Pediatric HIV Infection

Pediatric HIV Infection

Updated August, 2009

Dr. Mehri S. McKellar, Dr. Sabrina Bakeera-Kitaka, Dr. Robert Colebunders

OVERVIEW

Since the introduction of protease inhibitors, HIV mortality in children has decreased by approximately 80-90% (12, 27, 40, 58). Opportunistic infections have likewise decreased since the pre-highly active antiretroviral therapy (HAART) era (26). With data generated from clinical trials and advances in laboratory monitoring including resistance testing, clinicians now have the ability to better select effective initial treatment regimens while preserving new drugs and drug classes for second or third-line regimens. At the same time, the availability of new drugs and drug formulations has led to regimens with less dosing frequency, fewer toxicities, and better palatability. This is very important for children, as the availability of pediatric formulations and solutions has been and continues to be limited. These improvements should lead to better adherence overall and decreased resistance. Given these therapeutic advances, HIV practitioners are now charged with what appears to be a more realistic goal in both pediatric and adult HIV care and treatment – maximal viral suppression in order to preserve immunological function, prevent disease progression and avert the development of resistance.

DIFFERENCES BETWEEN ADULTS AND CHILDREN

Although the pathogenesis of HIV infection and the general virologic and immunologic principles are similar for all HIV-infected persons, there are some unique considerations for HIV-infected infants and children. One of these differences is that HIV virologic tests (HIV RNA or DNA) are necessary in order to diagnose HIV infection in infants less than 18 months due to the crossover of the maternal HIV antibody. Another significant difference in children is that plasma HIV RNA levels are markedly higher and persist at high titers, reaching steady-state values seen in adults only after approximately 5 years of infection. With regard to laboratory monitoring, CD4 cell counts are age-specific; typically CD4 percentages are used to monitor children < 5 years old. Another noteworthy difference is that drug dosing needs to be frequently revisited in pediatric patients given the changes in the pharmacokinetic parameters with age and development.

EPIDEMIOLOGY

Worldwide, both the annual number of new HIV infections and the annual rate of AIDS deaths in children have declined since 2002-3 (65). This is in part due to successful prevention of mother-to-child transmission (PMTCT) and treatment scale-up programs. In 2007 the number of children living with HIV infection increased to 2 million – almost 90% of whom live in sub-Saharan Africa (65).

In resource-rich countries, the use of antiretroviral therapy during pregnancy in HIV-infected women has resulted in a dramatic decrease in the transmission rate to infants. The transmission rate is currently less than 2% in the United States; in 2007 there were only 139 reported perinatal HIV infections (36). The number of perinatal infections in the U.S. continues to decline in part due to the 2006 recommendations by the Centers for Disease Control (CDC) for a “universal opt-out” policy, in which all pregnant women are tested for HIV as part of the routine panel of prenatal tests unless the patient declines the test (6).

In resource-limited countries, where access to prevention, testing and treatment is difficult, perinatal infection continues to represent a major and overwhelming global health problem, requiring its own solutions. It is estimated that 90% of children living with HIV acquired the virus during pregnancy, birth or breastfeeding – all of which are forms of HIV transmission that can be prevented (65). The impact of PMTCT has not yet been realized in sub-Saharan Africa; as one tragic example, it was recently announced that 30% of children admitted to the hospital pediatric ward in Mozambique have HIV(54).

Growing older, perinatally-infected children will bring new challenges of adherence issues, drug resistance and management of multiple drugs. Adherence is a key issue for sustainable virologic suppression. When a child gets older, it will become essential to explain in an appropriate way why he/she has to take antiretrovirals. Full disclosure should be reached when the child and parents are both ready for it, but preferentially before adolescence as other issues such as reproductive health will come up during this time period.

TESTING

HIV infection can be definitively diagnosed in most non-breastfed HIV-infected infants by age one month and in virtually all infected infants by age 4 months through the use of virologic assays (92). Early diagnosis of infection is important, given the potential for rapid disease progression in infants. In an analysis of data from 7 randomized MTCT intervention trials in Africa, 35% of infected children were estimated to have died by age 1 year and 52% by 2 years of age, without treatment (55). In this same study, children with evidence of early infection (before 4 weeks of age) were at higher risk of death within 12 or 24 months of becoming infected than those who acquired infection after 4 weeks of age through breastfeeding (55).

In infants under 18 months, HIV antibody tests such as the ELISA, Western blot and the recently approved rapid tests are not used due to the transplacental transfer of maternal HIV antibodies. Close to 100% of infants born to HIV-positive mothers will have a positive antibody test at birth (45). The median age for the disappearance of antibodies in uninfected children is 10 months (16), although the antibodies may persist until 18 months (64). As a result, virologic tests should be utilized. This includes either detection of HIV by DNA or RNA polymerase chain reaction (PCR). A positive virologic test indicates infection and should be confirmed by a repeat virologic test (92). Of note, the antibody test may be helpful and less costly than PCR for assessing if an infant is “at risk” for HIV, such as in the case when the infant is transported to another institution from the mother whose HIV status is unknown. If the ELISA is positive, the infant would then need to undergo virologic testing.

