dysfunction. Before treatment is started with supplemental parenteral vitamin B-12 and oral folic acid, serum folate and vitamin B-12 levels must be measured.

A low or normal indirect bilirubin value suggests secondary myelosuppression or neoplastic marrow infiltration.

A high mean corpuscular volume (MCV) indicates iatrogenic pharmaceutical suppression of erythropoiesis. A low MCV suggests iron deficiency anemia. A normal MCV suggests HIV anemia, anemia related to chronic disease, an infectious etiology, or neoplastic marrow invasion.

Parvovirus B19 and many pharmaceutical agents cause neutropenia in addition to anemia.

Ancillary hematologic laboratory tests may help clarify the differential diagnosis, and an investigation of an infectious etiology may be warranted if the CD4+ count is low.

Several etiologies may be involved, resulting in laboratory values that may not be correlated with a particular type of anemia. Clinical evaluation and correlation with laboratory values is necessary. Bone marrow biopsy may be necessary if laboratory and clinical findings are inconclusive.

Serum erythropoietin levels of less than 500 IU/L and anemia due to bone marrow suppression as a result of infection, inflammation, or pharmaceutical agents should be managed with erythropoietin. Other causes of anemia must be ruled out and managed before erythropoietin is given.

Erythropoietin should be started at a dosage of 100 U/kg given subcutaneously 3 times per week; this may be increased to 200 U/kg/dose. After the hematocrit returns to normal, dosing should be decreased to once every week or every other week to maintain a stable hematocrit. Adverse effects include pain at the injection site and fever. Supplemental iron should always be given with erythropoietin therapy.

Neutropenia

Neutropenia is relatively common in advanced HIV disease. In 25% of patients with moderate neutropenia, bacterial infections develop, most often within 24 hours of the onset of neutropenia. The following myelosuppressive drugs—especially zidovudine, trimethoprim-sulfamethoxazole, and ganciclovir—can induce neutropenia:

Infectious agents such as parvovirus B19 can cause myelosuppression, as can invasive neoplastic processes of the marrow.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are used to treat neutropenia and to promote granulocyte production and function. GM-CSF has more adverse effects than G-CSF, and it promotes viral replication. However, GM-CSF does not increase the viral load if it is used with ART.

G-CSF is started at a dosage of 5 mcg/kg/day, and it is given until neutropenia resolves. Titration to once or twice per week is typical. Adverse effects of G-CSF are minimal and include bone pain and elevations in lactate dehydrogenase (LDH) and alkaline phosphatase levels. GM-CSF is started at a dosage of 5 mcg/kg/d given subcutaneously for 5 days and then titrated to effect. Adverse effects include flulike symptoms, myalgias, bone pain, fatigue, and fever.

Hospital Admission

Based on the patient's living arrangements and stage of infection, inpatient care may be warranted at some time during the patient's illness. The extensive testing required to rule out an underlying infection or a malignancy may be easiest performed if the child is admitted to a health care facility.

If an infection or a malignancy is detected, hospital admission may be appropriate. For example, if intravenous antibiotics are given, a child is usually admitted to the hospital. A serious reaction to an antiviral drug may also mandate hospitalization to follow up on the progression of the reaction and to observe the patient if new drugs are begun.

Diet

Malnutrition with an accompanying failure to thrive is not uncommon in children infected with HIV. The patient's dietary habits should be reviewed on a regular basis, and a nutritional specialist should be involved in the patient's treatment.

Poor appetite results in poor nutritional intake. Appetite stimulants can be useful.

High-energy, high-protein nutritional supplements are commonly needed. Caretakers must be instructed to avoid giving the child any food or water that has a high risk of being contaminated with any infectious agent. HIV and accompanying opportunistic infections can worsen GI symptoms.

Nasogastric, nasojejunal, and/or gastrostomy tubes may be needed to support the patient's nutritional and fluid status. Gastrostomy tubes are well tolerated, and they are often more comfortable than nasogastric or nasojejunal tubes.

Parenteral hyperalimentation may be necessary when the patient's GI tract cannot support substantial feedings.

Treatment Compliance

Medication compliance is a central issue. This is particularly important with regard to ART because missing even 1 dose can easily lead to subtherapeutic levels of many drugs used in ART. Subtherapeutic levels promote the development of drug resistance.

The treatment regimen may be difficult. Patients must take multiple doses of several ARDs every day, as well as prophylactic antibiotics and supplemental vitamins. Therefore, the risk of missing a dose is high. New ARDs are being developed to simplify the medical regimen. The simplest dosing regimen should be carefully selected to help avoid this pitfall.

Noncompliance with prescribed medications is multifactorial and major in some populations. In general, children do not like to take medications, especially if they taste bad. Several drugs have an unpleasant taste. Adverse effects (eg, GI upset, diarrhea, allergy) may cause the caretaker to discontinue a medication without informing the physician. Many drugs can cause compliance problems, even in the most reliable individuals.

The caretaker or child should bring the medications to each clinic visit. The bottles should be checked against a list of prescribed medications kept in the chart.

The caretaker or patient should be questioned regarding the particular time and method of administration, and he or she should be asked to state the names of the medications without referring to the bottles. Although some caretakers cannot perfectly complete this task, they may still be giving the medications correctly. This assessment method allows the physician to judge the caretaker's familiarity with the medications and to detect any problems with drug administration.

Known adverse effects of drugs should be directly addressed. Some caretakers or patients are frightened or embarrassed to disclose adverse effects that may be preventing them from properly using the medications. For example, though a patient may be taking a medication regularly, it may induce frequent vomiting, which affects drug delivery. Adolescent patients may avoid taking the medications at school to prevent their peers from knowing about their disease.

Partial compliance can be worse than no compliance because resistance occurs when drugs are given at subtherapeutic doses. Drug resistance develops rapidly. If the patient is not taking a medication, the virus does not develop resistance to it, and the medication is still useful for future treatment of the virus.

Administering medications with chocolate or peanut butter can help. Some medications can also be mixed in chocolate milk or pudding. If such a technique is used, proper dental hygiene is important to wash out the sugar after a drug is administered.

Placement of gastrostomy tube for drug administration is a feasible option in children who cannot be compliant. Such a device also is useful for nutritional supplementation. This option must be planned in advance because the potentially tenuous condition of children with advanced HIV can make surgical procedures risky.

A home visiting nurse or a family member experienced in healthcare may be able to assist and instruct primary caregivers in giving medications.

Deterrence/Prevention

The risk of vertical transmission may be reduced. Most children are infected by means of vertical transmission. Proper treatment of the mother during pregnancy and delivery and proper treatment of the neonate can reduce the risk of vertical transmission. Prenatal, perinatal, and postnatal treatment along with elective cesarean delivery lower the transmission rate to as low as 2%.

Risk factors for vertical transmission are divided into the 4 categories, as shown in Table 6.

Table 6. Risk Factors for Vertical Transmission



View Table

See Table

Transmission can occur during 3 periods: prenatal or in utero, perinatal and delivery, and postnatal. Prenatal transmission is implicated in 15-38% of vertically acquired HIV infections. Most vertical infections occur during delivery.

Although the concentration of HIV in the cervicovaginal secretions is lower in women with lower viral loads, HIV particles exist in the cervicovaginal secretions of women with undetectable viral loads.

Any factor that reduces contact between the neonate and maternal blood or cervicovaginal secretions reduces vertical transmission. This observation is supported by the decreased transmission rates noted with elective cesarean delivery. However, this protective effect occurs only when women were treated with zidovudine during pregnancy.

The postpartum complication rate increases with elective cesarean delivery. Therefore, it remains to be determined whether regimens involving highly active ART (HAART) can substantially reduce vertical transmission during vaginal delivery and thereby improve morbidity and mortality rates for both mother and child.

Postnatal vertical transmission occurs with breastfeeding; the transmission incidence is 0.7% per month.

Although recommendations state that women infected with HIV should not breastfeed, the World Health Organization advises women in developing countries to breastfeed because death rates related to infectious diarrhea and dehydration are higher than those related to AIDS.

The CDC has approved the following regimen to reduce vertical HIV transmission:

Unfortunately, antepartum treatment is not without risk to the fetus. In a study of HIV-negative infants born to HIV-positive mothers, Lipshultz et al concluded that fetal exposure to ART was associated with various cardiac effects, including reduced left ventricular (LV) dimension, LV mass, and septal wall thickness z-scores, as well as increased LV fractional shortening and contractility up to age 2 years.[21] These effects are more pronounced in girls than in boys Exposure to ART in utero may impair myocardial growth while improving depressed LV function.

