Chapter 53. Care of the HIV-Infected Child

In June 1981, the first cases in the United States of what was later called acquired immunodeficiency syndrome (AIDS) were reported.1 In the decades since, the human immunodeficiency virus (HIV) epidemic in the United States has resulted in more than 900,000 individuals diagnosed with AIDS, as reported to the Centers for Disease Control by the end of 2004.2 In general population, the number of new AIDS cases reported annually increased rapidly in the 1980s and peaked in 1992 with an estimated 78,000 cases diagnosed. In 1998, the epidemic stabilized and since then approximately 40,000 AIDS cases have been diagnosed annually.

Among children younger than 13 years, the proportion of all AIDS cases decreased from 1.4% (7668 cases) in 1981–1995 to 0.2% (341 cases) in 2001–2004.3 The number of children reported with newly diagnosed AIDS dropped to 48 in 2004, primarily because of the identification of HIV-infected pregnant women and the effectiveness of antiretroviral prophylaxis in reducing mother-to-child transmission of HIV.2,4 The successes achieved in controlling perinatal infection have not been mirrored in other at-risk pediatric groups. The 2005 Youth Risk Behavior Survey reported that 47% of high school students engaged in sexual intercourse at least once and 37% of sexually active students had not used a condom during their most recent act of sexual intercourse.5 More than half of all HIV-infected adolescents are estimated to be unaware of their infection.6 In a survey of 18–24-year-old men who have sex with men (MSM), 14% were found to be HIV-infected and 79% of these HIV-infected MSM were unaware of their infection.7 This is an area where the pediatric practitioner can make a difference—among adolescents who were tested for HIV, 58% cited their provider's recommendation as their reason for testing.8

These national achievements are, however, overshadowed by the global picture of the AIDS epidemic. Despite increased access to effective treatment and prevention programs, both the number of people living with HIV and the number of deaths due to AIDS continue to grow. In each day of 2006, new HIV infections occurred in 1450 children and 10,400 adults while 1000 children and 7000 adults died as a result of AIDS.9 The social fabric of nations is being altered by HIV, a virus that has resulted in 12 million AIDS orphans in Africa alone.

This chapter will focus on the care of the HIV-infected child in the United States. See Chapter 52 for an approach to the HIV-exposed child, Chapter 54 for a more detailed discussion of infections in HIV-infected children, and Chapter 55 for a discussion on postexposure prophylaxis.

The diagnosis of HIV infection depends on the laboratory detection of human immunodeficiency virus, or antibody directed against the virus, in a body fluid. This is performed either directly by virologic testing or indirectly by demonstrating the antibody to the virus. The diagnosis of AIDS combines clinical skills with laboratory diagnostics and is based on the detection of one or more AIDS-defining diagnoses in an individual who is HIV-infected (Table 53–1).

In 2006, it is estimated that there were 11,000 children younger than 15 years in North America who were living with HIV. In the same time period, there were less than 100 AIDS-related pediatric deaths. Despite these encouraging figures, prevention of mother-to-child transmission (PMTC) is an area that requires additional attention—estimates suggest that 100–200 North American children were infected with HIV in 2006 alone. The pediatrician has an important role to play when screening all newborns for HIV—initially by history and then by targeted testing of those whose mothers have not been tested for HIV during pregnancy or by retesting in those whose mothers have engaged in high-risk activity since their initial HIV test which usually occurs early in pregnancy. HIV-infected infants are still slipping through the net in the United States—the reasons for this include not offering the mother HIV testing, maternal refusal of HIV testing, or lack of maternal prenatal care. In addition, a single negative HIV test in early pregnancy will miss those women who seroconvert later in that pregnancy. The latter situation has resulted in the CDC guidelines recommending repeat HIV testing in the 36th week of gestation in all pregnant women where the population HIV seroprevalence is >1/1000.10

HIV is an RNA virus of the retrovirus family. HIV replicates via DNA intermediaries using the viral enzyme reverse transcriptase, a replication pathway that differs from the usual flow of genetic material in which cells use DNA to form RNA intermediaries. The retrovirus family is classified into seven different groups or genera. HIV is one of the primate lentiviruses, a group which includes HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Primate lentiviruses infect T-lymphocytes thereby having the potential to cause severe immunodeficiency. See Chapter 54 for a more detailed discussion of the pathogenesis of immunodeficiency caused by HIV.