The p24 antigen is no longer recommended due to its lower sensitivity in the neonatal period (30). However, in recent years an ultrasensitive p24 technique has been developed, which yielded an overall sensitivity and specificity of 91.7% and 98.5%, respectively, in 802 plasma specimens from 582 Malawian infants and children of 0 to 180 days (20). After exclusion of infants less than 7 days of age, the sensitivity and specificity were 93.7% and 98.3 %, respectively, which is still below the current World Health Organization’s (WHO) guidelines for diagnostic tests for HIV(20, 24). In Haiti a simplified test was performed using overnight (16 hours) p24 antigen solid-phase incubation ELISA without amplification which attained comparable diagnostic accuracy to the ultrasensitive p24 assays (24). The test was also adapted to be used on dried blood spots on filter paper, with similar results to the ultrasensitive p24 assay (43).

Of the virologic assays, HIV DNA PCR is often recommended as the preferred test for infants. This technique is used to detect HIV DNA within the peripheral blood mononuclear cells (PBMCs). The sensitivity of a single HIV DNA performed at < 48 hours of age is less than 40% but increases to over 90% by 2 weeks (13). By age 28 days, the sensitivity and specificity has been reported as high as 96% and 100% respectively (11).

HIV DNA PCR is also measurable using heel-stick dried blood spots, from which HIV DNA can be extracted and amplified. In one study in South Africa which included 206 heels sticks, the sensitivity and specificity of dried blood spots was 98.3% and 98.9%, respectively. The majority of the children tested were approximately 6 weeks old (59). This may a cheaper and more practical solution for countries lacking laboratory resources.

Although data is more limited regarding its use, RNA PCR appears to be equally sensitive and specific for early diagnosis of HIV infection. HIV RNA assays detect extracellular viral RNA in the plasma. Several studies have demonstrated sensitivities of 25-40% during the first weeks of life, increasing to 90-100% by 1-3 months of age (11, 44, 73, 76). Similarly, specificity is comparable between the two tests, although with low levels of HIV RNA (< 10,000 copies/mL) the test should be repeated before being interpreted as positive in infants as it may not be reproducible (92). Some clinicians use the HIV RNA assay as the confirmatory test for infants who have an initial positive HIV DNA PCR test. In addition to providing virologic confirmation of infection, the expense of a repeat HIV DNA test is spared, and RNA viral loads can be used to guide treatment decisions (92).

Prophylactic antiretroviral therapy could theoretically affect the predictive value of virologic testing in neonates by lowering the viral load to undetectable levels. Zidovudine (AZT) monotherapy, however, did not delay detection of HIV by culture technique in infants in the PACTG protocol 076 (9). As HIV DNA PCR detects PBMC infection and not plasma levels, this test will remain positive in individuals receiving antiretroviral treatment (ART) [26], and false negatives should not occur. Interestingly, in several studies maternal antenatal treatment with ART and/or with infant antiretroviral prophylaxis did not appear to have a profound effect on the sensitivity or specificity on RNA levels (73, 93).

For non-subtype B, HIV RNA assays may be more sensitive than HIV DNA PCR (56, 93). In situations where non-subtype B perinatal exposure is suspected and the HIV DNA PCR is negative, repeat testing using the RNA assay should be performed.

CLINICAL MANIFESTATIONS

Opportunistic Infections

Since the introduction of HAART therapy, there has been a substantial reduction in the incidence of opportunistic infections (26). The natural history of opportunistic infections in children may differ from that observed in HIV-infected adults (52). Many opportunistic infections in adults are secondary to reactivation of previously-acquired opportunistic pathogens, often acquired before being infected with HIV when host immunity was intact (52). Opportunistic infections among HIV-infected children more often reflect primary infection with the pathogen, occurring at a time when the child’s immune system may already be compromised (52). This can lead to different manifestations of disease among children when compared to adults. For example, young children with Mycobacterium tuberculosis are more likely to have extra-pulmonary and disseminated infection than adults, even without concurrent HIV infection (52).

It is important to remember that an important mode of acquisition of opportunistic infections is from an infected mother to her child, both perinatally and in the home once the child is born. Multiple difficulties exist in making laboratory diagnoses of various infections in children. Diagnosis is often compounded by a child’s inability to describe their signs and symptoms. Diagnosing lung infections, for example, is difficult because children generally do not produce sputum, and more invasive procedures may be needed. For infections where the primary diagnostic modality is the presence of antibody, the ability to make a diagnosis in infants may be complicated by transplacental transfer of maternal antibody that can persist in the infant for 12-15 months (52).

Similar to antiretrovirals, treatment for opportunistic infection can be made difficult due to drug pharmacokinetics and the lack of pediatric dosing in children, particularly when < 2 years of age.

