CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

41. Human Immunodeficiency Virus Infection

Elizabeth J. McFarland, MD

image General Considerations

Human immunodeficiency virus (HIV) is a retrovirus that primarily infects cells of the immune system, including helper T lymphocytes (CD4 T lymphocytes), monocytes, and macrophages. The function and number of CD4 T lymphocytes and other affected cells are diminished by HIV infection, resulting in profound effects on both humoral and cell-mediated immunity. In the absence of treatment, HIV infection causes generalized immune incompetence, leading to conditions that meet the definition of acquired immunodeficiency syndrome (AIDS) and, eventually, death. The clinical diagnosis of AIDS is made when an HIV-infected child develops any of the opportunistic infections, malignancies, or conditions listed in category C (Table 41–1). In adults and adolescents, the criteria for a diagnosis of AIDS also include an absolute CD4 T-lymphocyte count of 200 cells/μL or less.

Table 41–1. Centers for disease control and prevention clinical categories of children with human immunodeficiency virus infection.

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Highly active antiretroviral treatment (HAART) can forestall disease progression for many years (≥ 20 years) if taken consistently. However, current treatment fails to eradicate the virus and treatment must be lifelong. The full duration of the favorable outcome of therapy is not yet defined, and it is not known whether adverse effects due to medications and incomplete immune restoration will limit use or impact mortality. Nevertheless, HIV infection can be considered a chronic disease for people with access to treatment rather than an acutely terminal disease.

Early diagnosis offers the opportunity to optimize treatment outcomes for children, adolescents, and adults. Treatment reduces the risk of transmission to others and thus has a public health benefit as well. In an effort to improve early diagnosis, the Centers for Disease Control and Prevention (CDC) recommends that HIV screening tests be conducted in routine health care settings with patient knowledge and right to refuse for patients aged 13–64 years and that all adults should be tested at least once for HIV during their lives. In 2011, the American Academy of Pediatrics recommended at least one-time testing for 16- to 18-year-old adolescents, irrespective of risk factors, living in areas of high (≥ 0.1%) or unknown seroprevalence. In areas of lower seroprevalence, testing is encouraged for all sexually active adolescents and those with other risk factors for HIV infection.

American Academy of Pediatrics Policy Statement: Adolescents and HIV infection: the pediatrician’s role in promoting routine testing. Pediatrics 2011;128:1023–1029 [PMID: 22042816].

image Epidemiology

The World Health Organization (WHO) estimated in 2012 that there were 32 million adults and 3.3 million children living with HIV (http://www.who.int/hiv/data/2012_epi_core_en.png). Over 90% live in low- and middle-income countries, primarily sub-Saharan Africa and South and Southeast Asia. Although the number of new infections is estimated to have peaked globally in 1997, infection and mortality rates remain high. Among children younger than 15 years, there were 260,000 new infections and 210,000 deaths in 2012. High rates of new pediatric infections are the result of ongoing mother-to-child transmission (MTCT) in resource-limited settings where access to preventative measures is often not accessible; fewer than 60% of pregnant women received recommend treatment in 2011.

MTCT rates are 20%–40%, overall, if there is no intervention. Transmission occurs in utero, at the time of labor and delivery (peripartum), or during breast-feeding (postnatal transmission). However, MTCT can be reduced to less than 1%–2% with prenatal, perinatal, and postnatal interventions (see Prevention section). The successful implementation of these interventions in the United States has made new vertically acquired HIV cases rare (< 200 cases annually). In the United States, the number of children younger than 13 years living with HIV was estimated at 2936 in 2011. As a result of effective antiretroviral (ARV) treatment, perinatally infected children who receive treatment are surviving into adolescence and young adulthood. In the United States, perinatally infected individuals comprised 22% of those living with HIV in the 13- to 24-year-old age group.

After puberty, infections result primarily from sexual contact (men having sex with men [MSM] and heterosexual), with a smaller proportion resulting from injecting drug use. In 2011, there were approximately 50,000 new infections in the United States among which youth are overrepresented, since the proportion of new infections among young people aged 13–29 years exceeds this age group’s proportion in the total population (39% of new HIV infections vs 21% in the total population). Young adults, age 20–24 years, had the highest rates of new HIV infections (36.9/100,000 people) in 2009. Most at risk are young black MSM, in whom new infections increased 48% between 2006 and 2009.

Occupational exposure resulting from accidental needle sticks or, rarely, mucosal exposure to blood may occur. As a result of careful donor screening and testing of donated blood, HIV transmission resulting from blood products is now extremely rare in the United States (1:2,000,000 transfusions). Casual, classroom, or household contact with an HIV-infected person poses no risk of transmission.

Centers for Disease Control and Prevention (CDC), HIV/AIDS, Statistics and Surveillance, Statistics Center: http://www.cdc.gov/hiv/topics/surveillance/index.htm. Accessed January 25, 2014.

Centers for Disease Control and Prevention (CDC) HIV/AIDS Statistics and Surveillance, National Center for HIV/AIDS, Viral Hepatitis, STD & TB prevention, Division of HIV/AIDS Prevention, Epidemiology of HIV infection (through 2011) slide set: http://www.cdc.gov/hiv/topics/surveillance/resources/slides/general/slides/Epi-HIV-infection.pdf. Accessed January 25, 2014.