HIV is a zoonosis that resulted from a primate-to-human cross-species transmission. Chimpanzees are the host for SIVcpz. The chimpanzee subspecies Pan troglodytes troglodytes is the origin of HIV-1. Transmission is estimated to have occurred between 1920 and 1930 in western equatorial Africa. Sooty mangabey monkeys are the host for SIVsmm. HIV-2 is closely related to SIVsmm and transmission is estimated to have occurred in the 1940s also in western Africa. The mode of cross species transmission in both types of HIV is thought to be exposure of humans to infected primate blood during hunting. Phylogenetic studies using molecular clock analyses have revealed that HIV-1 and HIV-2 have each arisen several times: in the case of HIV-1, the three groups (M, N, and O) are the result of independent cross-species transmission events.11

A hallmark of HIV is the broad genomic diversity of viruses within an individual and between infected individuals. This diversity of genetic material results from the high replication rate of the virus coupled with a high mutation rate and the occurrence of recombinations. In an infected person, about 10 billion viral particles are produced each day. The high mutation rate is the product of an “error-prone” viral reverse transcriptase, which lacks the ability to proofread DNA. Recombination may occur when a cell is coinfected by two different but related viruses; when these parent virions replicate, one RNA strand from each provirus can be encapsulated into a single new virion. The reverse transcriptase of this new “heterozygous” virion may move back and forth between the two RNA templates thus synthesizing a recombinant DNA sequence, which is a hybrid of the two parent HIV virions. The process of recombination may result in dramatic evolution of the virus and has proved to be a major obstacle to the development of a broadly effective HIV vaccine.

HIV-1 has three groups—O, M, and N. Ninety-five percent of global infections are caused by Group M subtypes A, B, C, or D or circulating recombinant forms (CRF), most commonly CRF_AE or CRF_AG. The greatest variation of HIV subtypes occurs in Cameroon in west Africa. HIV-1 subtypes differ from each other by about 10% of their nucleotide sequences coding for the enzymes reverse transcriptase and protease. The clinical significance of HIV-1 subtypes is an active area of research—group O is resistant to a class of antiretrovirals, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) and group N susceptibility has yet to be studied in detail. Subtype C has greater genetic variability than subtype B and this may result in different clinical outcomes including greater transmission potential.

HIV-2 is found predominantly in western Africa and the countries that were former Portuguese colonies such as Mozambique, Angola, and Brazil. With an increasing number of west Africans relocating to the United States, it is important that pediatricians are aware of some of the features of HIV-2. Compared to HIV-1, HIV-2 is less easily transmitted. Coinfection with HIV-1 may occur but initial infection with HIV-2 confers a significant reduction of 50–70% in the subsequent risk of acquiring HIV-1. Commercially available assays detect both HIV-1 and HIV-2 antigen but do not discriminate between the two types. However, there is no commercially available assay to detect HIV-2 plasma viral load. Clinically, HIV-2 presents with a similar spectrum of illnesses to HIV-1 but demonstrates a slower rate of progression to AIDS, a lower viral load, a lower rate of viral diversity, and a slower CD4 decline. Similar to HIV-1 group O, HIV-2 is also resistant to the NNRTI class of antiretrovirals.

