There is a remarkable gap in the nature of HIV disease among infants and children between developed countries and the rest of the world. HIV infection has increased among women globally, but in developed countries, remarkable gains have been made in the prevention of mother-to-child transmission and in the treatment of infected children. Relatively few new infections occur. In developed countries, then, much of the focus is on early diagnosis, long-term management and antiretroviral use. These gains have not been shared by most of the rest of the world, where the number of children infected through perinatal transmission has increased at devastating rates and antiretroviral treatment is rarely available. Since the beginning of the epidemic, over 4 million children have died from AIDS.(1)
The epidemiology, natural history, and treatment of HIV disease are in many ways similar among adults and children. This chapter will focus on aspects of HIV disease specific to infants and children. For manifestations with limited differences between children and adults additional information is available in other chapters of the Knowledge Base.
The epidemiology of HIV among children results from the interplay of several factors: the rising incidence of HIV among women of childbearing age, the dramatic effect of treatment on mother-to-child transmission, and the changing rate of disease progression and overall survival with advances in prophylaxis and antiviral therapy. Worldwide, women constitute approximately 47% of HIV-positive adults.(1) In the United States, women make up an increasing proportion of all AIDS cases and reported HIV infection. Between July 1999 and June 2000, women made up 24% of all reported cases of AIDS in the U.S.(2) Confidential HIV reporting is limited to 35 states, and is not performed in several states with the greatest number of women with AIDS. Nonetheless, women made up 33% of new reports of HIV infection during the same period, suggesting an even higher rate of new infections among women.
In contrast, the number of children diagnosed with AIDS in the United States has fallen dramatically since 1993.(Figure
1) Only 224 cases of AIDS in children less than 13 years old were diagnosed between July 1999 and June 2000, down from a high of 959 reported in 1993. The overwhelming proportion of cases were due to perinatal transmission; of 202 children with a reported risk factor, 195 (97%) had a mother with HIV. When reporting delays are adjusted for, it is estimated that only 155 new cases of pediatric AIDS were diagnosed in 1999. This remarkable success can be attributed to improved HIV testing among pregnant women, use of increasingly active antiretroviral therapy during pregnancy, and more effective treatment of infected children.
The highest incidence rates of AIDS in women in the United States occur in the District of Columbia, New York, Florida, Maryland, and in Puerto Rico and the Virgin Islands. The greatest rate of increase however has been in the South. The greatest number of infected children live in New York, Florida, New Jersey, Texas and California. HIV-infected women and children in the United States are disproportionately Black or Hispanic. More than 80% of children diagnosed with AIDS in the most recent reporting period were Black or Hispanic.(Figure
New infections occurring among children in the United States are likely to occur for a limited number of reasons: failure of women to seek prenatal care, failure of physicians to screen and treat, failure to suppress maternal viremia due to drug resistance or poor adherence, and immigrants from countries with high rates of HIV among women.(3) Children from medically underserved settings are therefore at increased risk. If these missed opportunities for prevention can be identified, new cases in the United States can be virtually eliminated.
Internationally, the burden of HIV and AIDS on children is staggering. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that 600,000 children were newly infected with HIV in 2000.(1) An estimated 1.4 million children are living with HIV and 4.3 million have already died since the beginning of the epidemic. Roughly 90% live in Africa, but HIV infection rates among women are increasing dramatically in China, India, areas of Southeast Asia, and in the former Soviet states.
A crucial aspect of HIV among women and children is the large number of orphans. Lee estimated that in the United States between 1980 and 1998, 51,473 women died of AIDS leaving 97, 395 orphaned children. Of these, 20,717 (22%) were HIV-infected.(4) Worldwide, an estimated 13.2 million children have been orphaned.
The early diagnosis of HIV infection in children born to HIV-infected mothers has been challenging. Passive transfer of maternal IgG antibody to the child leads to detectable antibody in uninfected children for up to 15 months. Polymerase chain reaction (PCR)-based techniques have changed the approach, and now allow diagnosis by 14 to 30 days of life in most children. Demonstration of virus by PCR of HIV DNA from peripheral blood mononuclear cell (PBMC), PCR of HIV RNA from plasma, or detection of virus by PBMC co-culture in peripheral blood from the infant (not cord blood) is presumptive evidence of infection. Positive tests must be confirmed with a separate sample as soon as possible.(5) Two positive assays drawn at two separate time points are considered diagnostic of infection.
Qualitative DNA PCR is currently the accepted standard, but several studies demonstrate that quantitative RNA PCR assays are at least as sensitive and specific.(6-10) In addition, quantitative RNA assays are more widely available, have faster turnaround, require smaller blood volumes, and provide additional clinical information. False positives can occasionally occur with either assay; low copy number may help identify false positive results if quantitative RNA PCR is used for the diagnosis of perinatal infection. Low viral loads (less than 5,000 copies/mL) are rare in infected infants and should be viewed with skepticism.