Centers for Disease Control and Prevention (CDC), HIV/AIDS, Topics, HIV among youth: http://www.cdc.gov/hiv/youth/index.htm. Accessed April 19, 2013.

World Health Organization (WHO) HIV/AIDS Data and Statistics, Global epidemic and health care response (PowerPoint slides): http://www.who.int/hiv/data/en/. Accessed January 25, 2014.

image Mode of Transmission and Pathogenesis

In most cases, HIV infection occurs via mucosal exposure. Information on the early events of HIV infection is based on nonhuman primate models and studies in adults infected by sexual transmission; the events in MTCT are less well studied. At the time of exposure, virus breaches the mucosal barrier, is transported to regional lymph nodes, replicates, and spreads throughout all lymphoid tissues. Based on nonhuman primate models, replicating virus is found throughout the lymphoid tissue by 48 hours postinfection. During the first days after infection, there is a massive loss of mature CD4 T-helper lymphocytes, especially in the gut mucosa. Approximately 2 weeks after exposure, high levels of HIV are detected in the bloodstream. In adults, the level of viremia declines, without therapy, concurrent with the appearance of an HIV-specific host immune response, and plasma viremia usually reaches a steady-state level about 6 months after primary infection. The amount of virus present in the plasma at that point, known as the “set point,” and thereafter is predictive of the rate of disease progression for the individual. A period of clinical latency usually occurs, lasting from 1 year to more than 12 years, during which the infected person is asymptomatic. However, ongoing viremia and immune activation causes subclinical injury to the immune and other organ systems. The virus and anti-HIV immune responses are in a steady state such that CD4 T-lymphocyte parameters may be stable. Eventually, the balance favors the virus, and the viral burden increases as the CD4 T-lymphocyte count declines, at which time the individual becomes susceptible to opportunistic infections.

Infants with in utero HIV infection have virus detectable in the blood at birth. Those infected peripartum test negative for virus at birth but have virus detected by 2–4 weeks of age. Infant viremia rises steeply, as is also seen in adults reaching a peak at age 1–2 months. In contrast with adults, infants will have only a very gradual decline in plasma viremia that extends to age 4–5 years. Up to 50% of infants will have rapid disease progression to AIDS or death by age 2 years. Although this rapid progression is associated with high-level viremia, measurement of plasma virus and/or CD4 T-lymphocyte parameters do not identify all infants at risk for rapid progression.

Siewe B, Landay A: Key Concepts in the early immunology of HIV-1 infection. Curr Infect Dis Rep 2012 Feb;14(1):102–1029. doi: 10.1007/s11908-011-0235-3 [PMID: 22203492].

PERINATALLY HIV-EXPOSED INFANT

image Clinical Findings

Newborns with perinatal HIV infection are rarely symptomatic at birth, and there is no recognized primary infection syndrome in these infants. Physical features are not different from uninfected neonates. However, 30%–80% of infected infants have symptoms within the first year of life. Hepatomegaly, splenomegaly, lymphadenopathy, parotitis, and recurrent respiratory tract infections are signs associated with slow progression. Severe bacterial infections, progressive neurologic disease, anemia, and fever are associated with rapid progression. Early ARV therapy can slow or prevent disease progression. Hence, early diagnosis is critical and can be accomplished using laboratory testing during the first months of life.

image Laboratory Diagnosis

Infants born to HIV-infected mothers will have HIV antibody until 6–18 months of age, regardless of infection status, owing to transplacental passage of maternal antibody. Therefore, diagnosis must be made by direct detection of virus. Age-specific laboratory criteria defining infection status are outlined in Table 41–2. The preferred test for infant diagnosis is detection of HIV DNA or RNA in blood, collectively referred to as nucleic acid amplification testing (NAT). Positive HIV NAT at any age requires repeat testing for confirmation since false positives may occur. Positive HIV NAT on two occasions indicates HIV infection.

Table 41–2. Age-specific laboratory criteria defining infection status.

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HIV NAT is positive in blood at birth for the fraction of infants infected in utero but negative for infants who acquire infection at birth. Almost all infected infants, with either in utero or peripartum acquisition, will have detectable HIV by 2 weeks of life and over 95% will have detectable virus by 4 weeks, allowing for early diagnosis. Thus, infection can be “presumptively” excluded by negative HIV NAT at age 2 and 4 weeks, in the absence of breast-feeding. Definitive evidence of absence of infection is defined by negative HIV NAT at greater than 1 and 4 months. After 12–18 months of age, for infants with negative HIV NAT, many clinicians will obtain HIV antibody testing to demonstrate reversion to seronegative status, thereby confirming the absence of infection.

Breast-fed infants may acquire HIV at any time until they are fully weaned, and virus may not be detected until as long as 6 weeks after the exposure. Therefore, breast milk–exposed infants should be retested at 6 weeks after their last exposure to identify or presumptively exclude infection.

image Management and Outcome of the Perinatally HIV-Exposed Infant

HIV-infected infants have a high risk of Pneumocystis jiroveci pneumonia (PCP), with the peak incidence at age 2–6 months. Thus, prophylaxis for P jiroveci pneumonia is given to infants born to HIV-infected mothers beginning at age 4–6 weeks. PCP prophylaxis may be deferred for infants who are demonstrated to be presumptively HIV-uninfected by age 6 weeks. Infants with ongoing HIV exposure via breast-feeding are recommended to continue PCP prophylaxis until HIV infection has been excluded after cessation of breast-feeding.