In the pre-HAART era, the most common opportunistic infections among children in the U.S. (event rates >1.0/100 child-years) were serious bacterial infections (with pneumonia and bacteremia being most common), herpes zoster, disseminated Mycobacterium avium complex (MAC), Pneumocystis jivoreci (formerly carinii) pneumonia (PCP), and oral candidiasis (26). Although the majority of infections occurred among children who were substantially immunocompromised, HIV-positive children from all levels of immune strata suffer more bacterial infections, herpes zoster, and tuberculosis than children without HIV. Since the onset of HAART, the number of infections has significantly decreased (26). Bacterial pneumonia, herpes zoster, dermatophyte infections and oral candidiasis are now the most common first-time infections (26).

Antibiotic prophylaxis against PCP with co-trimoxazole is recommended for infants with indeterminate HIV status starting at 4-6 weeks of age until they are determined to be HIV-uninfected. Children who are HIV-positive should continue to receive prophylaxis for the first year of life regardless of their immune status. Need for subsequent prophylaxis after 12 months of age should be determined on the basis of CD4 percentages or overall clinical status. The CDC recommends prophylaxis for all children aged 1 to 5 years with CD4 counts of <500 cells/mm3 or CD4%<15, and for all children aged >6 years with CD4 counts <200 cells/mm3 or CD4%<15 (8). When the child is > 5 years, adult guidelines can essentially be followed. Children with a history of PCP should continue to receive chemoprophylaxis regardless of their CD4% in order to prevent recurrence. Of note, the World Health Organization recommends PCP prophylaxis in children aged 1-5 with a CD4%<25 or who are symptomatic (WHO clinical stages 2,3, or 4) . Once a child is started on co-trimoxazole, the WHO recommends that treatment is continued until 5 years of age regardless of symptoms or CD4%. The WHO also proposes offering co-trimoxazole prophylaxis to all children living with HIV irrespective of their age or CD4 level in countries with high burden of morality and morbidity due to other infectious diseases such as malaria and bacterial infections (88).

TIMING OF TESTING

The current U.S. National Institutes of Health (NIH) guidelines recommend that virologic testing be performed at age 14-21 days; 1-2 months; and 4-6 months. Some experts will also perform virologic testing at birth (92). The WHO guidelines suggest that virological testing is performed at age 4-6 weeks or any time subsequently in infants known to be exposed to HIV (89).

HIV is diagnosed by two positive HIV virologic tests performed on separate blood samples, regardless of age. A positive HIV antibody test with confirmatory Western blot (or IFA) at age >18 months also confirms HIV infection.

HIV infection can be presumptively excluded in non-breastfed infants with two or more negative virologic tests with one test obtained at > 14 days of age and one obtained at > 1 month of age; or one negative virologic test result obtained at age > 2 months; or one negative HIV antibody test result obtained at > 6 months of age (92). HIV infection can be definitively excluded in a non-breastfed infant with two or more negative virologic tests with one obtained at age > 1 month and one at > 4 months; or 2 negative HIV antibody tests from separate specimens obtained at > 6 months (92). Loss of HIV antibody in a child with a negative virologic test confirms that the child is HIV-uninfected (92).

In the 2008 revised surveillance case definition of HIV infection (64a), laboratory-confirmed evidence of HIV infection is now required for all reported cases of HIV infection among children aged 18 months to <13 years. Laboratory criteria for children aged <18 months at the time of diagnosis include revisions to one category: presumptively uninfected with HIV. No substantial changes have been made to the remaining three categories (definitively HIV infected, presumptively HIV infected, and definitively uninfected with HIV). Because diagnostic laboratory testing for HIV infection among children aged <18 months might be unreliable, children in this age group with perinatal HIV exposure whose illness meets the AIDS case definition on the basis of clinical criteria are considered presumptively HIV infected when the mother has laboratory-confirmed HIV infection. No changes have been made to the conditions listed under the AIDS criteria in the 1987 pediatric surveillance case definition for AIDS for children aged <13 years.

LABORATORY MONITORING

In HIV-infected children, as in infected adults, the CD4 count and percentage declines with the progression of disease. In children under 5 years, CD4% is the preferred test for monitoring immune status as it varies less with age than the absolute count and provides a more stable marker (14, 35, 92). CD4% and absolute count should be measured at the time of diagnosis of HIV infection to establish a baseline and then at least every 3-4 months thereafter, whether the child is on or off antiretrovirals, in order to monitor immune function.

Plasma HIV RNA viral loads should likewise be measured at baseline and then every 3-4 months when on therapy. Viral loads in perinatally-infected infants generally remain higher than in adults (1). In one prospective study, viral loads increased rapidly after birth, peaked at 1 month of age (median 318,000 copies/mL), and then slowly declined to a median of 34,000 copies/mL at 24 months (73). This is in contrast to the rapid decline seen in adults after primary HIV infection (37). Over the next few years, the HIV RNA load in children continues to decline (53). This pattern most likely reflects an immature but developing immune system that has some difficulty with initial containment of the virus but then improves with age.