Detection of virus within a few days of birth is considered evidence of in utero infection, which occurs for 30 to 45% of infected children.(11) In a meta-analysis of data from 271 infected children, HIV DNA PCR was only moderately sensitive within 48 hours of birth (38%; 90% confidence interval [CI], 29% to 46%). There was little change in the first week of life, but by day 14, the sensitivity was 93% (90% CI 76%-97%).(12) This increase in detection reflects the ability to detect children infected in the peripartum period. Use of zidovudine monotherapy during the first 4 to 6 weeks of life does not seem to interfere with diagnosis.(13)
| Management of the HIV-Exposed Infant|
A reasonable diagnostic strategy is to perform PCR testing within 48 hours of birth, then at 14 to 30 days of life. A positive test should be repeated immediately and a quantitative measure of plasma RNA should be included. Early diagnosis allows rapid implementation of antiviral therapy for infected children, presumably during acute infection. For children who have two negative tests initially, testing should be repeated at 3 to 4 months of age. According to consensus guidelines, a child is considered uninfected if PCR is negative on 2 occasions, one at 1-2 months of age and the other after 4 months of age.(5,14) However, many experts prefer to test between 14 days of life and 1 month to allow earlier diagnosis, and there is no evidence that this reduces sensitivity. Thus, testing at 14 days to 1 month could be substituted for test at 1-2 months. Infants with repeatedly negative viral tests should be followed for evidence of loss of HIV antibody.
Zidovudine should be administered to all children born to HIV infected mothers using the ACTG 076 protocol of 2mg/kg every 6 hours beginning within a few hours of birth, and continuing for 4-6 weeks. In women for whom intrapartum nevirapine is being considered because of inadequate prenatal treatment or failure to suppress maternal viremia, it is reasonable to also include a dose for the infant within 48 hours of birth, as was done in the HIVNET 012 and SAINT studies.(15,16) This provides nevirapine concentration in the infant that remains well above the IC90 for wild type HIV for more than 7 days.(17) In the HIVNET trial, monotherapy with nevirapine resulted in evidence of nevirapine resistance in 17 (18%) of 95 mothers and 9 (45%) of 20 of the infected infants.(18) A possible strategy for decreasing the emergence of nevirapine resistance, where resources permit, may be to use nevirapine in combination with other agents. Clinical trials of alternate strategies are still needed.
There is no consensus on the management of children born to mothers with documented resistance to zidovudine. Increased rates of transmission have been documented when the mother has circulating resistant virus(19), and it is logical to use drugs that would be predicted to be active against the maternal strain.
Pneumocystis prophylaxis is recommended for all HIV-infected infants and those of unknown status beginning at 4-6 weeks of age. For children who are documented to be uninfected and have normal CD4 cell counts, prophylaxis can be stopped by 4 to 6 months of age.
| Natural History|
| Clinical Progression|
The natural history of HIV disease in children differs from adults in that there is a bimodal distribution of time to progression (measured by age at AIDS diagnosis) (Figure
3) and shorter overall survival.(20-22) Roughly 20% of untreated children are rapid progressors. These children present with symptoms early and progress to severe immunosupression (CDC category C) within the first year of life. The annual rate of progression then declines to 3-6% per year in the absence of effective treatment.(23,24) A small group, perhaps 5-10%, are long-term survivors.(25) A bimodal distribution has also been demonstrated in Africa, but overall survival is dramatically shorter.(26)
Several factors have been identified which help predict rapid progression in infants, although none is fully predictive. Several studies demonstrated that infants with in utero infection were more likely to have rapid progression.(27-32) Low CD4 percent and early onset of adenopathy and splenomegaly were associated with rapid progression in the French Pediatric Cohort(27) and in the Women and Infants Transmission Study (WITS).(32) In the WITS and in the Italian prospective cohort, maternal treatment with zidovudine was associated with rapid disease progression in infants. This observation has not been fully explained, and does not appear to result from predominantly eliminating intrapartum transmission.(33,34) Marked depletion of both CD4 and CD8 to below the 5th percentile for age, felt to represent thymic destruction, has also been associated with rapid progression both among those infected in utero and intrapartum.(30)
| Viral Load|
HIV viral load is a predictor of prognosis in children as in adults, but the natural history of viral load differs. In infants infected in utero, viral copy number is relatively low at birth but rises to very high levels by 1 to 2 months of age. In one prospective study, the median peak was 318,000 copies.(35) In contrast to adults, copy number declines slowly over the next several years.(35-37) Higher copy number measured after several weeks of age is a predictor of decreased survival and more rapid progression.(29,35-37) In one study of children followed from birth, infants with more than 100,000 copies had significantly higher mortality rates; this was most dramatic if the CD4 percentage was also less than 15%.(36) Another important analysis, based on children participating in PACTG trial 152, confirmed that viral load and CD4 percent are both independent predictors of progression or death at all ages.(37) In a pooled analysis of 4 separate trials, increases in CD4 cells and decreases in viral load 24 weeks after starting antiviral therapy were shown to be independent predictors of improved outcome in children.(38)
Despite these aggregate results, the predictive value of viral load for risk of progression and death is modest for an individual child, especially during the first year of life. Consequently, there is no reliable method of identifying infants who are likely to remain long-term nonprogressors without therapy.