During the period of postnatal ARV prophylaxis, some infants have reversible anemia or neutropenia that is usually not clinically significant. Subsequently, children who have been exposed to HIV and to ARV drug prophylaxis (but who remain uninfected) are generally healthy. Ongoing studies have found alterations in some growth, neurocognitive development, immune, and organ function parameters, but their clinical significance is not yet known. Some studies have found symptoms consistent with mitochondrial toxicity; other studies have failed to confirm the findings. There is biological plausibility for this toxicity because the nucleoside analogue drugs used during pregnancy and postnatally to prevent transmission may cause mitochondrial toxicity. The issue remains controversial, but at present it is clear that the benefit of prenatal and postnatal treatment to prevent HIV transmission outweighs the potential risk. Ongoing studies are important to elucidate the affects of in utero and perinatal HIV and ARV exposure.

Burgard M et al: Performance of HIV-1 DNA or HIV-1 RNA tests for early diagnosis of perinatal HIV-1 infection during anti-retroviral prophylaxis. J Pediatr 2012;160(1):60–66 [PMID: 21868029].

Centers for Disease Control and Prevention: Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged < 18 months and for HIV infection and AIDS among children aged 18 months to < 13 years—United States, 2008. MMWR Recomm Rep 2008;57(RR-10):1–9 [PMID: 19052530].

Havens PL, Mofenson LM: Committee on Pediatric AIDS. Evaluation and management of the infant exposed to HIV-1 in the United States. Pediatrics 2009;123:175–187 [PMID: 19117880].

Nielsen-Saines K et al: ACTG 5190/PACTG 1054 Study Team: Infant outcomes after maternal antiretroviral exposure in resource-limited settings. Pediatrics 2012;129(6):e1525–1532. doi: 10.1542/peds.2011-2340 [PMID: 22585772].

ACUTE RETROVIRAL SYNDROME

Among adolescents and adults with primary acute HIV infection, nonspecific symptoms (eg, flu- or mild mononucleosis-like illness) beginning 2–4 weeks after exposure occur in 30%–90%, but they are frequently not severe enough to be brought to medical attention. This acute retroviral syndrome, with symptoms of fever, malaise, and pharyngitis, is often indistinguishable from other similar viral illnesses. Less common but more distinguishing features are generalized lymphadenopathy, rash, oral and genital ulcerations, aseptic meningitis, and thrush. In the early weeks after acute, behaviorally acquired infection, HIV antibody may be absent. Most patients will seroconvert by 6 weeks after exposure, but occasionally seroconversion does not occur for 3–6 months. When acute HIV infection is suspected, nucleic acid amplification tests will detect HIV infection. Additional information on behaviorally acquired HIV is found in Chapter 44.

Hecht FM et al: Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS 2002;16(8): 1119–1129 [PMID: 12004270].

Kinloch-de Loes S et al: Symptomatic primary infection due to human immunodeficiency virus type 1: review of 31 cases. Clin Infect Dis 1993;17(1):59–65 [PMID: 8353247].

PROGRESSIVE HIV DISEASE

A. Clinical Findings

1. Disease staging—The CDC has developed disease staging criteria for HIV-infected children (Table 41–3; see Tables 41–1). The criteria incorporate clinical symptoms ranging from no symptoms to mild, moderate, and severe symptoms (categories N, A, B, and C, respectively) and immunologic categories 1, 2, or 3 (defined by age-adjusted CD4 T-lymphocyte counts) corresponding to no, moderate, or severe immune suppression, respectively. Each child’s disease stage is classified both by clinical and CD4 T-lymphocyte category. The WHO has established a similar clinical staging system that is used widely outside the United States (Table 41–4). Staging criteria characterize the degree of disease progression and are predictive of mortality risk for children older than 2 years who are not receiving ARV therapy. Disease stage is used in determining when to initiate ARV therapy.

Table 41–3. Immunologic categories based on age-specific CD4 T-lymphocyte counts and percentages of total lymphocytes.

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Table 41–4. World Health Organization clinical staging of HIV for infants and children with established HIV infection.

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2. Infections related to immunodeficiency—Progressive immune dysfunction of both humoral and cell-mediated responses results in susceptibility to infections. Bacteremia, especially due to Streptococcus pneumoniae, occurs at rates of 3 per 100 child-years without HAART and decreases to 0.36 per 100 child-years with HAART, but this remains at least three times higher than in HIV-uninfected children. Infections with Mycobacterium tuberculosis are a major cause of morbidity in countries with high rates of endemic tuberculosis (TB). Given the frequency of coinfection, diagnosis of M. tuberculosis in a child is an indication for HIV testing. Likewise, children with HIV infection and their family members should have regular evaluation for M. tuberculosis exposure and testing if appropriate. Herpes zoster (shingles) occurs 10 times more frequently among untreated HIV-infected children compared with age-matched healthy children.