The prognostic value of CD4% and viral load testing was assessed in the HIV Pediatric Prognostic Markers Collaborative Study, a large meta-analysis of 17 studies including 3,941 children, which looked at the 12 month risk of developing AIDS or death based on age and baseline CD4% and viral loads (10). Infants in the first year of life experience proportionately higher risk than older children for any given CD4 stratum. These risk profiles have gone on to form the rationale for recommendations on when to initiate therapy in a treatment-naïve HIV infected child (92). CD4 counts are best checked when patients are clinically stable

High HIV RNA levels in infants age < 12 months have been correlated with disease progression and death, but RNA levels overlap considerably in young infants with rapid disease progression and those without (73), and this association was more gradual when compared with CD4% (14). In a recent study of Kenyan infants, infants who experienced acute primary HIV infection syndrome had higher RNA loads later in infection than did infants who did not experience symptoms. However, there was no association between the acute syndrome and increased mortality, although the overall mortality of the group was very high (> 40% by 24 months of age) (66). High RNA levels (i.e. levels of > 100,000 copies/mL) in older children, similar to adults, have been associated with high risk of disease progression and mortality, particularly if the CD4 percentage is < 15% (53).

More frequent CD4% and RNA monitoring should be considered in infants less than age 12 months, as young infants may have rapid disease progression, which is typically defined as CDC class C clinical event or death (73). More frequent monitoring should also occur in children with suspected clinical, immunologic or virologic deterioration, to confirm an abnormal value; or when initiating or changing therapy.

Guideline: Aberg JA, et al. Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2009;49:651-681.

TREATMENT

One of the many challenges in treating HIV is that it is a relatively new infection, identified just over 20 years old, with dynamic treatment guidelines and new data continuously evolving from clinical trials. In children, this is more complicated as most antiretrovirals are approved for use in pediatrics based on efficacy data extrapolated from adult studies, with limited pediatric pharmacokinetic and pharmacodynamic data. As with other medications used in pediatrics, adult dosages often do not directly translate to pediatric doses, which can lead to inadequate dosing and decreased efficacy in children. For example, in the CHIPS cohort in the U.K. and Ireland, children were estimated to be underdosed 6-62% of the time when the total daily dose was compared to the current recommended dose (51). A recent study evaluating the use of lopinavir/ritonavir, the recommended protease inhibitor for children, found that significantly more children less than two years old had inadequate minimum concentrations (Cmin) at the recommended dose of 230/57.5 mg/m2 twice daily (83). Pharmacokinetic data differs in children based on their growth and development and should be made available for the different age groups. Failing to account for growth and to change the dose with increases in height or weight will lead to suboptimal dosing. Rounding down doses is another contributing factor for underdosing (51).

As of February, 2009, there are 25 antiretrovirals approved for use in HIV-positive adults and adolescents: 17 of them have an approved pediatric treatment indication, and 16 are available in a pediatric formulation (92). In children, antiretroviral treatment with at least 3 drugs from 2 different classes is recommended; such regimens have been associated with enhanced survival and reduction in opportunistic infections and other complications of HIV infection. Treatment has also resulted in improved growth and neurocognitive function, as well as improved quality of life in children (7, 72, 78). In the U.S. and United Kingdom, an 81% decline in mortality was reported in HIV-infected children between 1994 and 1999, concomitant with increased use of ART (71). Significant declines in HIV-related hospitalizations in children have been observed in the U.K. and Europe over the same time period (25, 85).

Treating children is associated with the same challenges as with adults. Some of these challenges include preserving effective regimens for the future and avoiding short and long term toxicities, such as lipodystrophy and other metabolic complications (3, 69), which are starting to be identified in children. Resistance can develop in children who receive regimens containing 1 or 2 drugs that incompletely suppress viral replication. Additionally, drug resistance may be seen in drug-naïve children who were exposed to maternal/infant antiretroviral prophylaxis (15, 39) or from circulating resistant strains in the community that led to the infection of the mother. Previous ART history or exposure thus becomes an important factor in selecting a treatment regimen.

Additional factors to consider when choosing treatment include other co-morbidities such as tuberculosis, hepatitis B, chronic renal or liver disease. This has become particularly true in co-infection with hepatitis B, which shares some of the same antiviral treatments with HIV.

Given the chronic nature of the infection, once treatment is started in a child, most likely, it will be life-long. In February, 2009, the NIH Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children recommended several preferred and alternative regimens. A combination ART regimen in treatment-naïve children generally contains two classes of drugs – two nucleoside analogue reverse transcriptase inhibitors (NRTIs), either combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). The most appropriate regimen for a child, however, depends on multiple factors, including the child’s age, the availability and palatability of the appropriate drug formulations, the child’s social support system, the child and caregiver’s ability to adhere to the regimen, and the previous antiretroviral treatment history.