| Immune Function|
Total CD4 counts in normal infants are considerably higher than in adults, and gradually decline to adult levels by about 6 years of age.(39) In contrast, the percent of lymphocytes that are CD4-positive among normal children is not age related. Thus, the levels of CD4 count that identify stages of immune suppression vary with age; the levels of CD4 percent do not.(Table
1) Children generally have greater thymic function and a greater proportion of circulating CD4 and CD8 cells of the naive phenotype. As with adults, HIV disease in children leads to progressive decline in CD4 cell number and percent. In addition, infected children have loss of thymic volume and activity(40,41), T cell receptor diversity, and skin test reactivity.(42) Elevated IgG levels are common but occasionally children will develop hypogammaglobulinemia. However, there is often a functional defect in B cell function.
CD4 count and percent are strong predictors of disease progression and mortality, but the use of CD4 levels along with viral RNA together provides more information.(36,37) In the first 6 months, the presence of markedly low CD4 count (<1900 cells/microliter) along with low CD8 count (<900 cells/microliter) predicts rapid progression.(30)
| Clinical Manifestations|
The clinical manifestations of HIV disease in children differ in important ways from those seen in adults. Children have less effective immune control of HIV leading to higher plasma viral loads and perhaps higher tissue loads. Developing organ systems may be more susceptible to direct, virally mediated damage. Specific organ manifestations including encephalopathy and cardiomyopathy are more common among children.
The developing immune system has less effective innate and specific immune responses to common viral and bacterial pathogens. Recurrent bacterial infections are prominent, particularly with encapsulated organisms including Streptococcus pneumoniae, Haemophilus influenzae, and non-typhoid serotypes of Salmonella. Two or more bacteriologically documented systemic infections (bacteremia, meningitis, osteomyelitis, septic arthritis, pneumonia, or abscess of organ or body cavity) constitute an AIDS-defining condition for children. Recurrent bacterial infection is the second most common AIDS-defining condition reported to the CDC.
Many important AIDS-defining illnesses among adults are most often the result of reactivation of past infection rather than primary infection, including CMV disease, CNS toxoplasmosis, histoplasmosis, and tuberculosis. CMV disease is an important illness in children but toxoplasmosis, histoplasmosis and tuberculosis are uncommon compared to adults.
Ideally, prenatal HIV testing will identify most infants born to infected mothers. Use of antiretrovirals during pregnancy and delivery will prevent transmission in up to 99%.(43) Conversely, the birth of children with unrecognized HIV infection results from failure to screen pregnant women or to provide adequate prenatal care. The most common presenting signs of HIV infection in infants, recognized since the early 1980's, include failure to thrive, hepatosplenomegaly, and diffuse adenopathy. These findings in any child should prompt consideration of HIV infection. Children with HIV may also present with frequent or chronic diarrhea, frequent minor bacterial infections such as otitis media and sinusitis, and refractory thrush. Extensive warts or molluscum contagiosum, or severe refractory non-infectious skin manifestations such as atopic dermatitis should raise the suspicion of HIV infection.
| Clinical Classification|
The 1994 revised clinical classification of Pediatric HIV infection is shown in Table
2. In this scheme children are classified as asymptomatic (Category N), mildly symptomatic with HIV-related symptoms (Category A), moderately symptomatic (Category B) with significant HIV-related symptoms but no Category C symptoms, and Category C which includes AIDS-defining illnesses as outlined in the 1987 case definition.(44) Wasting syndrome is defined as wasting in the absence of a concurrent illness other than HIV infection that could explain:
Encephalopathy is also strictly defined based on findings that must be present for at least 2 months in the absence of concurrent illness that could explain them. The scheme is hierarchical; once a child progresses to a given clinical class, reclassification to a less advanced class does not occur, even if clinical improvement has taken place.
persistent weight loss >10% of baseline
downward crossing of at least two of the following percentile lines on the weight-for-age chart (95th, 75th, 50th, 25th, 5th) in a child >=1 year of age
<5th percentile on weight-for-height chart on two consecutive measurements >30 days apart
chronic diarrhea (i.e., at least two loose stools per day for >30 days)
documented fever (for >30 days, intermittent or constant).
In addition to providing a useful standard for evaluating children, the revised classification system has been shown to be useful for establishing prognosis and modeling the course of disease(45), although further modifications have been proposed.(46)
Most children will present for medical care with category A symptoms, but due to the non-specific nature of these symptoms, HIV may not be suspected or diagnosed. Many women with HIV infection do not have easily identified risk factors, so a high index of suspicion is needed. Hepatomegaly and lymphadenopathy are the most common category A findings.(45) Parotitis is less common but more striking. The histologic findings demonstrate a dense infiltrate of CD8 cells within the gland. Cystic degeneration may be seen, and lymphoma within the parotid may develop in rare cases. The triad of lymphadenopathy, splenomegaly, and failure to thrive is strongly suggestive of HIV infection, and testing should be performed.