Late-stage immunodeficiency is accompanied by susceptibility to a variety of opportunistic pathogens. Pneumonia caused by P jiroveci is a common AIDS-defining diagnosis in children with unrecognized HIV infection who, therefore, are not receiving PCP prophylaxis. The incidence is highest between ages 2 and 6 months and is often fatal during this period. Symptoms are difficult to distinguish from those of viral or atypical pneumonia (see Chapter 43). Persistent candidal mucocutaneous infections (oral, cutaneous, and vaginal) are common. Candidal esophagitis occurs with more advanced disease. Cytomegalovirus (CMV) infections may result in disseminated disease, hepatitis, gastroenteritis, retinitis, and encephalitis. Disseminated infection with Mycobacterium avium complex (MAC), presenting with fever, night sweats, weight loss, diarrhea, fatigue, lymphadenopathy, hepatomegaly, anemia, and granulocytopenia, occurs in infected children who have CD4 T-lymphocyte counts below 50–100/μL. A variety of diarrheal pathogens that cause mild, self-limited symptoms in healthy persons may result in severe, chronic diarrhea in HIV-infected persons. These include Cryptosporidium parvumMicrosporidiaCyclosporaIsospora belliGiardia lamblia, and bacterial pathogens. Chronic parvovirus infection manifested by anemia can occur.

3. Organ system disease—HIV infection may directly affect a variety of organ systems and produce disease manifestations that include encephalopathy, pneumonitis, hepatitis, diarrhea, hematologic suppression, nephropathy, and cardiomyopathy. On average, HIV-infected children have lower than normal neuropsychological functioning. In many children, neuropsychological deficits do not normalize when ARV therapy is started, despite suppression of viremia. Findings include acquired microcephaly, progressive motor deficit, ataxia, pseudobulbar palsy, and failure to attain (or loss of) developmental milestones.

Lymphoid interstitial pneumonitis, which is common in untreated children with HIV infection, is characterized by a diffuse peribronchial and interstitial infiltrate composed of lymphocytes and plasma cells. It may be asymptomatic or associated with dry cough, hypoxemia, dyspnea or wheezing on exertion, and clubbing of the digits. Children with this disorder frequently have enlargement of the parotid glands and generalized lymphadenopathy.

4. Malignancy—Children with HIV are at increased risk of malignancy. The most commonly occurring tumors are non-Hodgkin lymphomas which may occur at unusual extranodal sites (central nervous system, bone, gastrointestinal tract, liver, or lungs). Human papillomavirus infection of the cervix is more likely to progress to neoplasia, and the rate of progression is not altered by HAART. Carcinoma due to anal human papillomavirus is also a concern. Kaposi sarcoma, a skin/mucus membrane malignancy, common in HIV-infected gay males with advanced disease, is also observed among HIV-infected African children, but it is rare in children in the United States.

B. Laboratory Findings

Established HIV infection in children older than 18 months may be diagnosed by detecting HIV antibody by immunoassay) or by rapid antibody tests. A confirmatory test, usually a Western blot, immune fluorescent antibody, or a second rapid test from a different manufacturer using a different antigen or test principle, must be performed because rare individuals have cross-reacting antibodies which result in a false-positive ELISA or rapid tests.

The hallmark of HIV disease progression is decline in the absolute number and percentage of CD4 T lymphocytes and an increasing percentage of CD8 T lymphocytes. The CD4 T-lymphocyte values are predictive of the child’s risk of opportunistic infections. Healthy infants and children have CD4 T-lymphocyte numbers that are much higher than in adults; these gradually decline to adult levels by age 5–6 years. Hence, age-adjusted values must be used when assessing a child’s absolute CD4 T-lymphocyte count (see Table 41–3). CD4 T-lymphocyte percentage, which does not vary significantly with age, is also a useful parameter.

Hypergammaglobulinemia of IgG, IgA, and IgM is characteristic. Late in the disease, some individuals may become hypogammaglobulinemic. Hematologic abnormalities (anemia, neutropenia, and thrombocytopenia) may occur due to effects of HIV disease. The cerebrospinal fluid (CSF) may either be normal or may be associated with elevated protein and a mononuclear pleocytosis; HIV nucleic acid testing may be positive in CSF.

C. Differential Diagnosis

HIV infection should be in the differential diagnosis for children being evaluated for immunodeficiency. Depending on the degree of immunosuppression, the presentation in HIV infection may be similar to that of B-cell (eg, hypogammaglobinemia), T-cell, or combined immunodeficiencies (eg, severe combined immunodeficiency) (see Chapter 33). HIV infection should also be considered in the evaluation of children with failure to thrive, developmental delay, chronic lung disease, and M tuberculosis infection. Chronic HIV infection presenting with generalized lymphadenopathy or hepatosplenomegaly may resemble infections with viruses such as EBV or CMV in children or adolescents. Because blood tests are definitive for the diagnosis of HIV infection, the diagnosis can be readily established or excluded. In rare cases, HIV-infected children with hypogammaglobulinemia have falsely negative antibody tests but may be diagnosed with a nucleic acid–based test. Absence of maternal risk factors or history of negative test results during pregnancy should not dissuade from testing for HIV if the patient has signs consistent with HIV-associated disease since maternal acquisition of HIV late in pregnancy can result in transmission to the infant and may be missed by maternal prenatal HIV testing.

Centers for Disease Control and Prevention: 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Recomm Rep 1994;43(RR-12):1 [PMID: 7908403].

Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf. Accessed January 25, 2014.

Gona P et al: Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292 [PMID: 16849662].

Smith R et al: Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence. Pediatr Infect Dis J 2012;31:592–598 [PMID: 22592486].

Steenhoff AP et al: Invasive pneumococcal disease among human immunodeficiency virus-infected children, 1989–2006. Pediatr Infect Dis J 2008;27:886–891 [PMID: 18776825].

Weinberg A et al: Immune correlates of herpes zoster in HIV-infected children and youth. J Virol 2012 Mar;86(5):2878–2881. doi: 10.1128/JVI.06623-11. [Epub 2011 Dec 14] [PMID: 22171274].

image Treatment

HIV infection calls for specific ARV treatment to prevent progressive deterioration of the immune system as well as prophylactic measures at late stages of HIV infection to prevent opportunistic infections. Guidelines for the treatment of HIV and prevention of opportunistic infections developed by US national working groups of pediatric HIV specialists are published by the U.S. Public Health System at: http://www.aidsinfo.nih.gov. The treatment paradigm changes frequently; therefore, prior to initiating treatment, expert consultation should be obtained.

A. Specific Measures

1. Principles of HIV treatment—Treatment of HIV is aimed at suppressing viral replication, thereby increasing/maintaining immune function. ARV treatment that reduces HIV replication is associated with an increase in CD4 T-lymphocyte count and reconstitution of immune function. HIV has a high spontaneous mutation rate that leads to emergence of drug resistance if viral suppression is incomplete. Prevention of resistance mutations requires that virus is not replicating and has no opportunity to generate new mutations. Thus regimens that fully suppress viral replication are key to long-term treatment success.

The current standard regimens are combinations of three drugs, including at least two drugs with different mechanisms of action. Optimally, children on ARV treatment will have laboratory monitoring every 3–4 months to confirm viral suppression and maintenance of CD4 T lymphocytes. If plasma virus becomes consistently detectable (> 400 copies/mL), the underlying cause must be determined, and, if necessary, a change in the medication combination is made. Regular viral load testing is cost-prohibitive in many resource-limited settings, so monitoring the response to ARV treatment must rely on clinical assessment, preferably supplemented with periodic CD4 T-lymphocyte testing. This approach has the risk of continuing a regimen that is not fully suppressive, which may result in accumulating drug resistance mutations. Despite this risk, ARV treatment has resulted in markedly reduced mortality in resource-limited-settings, as it has in settings with viral load monitoring.

Within 3–6 months of successful ARV treatment, circulating HIV declines to below the limit of detection and CD4 T-lymphocyte counts improve and may normalize. However, HIV persists in long-lived resting cells, and cessation of ARV treatment results in resumption of viremia and decline in CD4 T lymphocytes. Therefore, treatment for HIV with currently available modalities must be lifelong.

Strict adherence to the prescribed treatment is critical. A wide range of issues will impact adherence, including convenience and tolerability as well as psychosocial factors such as developmental stage, mental health of child and caregiver, HIV knowledge, and beliefs about treatment. Programs and services that enhance adherence are essential adjuncts of any HIV treatment regimen.

2. Criteria for initiation of antiretroviral medications—Many individuals with HIV will have slow disease progression and are asymptomatic for several years. This has led to debate about the optimal timing for initiation of ARV treatment. The current paradigm has shifted toward earlier initiation. Early treatment has advantages of more complete immune reconstitution and reduced risk of HIV disease complications but presents potential risks of increased medication toxicity and development of viral resistance. Country-specific treatment guidelines are published and updated when new evidence is available. The criteria for initiation may differ among countries, particularly for resource-rich versus resource-limited settings. WHO recommendations are found at http://www.who.int/hiv/topics/paediatric/en/index.html.

The United States guidelines recommend clinicians consider treatment for all HIV-infected children even at early stages of the disease. Infants diagnosed early have a 30%–50% risk of progression to AIDS or death by age 12–24 months, and there are no tests that reliably identify these rapid progressions. A randomized trial that compared early versus deferred treatment for infants demonstrated a survival benefit for early treatment. Therefore, infants younger than 12 months per US guidelines and 24 months per WHO guidelines, irrespective of clinical or immunologic progression, should begin treatment as soon as possible after diagnosis. For children who have survived longer prior to diagnosis, the risk of rapid progression is less. However, those with evidence of clinical progression (CDC Classification B or C and WHO Stages 3 and 4) or with low CD4 T-lymphocyte counts (category 2 or 3) are at risk of progression within 12 months and should start treatment promptly. High plasma viral load (> 100,000 copies/mL) is also associated with near-term disease progression. For children lacking evidence of disease progression and with low viral loads, deferred treatment may be considered, but most clinicians recommend treatment to reduce the effects of HIV on growth, development, and organ systems.

3. Antiretroviral medications—The U.S. Food and Drug Administration (FDA) has approved 25 drugs categorized into five different drug classes for the treatment of HIV. Many of the drugs have pediatric indications for older children, but pharmacokinetic data and administration forms appropriate for infants and toddlers are not available for many. The mechanism of action of each class is described briefly as follows. Specific drugs in each class are listed in Table 41–5.

Table 41–5. U.S. Food and Drug Administration–approved antiretroviral drug class (mechanism of action) and specific drugs in class.