When to Initiate Therapy (Table 1)

The choice of whether to start early while an individual is still asymptomatic versus delaying therapy until symptoms develop continues to generate controversy among HIV experts. Starting aggressive therapy early may result in a lower viral set point and control of viral replication prior to the onset of rapid genetic mutation and potential evolution of resistance. Early therapy would also slow immune system destruction, thus preserving immune function and preventing clinical disease progression. Now that the drugs have become more advanced with less toxicities and lower pill burden, the trend appears to be more toward early treatment.

On the other hand, delaying therapy until later in the course of HIV infection, when clinical or immunologic symptoms appear, may result in reduced evolution of drug-resistant virus due to lack of drug selection pressure, greater adherence to the therapeutic regimen when the patient is symptomatic rather than asymptomatic, and reduced or delayed adverse effects of antiretroviral therapy.

CD4 counts and viral loads vary considerably by age in children; consequently, recommendations for when to start therapy are stratified by age. The NIH Working Group has recommendations based on 3 age groups: infants < 12 months, children 1 to < 5 years; and children and adolescents ≥ 5 years old.

Infants

The NIH Working Group recommends the initiation of antiretroviral therapy for all infants aged <12 months, regardless of clinical status, CD4 percentage or viral load (92). The risk of progression is greatest in the first year of life, and the ability to differentiate children at risk of rapid versus slower disease progression by clinical and laboratory parameters is most limited in young infants (17). In early reports, more than 15% of HIV-infected children progressed to AIDS or death within the first year of life without treatment. By 12 months, approximately 50% of children developed moderate immune suppression and 20% severe immune suppression (28).

Recent data from the CHER (Children with HIV Early Antiretroviral Therapy) trial showed that treating HIV-infected infants as early as the first 6-12 weeks of life significantly decreased risk of early death by 76% and HIV progression by 75% when compared to children who were deferred treatment (until the CD4% fell below 25% if aged < 1 year or below 20% if < 2 years) (86). Other data, although in slightly older infants, supports early treatment with ART as well. The Perinatal AIDS Collaborative Transmission Study which included 260 HIV-infected children in the U.S. showed that infants who received treatment early (prior to age 2 years, with nearly half starting in the first year of life) were significantly less likely to progress to AIDS or death compared with those who received no therapy (2). The French Perinatal Cohort study reported a 70% reduction in the incidence of AIDS-associated events before age 24 months among infants started early on ART; those who started treatment before 6 months had the best clinical outcomes (18).

Studies are conflicting on the durability of viral suppression with early initiation of ART. Studies have demonstrated that long-term suppression of HIV viremia can be achieved in the youngest and most immunologically immature infants. For example, in the PACTG 356 study, 52 infants were treated with 3 and 4 drug regimens. Those who began treatment at ≤ 3 months of age were more than twice as likely to maintain HIV RNA viral loads < 400 copies/mL for 200 weeks than infants who initiated therapy at age > 3 months (60% versus 30%; p=0.03) (46).

Nonetheless, the percentage of infants with viral load suppression is lower than what is typically reported in older children and adults. Studies in addition to the PACTG 356 study have indicated that the percent of infants with undetectable viral loads after 12-24 months ranges from 18-60% (17, 47). Possible explanations for the poor response in infants may be due to an immature immune system that has not yet developed HIV-specific immune responses (46). Inadequate antiretroviral drug levels may occur due to the lack of pediatric pharmacokinetic data or due to the fact that the child is growing with evolving body composition and drug metabolism (42). Adherence issues and difficulty in administrating oral regimens are also possible factors.

ARV-Naive HIV-Infected Children Age 1 Year or Older

Due to the lower risk of disease progression in children > 1 year, the option of deferring treatment can be considered for older children. Children with clinical AIDS or significant symptoms (CDC clinical categories B or C) are at higher risk of disease progression, and treatment is recommended for all ages, as with adults. However, children age > 1 year with mild clinical symptoms (CDC clinical category A or N) or who are asymptomatic are at lower risk of disease progression than those with more severe clinical symptoms.

The prognostic significance of a specific CD4 percentage or count varies with age (14). Younger children (ages 1-<5 years) with a CD4% of < 25% should be treated, regardless of symptoms or HIV RNA levels; likewise, older children (> 5 years) with an absolute CD4 count of <350 cells/mm3 should be started on therapy. For children who have higher CD4% or absolute counts but are mildly symptomatic and have high viral loads (>100,000 copies/mL) should also be considered for therapy.

TREATMENT RECOMMENDATIONS (Table 2)

The guidelines developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children (convened by the National Resource Centers at the Francois-Xavier Bagnoud Center, UMDNJ; the Health Resources and Services Administration, and the National Institutes of Health) are utilized here. These guidelines, also referred to as the NIH guidelines, were updated on February, 2009, and can be accessed at the following website: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf.

Given their complexity, treatment-resistant patients are not specifically discussed here; genotype and phenotype resistance testing are typically utilized to manage these patients. Children who are failing treatment should be managed in consultation with a pediatric HIV specialist. More information about treatment-resistant patients is available in the NIH guidelines.