A large-scale clinical trial (known as HPTN 052) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) found that immediate treatment of HIV-infected individuals with oral antiretroviral drugs reduced the risk of transmitting the virus to their uninfected sexual partners by 96%.[56]

Postexposure prophylaxis

The CDC has recommended basic and expanded HIV postexposure prophylaxis (PEP) regimens. For details, see the Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. Also see the Medscape Reference articles Antiretroviral Therapy for HIV Infection and Body Fluid Exposures.

An overview of the CDC recommendations for PEP are as follows:

An alternative expanded PEP regimen includes the basic PEP regimen plus one of the following:

Use of nevirapine for PEP is generally not recommended because of a risk of early onset rash and severe hepatotoxicity.

HIV vaccine

A study from Thailand suggests a possible benefit of vaccines in heterosexuals at risk for HIV-1 transmission.[57] In the randomized, multicenter, double-blind, placebo-controlled trial by Rerks-Ngarm et al, 16,402 healthy participants aged 18-30 years received either 4 priming injections of recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus 2 booster shots of recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E) or placebo.

In the per-protocol analysis, which excluded subjects who seroconverted during the vaccination series, the vaccine efficacy was 26.2%. In the modified-intention-to-treat analysis, which excluded subjects who had baseline HIV-1 infection, the vaccine efficacy was 31.2%. However, the 95% confidence intervals in these analyses were extremely wide (-13.3 to 51.9 and 1.1 to 52.1, respectively), which precludes concluding that the vaccine had proven efficacy.[57]

Among study subjects who developed HIV-1 infection, viremia and CD4+ T cell counts were unchanged by vaccination. This suggests that, if infection did occur, there was no apparent immunologic benefit from having received the vaccine.

Preexposure prophylaxis

Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg (Truvada) has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults, adolescents, and discordant couples.  Additionally, daily administration of emtricitabine 200 mg plus tenofovir alafenamide (TAF) 25 mg (Descovy) is approved for at-risk adults and adolescents for HIV-1 pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex. Daily emtricitabine/tenofovir is one prevention option that is part of the general guidelines for HIV prevention.[58]

Immunizations

Immunizations for most childhood diseases and other preventable pathogens should be given to the child with HIV infection. All typical childhood vaccines should be given, with the exception of live vaccines in selected children.

Inactivated poliovirus vaccine should be given instead of the live oral poliovirus vaccine, though this is a consideration only in developing countries where live oral vaccines are used.

The measles-mumps-rubella (MMR) vaccine should be given to all children whose disease is not in CDC immune category 3. The second dose should be given as soon as 1 month after the first dose to ensure early seroconversion. If a recent measles epidemic has occurred, the measles or mono-measles vaccine should be administered as early as possible to all children, except those whose disease is in CDC immune category 3.

Pneumococcal conjugate heptavalent vaccine (PCV 7) is recommended for all HIV-infected children aged 2–59 months. For children 24-59 months who have already received PPV 23, 2 doses of PCV 7 administered at least 2 months apart are recommended. Administering PCV 7 to older children with high-risk conditions, such as HIV infection, is not contraindicated.

Pneumococcal polysaccharide vaccine (PPV 23) should be given to children at 2 years of age, with 1 revaccination 3-5 years later.

Influenza vaccine should be given yearly to all children older than 6 months and to family members of the patient.

Administer 2 doses of single-antigen varicella vaccine at a minimum interval of 3 months to HIV-infected children 12 months of age or older in CDC clinical class N, A, or B with CD4+ T-lymphocyte counts 15% or higher and without evidence of varicella. Varicella vaccine was previously recommended for asymptomatic or mildly symptomatic HIV-infected children (CDC clinical class N or A) with age-specific CD4+ T-lymphocyte counts of 25% or higher. Otherwise, varicella vaccination is strictly forbidden, and exposure to varicella should be treated with intramuscular (IM) varicella-zoster immunoglobulin within 72 hours of exposure.

Measles, mumps, rubella and varicella (MMRV) vaccine should not be administered as a substitute for the component vaccines when HIV-infected children are being vaccinated. No data are available regarding the safety, immunogenicity, or efficacy of this combination vaccine in HIV-infected children.

All children should receive hepatitis A vaccine at age 12-23 months. Vaccination should be completed according to the approved schedules and integrated into the routine childhood vaccination schedule. Children who are not vaccinated by the age of 2 years can be vaccinated at subsequent visits.

The potential risks and benefits of administering rotavirus vaccine to infected infants must be considered because immunocompromised hosts sometimes have severe, prolonged, and even fatal rotavirus gastroenteritis. However, safety or efficacy data are not available for the administration of rotavirus vaccine to infants with HIV/AIDS and other clinical manifestations of HIV infection. Data from clinical trials are insufficient to support the administration of rotavirus vaccine to infants with indeterminate HIV status who were born to mothers with HIV/AIDS.

Use of the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines (Tdap) is not contraindicated in HIV-infected children. The immunogenicity of Tdap in persons with immunosuppression has not been studied and could be suboptimal. Tdap can be administered to children and adolescents aged 11-18 years at an interval of less than 5 years after Td vaccination, as the benefit of providing protection against pertussis is likely to be increased. Data from a Canadian study of children and adolescents support the safety of an interval as short as about 2 years between Td and Tdap vaccinations.

ACIP recommends routine immunization with meningococcal conjugate vaccine (serogroups A, C, W, and Y; Menactra or Menveo) for persons aged ≥2 months with HIV infection. HIV- infected children aged < 2 years should receive the vaccine in accordance with the age-appropriate, licensed, multidose schedule (ie, Menveo at aged 2, 4, 6, and 12 months). Persons aged ≥2 years with HIV infection who have not been previously vaccinated should receive a 2-dose primary series of MenACWY conjugate vaccine (Menactra or Menveo). Persons aged ≥2 years with HIV infection who have been previously vaccinated with 1 dose of meningococcal conjugate vaccine should receive a booster dose at the earliest opportunity, provided at least 8 weeks have elapsed since the previous dose, and then continue to receive boosters at the appropriate interval throughout life.[59]

Consultations

An infectious disease specialist usually provides primary care and coordinates the care of the other specialists. In general, assembling a team of specialists is the best approach for managing the medical care of a child with HIV infection. A human development specialist, a nutritionist, a psychologist, and a case manager should be involved in the treatment of every child with HIV infection.

Examinations by specialists should occur routinely. Obtain a neurodevelopmental evaluation every 3-6 months.

The patient should follow up with an ophthalmologist every 6-12 months. Obtain an ophthalmologic evaluation for CMV, tuberculosis, and toxoplasmosis infections, as well as for corneal ulceration, which is often secondary to underlying nutritional deficits.

Obtain dental examinations at age 1-2 years, with follow-up every 3-6 months. Obtain an audiologic evaluation at age 2 years or sooner if concern exists.

Surgical consultation may be indicated in patients requiring central venous access for long-term parenteral medication or hyperalimentation. Placement of subcutaneous ports is common in children requiring long-term parenteral therapy, but the risks of placing such a line should be weighed against the possible need for recurrent replacement because of repeated line infections.

A cardiologist, endocrinologist, gastroenterologist, nephrologist, neurologist, pulmonologist, and mental health specialist should be consulted when necessary.

Long-Term Monitoring

Children with HIV infection require regular monitoring, with intervals determined by age and clinical status (eg, every 2 wk initially in infancy, with an increase in intervals as the child ages and the immune status stabilizes). In younger children, evaluations should occur every 1-6 months. In older children, a review of systems is advised every 3 months and a physical evaluation should be performed every year. CD4+ counts must be checked every 3-6 months.

Accurate height and weight documentation at each visit is important because HIV infection is known to adversely affect growth rates in children. Children with improved height growth velocity may be less likely to exhibit virologic or immunologic failure and less likely to have clinical disease progression.[60] A decrease in the growth velocity should alert the clinician to worsening of the underlying disease or inadequate nutrition.

Dietary habits should be reviewed at each clinical visit. Aggressive nutritional management prevents growth failure and improves immune function.