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A. NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)—The NRTIs act as nucleotide analogues, which are incorporated into HIV DNA during transcription by the HIV reverse transcriptase. The result is chain termination and failure to complete provirus, preventing integration of HIV genome into cellular DNA.

B. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)—NNRTIs also inhibit HIV DNA synthesis but act at a different site on the viral reverse transcriptase enzyme so that cross-resistance with NRTIs does not occur.

C. PROTEASE INHIBITORS (PIs)—PIs bind the HIV protease and interfere with assembly of infectious virions. Most are given in combination (“boosted”) with a low dose of ritonavir, a second protease inhibitor, which inhibits their metabolism and thereby increases plasma levels.

D. INTEGRASE INHIBITOR (INSTIs)—These drugs inhibit the viral integrase enzyme and prevent integration of HIV-1 nucleic acid into the host genome.

E. ENTRY INHIBITORS—There are two approved entry inhibitors. Enfuvirtide binds to the viral envelope protein and interferes with HIV fusion with the host cell plasma membrane, thereby preventing entry of the virus into the cell. Enfuvirtide must be administered parenterally, which limits tolerability. Maraviroc is a chemokine receptor antagonist that binds one of the HIV coreceptor proteins (CCR5) on the host CD4 T lymphocyte. This blocks viral binding and prevents cell entry for virus that uses that receptor.

Abrams EJ et al: PEPFAR scale-up of pediatric HIV services: innovations, achievements, and challenges. J Acquir Immune Defic Syndr 201215;60(Suppl 3):S105–S112 [PMID: 22797731].

Bartlett JA, Shao JF: Successes, challenges, and limitations of current antiretroviral therapy in low-income and middle-income countries. Lancet Infect Dis 2009;9:637–649 [PMID: 19778766].

Buchanan AL et al: Barriers to medication adherence in HIV-infected children and youth based on self- and caregiver report. Pediatrics 2012 May;129(5):e1244–e1251. doi: 10.1542/peds.2011-1740 [PMID: 22508915].

Chadwick EG et al: Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. AIDS 2011;25(5):643–649 [PMID: 21297419].

Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children: Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2012 Nov 15:1–333. http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed January 25, 2014.

Rakhmanina N, Phelps BR: Pharmacotherapy of pediatric HIV infection. Pediatr Clin North Am 2012;59:1091–1115 [PMID: 23036246].

Van Dyke RB et al: Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr 2011;57(2):165–173 [PMID: 21407086].

World Health Organization: Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach: 2010 revision 1–206. http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html.

4. Complications of antiretroviral medications—ARV treatment may result in a range of adverse effects. Each medication has specific toxicities which are described in detail at http://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv-guidelines/113/appendix-a–pediatric-antiretroviral-drug-information. Common adverse events are gastrointestinal distress, hematologic toxicity (anemia, neutropenia), elevated liver enzymes, dyslipidemia (elevated LDL-cholesterol and triglycerides), glucose intolerance, and abnormal fat distribution (lipodystrophy). Reduced bone mineral content and renal dysfunction may result from drug effects as well as from direct effects of HIV. Several drugs (eg, nevirapine, abacavir) have been associated with severe hepatitis, sometimes associated with a systemic hypersensitivity reaction which may be life threatening if not identified early or upon rechallenge with the same medication. The nucleoside and nucleotide analogues have low-level affinity for the human mitochondrial DNA polymerase. Therefore, these analogues may be incorporated into mitochondrial DNA, which is one mechanism that may lead to adverse effects. Mitochondrial toxicity can result in lactic acidosis, a rare, but potentially fatal, complication. During the initial weeks of treatment, immune restoration may lead to worsening or unmasking of symptoms due to underlying infection with other organisms such as M tuberculosis, an event termed immune reconstitution inflammatory syndrome (IRIS).

Boulware DR, Callens S, Pahwa S: Pediatric HIV immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS 2008;3(4):461–467 [PMID: 19373006].

Fisher SD et al: Cardiovascular disease and therapeutic drug-related cardiovascular consequences in HIV-infected patients. Am J Cardiovasc Drugs. 2011 Dec 1;11(6):383–394 [PMID: 22149317].

Jacobson D et al: Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric AIDS/HIV Cohort Study. Am J Clin Nutr 2011;94:1485–1495 [PMID: 22049166; PMCID: 3252548].

Jacobson DL et al; Pediatric AIDS Clinical Trials Group P1045 team: Total body and spinal bone mineral density across Tanner stage in perinatally HIV-infected and uninfected children and youth in PACTG 1045. AIDS 2010 Mar 13;24(5): 687–696 [PMID: 20168204].

Rhoads MP et al: Effect of specific antiretroviral therapy (ART) drugs on lipid changes and the need for lipid management in children with HIV. J Acquir Immune Defic Syndr. 2011 Aug 15;57(5):404–412 [PMID: 21499114].

B. General Measures

1. Immunizations—Although vaccines are immunogenic in HIV-infected children, the magnitude and durability of the antibody responses to vaccines are often diminished even when administered to a child on effective ARV treatment. Additional doses to boost responses are recommended for some vaccines. More vigorous vaccine responses are found in children with suppressed plasma virus and restored CD4 T-lymphocyte counts. Therefore, for children who were immunized prior to establishment of effective ART, reimmunization should be considered and is recommended for some vaccines (eg, measles-mumps-rubella vaccine).