Category B symptoms indicate more severe disease. Based on Markov modeling, children spend the longest time in Category B, a mean of 65 months compared to 10 months in Category A and 35 months in Category C.(45)
| Bacterial Infections|
The incidence of invasive bacterial disease, including meningitis, bacteremia, or pneumonia is higher than among adults. Other bacterial infections, including sinusitis, otitis media, deep tissue abscesses, osteomyelitis, and septic arthritis are also more prominent.
| Cardiac Involvement|
Cardiac disease, including cardiomyopathy, congestive heart failure, and conduction defects is increasingly recognized.(47-49) Sub clinical myocardial dysfunction is extremely common when routine echocardiography is done.(50) However, in a prospectively studied cohort, the cumulative incidence of overt congestive heart failure was 12% at 2 years.(51) The etiology is poorly understood, but HIV RNA has been isolated from myocardial cells.(52,53) Left ventricular dysfunction is correlated with the presence of encephalopathy(50) and is an independent predictor of mortality.(54)
| Gastrointestinal Involvement|
Gastrointestinal complications of HIV are common in children. Thrush persisting more than 2 months is considered a category B symptom, but other oral manifestations are common.(55-58) These include candidiasis, linear gingival erythema, herpes stomatitis, necrotizing gingivitis, salivary gland enlargement and aphthous ulcers. Aphthous ulcers are more common in children who are HIV-infected and can involve the esophagus, stomach, rectum, or vulva. Both acute and persistent diarrhea are major causes of morbidity in developed countries.(59) In developing countries, diarrhea is a major cause of death; in Kinshasa, HIV-infected children had an 11-fold increase in risk of death from diarrhea compared to uninfected infants of HIV-infected mothers.(60) The spectrum of diarrheal pathogens is incompletely studied. In general, the pathogens are those common in uninfected children in the region, including Salmonella, Shigella, Campylobacter, rotavirus, and enterotoxigenic, enteroaggregative and locally adherent phenotypes of diarrhea-causing Escherichia coli. However, disease is more frequent, more severe, and more likely to be persistent.(59-62) Cryptosporidiosis and microsporidiosis are late complications.
| Pulmonary Involvement|
The most important pulmonary complications of HIV in children include bacterial pneumonia, Pneumocystis carinii pneumonia, and lymphoid interstitial pneumonitis (LIP). The classic reticulonodular findings of LIP may be noted on chest x-ray when the child is asymptomatic and has normal oxygen saturation. As the disease worsens, hypoxia and clubbing may develop. Severe LIP responds to steroids, but the presence of LIP is actually associated with improved survival compared to other manifestations of AIDS.(21)
| Renal Involvement|
Renal involvement occurs in 2 to 10% of HIV-infected children in the United States. HIV nephropathy can range from mild proteinuria to nephrosis, renal tubular acidosis, hematuria and acute renal failure.(63-66) In adults in the United States, there is a markedly increased risk of nephropathy among black persons with HIV infection; this appears to be true in children as well but the data are sparse.
| Central Nervous System Involvement|
Central nervous system involvement is a common and serious complication of HIV infection in children. Encephalopathy that meets the CDC definition represents the more severe end of the clinical spectrum. Among 1811 children followed in the Pediatric Spectrum of Disease Project, 23% were diagnosed with encephalopathy.(67) In the WITS study of 124 children with a median of 24 weeks of follow-up, 21% of children developed encephalopathy.(68) Milder neurologic dysfunction and developmental difficulties are even more common. A comparison of encephalopathy in adults and children in 2 prospective cohorts found striking differences between children and adults in early onset encephalopathy, but fewer differences later in disease.(69) The incidence of encephalopathy was 9.9% in children compared to 0.3% in adults in the first year, 4.2% compared to 0% in year 2, but about 1% per year thereafter in children as well as adults. Early onset encephalopathy was more severe, was associated with less immunosuppression, and resulted in more dramatic brain atrophy and prominent motor findings in children than in adults. It is hypothesized that the encephalopathy shared by older children and adults occurs by a different process than the devastating early onset encephalopathy of infants. A formal developmental or neurologic assessment should be performed periodically in all infected children.