Most children with HIV infection have some developmental delay. Developmental assessment and therapy (including physical, occupational, and speech therapies) should be available.

Social support staff should continually reevaluate the child's support system. Children with HIV infection have many issues and need extra support from inside and outside the family. Every attempt should be made to support the efforts of a caring family and child.

Monitor CD4+ levels or percentages in infants or patients newly diagnosed with HIV at 3- to 4-month intervals to assess patients' immune status. In children younger than 5 years, the 2010 Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children recommends using CD4 percentages over absolute CD4 counts for monitoring disease progression because of inherent age-related changes in absolute CD4 counts.[3]

Other laboratory values should be monitored as follows:

Maintain an established vaccination schedule in children who are HIV positive to protect them against vaccine-preventable illnesses (see Immunizations).

Obtain a cerebrospinal fluid analysis in patients with neurologic disease (based on risk factors of the area and the clinical presentation of the child).

Medication Summary

Antiretroviral (ART) drugs are used for the treatment of human immunodeficiency virus (HIV) infection and for postexposure prophylaxis (PEP). ART monotherapy does not produce sustained clinical benefits, such as improved survival. This failure is partly due to the development of drug-resistant variants of HIV. Resistance develops rapidly during monotherapy, and cross-resistance among related drugs is common.

Combination therapy with ARTs (a strategy analogous to the treatment of TB and other infectious diseases) has improved efficacy, minimized toxicity, and delayed drug resistance.

Classes of ARTs include the following:

Initial therapy should be started with a combination of 3 ARTs, including a backbone of 2 NRTIs plus an NNRTI, or 2 NRTIs plus a protease inhibitor.[3]

Numerous ARTs have been approved for pediatric usage and many are available as a pediatric formulation or capsule/tablet.

Abacavir (ABC, Ziagen)

Clinical Context:  Patients and parents must be cautioned about the risk of serious hypersensitivity reaction (HSR). Provide a medication guide and warning card. Test patients for the HLA-B*5701 allele before starting therapy to predict risk of HSR. Indicated for children aged 3 months or older.

Didanosine (ddI, dideoxyinosine, Videx, Videx EC)

Clinical Context:  This agent is a purine nucleoside analog with antiviral activity. Indicated for children (including neonates aged 2 week or older); however, because of significant toxicity (eg, peripheral neuropathy, lactic acidosis, hepatomegaly), it is not typically prescribed since there are safer agents available.

Lamivudine (3TC, Epivir, Epivir HBV)

Clinical Context:  Lamivudine is a dideoxynucleoside analog with antiretroviral activity. In combination with oral zidovudine, it produces substantial and sustained increases in CD4+ counts and decreases in viral load in HIV-infected patients. It is approved by the FDA for children aged ≥ 3 months for HIV and is a common component of most nucleoside backbone regimens. It is also approved to treat hepatitis B.

Stavudine (d4T, Zerit)

Clinical Context:  Stavudine is a synthetic thymidine nucleoside analog active against HIV-1. Although stavudine is approved by the FDA for use in infants and children, it is not typically prescribed because it carries a higher risk of adverse effects associated with mitochondrial toxicity and a higher incidence of lipoatrophy than other NRTIs.

Zidovudine (ZDV, AZT, Retrovir)

Clinical Context:  This agent is a thymidine analog that inhibits viral replication. It inhibits activity of HIV reverse transcriptase by competing with natural substrate for use by and incorporation into viral DNA. Frequent choice of NRTI backbone for ART. It has extensive experience in pediatrics including treatment and prevention of perinatal transmission.

Emtricitabine (Emtriva)

Clinical Context:  A synthetic nucleoside cytosine analog, emtricitabine competes with deoxycytidine-5'-triphosphate and incorporates into viral DNA, causing chain termination. It is approved by the FDA in children (starting at birth). It has minimal toxicity and is administered once daily as part of a dual-NRTI backbone.

Tenofovir DF (TDF, Viread)

Clinical Context:  This antiretroviral agent used in treatment of AIDS inhibits activity of HIV reverse transcriptase by competing with natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by causing DNA chain termination. It is administered as prodrug bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir, which is converted, in various enzymatic processes, to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate.

Administration with a high-fat meal enhances bioavailability. Prolonged intracellular levels allows for once-daily dosing. It is approved by the FDA for children aged 2 years or older.

Class Summary

NRTIs are nucleoside or nucleotide reverse transcriptase inhibitor analogs with antiretroviral activity. They are indicated for the treatment of HIV infection, and they delay the progression of the disease.

Efavirenz (DMP-266, EFV, Sustiva)

Clinical Context:  Efavirenz is used only in combination regimens. It is approved by the FDA for children aged 3 months or older who weigh at least 3.5 kg.

Nevirapine (NVP, Viramune, Viramune XR)

Clinical Context:  Nevirapine is indicated for use in combination with other ARDs for treatment of HIV-1 infection. It is approved by the FDA in children from infancy (aged ≥ 15 days) onward. The extended-release tablet is approved for use in children aged ≥ 6 years.

Rilpivirine (Edurant)

Clinical Context:  NNRTI indicated in combination with other ARTs for treatment of HIV-1 infection in treatment-naïve adolescents aged 12-17 years who weigh at least 35 kg with HIV-1 RNA ≤ 100,000 copies/mL.

Etravirine (Intelence)

Clinical Context:  Indicated in combination with other antiretroviral agents (ART) for treatment of HIV-1 infection in ART-experienced patients with evidence of viral replication and HIV-1 strains resistant to a NNRTIs and other antiretroviral agents in children aged 2 years or older and weigh at least 10 kg.

Class Summary

NNRTIs inhibit both DNA-directed and RNA-directed polymerase functions of HIV-1 reverse transcriptase. The different sites of action of nonnucleoside and nucleoside inhibitors suggest potential synergistic effects of these agents and their potential activity against nucleoside-resistant HIV strains.

Nelfinavir (Viracept, NPV)

Clinical Context:  Nelfinavir inhibits HIV-1 protease, resulting in the production of an immature and noninfectious virus. It is approved by the FDA in combination with 2 NRTIs in children aged ≥ 2 years and adolescents.

Lopinavir and ritonavir (Kaletra, LVP/r)

Clinical Context:  Lopinavir inhibits HIV protease and renders enzyme incapable of processing polyprotein precursors, leading to production of noninfectious, immature HIV particles. Ritonavir inhibits CYP3A metabolism of lopinavir, increasing plasma levels. It is approved for children (including infants aged > 14 days), children, and adolescents. This product is available in tablets (200 mg/50 mg LPV/r), pediatric tablets (100 mg/25 mg LPV/r), and PO solution (80 mg/20 mg LPV/r; 42.4% alcohol by volume).

Ritonavir (Norvir, RTV)

Clinical Context:  Ritonavir is an HIV protease inhibitor used as part of double or triple therapy with nucleosides and other protease inhibitors. It is used as a boosting agent to other ARDs.

Atazanavir (ATV, Reyataz)

Clinical Context:  Atazanavir is an azapeptide HIV-1 protease inhibitor. It prevents virion maturation by selectively inhibiting Gag and Gag-Pol polyproteins in HIV-1 infected cells. It is approved by the FDA for infants (aged ≥ 3 months who weigh at least 5 kg), children, and adolescents.

Darunavir (DRV, Prezista)

Clinical Context:  An HIV-1 protease inhibitor, darunavir selectively inhibits HIV-encoded Gag-Pol polyprotein cleavage in infected cells, preventing formation of mature virus particles. It is indicated to treat HIV disease not responding to other ARDs. Coadminister with low-dose ritonavir (ritonavir-boosted therapy decreases elimination and increases darunavir serum concentration).

Darunavir is typically coadministered with other anti-HIV agents (eg, NRTIs). Food increases maximum concentration (Cmax) and area under the concentration-time curve (AUC). Coadministered with ritonavir, it is approved by the FDA as a part of an ART regimen in treatment-naïve and treatment- experienced children aged ≥ 3 years.

Fosamprenavir (f-APV, Lexiva)

Clinical Context:  A prodrug of amprenavir (inhibitor of HIV protease), fosamprenavir is rapidly converted to amprenavir by cellular phosphatases in vivo. Amprenavir inhibits HIV-1 protease and binds its active site, preventing the processing of viral Gag and Gag-Pol polyprotein precursors and resulting in immature, noninfectious viral particles. Although approved by the FDA in children as young as 4 weeks, the AIDSinfo Panel members recommend use in children aged 6 months or older. The panel also recommends fosamprenavir only be used as boosted therapy, since unboosted fosamprenavir may select for mutations associated with resistance to darunavir.