The majority of cases of pediatric HIV infection in the United States are acquired perinatally or by sexual contact during adolescence. Less commonly HIV may be acquired through breastfeeding, sexual abuse, contaminated blood transfusion, or by exposure to premasticated food.12 Risk factors for perinatal acquisition of HIV include maternal, delivery, and neonatal factors. Maternal factors include acute HIV infection during pregnancy, advanced HIV disease with low CD4 count, and poor prenatal care including poor or nonadherence to antiretroviral therapy (ART). Delivery by vaginal route, rupture of membranes for more than 4 hours, use of a fetal scalp electrode, and episiotomy all increase the risk of viral transmission. Neonatal factors include prematurity (gestational age less than 36 weeks) due to immaturity of the immune system and poor compliance with postnatal zidovudine prophylaxis (see Chapter 52).

Adolescence is a time of experimentation and limit testing where unsafe sexual practices place many young men and women at risk for HIV infection. Additional risk factors include multiple sexual partners, traumatic sex, genital ulcer disease, such as syphilis, herpes simplex or chancroid, and anal sex. The most efficient transmission of HIV occurs during the phase of acute infection—a 26-fold increase relative to the rate in chronic infection. Appropriate use of highly active antiretroviral therapy (HAART) resulting in an undetectable viral load substantially reduces the risk of transmission in HIV-discordant couples although condom use is still advocated to decrease the risk even further. Male circumcision has been conclusively shown to decrease the risk of transmission from female to male and may also decrease the risk from male to female.13

The safety of the blood supply in North America relies on numerous steps including donor interview, selection, and serologic screening.14 Although all blood donations are tested for HIV-1 and HIV-2, a small residual risk of infections remains from donations collected during the “window period,” the period immediately following acute infection when a donor is highly infectious but screening tests are negative. Beginning in 1999, nucleic acid amplification (NAA) testing of blood and plasma donations was introduced in the United States. Estimates suggest that NAA testing on pooled units has decreased the preantibody seroconversion “window period” from 22 days to 13–15 days for HIV.14 The rigorous approach to optimizing the safety of the US blood supply has decreased the risk of acquiring HIV-1 or HIV-2 from a single unit of blood to an estimate of one in 2 million.

The pathogenesis of HIV is affected by the pathogenicity of the infecting virus itself as well as the immune system of the host. For example, three main variants of HIV-1 can be distinguished based on their ability to use the naturally occurring membrane receptors, CCR5 and CXCR4, during viral entry. Both of these receptors occur on T cells and are involved in immune system interactions. The three HIV-1 variants are those that selectively use CCR5 (called R5 variant), those that use CXCR4 (the X4 variant), and those that use either coreceptor (R5X4). R5 variants are most commonly responsible for transmission of HIV from one person to another and are also the predominant type of HIV during the long asymptomatic phase experienced by most adults. Genetically determined features of the host's immune system also play a role in pathogenesis. HIV infection is extremely rare, for example, in persons who are homozygous for a 32 base pair deletion within the CCR5 gene. In those who are heterozygous, HIV infection shows a more attenuated course.

Viral reservoirs represent an important aspect of HIV pathogenesis and a stumbling block to the eradication of HIV in individuals who are adherent to their HAART regimen. These reservoirs are resting CD4 cells and macrophages that can harbor proviral DNA. The long lifespan of these cells provides HIV with a long-lived latent reservoir of up to 30 years. Other hidden reservoirs or sanctuary sites for HIV include the central nervous system (CNS), the genitourinary system, and the gastrointestinal tract. Not only do these reservoirs help to prevent the eradication of HIV but they also archive drug-resistant virions for the lifetime of the patient. This explains the importance of considering all previous resistance tests when planning a change in antiretroviral regimen for a child.

HIV infection may present with an array of symptoms and signs. A history focused on risk factors for, and symptoms of, HIV is the first step toward evaluating the risk of infection. Pertinent risk factors include maternal HIV status, body fluid exposure such as intravenous drug use, sexual abuse, intercourse, and transfusion of blood products. Symptoms of HIV include a history of AIDS-defining conditions (Table 53–1), an unexplained chronic cough or any of the conditions listed in Table 53–3.