NNRTI-Based Regimens

For NNRTI-based regimens, choices would include: efavirenz in combination with 2 NRTIs for children age ≥ 3 years; or nevirapine with 2 NRTIs for children < 3 years or who require a liquid formulation. An alternative regimen would be nevirapine with 2 NRTIs for children age > 3 years.

Both nevirapine and efavirenz have approved pediatric indications. Nevirapine is available in a liquid formulation, while efavirenz is currently not, although that formulation is currently under study. There is also a pediatric fixed-dose combination tablet of lamivudine, stavudine and nevirapine which was approved by the U.S. Food and Drug Administration (FDA) in 2007 and is mainly used in developing countries by the President’s Emergency Plan for AIDS Relief (PEPFAR) treatment programs. This combination pill can be swallowed or dissolved in water for children who can not swallow tablets.

Advantages of using a NNRTI-based regimen include preservation of the PI class for future use, improved palatability, less pill burden, and perhaps less dyslipidemia and insulin resistance (48). The major disadvantage is that a single viral mutation can confer drug resistance, and cross-resistance often develops across the entire class.

Efavirenz is the preferred NNRTI for children age ≥ 3 years who can swallow capsules based on clinical trial experience in children. Results of efavirenz in children are comparable to those in adults (49, 70). Nevirapine is recommended only as an alternative in this age group, mainly due to the higher rate of toxicities observed in adult clinical trials. Rare but serious skin rash (including Stevens-Johnson syndrome) and hepatotoxicity can occur with both drugs but more frequently with nevirapine (4, 79, 82).

Results of studies comparing nevirapine with efavirenz in adults are conflicting, and no head-to-head comparative studies have been done in children. A recent study in Uganda recently revealed that children on nevirapine-based regimens (D4T/3TC/NVP) were almost 2.5 times more likely to have viral failure than those on efavirenz (ZDV/3TC/EFV) (odds ratio 2.46, 95% confidence interval: 1.23 to 4.90) (41). Efavirenz is not recommended for children < 3 years as it is available only in capsule form, and the appropriate dose has yet to be determined.

The major limitations of efavirenz are the central nervous system side effects. Mostly transient, these effects include fatigue, poor sleeping patterns, vivid dreams, poor concentration, agitation, and depression. These may appear less frequently in children than in adults (22). Efavirenz is contraindicated in adolescent females who are sexually active unless adequate contraception can be assured due to the drug’s teratogenicity and potential for fetal CNS malformations.

Nevirapine is recommended for children < 3 years, or those unable to take pills as it comes in liquid formulations. In a large adult trial, while virological efficacy was comparable between nevirapine and efavirenz, serious hepatic toxicity was more frequent in the nevirapine arm than the efavirenz arm, particularly in women with CD4 cells > 250 cells/mm3 (34). This may be less of an issue in pre-pubertal children as hepatotoxicity appears to be less frequent than in adults (84); however, nevirapine should not be used in post-pubertal adolescent girls with CD4 counts > 250 cells/mm3 (92).

PI-Based Regimens

Nine PIs are currently approved for treatment of HIV infection; 7 of which are approved for use in children (treatment-naïve and treatment-experienced) and have pediatric drug formulations. Advantages of PI-based regimens include excellent virologic potency, high barrier for development of drug resistance (requiring multiple mutations) and sparing of the NNRTI drug class. However, the drugs have potential for multiple drug-drug interactions due to their metabolism via hepatic enzymes and may be associated with metabolic complications such as dyslipidemia, fat redistribution and insulin resistance (80).

Currently, the preferred PI for the treatment-naïve child is co-formulated lopinavir/ritonavir based on virologic potency in both adult and pediatric studies (57). Studies have shown that lopinavir/ritonavir has a high barrier for the development of drug resistance with an excellent toxicity profile and the availability of appropriate dosing for children. In both ARV-naïve and -experienced children, lopinavir/ritonavir has demonstrated durable virologic activity and low toxicity (57). In a study of 44 treatment-naïve children, 84% had plasma HIV RNA < 400 copies/mL and 71% < 50 copies/mL after 48 weeks of therapy (67). Dosing and efficacy data is also available in infants under age 6 months.

Alternative PIs for children > 6 years old include atazanavir with low-dose ritonavir and fosamprenavir with low-dose ritonavir. Nelfinavir can also be used in children age > 2 years old. Since March 31, 2008, all nelfinavir manufactured and released by Pfizer meets the ethyl methane sulfonate (EMS) limits, which was a problem in the prior product (92)

Three other PI-based regimens are recommended for children only in special circumstances, such as when the patient can not tolerate ritonavir. Atazanavir without ritonavir may be used in children age > 13 years and >39 kilograms. Higher doses may be required to achieve adequate concentrations, and tenofovir and didanosine should not be used in the backbone NRTI regimen. Fosamprenavir without ritonavir can be used in children age > 2 years old. Lastly, older adolescents have the option to use saquinavir with low-dose ritonavir.

