Timing of infection

HIV progresses more rapidly in children with perinatal infection than among children infected at an older age or among adults. It has long been recognized that there was a bimodal distribution of clinical progression following perinatal infection [7–9]. About 20% of children had early onset of symptoms before the advent of effective therapy. These children have a rapid downhill course in the first 12 months of life, marked by rapid decline in CD4 count, and development of category C disease, often with pneumonia due to Pneumocystis jiroveci (formerly P. carinii pneumonia), or death.

There appear to be a number of predictors of rapid progression, including severe maternal disease [10], evidence of in utero transmission (positive PCR at birth), early hepatosplenomegaly [11], and higher viral loads after 1 month of life [12, 13]. CD4 and CD8 counts below the fifth percentile in infancy were associated with rapid progression among babies infected in utero in one study [14], perhaps reflecting early destruction of the thymus.

The natural history of HIV among adolescents who have acquired infection through adult behaviors generally parallels adults. However, younger age at infection for those with non-perinatally acquired HIV is associated with significantly slower progression in the absence of antiretroviral therapy (ART) [15, 16].

Declining CD4 count and CD4% are the hallmarks of HIV disease progression in children. CD4 count normally declines with age in young children, making interpretation somewhat difficult. CD4% is less age-dependent and is also useful in disease staging (Table 38.1) [17]. The revised CDC, PENTA, and WHO classifications use both immunologic status and clinical status for staging. Growth failure is a sensitive indicator of disease activity, and improved growth is a marker of successful ART.

Table 38.1 1994 revised human immunodeficiency virus pediatric classification system: Immune categories based on age-specific CD4 count and percentage

Predicting progression

Quantitative measurement of plasma viral RNA revolutionized the management of HIV in adults; similar data in children required a few more years to accumulate [13, 18, 19]. The kinetics of plasma HIV RNA in children differs from adults in several ways. First, children tend to have higher viral loads, with median peak values between 100,000 and 1,000,000 copies. Second, after primary infection, the viral load slowly declines during the first year of life, in contrast to the rapid 2–3 log drop in adults. Third, although viral load is consistently associated with prognosis, it has been difficult to establish specific levels that are sensitive and specific for high risk [20]. These differences may reflect a greater number of target cells and a limited ability to mount an immune response by the immature immune system. Children infected in utero tend to have modest viral loads at birth, but the peak value at 1–2 months is higher than those with presumed intrapartum infection.

A pivotal meta-analysis of survival data on 3,941 European and American children with HIV infection in the pre-HAART era demonstrated that CD4% and viral load were independent predictors of progression to AIDS or death over the next 12 months. CD4% was the strongest short-term predictor (Fig. 38.1) [20]. The risk of progression at a given CD4 level of viral load varied by age. Importantly, among children < 12 months, the risk of progression remained moderately elevated even when the CD4% was high or the viral load was low. A recent analysis of the same cohorts concluded that CD4 count may be more useful than CD4% in determining treatment initiation, particularly if only one has crossed a threshold [17].

Figure 38.1 Probability of developing AIDS in the next 12 months by age group.

(A) By CD4%; age groups (top to bottom) = 6 months, 1 year, 2 years, 5 years, 10 years.

Adapted from Dunn [20]. (B) By CD4 count; age groups = 6 months, 1 year, 2 years, 3 years, 4 years, 10 years. Adapted from HIV Paediatric Prognostic Markers Collaborative Study [35].

With the advent of three-drug combination ART for children, survival has increased dramatically. In a cohort of 1,000 children in the UK, there was an 80% decline in mortality and a 50% decline in progression to AIDS between 1997 and 2002, along with a 80% decline in hospital admission rates between 1996 and 2002 [21].

Diagnosis of HIV infection

Currently, the diagnosis of HIV infection in children born to HIV-infected mothers can be made in most infants by 2–4 weeks of age using methods that directly detect virus. Detection of virus by HIV DNA PCR of the infants’ peripheral blood mononuclear cells (PBMCs) or HIV RNA in plasma is presumptive evidence of infection but must be confirmed by repeat testing.