A developmental assessment should exclude features of HIV encephalopathy such as delay, regression, or stasis in developmental milestones. In the absence of antiretroviral therapy, HIV encephalopathy is progressive and three subtypes are recognized: subacute progressive, plateau, and static. The most severe symptoms are seen in children with subacute progressive encephalopathy who develop one or more of the following findings over weeks to months: loss of milestones, particularly motor or expressive language, cognitive deterioration, and apathy.15 Those with more advanced CNS diseases may present with seizures, choreoathetoid movements, and cerebellar signs.16 The plateau form of encephalopathy may present with any of these features but has a more indolent course. Typically there is no loss of existing skills; rather, the rate of acquisition of new skills is slowed. Static encephalopathy by contrast presents with nonprogressive neuromotor and cognitive impairments. These children continue to develop but at a slower rate than their uninfected peers. Intelligence quotient (IQ) testing reveals an IQ below the norm but this does not deteriorate over time.

An organ system-based approach to the physical examination facilitates an astute clinical assessment of the risk of HIV infection. Growth parameters may reveal failure to thrive (Figure 53–1) or stunting, particularly where the infection has followed a more indolent course. Acquired microcephaly in the setting of developmental delay (especially with loss of previously acquired skills) and pyramidal tract neuromuscular deficits, such as brisk deep tendon reflexes, completes the classic triad of HIV encephalopathy.15 Less severely affected children with HIV encephalopathy demonstrate brisk reflexes and hypertonicity that are confined to the legs. In severe case, all limbs are affected. Rarely, either hypotonicity or opisthotonus is the presenting sign of HIV encephalopathy. Neuroimaging of children with HIV encephalopathy classically reveals brain atrophy and bilateral calcifications of the basal ganglia and frontal white matter.17,18

The retinas need to be carefully examined for signs of opportunistic infectious retinitis such as cytomegalovirus (CMV) although evidence suggests that only children with CD4 counts less than 20/μL are at high risk for CMV retinitis.19

HIV-infected children may present with a number of signs localized to the respiratory tract. Upper respiratory clues include recurrent suppurative otitis media, recurrent or severe sinusitis, and episodes of epistaxis resulting from HIV-induced thrombocytopenia. The most common pulmonary conditions in HIV-infected children are Pneumocytis jiroveci pneumonia (PCP), lymphocytic interstitial pneumonitis (LIP), tuberculosis, and recurrent bacterial infections including bacterial pneumonia. Pulmonary infections in the HIV-infected child are discussed in Chapter 54.

LIP is an example of a condition seen in HIV-infected children that is rare in HIV-infected adults.20 In the era before effective antiretrovirals, LIP was diagnosed in 30–40% of children in the first decade of life.21 History may reveal a 2–4-year-old child with gradual progression of a nonproductive cough with decreasing exercise tolerance and the insidious onset of hypoxia. Presentation to hospital is often precipitated by an intercurrent viral infection with worsening of pulmonary symptoms. Clinical signs of LIP may include clubbing of the fingers, parotidomegaly (Figure 53–2), hepatosplenomegaly, and a diffuse reticulonodular pattern on chest radiography (Figure 53–3). Radiologically, the infiltrate may be difficult to differentiate from miliary tuberculosis, with a reticulonodular pattern present in all lobes, including the periphery. Pathologically, LIP is characterized by diffuse infiltration of the small airways and bronchi by lymphocytes and plasma cells. The cause of LIP is poorly defined. It is postulated that LIP is caused by an exaggeration of the host's pulmonary immune response to local infection, most commonly Epstein–Barr virus (EBV). In the era of antiretrovirals and following reconstitution of the host's immune system, this condition has all but disappeared.