Tipranavir (TPV, Aptivus)

Clinical Context:  A nonpeptidic protease inhibitor, tipranavir inhibits HIV replication. It is indicated for combination antiretroviral treatment of HIV-1 infected patients aged 2 years or older who are treatment-experienced and infected with HIV-1 strains resistant to >1 protease inhibitor. This agent must be coadministered with ritonavir 200 mg to attain therapeutic levels. It is ineffective if used alone without ritonavir-boosted levels. Results of genotypic or phenotypic testing and/or treatment history should guide use. It is available as 250 mg caps or as PO solution of 100 mg/mL.

Saquinavir (Invirase)

Clinical Context:  Saquinavir is an HIV protease inhibitor used as part of double or triple therapy with nucleosides and other protease inhibitors. It must be used in combination with ritonavir as a boosting agent. It is available as a 200-mg hard gel cap or 500-mg film-coated tablet. It is not approved by the FDA for use in children or adolescents aged <16 years. Limited data are available from investigational trials in children aged ≥ 2 years.

Indinavir (Crixivan, IDV)

Clinical Context:  This agent prevents formation of protein precursors necessary for HIV infection of uninfected cells and viral replication. Indinavir has not been approved by the FDA for use in the pediatric population. Although indinavir was one of the first protease inhibitors to be studied in children, its use in pediatrics has never been common and is currently very rare. Indinavir is not recommended by the AIDSinfo Panel members for use in children because of its unfavorable toxicity profile, limited efficacy data, and uncertain pharmacokinetics.

Class Summary

Protease inhibitors inhibit HIV protease, which is required for HIV replication and the formation of mature, infectious viral particles.

Raltegravir (RAL, Isentress)

Clinical Context:  Raltegravir is an HIV-1integrase strand transfer inhibitor (INSTI). It is indicated for use in combination therapy regimens for the treatment of HIV infection in children who weigh at least 30 kg.

Dolutegravir (DTG, Tivicay)

Clinical Context:  Dolutegravir is an integrase strand transfer inhibitor (INSTI) that inhibits catalytic activity of HIV-1 integrase, an HIV encoded enzyme required for viral replication. It is approved for use in children aged ≥ 12 years who weigh at least 40 kg.

Class Summary

HIV integrase is responsible for the transport and attachment of proviral DNA to host-cell chromosomes, allowing transcription of viral proteins.

Enfuvirtide (T-20, Fuzeon)

Clinical Context:  Enfuvirtide is a fusion inhibitor. It blocks entry of HIV into human immune cells by inhibiting gp41 protein, disrupting viral structural rearrangement to fuse with healthy immune cells and preventing HIV replication. In clinical trials, selected patients with multidrug resistance were twice as likely to achieve undetectable HIV-1 plasma levels (< 40 copies/mL) when enfuvirtide was added to optimized antiretroviral regimens. It is approved for children aged 6 years or older.

Class Summary

These agents disrupt HIV binding and, ultimately, fusion with host cells. Entry inhibitors bind to CCR5 chemokines coreceptors. Fusion inhibitors bind to the HR1 region of gp41.

Maraviroc (MVC, Selzentry)

Clinical Context:  Maraviroc is a selective chemokine receptor antagonist (CRA). It is imperative to test all patients for CCR5 tropism using a highly sensitive tropism assay before initiating the drug. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on maraviroc. It blocks viral entry via CCR5 co-receptor into host cells, reduces viral load, and increases T-cell counts in CCR5-tropic HIV-1 (ie, R5 virus). This agent is indicated for combination treatment with optimized background therapy in treatment-experienced adults infected with only R5 virus who have evidence of viral replication and have HIV-1 strains resistant to multiple antiretroviral agents. It is approved for children as young as 2 years old.

Class Summary

Selectively antagonizes the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells.

Cobicistat (Tybost)

Clinical Context:  Indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents (ARTs) in the treatment of HIV-1 infection in pediatric patients.

Class Summary

Cobicistat and ritonavir are CYP3A inhibitors. As single agents, they are indicated to increase systemic exposure of specific protease inhibitors. Cobicistat or ritonavir are often part of a complete regimen combinations ARTs. Ritonavir is also a protease inhibitor, but it is mostly used as a pharmacokinetic enhancer.

Emtricitabine/tenofovir/efavirenz (Atripla)

Clinical Context:  Contains emtricitabine and tenofovir (NRTIs), plus efavirenz (NNRTI). Indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients aged ≥ 12 years who weigh at least 40 kg.

Elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya)

Clinical Context:  Four-drug antiretroviral (ART) combination of elvitegravir (integrase strand transfer inhibitor [INSTI]), cobicistat (CYP3A inhibitor), and emtricitabine and tenofovir alafenamide (TAF), both nucleoside analog reverse transcriptase inhibitors (NRTIs). It is indicated as a complete treatment regimen for HIV-1 infection in adults and children aged ≥ 12 y (weight ≥ 25 kg) who are ART-naïve or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components.

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild)

Clinical Context:  Combination integrase inhibitor, CYP3A4 inhibitor (boosted therapy), and 2 NRTIs as a complete regimen for treatment of HIV infection in treatment-naive pediatric patients aged ≥ 12 y who weigh at least 35 kg. It is also indicated as replacement of the current antiretroviral regimen in patients who are virologically-suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Stribild.

Emtricitabine/rilpivirine/tenofovir DF (Complera)

Clinical Context:  Indicated as complete regimen for treatment of HIV-1 infection in treatment-naïve adults and adolescents aged 12 years or older (weight ≥ 35 kg) with HIV-1 RNA > 100,000 copies/mL, and in certain virologically-suppressed (HIV-1 RNA < 50 copies/mL) patients on a stable ART regimen at start of therapy in order to replace their current ART regimen. Combination consists of 2 NRTIs (ie, emtricitabine and tenofovir) and 1 NNRTI (ie, rilpivirine).

Emtricitabine/rilpivirine/tenofovir AF (Odefsey)

Clinical Context:  Indicated as complete regimen for treatment of HIV-1 infection in treatment-naïve adults and adolescents aged 12 years or older (weight ≥ 35 kg) with HIV-1 RNA > 100,000 copies/mL, and in certain virologically-suppressed (HIV-1 RNA < 50 copies/mL) patients on a stable ART regimen at start of therapy in order to replace their current ART regimen. Combination consists of 2 NRTIs (ie, emtricitabine and tenofovir) and 1 NNRTI (ie, rilpivirine).

Efavirenz/lamivudine/tenofovir DF (Symfi, Symfi Lo)

Clinical Context:  Three-drug combination of a non-nucleoside reverse transcriptase inhibitor, and two nucleo(t)side reverse transcriptase inhibitors and is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children who weigh at least 35 kg (Symfi Lo) or 40 kg (Symfi).

Bictegravir/emtricitabine/tenofovir AF (Biktarvy)

Clinical Context:  Three-drug combination of bictegravir (BIC), an HIV-1 integrase strand transfer inhibitor (INSTI), and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs). Indicated as a complete regimen for treatment of HIV-1 infection in adults and pediatric patients weighing ≥25 kg who are ART-naïve or replacing current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA

Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza)

Clinical Context:  Four-drug combination of darunavir (DRV), a protease inhibitor, cobicistat, and FTC and TAF is indicated for HIV-1 infection in adults and adolescents weighing at least 40 kg who have no prior antiretroviral (ART) treatment history or who are virologically suppressed (HIV-1 RNA

Class Summary

Complete fixed-dose regimens assist with medication adherence. Three- and four-drug combination products are available to decrease pill burden and administration frequency.

Emtricitabine/tenofovir AF (Descovy)

Clinical Context:  NRTI combination product. Indicated in combination with other ART agents (eg, NNRTIs, PIs) for the treatment of HIV-1 infection in adults and pediatric patients aged ≥ 12 y (weight ≥ 35 kg). It is also indicated, in combination with other ARTs other than protease inhibitors that require a CYP3A inhibitor, for the treatment of HIV-1 infection in children weighing 25-35 kg. Tenofovir alafenamide (AF) is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than tenofovir DF, as well as an improved renal and bone safety profile.