AIDS-associated malignancies in children differ from those in adults. Non-Hodgkin's lymphoma is the most common malignancy, and GI tract involvement is common.(70) The second most commonly reported malignancy is leiomyosarcoma, a disease that is extraordinarily rare in adults.(71) Kaposi's sarcoma, common among HIV-infected gay men, is very rare in children in developed countries.
| Antiretroviral Therapy|
Antiretroviral therapy is associated with improved clinical well-being in children. Monotherapy with zidovudine, didanosine, or stavudine demonstrated improved immunologic parameters, neurodevelopmental status, and growth.(72-74) Combination therapy with zidovudine and didanosine, zidovudine and lamivudine, or didanosine and stavudine was subsequently shown to be superior to monotherapy.(75-77) The use of protease inhibitor-containing triple combinations, either in treatment-experienced or treatment-naive children confers significantly greater immunologic and virologic benefit than two-drug therapy.(78-80)
Triple combination therapy is associated with a significant survival benefit in children, as in adults, as demonstrated in prospective cohort studies through the PACTG(81) and in Europe.(82) The Italian HIV National AIDS registry study estimated that there was an almost 70% reduction in the relative hazard of death associated with triple therapy compared to no antiviral therapy.
| Immune Reconstitution in Children|
The pattern of immune reconstitution in children differs from that of adults.(83,84) It is likely that this is related to greater thymic activity in children.(40,85) Compared to adults, children have an earlier and larger increase in naive CD4 cells, and larger overall increases in CD4 count. In small studies, children have shown improvement in response to recall antigens and broadening of the T cell receptor repertoire.(42)
| When to Start|
To develop consensus guidelines for antiviral therapy, a working group was convened by the National Pediatric and Family HIV Resource Center (NPHRC), the Health Resources and Services Administration (HRSA), and the National Institutes of Health (NIH).(5) The guidelines recommend that, under ideal circumstances, treatment should be started in any infant diagnosed in the first year of life, regardless of clinical or immunologic status. Therapy should, however, be initiated only after all issues related to adherence have been addressed. This recommendation is based on the notion that with early diagnosis, infants can be treated during or close to primary infection. There are, however, no large or controlled trials to guide the timing or demonstrate the benefits of early initiation. Theoretical advantages of early treatment include preservation of HIV- specific CD4 help(86), prevention of dissemination to tissue compartments, and prevention of HIV-mediated damage of the developing nervous system. Moreover, immunologic control of viremia is inadequate in infants, demonstrated by high viral loads and limited HIV-specific CTL response. In limited numbers of patients, early control of viremia can result in prolonged suppression of viremia, accompanied by normalization of immune function, loss of HIV antibody expression, and waning of HIV-specific CTL responses.(87,88) While delaying therapy might be appropriate in infants who will be not be rapid progressors, it is not possible, using known risk factors, to adequately identify such infants.
Early initiation of therapy is associated with several potential problems. Adherence to complex regimens with unpleasant formulations is difficult; yet adherence is the key determinant of success.(89,90) The pharmacokinetics of antiretroviral drugs in neonates is incompletely studied, but available data demonstrate wide intra-patient variability and changes with age. Inadequate adherence and inadequate dosing contribute to the development of resistance. Cross-resistance and the limited number of agents with liquid formulations make it possible to exhaust options quickly. It is becoming clear that metabolic complications of combination antiretroviral therapy affect a significant proportion of children. Fat accumulation, fat atrophy, glucose intolerance, dyslipidemia and lactic acidosis have all been described in children, although the prevalence, risk factors and reversibility are poorly understood.(91-93) For each infant, the clinician must weigh the potential benefits of early therapy in light of the caregiver's ability to follow a regimen, the presence of markers of rapid progression, the timing of diagnosis, and the evolving state of knowledge. It is important to involve the caregivers or parents in the decision. When initiating therapy in infants, monitoring protease inhibitor concentrations should be strongly considered if available.
For children older than one year, the decision on when to start therapy is more complex. The Working Group outlined two strategies.(5) The first is to initiate antiretroviral therapy in all children regardless of immunologic status or symptoms. This seems unrealistic for most patients and their caregivers with currently available therapy. The other strategy is to defer therapy in children with normal immune status who are at low risk of disease progression. Therapy should be considered when there is evidence of high or climbing viral load, immunologic deterioration (i.e. immune category 2 or rapid decline in CD4 percent), or the development of clinical symptoms. A viral load of greater than 100,000 RNA copies/mL is associated with an increased risk of death and more rapid CD4 decline. Since viral load is closely related to the rate of immunologic decline, evidence of immunodeficiency or moderate symptoms may be the most reasonable criteria for starting treatment.
These guidelines are based on limited data. They are also limited in their ability to convey the importance of individualizing the decision based on the clinical and social situation. It is difficult to accurately predict the ability of a child and the caregivers to adhere to therapy. In adults, the balance is shifting towards later initiation of therapy, based on the substantial immune reconstitution that occurs even in individuals with CD4 counts of 200 to 350 cells, and the concerns about long-term adherence and complications. In children, the capacity for immune reconstitution is more robust than adults, with greater restoration of naive T cells. This might argue for delayed initiation of therapy. However, other consequences of untreated infection in children must also be considered, including growth failure and encephalopathy, which may not be reversible. Whenever possible, children should be offered the opportunity to participate in studies of antiviral therapy, and treatment should be planned by physicians with expertise in HIV in children.