The cardiovascular system may be affected primarily by HIV, such as HIV-cardiomyopathy, or secondarily, such as the development of cor pulmonale following recurrent bouts of pneumonia or LIP, or hyperlipidemia as a consequence of antiretrovirals. In the pre-HAART era, subclinical cardiac abnormalities in HIV-infected children were common, persistent, and often progressive.22 Cardiac manifestations such as dilated cardiomyopathy and inappropriate left ventricular (LV) hypertrophy have been shown to limit survival in children not on HAART and depressed LV function correlates with the degree of baseline immune dysfunction. In HIV-infected children with cardiac involvement, carnitine, selenium, and multivitamin supplementation should be considered, especially in those with wasting or diarrhea syndromes.23 Monthly intravenous immunoglobulin (IVIG) infusions have been demonstrated to preserve LV parameters in HIV-infected children including ventricular recovery in some children with recalcitrant HIV-related cardiomyopathy. HAART, particularly the protease inhibitors (PI), maybe associated with the development of dyslipidemia and the metabolic syndrome necessitating monitoring of lipid profiles in all children on PI therapy. The pericardium may also be affected in HIV-infected children. Small asymptomatic effusions in end-stage children with AIDS are often nonspecific in nature, and maybe caused by the proinflammatory milieu found in advanced AIDS. In contrast, large or symptomatic effusions are often associated with infection or malignancy, and warrant thorough investigation and etiology-specific treatment.23

HIV nephropathy is characterized by progressive proteinuria, at times a nephrotic syndrome, late stage azotemia, normal blood pressure, and enlarged, hyperechoic kidneys with eventual progression to end-stage renal disease (ESRD) in the absence of HAART.24 The clinical course of HIV nephropathy in children is less fulminant than adults. Renal biopsy results are variable but the most common findings are those of focal segmental glomerulosclerosis.25 Advances in management including HAART and angiotensin antagonists to control proteinuria have decreased the incidence of renal failure. In addition, HAART may itself lead to renal damage. Of the antiretrovirals, the nucleotide reverse transcriptase inhibitor, tenofovir, has been most frequently associated with impaired renal function. Indinavir, a PI, may induce renal stones particularly when it is boosted with ritonavir and in patients who are not adequately hydrated.

The cutaneous findings in HIV-infected children are numerous and generally relate to integumentary manifestations of the host's immune dysfunction. These vary from recalcitrant eczema to severe forms of cutaneous infections such as scabies, zoster, or herpes. Drug reactions, such as Stevens Johnson syndrome (Figure 53–4), may be precipitated by trimethoprim-sulfamethoxazole or other agents such as nevirapine or abacavir. Kaposi's sarcoma was a cutaneous malignancy of elderly males in the pre-HIV era but in now an AIDS-defining condition. It is less frequently seen in pediatrics but a careful examination of the skin and palate is important to help rule out this condition (Figure 53–5).

The gastrointestinal tract may be affected at any point from the mouth to the anus with most presentations being a manifestation of impaired immunity. In the mouth, oral thrush and dental caries are the most common features. Esophageal candidiasis may present with dysphagia, odynophagia or failure to thrive. Herpes simplex and CMV can also cause a painful esophagitis. Chronic diarrhea was a frequent presentation in the pre-HAART era; refer to Chapter 54 for a list of potential opportunistic pathogens. Many HIV-infected children will have clinically signs localized to the reticuloendothelial system such as diffuse lymphadenopathy or hepatosplenomegaly.

Musculoskeletal findings are not usually a characteristic feature of HIV-infected children. When they do occur, they are usually the result of an opportunistic infection of a muscle, bone, or joint.

Hematologically, in the late stage of HIV infection, anemia, leukopenia, and lymphopenia may result from HIV itself, or from opportunistic infections, such as disseminated MAC infection. In contrast, idiopathic thrombycytopenic purpura (ITP), secondary to HIV, may be seen earlier in the course of the illness. Up to 10% of children and adults may present with thrombocytopenia.

Children infected with HIV may present with a broad range of signs and symptoms. The complete differential diagnosis includes consideration of the different causes of immune deficiency as well as the varying presentations of opportunistic infections. The differential diagnosis is also affected by the age of a child—a 3-month-old who presents with failure to thrive secondary to recurrent urinary tract infections may show many clinical features suggestive of HIV whereas an adolescent presenting with features suggesting acute EBV infection may in fact have acute HIV seroconversion illness. Noninfectious conditions such as malignancies or autoimmune diseases may also mimic the clinical picture of HIV.