Viral culture is no longer used for diagnosis of HIV in infants. Currently, either detection of DNA or RNA by PCR is the test of choice. HIV DNA PCR is only moderately sensitive in the first 48 hours of life (38%; 90% confidence interval [CI], 29–46%). Sensitivity rises rapidly during the second week; 93% of infected children (90% CI, 76–97%) were PCR positive by 14 days of age. Quantitative RNA PCR is at least as sensitive and specific as DNA PCR, and offers the advantages of using smaller blood volumes, providing important prognostic data [22, 23], and being more sensitive for detecting non-clade B strains [24]. False positives can occur; levels < 5,000 copies/mL should be considered suspect. Measurement of p24 antigen, either conventionally or with immune dissociation, is not recommended for the diagnosis of neonatal HIV infection because it is less sensitive and specific than PCR.

Many experts recommend obtaining a first sample for DNA or RNA PCR during the first 48 hours of life, especially if the infant is at higher risk of infection. Cord blood should not be used because of the possibility of contamination with maternal blood. A positive viral test in the first 48 hours of life presumptively identifies children infected in utero who may have a more rapid disease course. However, plasma RNA measurement after the first month of life may be more prognostic than time of first positive test.

For infants with an initial negative test or who are not tested at birth, testing should be repeated at 14–21 days of life. Testing at 14 days offers the potential to stop zidovudine monotherapy for patients with presumed infection and begin combination therapy during the period of acute infection. For infants with initial negative tests, testing should be repeated again at 1–2 months of age. An infant with two negative virologic tests, one at ≥ 14 days and one at ≥ 1 month of age, can be viewed as presumptively uninfected. Thus, one does not need to initiate PCP prophylaxis. Testing should be repeated at 4–6 months of age for definitive exclusion of HIV infection.

Any positive test should be confirmed immediately by testing of a separate blood sample. Two positive tests should be considered diagnostic of infection. Many experts recommend checking HIV antibody at 12 months to document the clearance of maternal antibody. If antibody is still detectable, testing should be repeated until antibody becomes undetectable.

Monitoring in the HIV-exposed or HIV-infected infant

Infants born to HIV-infected women should receive oral AZT during the first 6 weeks of life, based on the PACTG 076 protocol. Myelosuppression is common with both AZT and trimethoprim-sulfamethoxazole, and the complete blood count should be monitored. Plasma viral RNA and CD4 count and percentage should be monitored immediately once the diagnosis of HIV is established, and followed every 3–4 months. When starting ART, plasma viral RNA and CD4 count should be measured at baseline, after 1 and 2 months, and every 3–4 months thereafter. A suggested monitoring scheme is shown in (Table 38.2).

Table 38.2 Suggested schedule for routine monitoring of HIV-exposed and infected infants

Vaccination

Timely vaccination is important for HIV-infected children. Guidelines are available [25]. Inactivated vaccines (hepatitis B, Haemophilus influenzae type B, diphtheria-tetanus-pertussis, IPV) are given according to the schedule recommended for all children. Measles, mumps, and rubella (MMR) and varicella vaccines are live-attenuated, which pose a theoretical risk to severely immunocompromised children. The vaccines should not be given to those with CD4% less than 15%. HIV-infected children without immunosuppression should receive their first dose of MMR as soon as possible after the first birthday. The second dose does not need to be delayed until school entry; it can be given as soon as 1 month after the first dose. Annual immunization against influenza is recommended for all HIV-infected children. Initially, two doses are given, separated by at least 1 month.