Several new PI’s, including darunavir and tipranavir, have been approved in the last few years with the target population being highly-experienced patients with pre-existing viral resistance to other PI’s. In December 2008, the U.S. Food and Drug Administration approved the use of darunavir with low-dose ritonavir in children age > 6 years old (19). Until there is more data to evaluate its safety and efficacy, darunavir is not currently recommended for initial therapy. Likewise, tipranavir should only be used in treatment-experienced children.

NRTIs In Pediatrics

Currently 6 NRTIs (zidovudine, didanosine, stavudine, abacavir, lamivudine and emtricitabine) are FDA-approved for use in children less than 13 years old. All of these medications come in pediatric formulations. A combination of these drugs typically makes up the “backbone” of the pediatric ART regimen, combined with either a NNRTI or PI.

The NIH is currently recommending abacavir plus either lamivudine or emtricitabine as one of 3 preferred NRTI backbone combinations (92). When available, HLA B*5701 genetic testing should be performed for HIV-infected children prior to initiating abacavir-based therapy due to the increased risk for the rare but life-threatening hypersensitivity reaction among HLA B*5701+ patients. Abacavir-containing regimens have been shown to be equally or possible more potent than zidovudine-containing regimens (29). Recently, PENTA 13, an open-label pharmacokinetic study, demonstrated that once daily abacavir/lamivudine obtained concentration levels that were non-inferior to those achieved with twice daily (5). This simplified dosing regimen would greatly improve adherence.

Another preferred NRTI combination consists of didanosine plus emtricitabine, although didanosine is complicated by the recommendation it should be given when fasting which is difficult when feeding infants. A comparison of didanosine given with or without food in children found that systemic exposure was similar, but that the fraction absorbed was lower and slower with food (77).

The preferred combination with the most experience in children is zidovudine plus lamivudine. While there is less experience with emtricitabine, it is relatively interchangeable with lamivudine and has been shown to have the same plasma area under the concentration-time curve (AUC) in pediatrics as in adults (87). Emtricitabine’s advantages include once daily-dosing and availability as an oral solution.

Alternative dual NRTI combinations include zidovudine in combination with either abacavir or didanosine. In adolescents who are post-pubertal or Tanner stage 4, tenofovir plus either lamivudine or emtricitabine can be used. Only in special circumstances should stavudine plus either lamivudine or emtricitabine be used given the higher risk of lipoatrophy and hyperlactemia with stavudine versus other NRTI drugs (38). Stavudine plus didanosine should only be used for salvage therapy in treatment-experienced children given the greater rates of neurotoxicity, lactic acidosis, and lipodystrophy seen more frequently with this combination than with other therapies (33).

Tenofovir has now been used off-label in children as part of salvage therapy regimens. Small studies suggest that tenofovir is well-tolerated and effective (32, 63) in pediatric patients, and it is being studied in combination with other NRTIs as an investigational oral suspension and in a “sprinkle” formulation. One of the benefits would be its activity against hepatitis B. At this time, however, there is insufficient safety data to recommend it. Due to its potential bone and renal toxicity, the drug is only recommended in children when there are no other options available. Decreased bone mineral density has been seen in pre-pubescent treatment-experienced children when taking tenofovir for 48 weeks (23). Renal toxicity has been seen as well, most often with concurrent didanosine and lopinavir/ritonavir use (63). For adolescents in Tanner Stage 4 or who are post-puberty, tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI combination.

In addition, a triple NRTI regimen such as zidovudine, lamivudine, and abacavir is only recommended in special circumstances such as when a preferred or alternative NNRTI-based or PI-based regimen cannot be used as first-line therapy in treatment-naïve children. This situation may occur when the patient is on anti-tuberculosis medications due to the drug-drug interactions (e.g. nevirapine or lopinavir/ritonavir with rifampin). One advantage of this regimen is its simplicity and lower pill burden particularly when using the single pill combination. Data on the efficacy of triple NRTI regimens for treatment-naïve children is limited. In adult trials, these regimens have shown less potent virological efficacy when compared to NNRTI- or PI-based regimens (31, 60), although a recent trial from Uganda suggested this regimen is still a valid option (75).

New Classes of Drugs

Enfuvirtide, or T-20, is the only entry inhibitor approved for use in both adults and children currently. It works by blocking the fusion of the virus to the target cell. Dosage recommendations exist for children aged 6 years or older. A recent multicenter, open-label, non-randomized study showed the safety and efficacy in the pediatric population (90). Of importance in this study was that efficacy in adolescents (>11 years old) was inferior, most likely due to adherence. Toxicities are primarily local site reactions.

Maraviroc, another entry inhibitor that works by blocking the CCR5 receptor, was approved for use in adults in 2007. However, its safety and efficacy has not yet been established in pediatric patients (50).

Also in 2007, the integrase inhibitor raltegravir was approved for use in adults (62). Interim findings from the ongoing IMPAACT study (ACTG P1066), a prospective, non-randomized, open label study for treatment-experienced children and adolescents, were presented at the 2009 Conference on Retroviruses and Opportunistic Infections in Montreal, Canada. After 12 weeks, 88% had less than 400 copies/mL. Raltegravir was found to be well tolerated. Researchers are currently developing a chewable formulation (91).