| What to Start|
The goal of the initial antiretroviral regimen should be suppression of the viral load to below the limits of quantification. This goal is easier to achieve during the initial regimen than in later regimens. Combination regimens with 3 drugs are preferred.(Table
3) Once initiated, antiretroviral therapy will likely be life long. Therefore, the choice of initial regimens should consider not only efficacy but also maintaining future options. The greatest body of data in children is from studies using two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and a protease inhibitor. Nelfinavir (Viracept) and ritonavir (Norvir) are available in pediatric formulations and are preferred for children too young to swallow pills. Nelfinavir is available as a powder, but crushed tablets are generally better tolerated and have higher bioavailablity. In children who can swallow capsules, indinavir (Crixivan) or saquinavir soft-gel capsules (Fortovase) may be used. The guidelines cautiously suggest the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva) as an alternative to protease inhibitors for children who can swallow pills, based on studies in adults that show efavirenz plus 2 NRTIs to be at least as effective as protease inhibitor-based regimens. However, no trials in children have evaluated this regimen.
Based on small studies of the NNRTI nevirapine (Viramune) plus 2 NRTIs in infants, the overall response rate appears to be less than for protease inhibitor-based regimens.(94) Response rates in infants tend to be lower than in older children due to very high viral loads and different pharmacokinetics. There are data from adult studies that suggest that nevirapine with zidovudine and lamivudine (3TC) is at least equivalent to a nelfinavir-based regimen(95), and clinical experience in older children suggests it is a reasonable alternative as first-line therapy. Amprenavir (Agenerase) is a potent protease inhibitor that is available in liquid formulation. However, the liquid formulation contains propylene glycol and large amounts of vitamin E. At the recommended dose, children will receive 138 IU/kg/day of vitamin E. Because the safety in infants is unknown, amprenavir is not recommended as first-line therapy in children less than 3 years of age. However, it may be considered as a component of salvage therapy.
A trial of a 4-drug regimen of efavirenz, nelfinavir, and 2 NRTIs in nucleoside analog-experienced children demonstrated that 76% of children maintained viral loads below the limit of quantification at 48 weeks.(96) Although cross-trial comparisons are hazardous, similar trials of nelfinavir or ritonavir achieved rates of suppression of 30% to 42%.(78,97) Preliminary results of a trial using lopinavir/ritonavir (Kaletra) with stavudine and lamivudine demonstrated viral suppression in 71% of treatment naive, and 69% of nucleoside-experienced, children.(98) This suggests that more potent regimens may be needed in young children compared to adults. In adults, pharmacokinetic enhancement of protease inhibitors with low dose ritonavir is frequently used to improve the levels and decrease inter-patient variability and food effect. In addition to lopinavir/ritonavir, preliminary data in children exist for ritonavir plus indinavir(99) and ritonavir plus saquinavir.(100) Until better pharmacokinetic and safety data are available, these combinations are probably best reserved for salvage therapy and children at high risk of treatment failure, possibly including those with very high viral loads.
The optimal dosages of antiviral drugs for children differ by age, route of elimination, and body composition. Doses per body weight are generally higher than those used in adults. Children who are not yet pubertal (Tanner stage 1-2) should be dosed according to pediatric guidelines; those in later adolescence (Tanner 4-5) should be dosed as adults.
Additional studies continue to optimize dosing, and some recommended doses differ from those in the FDA-approved package insert. Up-to-date information is available in the Working Group recommendations(5), accessible at AIDSinfo Pediatric Guidelines and Adult and Adolescent Guidelines.
Children should be followed frequently after beginning antiretroviral therapy. A visit 2 to 4 weeks after initiating therapy can be used to assess adherence, side effects, and tolerability. Liver enzymes and a complete blood count should be obtained to check for toxicity. Viral load should fall by at least 1 log10 (10 fold) in the first 7 to 10 days of therapy in an active initial regimen. Failure to achieve this may indicate problems with adherence, resistance, or drug levels. Initially, monthly visits allow for close monitoring for side effects and adherence. At a minimum, blood work should be monitored every three months.
Complications of antiretroviral therapy in children include myopathy, pancreatitis, dyslipidemia, insulin resistance, glucose intolerance, changes in body shape, and lactic acidosis.(91-93,101) Routine clinical monitoring should include liver enzymes, glucose, electrolytes and anion gap, total cholesterol, and triglycerides. The clinical utility of routine monitoring of serum lactate has not been demonstrated.