Since infections with encapsulated bacteria are prominent among HIV-infected children, the potential benefit of pneumococcal vaccine is large. Unfortunately, children < 2 years old respond poorly to polysaccharide vaccines. In February 2010, a new 13-valent pneumococcal conjugate vaccine (PCV-13) was approved by the FDA, which offers expanded coverage of the serotypes causing the majority of invasive pneumococcal disease (IPD) in children. PCV-13 is recommended for all children younger than 72 months with an underlying medical condition, including HIV. In addition, children aged 6–18 years may receive one dose of PCV-13. A single dose of PCV-13 should be given to children younger than 6 years who were previously vaccinated with PCV-7. After completion of the PCV-13 series, the 23-valent pneumococcal vaccine (PPSV23) should also be given after 24 months of age. Re-vaccination should be offered 5 years after the first dose of PPSV23 [26].

Vaccination is also important for HIV-infected adolescents. They should receive pneumococcal and annual influenza vaccinations. Their immunization status to hepatitis A, hepatitis B, and measles should be reviewed and updated. Meningococcal conjugate vaccine and tetanus diphtheria acellular pertussis (Tdap) are recommended for all adolescents. Human papillomavirus vaccine is licensed for use in both females and males; however, no specific recommendations exist regarding its use in HIV-infected children and adolescents [4, 27]. Given the increased risk of HPV-related disease among HIV-infected persons, HPV vaccine (HPV4) should be strongly considered for both female and male HIV-infected adolescents.

Principles of therapy

The goal of ART in children, as in adults, is to suppress viral replication to extremely low levels to prevent loss of CD4 cells and to allow immune reconstitution. If viral replication continues in the face of antiretroviral agents, ongoing mutation will lead to drug resistance. Combination therapy with three or more agents offers the greatest opportunity to achieve maximal suppression. The ability to adhere to a regimen is a key determinant of continued viral suppression. The complexity of HIV therapy in children and adolescents and the rapidly changing evidence base suggest that children with HIV should receive care from physicians with substantial expertise in HIV and in conjunction with multidisciplinary teams. Whenever possible, children should be offered the opportunity to participate in clinical trials.

It is important, however, to appreciate ways in which children differ from adults. The majority of HIV-infected children are infected around the time of delivery, and therapy can potentially be started during primary infection. Theoretically, this offers children an advantage that is rare in adults. Intact thymic architecture offers the potential for greater immune reconstitution, and in one study, thymic volume on CT scan correlated with completeness of immune reconstitution [28].

However, many of the differences lead to challenges. In general, clinical trial data in children are limited and pharmacokinetic studies may be inadequate. The disposition of drugs changes during growth and development, changing from infancy into childhood, and again during adolescence. In general, volume of distribution is larger, and clearance is faster, which may require more frequent dosing. In general, rates of viral suppression below the limits of quantification have been lower in trials among children and adolescents than among adults. The developing central nervous system of children appears to be more vulnerable to damage by HIV. Regimens, therefore, should be highly active in the CNS. Young children usually require liquid formulations, which may be unpalatable or unavailable. Young children are dependent on the caregiver’s ability to give medications consistently, on schedule, and despite protests. Older children may be concerned about taking antiviral therapy in public, at school, or at friends’ houses. The social problems which are common in families with HIV-infected children (poverty, homelessness, parents who may be ill or absent, substance abuse, mental illness, isolation, fear of disclosure) compound the problems of complex regimens, unpleasant tasting medicine, and sometimes resistance from the child or adolescent. Thus, problems with adherence can be daunting.

When to start

Recommendations on starting therapy and preferred regimens have been formulated by the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children in the US and the Paediatric European Network for Treatment of AIDS (PENTA) (Table 38.3) [24, 29]. These guidelines are generally concordant but have subtle differences. The decision to start therapy balances the probability of developing severe clinical disease in the near term and the risk of irreversible damage to the immune system or developing organs with the known difficulties of maintaining suppression in children, short-term side effects, the risk of developing drug resistance, and the possibility of running out of effective agents. In addition, uncertainty remains about the importance and frequency of long-term toxicities in children, including abnormalities of lipid, glucose, and bone metabolism.

Table 38.3 When to start therapy: Comparison of DHHS 2011, PENTA 2009, and WHO 2010 recommendations

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