In 2008, etravirine, considered to be a second-generation NNRTI, was approved by the FDA in treatment-experienced adults. Again, its safety and efficacy in children < 16 years has not been established (81).

Drug Resistance

HIV drug resistance due to mutations now poses the newest challenge. In a recent study performed in the United States, 24% of children were found to have resistance to NRTIs prior to starting ART, and 19% had resistance to NNRTIs (61). Furthermore, maternal history did not always provide a clear explanation for the drug resistance patterns encountered. Two of the 4 infants with virus containing NNRTI resistance mutations had not been exposed to nevirapine during pregnancy (61).

For antiretroviral dug resistance testing, several genotypic (GT) and phenotypic (PT) assays are available. GT assays detect specific HIV genetic mutations contributing to resistance. PT assays directly measure the ability of a viral isolate to grow in the presence of a drug. Virtual phenotyping is a method of predicting phenotype based on the genotype of a viral isolate. Using GT, PT or virtual phenotype can be helpful to the clinician when changing ART due to virologic failure. Resistance testing is now recommended prior to the initiation of therapy due to the possibility of perinatal HIV infection by a drug-resistant virus from the mother.

Adherence

Adherence to ART is particularly critical in the treatment of pediatric HIV infection. Data on ART suggests that medication adherence is a strong predictor of therapeutic impact (21). Lack of adherence to prescribed regimens can lead to sub-therapeutic levels of antiretroviral medications, which enhances the risk of the development of drug resistance and likelihood of virologic failure.

Despite the benefits of treatment and adverse consequences of disease progression, adherence is reportedly suboptimal among children, and perhaps worse among adolescents. Factors for poor adherence include pill burden, frequency of medications, and patients’ lack of awareness of their own diagnosis, social stressors, and poor support systems.

Adherence varies widely in studies, ranging from 20-100% depending on how adherence was assessed (e.g. whether via pill count or by self-reporting measures), how ‘optimal adherence’ was defined, and how findings were reported (74).

Participation by the caregivers and child in the decision-making process is crucial. Issues related to adherence to therapy should be fully assessed, discussed and addressed with the child’s caregiver and the child (when age-appropriate) before the decision to initiate therapy is made. Potential problems should be identified and resolved prior to starting therapy, even if this delays initiation of therapy.

CONCLUSION

The use of PMTCT has significantly dropped the number of children born with HIV in Western countries, but yet pediatric HIV/AIDS remains a medical challenge in the developed world – in part due to the migration of HIV-infected children from higher prevalence countries, the fact that more children are living longer with the disease, and that the numbers of sexually-acquired infection among young adolescents are increasing. In resource-limited countries, pediatric HIV infection poses more than just a medical challenge – but rather a devastating health crisis. Antiretroviral medications are becoming more widely available in these settings which will certainly save lives. With increasing exposure to antiretrovirals, however, there will be growing resistance, making antiretroviral management increasingly complex. This is coupled with the fact that adherence is already difficult in children, particularly when there are many pills which are often unpalatable. Genotype testing, currently cost-prohibitive in many parts of the world, will become more critical including at baseline in the treatment-naïve patient. As HIV management becomes more technical, many of these patients will certainly require assistance by pediatric HIV sub-specialists. This is another problem in resource-limited settings where health care workers are in dire shortage.

At the same time, there is hope. The last 2 years has been very beneficial to the world of antiretrovirals as several new classes of medications have been approved including the integrase inhibitor raltegravir, the CCR5 inhibitor maraviroc, and the new NNRTI etravirine. As of yet, none of these drugs have been officially approved for use in children. Pediatric clinical trials and pharmacokinetic research continue to lag behind adults. For many currently available antiretrovirals there still are no proper dosing recommendations nor are there solutions readily available for children who can not swallow pills. This, too, appears to be changing slowly as fixed drug combination pills, designed specifically for children and infants, become more widely used.

KEY ISSUES

* Management of HIV infection in the pediatric population is rapidly evolving and increasingly complex. Treatment of these patients typically should include assistance from a pediatric HIV specialist.

* The overall consensus is that treatment in children should be more aggressive in children than in adults, given that the risk of life-threatening complications of HIV is greatest in infants.

* Antiretroviral therapy is now recommended for all infants < 12 months, regardless of CD4 lymphocyte parameters and HIV viral load. * When feasible and/or accessible, drug resistance testing should be performed before initiation of therapy. This applies not only to those exposed perinatally to nevirapine, but in all infants.

* There is a need to expand the number of pediatric formulations of current antiretrovirals as well as develop new agents for pediatric use, including against highly-resistant variants.

* There is likewise a need for more pharmacokinetic data in the highly variable population of HIV-infected children.

* More work needs to be done on improving adherence in children and adolescents, as poor adherence leads to increased resistance and virologic failure.

TABLES

Table 1: Indications for initiation of antiretroviral therapy in children infected with HIV (12)

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