The tests used to diagnose HIV infection and their relative merits are summarized in Table 53–4. The broad principles to remember when testing a child for HIV are the following:

1. Maternal anti-HIV IgG antibody may persist for as long as 18 months necessitating viral specific testing in children under 18 months of age.

2. It is currently not possible to reliably diagnose HIV in children under the age of 2 weeks:

   • a. The sensitivity of a single HIV DNA PCR test performed at <48 hours of age is less than 40%, but increases to over 90% by 2–4 weeks of age.
   • b. By 28 days of age, HIV DNA PCR has a 96% sensitivity and 99% specificity.

3. A single positive HIV test should always be confirmed with a second test to minimize the chance of a false-positive result.

4. HIV DNA PCR is used to diagnose HIV whereas the HIV RNA PCR assay is used to quantify HIV plasma viral RNA (the viral load) in a child who is already known to be HIV-infected.

5. HIV culture is regarded as the gold standard but is not widely available.

The high sensitivity and specificity of currently available DNA PCR tests is reassuring when testing a child with possible subtype B HIV infection. However, false-negative results have been reported in infants infected with nonsubtype B HIV.26,27 Currently available HIV RNA PCR assays have improved sensitivity to detect nonsubtype B infection but even these assays may miss some non-B HIV subtypes.28,29 The cautious clinician will therefore take a careful history to establish which children are at high risk of non-B subtype infection—those whose parents are from Africa or Southeast Asia—and these children should not only be tested by HIV DNA PCR but also have repeat testing using one of the newer RNA assays. Occasionally nonsubtype B infection will continue to be suspected in children who test negative on both DNA and RNA testing. These children should be followed by an HIV expert, be monitored clinically, and have HIV serologic testing at 18 months of age.

Following the introduction in 1996 of effective antiretroviral medications in the form of HAART, HIV has been changed from a progressive illness with certain mortality to a chronic disease more similar to asthma or diabetes. This dramatic change in the outlook of children infected with HIV depends on early diagnosis, appropriate management, and excellent adherence to HAART regimens. Significant advances have been made in all of these areas but challenges remain, particularly in ensuring an early diagnosis and optimizing adherence.

Management of the HIV-infected child may be conveniently divided into two areas—HIV-specific management and general pediatric care. Key aspects of HIV specific management include regular follow-up visits with a clinician and team experienced in caring for HIV-infected children and monitoring of salient laboratory tests. Children who are stable on HAART are seen every 3 months by a multidisciplinary team including a pediatrician, social worker, nurse, and nutritionist. Annual neurodevelopmental testing is also suggested to screen for subtle signs of HIV encephalopathy. A psychologist is also a key member of the team given that many HIV-infected children benefit from regular counseling sessions. If the psychosocial aspect of care is neglected, it is likely that the child will be nonadherent both to clinic visits and to the rigorous medication regimen.

At the three-monthly visit, a careful history, physical examination, review of the previous laboratory tests, and selected follow-up laboratory tests are done. The history reviews current medications including possible side effects and a careful discussion of adherence. Where available, adherence by history should be correlated with pharmacy refill data as the earlier nonadherence is detected, the less likely resistance to the current HAART regimen is to develop. A brief developmental screen, particularly in children under the age of 2 years, will reveal the need for more detailed testing. A general physical examination focuses on appropriate growth and features of HIV as discussed in the clinical presentation section. Laboratory monitoring of HIV-infected children is somewhat center-specific but most practitioners would do a minimum of the following:

• Every 3 months: CBC, CD4 count and percentage, RNA PCR quantitative viral load, electrolytes, and liver transaminases
• Every 6 months: full liver function tests, lipid screening, urine analysis

Additional testing may be warranted depending on the findings on history and examination. Age group specific laboratory testing may also be indicated such as screening for sexually transmitted diseases and Papanicolaou smears in adolescents.