Additionally, it is indicated for HIV-1 preexposure prophylaxis (PrEP) for at-risk adults and adolescents to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex.

Emtricitabine/tenofovir DF (Truvada)

Clinical Context:  Indicated, in combination with other antiretroviral agents (eg, NNRTIs, PIs), for the treatment of HIV-1 infection in adults and pediatric patients who weigh at least 17 kg and can swallow the tablet whole.

Additionally, it is also indicated in combination with safer sex practices for preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents at high risk. 

Lamivudine/zidovudine (3tc/zdv, Combivir)

Clinical Context:  Combination of 2 NRTIs. It is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in children who weigh at least 30 kg, adolescents, and adults.

Lamivudine/zidovudine/abacavir (Trizivir)

Clinical Context:  Abacavir is a nucleoside reverse transcriptase inhibitor, which interferes with HIV viral RNA dependent DNA polymerase and inhibits viral replication. Lamivudine and zidovudine are thymidine analogs that inhibit viral replication. Indicated in combination with other ARTs for HIV infection in adults and children aged ≥ 12 years who weigh at least 40 kg.

Lamivudine/abacavir (Epzicom)

Clinical Context:  Abacavir is a nucleoside reverse transcriptase inhibitor, which interferes with HIV viral RNA dependent DNA polymerase and inhibits viral replication. Lamivudine is a thymidine analog that inhibit viral replication. Indicated in combination with other ARTs for HIV infection in adults and children who weigh at least 25 kg.

Abacavir/dolutegravir/lamivudine (Triumeq)

Clinical Context:  Indicated for human immunodeficiency virus type 1 (HIV-1) infection in combination with other ARTs in adults and children weighing ≥ 40 kg.

Lamivudine/tenofovir DF (Cimduo)

Clinical Context:  Combination contains 2 NRTIs (lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg) that is indicated in combination with other ARTs for HIV-1 infection in adults and children who weigh at least 35 kg.

Class Summary

Combination ARTs are helpful to promote compliance with complex medication regimens.