Measurement of drug levels, or therapeutic drug monitoring (TDM), has not yet been adopted as an official recommendation. Few commercial assays are validated, target drug levels are poorly defined, and the optimal timing of levels is unknown. However, TDM is widely used in Europe, and the arguments for TDM in children are compelling. Drug absorption and metabolism varies with age in early childhood and during adolescence. Intra-patient variability is striking for many protease inhibitors(102-104), and protease inhibitor levels are strongly associated with virologic outcome.(105)
Although the ideal virologic goal of therapy is suppression of viremia below the level of quantification, the majority of children may not achieve this goal, particularly with a second-or third- line regimen. It is therefore prudent to optimize the initial regimen. Four-drug regimens and therapeutic drug monitoring may help improve response. The long-term goals are not exclusively viral suppression but include maximizing immune function and overall health, minimizing side effects, improving survival and quality of life, and maintaining options for long-term therapy. While complete suppression of viremia may be difficult to maintain in treatment-experienced children, adults and children on combination therapy may continue to show immunologic and clinical benefit for prolonged periods despite viral rebound.(106,107)
The Working Group has published guidelines on when to change therapy.(5) These define three types of criteria: clinical, virologic, and immunologic. Progression of symptoms to a new CDC category or significant decline in immunologic function are fairly straightforward indications of inadequate treatment effect. Virologic criteria are more problematic. Failure to achieve a reasonable virologic response (at least 1 log reduction) after 8-12 weeks of treatment predicts a poor response. In patients who have had a prolonged response to an initial regimen, it may be reasonable to consider changing therapy if there is consistent rebound to detectable levels, or a greater than 1 log increase over the nadir. However, in children who have been exposed to multiple drugs or those with erratic compliance, it may be reasonable to continue current therapy provided the viral load remains at least 1 log below pretreatment levels and the CD4 percent is stable or increasing. The decision to continue or change therapy will be influenced by the likelihood of putting together a successful regimen, the ability to maintain adherence, and side effects. When regimens are changed, at least two, and ideally three or four, drugs that are predicted to be active should be included in the new regimen. To achieve this in highly treatment-experienced children, participation in clinical trials of investigational drugs may be necessary.
Before a new regimen is initiated, every effort must be made to assess and improve adherence. If available, determination of serum drug levels may be useful. Resistance testing should be used to guide selection of new therapy for treatment-experienced children. Because principles of salvage therapy are evolving and data on children are limited, data from adults should be followed to help inform salvage therapy in children.
Adherence is a key determinant in the success of antiretroviral therapy in children, as it is in adults.(89,90) There are additional problems with adherence in children. Oral formulations of antiretroviral agents may be gritty (nelfinavir), or remarkably foul tasting (ritonavir). Adherence depends both on the child's willingness to take the medicine and the caregiver's ability to provide the medicine on time. The caregiver's ability to provide for the child may be affected by lack of consistent housing or transportation, HIV disease, substance abuse, or mental illness. Fear of disclosure can be an obstacle to taking medication at school, day care, relatives' homes, or on sleep-overs with peers. In developed countries where many children under treatment are long-term survivors; treatment fatigue is an increasing problem.
Adolescence poses unique problems. It is a time of identity-seeking, establishment of independence, and of rebellion against authority. Chaotic life style, irregular meals, and desire for conformity can interfere with taking medication on a structured schedule. During this period, heightened concerns about privacy and about disclosure of HIV status often emerge. All of these factors contribute to poor adherence with medical therapy. In the REACH study, a prospective cohort study of HIV-infected adolescents, only 41% of youth reported full adherence.(108)
Most adolescents who have acquired infection through sexual contact or injection drug use are relatively recently infected. Immune reconstitution can be particularly brisk among adolescents.(109) Thus, among those with relatively well-preserved immune function, it may be wise to consider delaying treatment until adherence can be assured. A possible exception may be those diagnosed during acute primary infection, for whom the benefits of immediate therapy may be substantial.(86) However, adolescents entering care are often those with advanced illness. In the REACH cohort, 27% of the young women and 35% of the males had AIDS at entry.(110) Long-term survivors of perinatal infection are a heterogeneous group. Some may have significant immune compromise and have substantial treatment experience; effective treatment options are limited for these patients.
Supporting adherence requires a multifaceted approach. A team effort, involving physicians, nurses, pharmacists, and perhaps peer support is helpful. Interventions should focus on both child and caregivers and must address social problems that adversely affect adherence.. Devices that have been used with some success include pillboxes, watches with multifunction alarms, and pictorial medication reminders. Gastrostomy tubes have proven extremely useful for some children, and are surprising well accepted by children and caregivers.(111) They are particularly appropriate for complex salvage regimens.
| Prophylaxis of Opportunistic Infections|
The principles of prevention of opportunistic infections are similar between children and adults (Table
4).(112) However, the majority of pediatric cases of Pneumocystis carinii pneumonia occur during the first year of life and may occur before HIV infection is documented or CD4 decline has been observed.(113) Prophylaxis against Pneumocystis carinii pneumonia, therefore, is routinely initiated in infected children and those whose HIV status is indeterminate at one month. Since HIV infection cannot be excluded in exposed infants until 3 to 4 months of age, prophylaxis is routinely given from the time perinatal zidovudine is stopped until results of the second viral study obtained after 2-4 weeks of age are known. With the low probability of infection in an infant whose mother had an undetectable viral load at delivery and was receiving combination antiretroviral therapy, the risk-benefit ratio of Pneumocystis prophylaxis may be changing. Prophylaxis for tuberculosis, M. avium complex, and vaccine-preventable diseases (including varicella) is also strongly recommended. Routine use of fungal disease prophylaxis, CMV prophylaxis, and intravenous immunoglobulin is not routinely recommended. In developing countries, trimethoprim-sulfamethoxazole has an important role in preventing pneumonia, diarrhea, and bacteremia in addition to Pneumocystis carinii.