The need for prophylactic antibiotics should be reviewed at each visit. Trimethoprim sulfamethoxazole is used to prevent PCP and a weekly macrolide is used to prevent Mycobacterium avium complex (MAC) infection. See Chapter 54 for a more detailed discussion of prophylaxis including indications of when to start prophylactic antibiotics.

The diagnosis of HIV, unlike many other illnesses, may still result in stigmatization in many communities in the United States. When considering the best way to communicate with an HIV-infected child about his/her illness, a thoughtful approach to HIV disclosure is particularly important. As with all chronic illnesses of childhood, the pediatrician needs to adhere to the following tenets:

1. Communicate with the child in a developmentally appropriate way.

2. Always tell the truth:

   • a. There is no merit in telling a child that she takes her HIV medications to treat her cough as when the cough resolves, there is a good chance that her adherence will suffer as a result.

3. Maintain a positive relationship with both the child and family.

4. Understand the family's dynamics and social situation.

The timing and technique of disclosing a child's HIV status varies from clinic to clinic. Disclosing the diagnosis of HIV to a child is a controversial and emotionally charged issue among both the health care team and parents and caregivers of these children.30 There is emerging evidence that complete disclosure by caregivers to their children coupled with strong parental relationships predict good adherence.31 Less clear is the effect and timing of disclosure in families where the parental relationship is poor. The benefits of disclosure include that the child can participate more actively in their health care, improvement in the child–caregiver relationship, the veil of secrecy has been lifted allowing for more open support and a result dispelling of any false reasons for the child taking medicine such as, “I have cancer and no one has told me.” The risks of disclosure include inadvertent disclosure of the “family's secret” by the child, stigma, breakdown of the child–parent relationship particularly if disclosure occurs in late or mid-adolescence, and a lack of support in the home. Many practitioners advocate a staged approach to disclosure where the child is gradually introduced to some of the broad concepts of HIV. The actual time of full disclosure is usually a negotiated one between the caregivers and the health team and takes into account the developmental level of the child.

In many urban settings, general pediatric care is provided by the HIV clinic but in more rural areas this is frequently the responsibility of the general pediatrician. Table 53–5 describes the recommendations for immunization in an HIV-infected child. In addition to standard pediatric practice, the annual visit should pay particular attention to adherence, development, psychosocial wellbeing, and medication side effects. A proactive approach to healthy eating habits is another important area as the PIs are associated with changes in the blood lipid profile and a predilection to the metabolic syndrome.

Recommendations for the initiation of HAART are more aggressive in children than adults as HIV disease progresses more rapidly in children. The decision to initiate or withhold HAART should be made in conjunction with an HIV specialist and after consulting the latest HIV guidelines available at www.aidsinfo.nih.gov/Guidelines. The general trend is to recommend the initiation of HAART in all HIV-infected children under the age of 12 months. Reasons include that the youngest children are at greatest risk for rapid disease progression including HIV encephalopathy and life-threatening opportunistic infections. After the age of 12 months, clinical, immunologic, and social parameters are used to decide when to initiate therapy.

The six classes of antiretrovirals are shown in Table 53–6. HAART is defined as the initiation of at least three antiretrovirals, usually from at least two different classes. Occasionally a regimen of three NRTIs is used but this is unusual. Triple therapy is important to minimize the development of resistant virus. This was well illustrated when in the early days of antiretroviral development zidovudine monotherapy was used—patients initially showed a clinical and immunologic response but the response usually waned within 6 months due to viral resistance to zidovudine.