What is the prevalence of pediatric human immunodeficiency virus (HIV) infection and how is HIV transmitted?What are the benefits of starting highly active antiretroviral therapy (HAART) early in pediatric HIV infection?What are the signs and symptoms of pediatric HIV infection?What are the signs and symptoms of pediatric HIV infection observed in the physical exam?What are the recommendations for diagnosing pediatric HIV infection?How is an enzyme-linked immunosorbent assay (ELISA) used to diagnose HIV infection in older children and adults?What is the role of rapid HIV tests in the workup of HIV?What are the classes of antiretroviral agents used in the treatment of pediatric HIV infection?What is the recommended antiretroviral regimen for the initial treatment of infants, children, and adolescents with HIV infection?When should infants and children with HIV infection begin treatment?Which medications other than antiretroviral drugs (ARDs) are used in the treatment of pediatric HIV infection?How common is human immunodeficiency virus (HIV) infection in children?What is the role of prenatal HIV testing in the diagnosis of HIV infection?How is human immunodeficiency virus (HIV) transmitted in adolescents?Which demographic group has an increasing incidence of HIV infection?How does HIV infection progress in pediatric patients?What are the WHO estimates on the incidence and prevalence of pediatric HIV infection, and how are primary caregivers affected?What are the strains of HIV, and which is most commonly observed in acquired immunodeficiency syndrome (AIDS)?What is the most common route of transmission of pediatric HIV infection?How is pediatric HIV infection contracted other than through vertical transmission?What is the presentation of pediatric HIV?How is HIV infection transmitted?When do most vertical HIV infections occur?What is the virology of HIV?How does HIV attach to a host cell?In which populations has a genetic defense against HIV infection been observed, and how common is it?What is the mechanism of treatment resistance in HIV infection?What happens when the HIV virus core enters the cell cytoplasm of the host?What causes HIV viremia, and how long does it take for viral loads to diminish in pediatric HIV infection?How does the pathophysiology differ between vertically transmitted HIV infection and HIV acquired via blood transfusion?When do antibodies to gp120 develop in HIV infection and what is the result?What causes the immunocompromised state and the proliferation of opportunistic infections and malignancies in pediatric HIV infection?What do CD95+ T-cell levels indicate in HIV infection?How do hematopoietic disturbances occur in HIV infection?How is cytokine dysregulation characterized in HIV infection, and what is the result?What are the effects of hematopoietic disruption in HIV infection?How common is thrombocytopenia in HIV infection and which patients are at highest risk?How common is anemia in HIV infection?What is the etiology of anemia in HIV infection?How common is neutropenia in HIV infection and what is its etiology?What are the neurologic effects of pediatric HIV infection?What are the mechanisms of viral resistance development in the HIV infection?Why does human immunodeficiency virus (HIV) resistance develop?What is the etiology of pediatric HIV infection?How does the prevalence of HIV-1 subtypes differ by geographic region?How is pediatric HIV infection most commonly acquired, and are girls or boys most likely to be affected?What is the HIV seroprevalence rate in pregnant women in the US?Why does perinatal HIV transmission occur?What are the CDC statistics on pediatric HIV infections in the US?What are the CDC statistics on acquired immunodeficiency syndrome (AIDS) in the US?Why is the incidence of pediatric acquired immunodeficiency syndrome (AIDS) decreasing?How common is HIV disease-related death in children younger than 15 years in the US?What are the CDC statistics on the race- and sex-related demographics on HIV infection in the US in adolescents and young adults aged 13-24 years?What is the worldwide prevalence of HIV infection?Which type of HIV virus most commonly causes HIV infection worldwide?What is the HIV seroprevalence rate among pregnant women worldwide?What is the prevalence of HIV infection worldwide?What is the HIV seroprevalence rate among pregnant women in Asia, and why might the statistics be misleading?How do perinatal HIV transmission rates compare in Europe and Africa?Which HIV type is associated with different geographic regions around the world?What are the statistics on pediatric HIV infection in sub-Saharan Africa?Why is it difficult to determine the prevalence of HIV infection in Asia and Europe, and what factors contribute to increased rates in young females and infants?What is the worldwide death rate of pediatric HIV in children younger than 15 years?What are the HIV disease-related infant death rates in sub-Saharan Africa?Which comorbidities are associated with high rates of mortality in hospitalized, HIV-infected/exposed children in sub-Saharan Africa?What are the race-related demographics of pediatric HIV infection in the US?What are the sex-related demographics of pediatric HIV infection?When is pediatric HIV infection usually identified in infants and children?What are the age-related demographics of HIV infection?What is the importance of antiretroviral drugs in pediatric HIV infection?Which factors influence the outcome of pediatric HIV disease?Which factors can influence the progression of pediatric HIV infection?How do hematologic disturbances affect the prognosis of pediatric HIV infection?Which factors are associated with rapidly progressive HIV disease in infants?What is the role of viral load in the progression of pediatric HIV infection?What are the baseline CD4+ T-lymphocyte percentages and associated intermediate-term risk of death in pediatric HIV infection?What are the baseline HIV RNA copy number (copies/mL) and associated intermediate-term risk of death in pediatric HIV infection?What is the prognosis of vertically acquired HIV infection?What is the prognosis of HIV-infected children in resource-poor nations?What are the challenges of educating parents about the importance of compliance with medications and health care visits in pediatric HIV infection?What patient education information is available on pediatric HIV infection?How is pediatric HIV infection diagnosed?When do children with vertically transmitted HIV infection become symptomatic?Which conditions are associated with a high index of suspicion for pediatric HIV infection?What is the common presentation of pediatric HIV infection?What are the signs of moderate-to-severe cellular immune deficiency associated with HIV infection?Which growth factors are associated with pediatric HIV infection?Which developmental factors are associated with pediatric HIV infection?What are common early signs of pediatric HIV infection?What is the most common oral disease associated with pediatric HIV infection and how does it manifest?What are the symptoms of candidal esophagitis in pediatric HIV infection?What are the characteristics of candidal periodontal disease in pediatric HIV infection?Which Candida species cause oral infection in pediatric HIV infection?How does candidiasis manifest in pediatric HIV infection?Which oral conditions besides candidiasis are associated with pediatric HIV infection?How common are dental caries in pediatric HIV infection?What are the common oral manifestations of pediatric HIV infection?How does dermatophytosis manifest in pediatric HIV infection?Which deep fungal infections are seen in pediatric HIV infection, and how common are they?How does herpetic infection manifest in pediatric HIV infection?What is the manifestation of skin lesions in pediatric HIV infection?What is the relationship between varicella-zoster infection and the CD4+ count in pediatric HIV infection?How is herpes zoster associated with pediatric HIV infection?What is the manifestation of human papillomavirus (HPV) infection in pediatric HIV infection?How does molluscum contagiosum manifest in pediatric HIV infection and AIDS?Why are recurrent bacterial infections seen in pediatric HIV infection?How do Pseudomonas aeruginosa infections manifest in pediatric HIV infection?What is the presentation of bacillary angiomatosis in pediatric HIV infection?What is the presentation of mycobacterial infections in pediatric HIV infection?What is the presentation of M haemophilum infection in pediatric HIV infection and AIDS?What is the role of Pneumocystis jiroveci (formerly P carinii) pneumonia (PCP) in AIDS and how does it manifest in pediatric HIV infection and AIDS?What is the presentation of scabies in pediatric HIV infection?What is the manifestation of measles infections in children where pediatric HIV infection is endemic?What is the manifestation of noma (cancrum oris) in the setting of pediatric HIV infection?What is the manifestation of seborrheic dermatitis in the setting of pediatric HIV infection?What are the effects of vitamin deficiencies in pediatric HIV infection?Which metabolic abnormalities are associated with pediatric HIV infection?Which skin conditions have been reported in pediatric HIV infection?How should unusual skin lesions be evaluated in pediatric HIV infection?What are the types of neoplasia associated with pediatric HIV infection?What is the prevalence of HIV-associated malignancies in pediatric HIV infection?What is the incidence of Kaposi sarcoma in pediatric HIV infection?What are the physical findings of pediatric HIV infection?How often should anthropometric measurements be obtained in pediatric HIV infection?What are the characteristics of encephalopathy in pediatric HIV infection?What is the presentation of fat redistribution syndrome in pediatric HIV infection?What diagnostic criteria and tools are used to monitor the anthropometric findings in pediatric HIV infection?What are the head, eyes, ears, nose, and throat (HEENT) findings in pediatric HIV infection?What are the cardiac findings in pediatric HIV infection?What are the pulmonary findings in pediatric HIV infection?What are the abdominal findings in pediatric HIV infection?What are the lymphatic findings in pediatric HIV infection?What are the neurologic findings in pediatric HIV infection?What are the skin/cutaneous findings in pediatric HIV infection?What are the extremity findings in pediatric HIV infection?What is the most common opportunistic infection in vertically transmitted HIV infection?What is the presentation of Pneumocystis jiroveci (formerly P carinii) pneumonia (PCP) in pediatric HIV infection?What systemic complications are associated with pediatric HIV infection?How common is chronic diarrhea in pediatric HIV infection, and which diagnostic tests are useful in the workup?What is the cause of chronic diarrhea in pediatric HIV infection and how is it treated?How does pancreatitis develop in pediatric HIV infection?Which signs and symptoms are associated with disseminated Mycobacterium avium complex (MAC) infection in pediatric HIV infection?How is wasting syndrome characterized in pediatric HIV infection?What is the prevalence of HIV nephropathy in pediatric HIV infection?What is the presentation of pediatric HIV nephropathy?What treatments are available for pediatric HIV nephropathy?Can non-HIV nephropathy develop in pediatric HIV infection?What is the presentation of pediatric HIV infection/AIDS in young patients without a history of immunodeficiency or severe illness?How can a diagnosis of pediatric HIV infection be missed in a neonate?What is the role of nonopportunistic infections in the differential diagnosis of pediatric HIV infection?What are the iatrogenic complications of the treatment of nonopportunistic infections in pediatric HIV infection?What are the common recurrent infections in patients with pediatric HIV infection and how can they be treated?Which factors increase the risk for bacterial infection in pediatric HIV infection?What are the differential diagnoses for Pediatric HIV Infection?What are the CDC recommendations for prenatal HIV testing?What are the ACOG guidelines on HIV testing during pregnancy?How is pediatric HIV infection diagnosed?What are the recommendations for diagnosing pediatric HIV infection in infants?How is a diagnosis of pediatric HIV infection excluded?How is immune status assessed in pediatric HIV infection?How are patients with pediatric HIV infection monitored for opportunistic infections?How often are HIV RNA levels assessed in pediatric HIV infection?Which screening tests are performed in the infants of HIV positive mothers?Which lab values are associated with fatality in pediatric HIV infection?Which imaging studies and procedures are performed for baseline determinations in pediatric HIV infection?What are the CDC recommendations for HIV testing?What are the AAP recommendations for HIV testing in adolescents?Which tests are used in the initial diagnosis of HIV infection?How is HIV DNA polymerase chain reaction (PCR) used in the diagnosis of HIV?How are viral cultures used in the detection of HIV?Which tests are used to diagnose HIV infection in older children and adults?What is the role of rapid HIV tests in the workup of HIV infection?Which rapid HIV screening tests are approved by the FDA for use in the US?How are HIV RNA assays used in the diagnosis of pediatric HIV infection?How is the APTIMA assay used in the workup of pediatric HIV infection?How is the viral load quantified in the workup of pediatric HIV infection?What is the sensitivity of viral load tests used in the workup of pediatric HIV infection?What are the expected patterns of viral loads in vertically acquired HIV infection in infants?What is the effect of viral resistance to antiretroviral therapy (ART) in pediatric HIV infection?Which resistance assays can be performed in the workup of pediatric HIV infection?When is resistance testing recommended in pediatric HIV infection?How accurate are the genotype and phenotype resistance assays in the workup of pediatric HIV infection?What causes viral rebound in pediatric HIV infection and how can it be addressed?What is the role of CD4+ lymphocyte count in monitoring disease progression in pediatric HIV infection?How common is consumptive thrombocytopenia in pediatric HIV infection?How common is anemia in pediatric HIV infection?What causes a high mean corpuscular volume (MCV) in pediatric HIV infection?What may anemia portend in pediatric HIV infection?What are the causes of pancytopenia in pediatric HIV infection?How common is neutropenia in pediatric HIV infection?How is folate deficiency characterized in blood smears in the workup of pediatric HIV infection?Why are serum electrolytes monitored on a regular basis in the workup of pediatric HIV infection?How are other lab tests used in the workup of pediatric HIV infection?How often should quantitative immunoglobulin levels be tested in the workup of pediatric HIV infection?What is the role of renal ultrasonography in the workup of pediatric HIV infection?How is HIV nephropathy characterized in renal CT scans used in the workup of pediatric HIV infection?What is demonstrated on renal scintigraphy