All inactivated vaccines are safe to administer to HIV-infected children. Annual immunization with inactive influenza vaccine after age 6 months is recommended for HIV-infected children and their close contacts. For live attenuated viral vaccines, the immune status of the child must be considered. Varicella and mumps-measles-rubella vaccines (but not the combined measles-mumps-rubella-varicella vaccine) are recommended for HIV-infected children, provided they are only mildly symptomatic (CDC Class N or A; see Table 41–1) and have CD4 T-lymphocyte parameters consistent with CDC category 1 or 2 (see Table 41–3). Current studies are investigating rotavirus vaccine in HIV-exposed and HIV-infected infants. The majority of infants born to HIV-infected women in the United States will be HIV-uninfected, so rotavirus is recommended even though it will be initiated before HIV infection is definitively excluded by early testing. Live attenuated influenza vaccine (LAIV) is not recommended for HIV-infected individuals, although initial studies have not identified safety concerns; close contacts may receive LAIV. Yellow fever vaccine is contraindicated in symptomatic HIV infection or with low CD4 T-lymphocyte count (< 200 cells/μL or CD4 < 15% if age < 6 years), but the benefits may outweigh the risk for asymptomatic individuals with higher CD4 T-lymphocyte counts. Bacille Calmette-Guérin (BCG), oral polio, smallpox, and live typhoid vaccines should not be given to HIV-infected people.

For some vaccines, additional doses or changes to the routine schedule are recommended. Children who have not received Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugate vaccine (PCV13) series as infants (eg, immigrants) may benefit from Hib vaccine (two doses between 12 and 59 months of age; one dose after 59 months of age) and two doses of PCV13 (separated by 8 weeks) which may be given after the usual cutoff age of 60 months. The 23-valent pneumococcal polysaccharide vaccine (PPSV) should also be given after age 2 years (and after a PCV13 series), with a second dose given at 3–5 years later. Although HIV infection is not an absolute indication for early administration of meningococcal conjugate vaccine (MCV), because antibody responses to the vaccine may be suboptimal, HIV-infected children who are vaccinated should receive a two-dose primary series. The response to hepatitis B vaccine is particularly unreliable in people with HIV infection. Therefore, a test for hepatitis B surface antibody should be obtained after the three-dose series. If the titer is less than 10 mIU/mL, a second series of three vaccinations is recommended.

2. Prophylaxis for infections—Children with suppressed CD4 T-lymphocyte numbers benefit from primary and secondary prophylactic treatment to prevent opportunistic infections. Children who have had their CD4 T-lymphocyte counts restored with ARV therapy to category 1 or 2 for over 3 months can be taken off prophylactic treatments.

Antibiotic prophylaxis for P jiroveci pneumonia has been extremely effective. HIV-infected infants should receive Pneumocystis prophylaxis until age 12 months, after which prophylaxis is based on assessment of symptoms and age-adjusted CD4 T-lymphocyte counts every 3 months. Children with low CD4 T-lymphocyte parameters (CDC category 3; see Table 41–3) should continue/begin PCP prophylaxis. Published guidelines from the CDC for P jirovecipneumonia prophylaxis are summarized in Table 41–6.

Table 41–6. Drug regimens for Pneumocystis jiroveci prophylaxis for children older than 4 wk.

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3. Psychosocial support and mental health—Evaluation and support for psychosocial needs of HIV-affected families is imperative. As with other chronic illnesses, HIV infection affects all family members and also carries additional social stigma. Emotional concerns and financial needs, which are more prominent than medical needs at many stages of the disease process, influence the family’s ability to comply with a medical treatment regimen. HIV-infected children often have comorbid mental health conditions. Rates of attention-deficit/hyperactivity disorder range from 20% to 50% in various studies. Hospital admissions for mental health disorders are more frequent among HIV-infected children. In one study, dual diagnosis of HIV and a mental health disorder occurred in 85% of adolescents who acquired HIV infection through high-risk behaviors. Ideally, care should be coordinated by a team of caregivers that is familiar with HIV disease and its comorbidities, newest therapies, and community resources.

Abzug MJ et al; International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1024 and P1061s Protocol Teams: Immunogenicity, immunologic memory, and safety following measles revaccination in HIV-infected children receiving highly active antiretroviral therapy. J Infect Dis 2012;206(4):512–522 [PMID: 22693229].

Crane HM et al: Optimal timing of routine vaccination in HIV-infected persons. Curr HIV/AIDS Rep 2009;6(2):93–99 [PMID: 19358780].

Gadow KD et al: Longitudinal study of emerging mental health concerns in youth perinatally infected with HIV and peer comparisons. J Dev Behav Pediatr 2012 Jul;33(6):456–468 [PMID: 22772819].