The goals of HAART include the following:

• Restoring and preserving immune function
• Rapid and sustained maximal suppression of viral replication as measured by an undetectable viral load
• Minimizing drug side effects and maximizing adherence
• Normal growth and development
• Improved quality of life
• Minimizing HIV-related morbidity and mortality

The first time a patient commences HAART is generally their best chance of achieving a favorable response. This is not to say that second or third line regimens do not work; rather it speaks to nonmedication factors that play a vital role in adherence to a lifelong medication. Hence, the decision to start HAART is a process and commitment which includes family, child, and the health team. The goal is to aim for 100% adherence and studies have shown that anything less than 95% adherence is associated with the development of resistant viral mutants. Adherence is optimized by selecting one person in the home who will supervise the medication regimen and take full responsibility for the child's therapy. Other important factors include the palatability of medications and the frequency of the regimen. The former may be addressed by consultation with an experienced HIV nurse who will advise giving medications with certain foods. Failing this, a gastrostomy tube may be required. Medication regimens are now more patient friendly with daily or twice daily regimens being the rule. This represents a dramatic improvement from the initial antiretroviral regimens, which required much more frequent dosing and a larger daily pill count.

After initiation of HAART, the viral load decreases in two phases. Initially in the first 6–10 weeks after commencing HAART, there is a rapid decrease secondary to inhibition of viral replication in activated CD4 cells. The second phase occurs over the subsequent 24 weeks and is characterized by a slower decrease due to inhibition of viral replication in resting CD4 cells and macrophages. The rate and magnitude of CD4 response vary from one child to another. In children with a sluggish increase in CD4 cells following HAART initiation, most HIV specialists would watch and wait as long as the viral load remains undetectable and the child is improving clinically. For treatment naïve children, the expectation is that the viral load should decrease by at least 1 log by 12 weeks of therapy, and be undetectable by 24 weeks of therapy, or soon thereafter.

All antiretrovirals are associated with some side effects. The common class-specific ones are summarized in Table 53–7. For a more complete list of drug side effects, consult the latest pediatric HIV treatment guidelines at www.aidsinfo.nih.gov/Guidelines. It is vital that the treating pediatrician is aware of both the common and uncommon side effects of these drugs as well as the various drug–drug interactions. The skills of a clinical pharmacist are often required with the latter as dose adjustments may be required. Initiating and maintaining HAART in an HIV-infected individual is always best done in close consultation with an HIV-treatment specialist.

The outlook for HIV-infected children has been dramatically altered for the better since the introduction of HAART. HIV-infected children now have the opportunity to grow and develop normally and to live healthy and productive lives. The caveat to this is that they are adherent to their medications. Without >95% adherence, the residual virus will develop resistance to one or more of the medications, resulting in a subsequent increase in viral load and finally a fall in CD4 count and percentage.

Clinically the key is to provide ongoing counseling and support around adherence. The master clinician will endeavor to discover a drop-off in adherence before laboratory markers alert him/her that this has occurred. The technique of using pharmacy refill data to check a patient's adherence record is a valuable aid in this regard.32

Although the acute threat of immune suppression caused by rampant HIV infection is now avoidable due to effective HAART, the long-term prognosis for HIV-infected children is still being studied. HIV-infected children are now surviving into adulthood and having families of their own. However, the long-term effects of HIV and HAART on longevity remain to be seen. There are conflicting data regarding cardiovascular risk and HAART; some studies have shown an increased risk, while others have shown no greater risk than the general population.33,34

The search for a cure for HIV is ongoing. Thus far viral eradication has proved elusive due to the immense mutational potential of the virus and ability to seek sanctuary in a number of sites including dormant CD4 cells. These resting CD4 cells and macrophages can harbor replication-competent virus for the duration of their lifespan of up to 30 years. Potential interventions to eradicate these latent reservoirs include attempts to induce the latent virions to replicate, hence making them susceptible to HAART.

Future directions in pediatric HIV include careful monitoring of long-term outcomes, optimizing adherence, minimizing new infections particularly in adolescents, and the roll out of antiretrovirals to the developing world. The prospect of an HIV vaccine, either therapeutic or preventative, is still some way off. 35

• There remains no cure for HIV although the virus can be controlled with HAART.
• A minimum of 95% adherence is required in order to prevent the development of viral resistance to HAART.
• All HIV-infected children under the age of a year should be commenced on HAART.