There are no rigorous data on stopping prophylaxis in children following immune reconstitution. However, a reasonable practice is to extrapolate from adult data and recommendations. Therefore, prophylaxis can probably be stopped in children who are responding to antiretroviral therapy who have sustained CD4 counts and percents above the threshold for initiating prophylaxis for 6 or more months.
Routine vaccination is more commonly provided in children than in adults. There are a few recommendations regarding HIV-infected children that differ from those for HIV-negative children.(Table
5) Encapsulated bacteria cause considerable morbidity for HIV-infected children, so Haemophilus influenzae and pneumococcal conjugate vaccines are important. Pneumococcal conjugate vaccine is recommended for children 2 to 5 years of age who have not already received it, followed by 23-valent pneumococcal polysaccharide vaccine. This prime-boost strategy induces higher antibody titers than 23-valent vaccine alone, which may be poorly immunogenic in HIV-infected children. Varicella vaccine is a live virus vaccine but it can be considered for HIV-infected children without immunosuppression. Measles, mumps and rubella vaccine can be safely given to HIV-infected children who do not have severe immunosuppression (category 3 disease).
| Other Management Issues|
The care of children with HIV is a complex undertaking. Ideally, a comprehensive care team should be available, including physician, nurse, pharmacist, social worker, and mental health professional. If the child lives with the natural mother, then her HIV care must be considered as well. Case management allows coordination of services, integration of multiple points of view and integration of clinical and community services.(114)
HIV infection entails special psychosocial problems for children.(115) The diagnosis carries with it the fear of rejection and the inability to feel "normal." Repeated medical visits, procedures, and complicated medical regimens are stressful and can make the child feel different and isolated. The appropriate time to discuss a child's HIV status varies with the child and the circumstances. Children's ability to assimilate complex information develops over time. Disclosure also implies disclosure of the parent's HIV status, which can be a difficult topic. While caregivers struggle with what to tell children and when, the truth is often less threatening than the unknown. School-age children should generally be aware of their diagnosis, although many children have not been told their diagnosis.(116) The multidisciplinary team should be involved in the discussion and should be available for support.
| Growth and Nutrition|
Growth failure is a prominent feature of untreated HIV infection.(117,118) Stunting, or low height for age, is more prominent than wasting. Growth velocity clearly increases with effective antiretroviral therapy but often does not return to normal.(119,120) Nutritional assessment is important in all infected children to maximize growth. It is particularly important in children with advanced disease who may suffer poor appetite, nausea, gastroparesis, increased metabolic demands, diarrhea, or malabsorption. Comprehensive nutritional assessment is useful for all HIV-infected children. Growth hormone has been used to treat persistent growth failure in some children.(121)
| Pain Management and End of Life Care|
Despite advances in antiretroviral therapy and prophylaxis of opportunistic infections, the majority of children living with HIV in developed countries will experience progression of disease. Most began therapy in earlier eras and have failed multiple regimens. As disease advances, the focus of care shifts from preventing disease progression to alleviating symptoms and controlling pain. This is a difficult transition for the care providers and the medical staff. It is particularly difficult when caring for children.
Pain assessment is an important part of caring for children with advanced disease.(115) It is likely that chronic pain is often under-treated. The art of pain management in terminally ill children was recently reviewed.(122) Concerns about "giving up on" the child, addiction, or diversion of drugs by family members should not interfere with adequate treatment of pain using long-acting and potent agents.
To prepare adequately for death, caregivers need to be honestly told about the medical situation, even though it may be difficult for the providers to accept that treatment has failed. Depending on age and maturity, the child should also be involved in these discussions. However, acknowledging that there is nothing more to do to treat HIV should not be viewed as giving up. Caregivers should decide if they would like the child to die at home or in the hospital. The end of life is a time when the medical providers are most needed. Hospice services, if available, are invaluable.
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|| ||Brundage RC, Kline MW, Lindsey J, et al. Pharmacokinetics of saquinavir (SQV) with nelfinavir (NFV) or ritonavir (RTV) in HIV-infected children. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL; February 4-8, 2001. (Abstract 728).|
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|| ||Fletcher CV, Fenton T, Powell C, et al. Pharmacologic Characteristics of Efavirenz (EFV) and Nelfinavir (NFV) Associated with Virologic Response in HIV-Infected Children. 8th Conference on Retroviruses and Opportunistic infection. Chicago, Il; 2001.|
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|| ||Moye J, Cervia J, Lindsey JC, et al. Impact of Protease Inhibitor (PI)-Containing Combination Antiretroviral Therapies on Height and Weight Growth in HIV-Infected Children. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL; February 4-8, 2001. (Abstract 515 ).|