PREVENTION

image Prevention of Mother-to-Child Transmission (PMTCT)

A number of ARV regimens given to the mother antenatally and during labor and to the infant in the first weeks after birth reduce MTCT rates to 1%–2% without breast-feeding and 3%–5% with breast-feeding. The United States Public Health Services publishes detailed guidelines that are updated frequently (http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf). In the United States, all identified HIV-infected pregnant women are prescribed HAART during pregnancy and labor, infant zidovudine for 6 weeks, and avoidance of breast-feeding. Infants receive combination ARV medications if they are born to women with a higher risk of transmission (no or late maternal ARV treatment and/or lacking viral suppression). Elective C-section prior to labor will also reduce transmission risk for women who have plasma virus 1000 copies/mL or greater. The same interventions are effective in resource-limited settings, but in these countries, breast-feeding has a demonstrated survival value and is therefore recommended. Extended maternal HAART or infant ARV prophylaxis throughout the period of breast-feeding reduces breast milk transmission. A non-HAART maternal regimen is also effective in reducing MTCT and is used in some countries that lack resources for starting HAART in pregnant women who have not had disease progression that qualifies for initiating HAART per country-specific guidelines.

Key to prevention of mother-to-child transmission (PMTCT) is identification of pregnant women with HIV infection. The CDC and the American College of Obstetrics and Gynecology recommend routine HIV testing, with an option to refuse, early in gestation for all pregnant women. Women with ongoing risk factors for HIV acquisition (multiple partners, sexually transmitted diseases [STDs], substance use) should be tested again in late gestation. A woman presenting in labor without previously documented HIV testing should have HIV testing using rapid test assays that yield results within 60 minutes or less. ARV medications, even if implemented as late as 48 hours postpartum, may reduce transmission by as much as 50%.

image Prevention of Sexual Transmission

Latex condoms used consistently and correctly are highly effective in preventing sexual transmission. Behavioral interventions to increase use of condoms and other safer sex practices are a cornerstone of prevention efforts. However, the success rate with behavioral interventions has been inadequate in most populations. Several biomedical prevention interventions, added to condom use, have demonstrated efficacy in randomized clinical trials. These include (1) male circumcision—approximately 50% reduction in female-to-male transmission; (2) preexposure prophylaxis (PrEP) for HIV-uninfected partners using daily tenofovir—44%–70% reduction for MSM and 60%–70% reduction for discordant heterosexual couples (summaries at http://www.cdc.gov/hiv/prep/); and (3) ARV treatment of HIV-infected individuals—96% reduction in the risk of transmission to HIV-uninfected partners. Finally, postexposure prophylaxis (PEP) using combination ARV drugs initiated within 72 hours after a known HIV exposure was associated with reduced transmission in case-cohort studies. The CDC supports a consult service for questions regarding postexposure prophylaxis (PEP line, 888-488-4911).

image Prevention Through Universal Precautions

Horizontal transmission (in the absence of sexual contact or injecting drug use) of HIV is exceedingly rare and is associated with exposure of broken skin or mucous membranes to HIV-infected blood or bloody secretions. Several cases have resulted from HIV-infected caregivers feeding children premasticated food; hence, families should be advised against this practice. Saliva, tears, urine, and stool are not contagious if they do not contain gross blood. A barrier protection (eg, latex or rubber gloves or thick pads of fabric or paper) should be used when possible contact with blood or bloody body fluids occurs. Objects that might be contaminated with blood, such as razors or toothbrushes, should not be shared. No special care is required for dishes, towels, toys, or bedclothes. Blood-soiled clothing may be washed routinely with hot water and detergent. Contaminated surfaces may be disinfected easily with a variety of agents, including household bleach (1:10 dilution), some commercial disinfectants (eg, Lysol), or 70% isopropyl alcohol.

The infant or child who is well enough to attend day care or school should not be treated differently from other children. The exception may be a toddler with uncontrollable biting behavior or bleeding lesions that cannot be covered adequately; in these situations, the child may be withheld from group day care. Families may choose to make the school health care provider and/or teacher aware of the diagnosis, but there is no legal requirement that any individual at the school or day care center be informed. The parents and child may prefer to keep the diagnosis confidential, because the stigma associated with HIV infection remains difficult to overcome. Because undiagnosed HIV-infected infants and children might be enrolled, all schools and day care centers should have policies with simple guidelines for using universal precautions to prevent transmission of HIV infection in these settings.

Centers for Disease Control and Prevention: Interim guidance for clinicians considering use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep 2012;61:586-589. [PMID: 22874836].

Centers for Disease Control and Prevention: Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep 2005;54(RR-2): 1–16 [PMID: 15660015]. http://aidsinfo.nih.gov/contentfiles/NonOccupationalExposureGL.pdf.

Centers for Disease Control and Prevention Guidelines: Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care setting. MMWR Recomm Rep 2006 Sep 22;55(RR-14):1–17 [PMID: 16988643].

Chi BH et al: Progress, challenges, and new opportunities for the prevention of mother-to-child transmission of HIV under the US President’s Emergency Plan for AIDS Relief. J Acquir Immune Defic Syndr 2012 Aug 15;60(Suppl 3):S78–S87 [PMID: 22797744].

Nielsen-Saines K et al; NICHD HPTN 040/PACTG 1043 Protocol Team. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012 Jun 21;366(25):2368–2379. doi: 10.1056/NEJMoa1108275 [PMID: 22716975].

Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. 2012 Jul 31: 1–235. http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf. Accessed January 25, 2014.

World Health Organization: Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. http://www.who.int/hiv/pub/guidelines/arv2013/download/en/index.html. Accessed January 25, 2014.