in the workup of HIV nephropathy in pediatric HIV infection?When is biopsy indicated in the workup of pediatric HIV infection?How is lymphoid interstitial pneumonitis (LIP) characterized on chest radiography in pediatric HIV infection/AIDS?What is the progression of lymphoid interstitial pneumonitis (LIP) in pediatric HIV infection/AIDS and how is it treated?What are clinical categories of pediatric HIV infection?What is clinical category N in pediatric HIV infection?What is clinical category A in pediatric HIV infection?Which conditions are included in clinical category B in pediatric HIV infection?Which conditions are included in clinical category C in pediatric HIV infection?Can a child with pediatric HIV infection be reassigned to a lesser class once an advanced class is assigned?What is the mainstay of human immunodeficiency virus (HIV) treatment?How effective is antiretroviral therapy (ART) in the treatment of pediatric HIV infection?What are the treatment goals in pediatric HIV infection?Which factors are important to consider in pediatric HIV infection treatment decisions about when to initiate antiretroviral therapy (ART)?Which opportunistic infections must be anticipated and treated in pediatric HIV infection?Which topics are included in the guidelines for the prevention and treatment of opportunistic infections in pediatric HIV Infection?How is wasting characterized in pediatric HIV infection?What causes abnormalities in psychological and neurologic development in pediatric HIV infection?Why might parents of HIV-infected children miss regular clinic appointments?How important is psychosocial support in pediatric HIV infection?What are the guidelines for the prevention and treatment of opportunistic infections in pediatric HIV Infection?What are the classes of antiretroviral drugs used in pediatric HIV infection?How do reverse transcriptase inhibitors (NRTIs, NNRTIs) work in pediatric HIV infection?Which patients with vertically acquired HIV infection should receive antiretroviral therapy (ART)?How effective is early antiretroviral therapy (ART) for HIV infection in children younger than 12 months (1 year)?Which antiretroviral therapy (ART) regimens are effective in achieving viral suppression in pediatric HIV infection?What are the age-related CD4 thresholds for initiating antiretroviral therapy (ART) in pediatric HIV infection?When is antiretroviral therapy (ART) for pediatric HIV infection indicated?How are antiretroviral therapy (ART) dosing regimens determined for adolescents with HIV infection?What is the recommended initial antiretroviral therapy (ART) regimen in infants, children, and adolescents with pediatric HIV infection?What are the preferred antiretroviral therapy (ART) regimens for children younger than 3 years with pediatric HIV infection?How effective is lopinavir/ritonavir combination therapy in children younger than 6 years with HIV-1 infection?What is the role of dolutegravir in the treatment of pediatric HIV infection?When is raltegravir indicated in the treatment of pediatric HIV infection?Which complete antiretroviral therapy (ART) regimens are available for HIV-1 infection in adults and children aged 12 years or older?Which agents are included in drug combinations for initial antiretroviral therapy (ART) in pediatric HIV infection?What are preferred antiretroviral therapy (ART) combination regimens and alternative regimens for pediatric HIV infection?What is the role of monitoring antiretroviral therapy (ART) progress pediatric HIV infection?What is the main goal of antiretroviral therapy (ART) in pediatric HIV infection?How is treatment failure defined in pediatric HIV infection?What constitutes virologic treatment failure in pediatric HIV infection?What is viral rebound in treatment failure for pediatric HIV infection?What constitutes immunologic treatment failure in pediatric HIV infection?What constitutes immunologic decline in pediatric HIV infection?What constitutes clinical failure in pediatric HIV infection?Is breastfeeding by women with HIV infection recommended?How is the risk of postnatal HIV transmission minimized?Is prophylaxis during breastfeeding associated with antiretroviral drug (ARD) resistance in pediatric HIV infection?How are adverse effects of drug interactions minimized in pediatric HIV infection?How are drug interactions classified in pediatric HIV infection?Which antiretroviral drugs (ARDs) may affect or be affected by absorption kinetics in pediatric HIV infection?What is the effect of antiretroviral drug (ARD) pharmacokinetic interactions in pediatric HIV infection?What is the role of the cytochrome P450 (CYP) system in drug metabolism in pediatric HIV infection?How can drug interactions among antiretroviral agents be beneficial in the treatment of pediatric HIV infection?How is treatment initiated in neonates at risk of vertically acquired pediatric HIV infection?What is the role of prophylaxis and treatment of opportunistic infections (OIs) in pediatric HIV infection?What is the relationship between highly active antiretroviral therapy (HAART) and immune reconstitution inflammatory syndrome (IRIS) in pediatric HIV infection?What may immune reconstitution inflammatory syndrome (IRIS) unmask in pediatric HIV infection?What are common sources of some of the opportunistic pathogens associated with pediatric HIV infection?What is the role of antibiotic prophylaxis in the treatment of pediatric HIV infection and which drugs are used?What is the role of Pneumocystis pneumonia (PCP) prophylaxis in pediatric HIV infection?What is the role of prophylaxis of viral infections in pediatric HIV infection?How are fungal infections in pediatric HIV infection prevented and treated?What are the symptoms and management of Cryptosporidium infections in pediatric HIV infection?How is cryptococcal meningitis diagnosed and treated in pediatric HIV infection?How can primary pulmonary and extrapulmonary disease occur in pediatric HIV infection and what are common presenting symptoms?What is the workup of suspected mycobacterial infection in pediatric HIV infection?What is the treatment for mycobacterial infection in pediatric HIV infection?How common is multidrug-resistant tuberculosis (TB) in HIV infection?Is efavirenz effective in the treatment of pediatric HIV infection in children who are also being treated for tuberculosis (TB)?How common is disseminated M avium-intracellulare complex (MAC) infection in pediatric HIV infection?What are the signs and symptoms of disseminated M avium-intracellulare complex (MAC) infection in pediatric HIV infection?Which GI symptoms are common in disseminated M avium-intracellulare complex (MAC) infection in pediatric HIV infection?Which tests are indicated in the workup of M avium-intracellulare complex (MAC) infection in pediatric HIV infection?What is the treatment for M avium-intracellulare complex (MAC) infection in pediatric HIV infection?Which drugs are used first in the treatment of M avium-intracellulare complex (MAC) infection in pediatric HIV infection?How often are blood cultures obtained for M avium-intracellulare complex (MAC) infection in pediatric HIV infection and how long does treatment last?When is M avium-intracellulare complex (MAC) infection prophylaxis started in pediatric HIV infection?How is toxoplasmosis acquired in pediatric HIV infection and which tests are indicated when it is suspected?How are children with pediatric HIV infection screened for opportunistic infections?What is the treatment approach to cytomegalovirus (CMV) infection in neonates with pediatric HIV infection?When are toxoplasmosis, syphilis, rubella, CMV, and herpes simplex (TORCH syndrome) screenings indicated in pediatric HIV infection?When is immunologic function assessment indicated in pediatric HIV infection and which tests are included?How common are thrombocytopenia, anemia, and neutropenia in pediatric HIV infection?How common is immune-mediated platelet destruction in pediatric HIV infection?Which regimens are used to increase platelet count in thrombocytopenia in pediatric HIV infection?Which regimens are used to increase platelet count in thrombocytopenia in Rh-positive patients with pediatric HIV infection?How can long-lasting responses be achieved for thrombocytopenia in pediatric HIV infection?What is the prevalence of iatrogenic anemia in pediatric HIV infection and which tests are included in the workup?When hemolytic anemia be suspected in pediatric HIV infection?What causes hemophagocytic syndrome in pediatric HIV infection?What are the effects of a low reticulocyte count, folic acid deficiency, or a vitamin B-12 deficiency in anemia and why are patients with pediatric HIV at risk for these deficiencies?Which serum levels must be measured before treatment is initiated for vitamin B-12 deficiency in pediatric HIV infection?What does a low or normal indirect bilirubin value suggest in pediatric HIV infection?What does a high, low, or normal MCV indicate in anemia in pediatric HIV infection?What causes neutropenia in pediatric HIV infection other than anemia?Which lab tests may help clarify the differential diagnosis of anemia in pediatric HIV infection?What is the etiology of anemia in pediatric HIV infection and how is it diagnosed?When should erythropoietin be used in the management of anemia in pediatric HIV infection and what is the recommended regimen?How common is neutropenia in pediatric HIV infection, and which myelosuppressive drugs can induce neutropenia?What causes myelosuppression in pediatric HIV infection other than myelosuppressive drugs?What is used to treat neutropenia in pediatric HIV infection and what is the recommended regimen?When is inpatient care indicated in pediatric HIV infection?What is the role of dietary management in pediatric HIV infection?Which foods should be included and avoided in the diets of children with pediatric HIV infection?Which types of feeding tubes are used to support the nutritional and fluid status of patients with pediatric HIV infection?What are the consequences of noncompliance with antiretroviral therapy (ART) regimens in pediatric HIV infection?Why is medication compliance difficult in pediatric HIV infection?How can medication compliance be monitored in pediatric HIV infection?What is the role of adverse drug reactions (ADRs) in medication noncompliance in pediatric HIV infection?How can partial compliance lead to drug resistance in pediatric HIV infection?How can medications be made more palatable in pediatric HIV infection?What are the options for managing medication compliance in children with pediatric HIV infection who are noncompliant?How is the risk of vertical transmission reduced in pediatric HIV infection?During which 3 periods can vertical transmission occur in pediatric HIV infection?What level of viral load is necessary for HIV particles to exist in the cervicovaginal secretions of women?Which factors may reduce the risk of vertical transmission of HIV from a mother to her infant?Which risk of vertical transmission of HIV is increased with elective cesarean delivery and when might vaginal delivery reduce that risk?What is the incidence of postnatal vertical transmission of pediatric HIV infection?Should women with HIV in developing countries breastfeed?What is the CDC-approved regimen to reduce vertical transmission of pediatric HIV infection?What are the adverse effects of antepartum treatment to reduce vertical transmission of HIV infection?Does antiretroviral therapy (ART) reduce the risk of transmitting HIV to an uninfected sexual partner?What are the CDC recommendations for postexposure prophylaxis (PEP) for HIV infection?Is there an HIV vaccine for heterosexuals at risk for HIV-1 transmission and how effective is it?Which childhood immunizations should be administered to children with pediatric HIV infection?Which children with pediatric HIV infection should receive a measles-mumps-rubella (MMR) vaccination?Which children with pediatric HIV infection should receive a pneumococcal conjugate heptavalent (PCV 7) vaccination?When is pneumococcal polysaccharide vaccine (PPV 23) recommended in children with pediatric HIV infection?How often should children with pediatric HIV infection receive an influenza vaccination?Which children with pediatric HIV infection should receive a varicella vaccination and which vaccine should be used?Can children with pediatric HIV infection receive a vaccination with a combination measles, mumps, rubella and varicella (MMRV) vaccine?When should children with pediatric HIV infection receive a hepatitis A vaccination?Should children with pediatric HIV infection receive a rotavirus vaccination?When should children with pediatric HIV infection receive a tetanus, diphtheria, and pertussis (Tdap) vaccination?When should children with pediatric HIV infection receive a meningococcal conjugate vaccine?What is the role of a multidisciplinary treatment approach in pediatric HIV infection?How often should children with pediatric HIV infection see an ophthalmologist?When should children with pediatric HIV infection obtain dental exams and audiologic evaluations?When are surgical consultations indicated in the treatment of pediatric HIV infection?Which specialists may need to be consulted for treatment of pediatric HIV infection?How is disease progression monitored in pediatric HIV infection?How is growth monitored in pediatric HIV infection?How are dietary habits monitored in pediatric HIV infection?How is developmental assessment and therapy monitored in pediatric HIV infection?How is social support monitored in pediatric HIV infection?How are CD4+ levels or percentages monitored in pediatric HIV infection?How are lab values monitored in pediatric HIV infection?How are children who are HIV positive protected against vaccine-preventable illnesses?Which test should be obtained in pediatric HIV infection with signs of neurologic disease?When are antiretroviral drugs (ARDs) used for the treatment of pediatric HIV infection and how effective are they?What are the 6 classes of antiretroviral drugs (ARDs) for pediatric HIV infection?What is the initial antiretroviral therapy (ART) regimen in pediatric HIV infection?Which medications in the drug class Complete Regimen Combinations are used in the treatment of Pediatric HIV Infection?Which medications in the drug class Pharmcokinetic Enhancers are used in the treatment of Pediatric HIV Infection?Which medications in the drug class Chemokine Receptor Antagonists are used in the treatment of Pediatric HIV Infection?Which medications in the drug class Fusion Inhibitors are used in the treatment of Pediatric HIV Infection?Which medications in the drug class Integrase Inhibitors are used in the treatment of Pediatric HIV Infection?Which medications in the drug class Protease Inhibitors are used in the treatment of Pediatric HIV Infection?Which medications in the drug class Nonnucleoside Reverse Transcriptase Inhibitors are used in the treatment of Pediatric HIV Infection?Which medications in the drug class Nucleoside or Nucleotide Reverse Transcriptase Inhibitors are used in the treatment of Pediatric HIV Infection?Which medications in the drug class HIV, ART Combos are used in the treatment of Pediatric HIV Infection?

Author

Delia M Rivera, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Disease and Immunology, University of Miami Leonard M Miller School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Richard E Frye, MD, PhD, Professor of Child Health, University of Arizona College of Medicine at Phoenix; Chief of Neurodevelopmental Disorders, Director of Autism and Down Syndrome and Fragile X Programs, Barrow Neurological Institute at Phoenix Children's Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Disclosure: Nothing to disclose.

Acknowledgements

Mark Abdelmalek, MD Chief, Division of Laser and Dermatologic Surgery, Assistant Professor, Department of Dermatology, Drexel University College of Medicine

Mark Abdelmalek, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, American Medical Association, American Society for Dermatologic Surgery, Pennsylvania Academy of Dermatology, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Kathleen B Elmer, MD Consulting Staff, Department of Dermatology, First Medical Group, Langley Air Force Base

Disclosure: Nothing to disclose.

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

Michael Loosemore, MD Fellow in Dermatological Surgery, The Methodist Hospital

Michael Loosemore, MD is a member of the following medical societies: American Academy of Dermatology, Massachusetts Medical Society, and Pennsylvania Academy of Dermatology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

Category  
< 1 y 1-5 y 6-12 y
1 - No suppression≥1500 (>25)≥1000 (>25)≥500 (>25)
2 - Moderate suppression750-1499 (15-24)500-999 (15-24)200-499 (15-24)
3 - Severe suppression< 750 (< 15)< 500 (< 15)< 200 (< 15)
Infection Indication First-Line Regimen Alternative Regimen
TBPPD test result >5 mmIsoniazid and pyridoxine qd for 9 moRifampin for 4 mo
ExposureIsoniazid and pyridoxine 3 times/wk for 9 mo, rifampin and pyrazinamide qd for 2 moConsult an infectious diseases specialist if the pathogen is multidrug resistant
PCPCD4+ finding*Trimethoprim-sulfamethoxazole qdTrimethoprim-sulfamethoxazole 3 times/wk
Fever of unknown origin for 2 wk, history of infectionDapsone, pyrimethamine, and leucovorinDapsone or aerosolized pentamidine in children >5 y
---AtovaquoneAtovaquone
ToxoplasmosisCD4+ count < 100 cells/mLTrimethoprim-sulfamethoxazole qdDapsone, pyrimethamine, and leucovorin
Positive immunoglobulin G findingNoneAtovaquone
Previous infectionSulfadiazine, pyrimethamine, and leucovorinClindamycin, pyrimethamine, and leucovorin
MAC infectionCD4+ finding**Azithromycin qwkRifabutin qd or clarithromycin bid
Previous infectionClarithromycin or azithromycin qd and ethambutolClarithromycin or azithromycin qd and ethambutol
Abbreviations: bid = twice daily; PPD = purified protein derivative; qd = every day; qwk = every week.



* See Table 4



**See Table 5



Drug Dose
Azithromycin20 mg/kg/dose (1.2 g maximum) PO qwk or



5 mg/kg/dose (250 mg maximum) PO qd



Clarithromycin7.5 mg/kg/dose (500 mg maximum) PO bid
Clindamycin20-30 mg/kg/d PO qid
Dapsone1-2 mg/kg/d (100 mg maximum) PO qd
Ethambutol15 mg/kg/dose (900 mg maximum) PO qd
Isoniazid10-15 mg/kg/dose (300 mg maximum) PO/IM qd
Leucovorin5 mg PO 3 times/wk
Pentamidine4 mg/kg/dose monthly
Pyrimethamine15 mg/m2/dose (25 mg maximum) PO qd
Rifabutin5 mg/kg/dose (300 mg maximum) PO qd
Rifampin10-20 mg/kg (600 mg maximum) PO/IV qd
Sulfadiazine85-120 mg/kg/d PO bid
Trimethoprim-sulfamethoxazole150/750 mg/m2/d PO bid
Abbreviations: bid = twice daily; PO = by mouth; qd = every day; qwk = every week.
Age or Status CD4+ Count, cells/mL CD4+ Percentage
6 wk to 1 yAnyAny
1-2 y< 750< 15
2-5 y< 500< 15
>5 y< 200< 15
Previous PCP infectionAnyAny
Age or Status CD4+ Count, Cells/mL
< 1y< 750
1-2 y< 500
2-6 y< 75
> 6 y< 50
Previous infectionAny
Period Factors That Increase Risk Factors That Decrease Risk
PrenatalAcute HIV infection



Viral load >10,000



Cigarette smoking



Illicit IV drug use



Viral load < 1000



Zidovudine treatment



Neutralizing antibodies



PerinatalRupture of membranes for >4 h



Chorioamnionitis



Emergency cesarean delivery



Surgical delivery



Episiotomy



Use of scalp electrodes



Elective cesarean delivery with zidovudine treatment
NeonatalPrematurity



Low birth weight



First-born twin



Full-term



Second-born twin



PostdeliveryBreastfeedingART