Antiretroviral Therapy and Medical Management of Pediatric HIV Infection

NRTI Agents

NRTI agents were the first class of antiretroviral drugs available for the treatment of HIV infection. Although resistance eventually develops to these agents during the course of long-term, single-drug therapy, combination therapy with these drugs may prevent, delay, or reverse the development of resistance.⁶⁰ This class of drugs generally is well tolerated with prolonged use, and toxicities associated with these drugs usually can be managed while continuing to administer therapy.

NNRTI Agents

There currently are two NNRTI agents approved for treatment of HIV infection, neither of which have pediatric liquid formulations that are approved for use. This class of drugs rapidly reduces viral load and therefore potentially has utility for preventing infection after accidental exposure to HIV and for preventing perinatal transmission. However, drug resistance develops rapidly after initiation of monotherapy, and cross-resistance is likely between the two drugs in this class.⁸⁴ Sustained suppression of viral load has been observed in some patients who have been treated with regimens combining NNRTI and NRTI agents.

PI Agents

PI agents are potent antiretroviral agents, especially when used in combination with NRTI and/or NNRTI therapy.⁹⁰Resistance has been reported with all PI agents when used as monotherapy and can develop rapidly even with combination therapy in the presence of subtherapeutic drug levels (as can occur when there is not adequate adherence to the prescribed drug regimen). The patterns of mutations are more complex than those observed with NRTI and NNRTI agents. A greater number of genotypic mutation sites can occur, and there is greater variability in the temporal pattern of development of these mutations and in the combination of mutations that lead to drug resistance. The mutation patterns associated with PI resistance overlap; resistance to one drug may result in reduced susceptibility to some or all of the other PI agents currently available. Therapeutic regimens consisting of two PI agents (eg, RTV and SQV or NFV and SQV soft gel capsules) combined with one or two NRTI agents are being evaluated in adults and children; early results are promising, showing potent antiviral activity. However, there are no safety data or appropriate recommendations regarding dosage in children available at this time. The practitioner should consider many factors when weighing the short- and long-term risks and benefits of using PI therapy. Among the most important in this regard is the capacity of the patient and family to maintain adherence to the prescribed regimen.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported in HIV-infected patients treated with any of the currently available PI agents.^91–93 In some cases, diabetic ketoacidosis has occurred, and in some patients who discontinued PI therapy, hyperglycemia has persisted. A causal relationship between PI therapy and these events has not been established, but health care providers should be aware of the possibility of hyperglycemia in patients receiving these drugs and monitor appropriately. Caregivers and patients should be taught to recognize the early symptoms of hyperglycemia to ensure prompt health care if such symptoms develop. There also have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia A and B treated with PI agents.⁹⁴ In some patients, additional Factor VIII was given, and in more than half of the reported cases, treatment with PI agents was continued or reintroduced.

Other Antiretroviral Agents That May Soon Be Approved for Use

A number of new drugs are being used in combination therapy in clinical trials and may be available in the future for use in infants, children, and adolescents for treatment of HIV infection. The following is a brief summary of these drugs.

Abacavir (1592U89) is an NRTI agent that has been investigated as part of combination therapy in adults and children and is available presently in a liquid formulation for children with HIV infection through a company-sponsored open label protocol. It is expected that this drug will be used in combination therapy for treatment of HIV and will be considered for approval by the FDA in 1998.

Preveon, [adefovir dipivoxil, bis-POM PMEA], is a reverse transcriptase inhibitor but belongs to a new class of antiviral agents called nucleotides. It is an oral drug with a prolonged half-life and is taken 1 time daily. This drug is being studied in clinical trials in adults.

PMPA, {9-[(R)-2-(phosphonomethoxy)propyl]adenine}, is an NRTI agent that has undergone phase I trials in adults. PMPA is administered intravenously; however, an oral prodrug, bis-POC PMPA, has been developed that has a prolonged half-life and is targeted for phase I trials in infants and children.

Sustiva, [efavirenz, DMP 266], is a new NNRTI that can be taken 1 time daily and is being studied in combination therapy. Phase I trials are underway in the pediatric population.

Amprenavir, (141W94/VX-478), is a new PI that is planned for phase I studies in the pediatric population as part of combination therapy for treatment of HIV infection.

Hydroxyurea is an oral drug used for treatment of certain cancers that has strong antiretroviral activity when combined with other drugs such as ddI. This drug has a mechanism of action that differs from that of other antiretrovirals in that it interferes with DNA formation by inhibiting a cellular enzyme, ribonucleotide reductase, necessary for the formation of special nucleotide units needed to form DNA. Studies of hydroxyurea in children are in the initial phases of development.

In addition to the drugs listed above, there also are new classes of drugs being developed that will work at different points in the viral life cycle. Among these are drugs that block binding of HIV to cells, integrase inhibitors (integrase is an enzyme that integrates the viral genetic material into the host genome) and zinc finger inhibitors (zinc fingers are parts of proteins that bind to nucleic acids and are essential for the assembly of new virus particles).

Issues Regarding Antiretroviral Dosing in Neonates

Data regarding the appropriate dosing of antiretroviral drugs in neonates are limited; ZDV is the best-studied antiretroviral drug in this age group. The recommended ZDV dosage for infants was derived from pharmacokinetic studies performed in full-term infants.¹⁰⁹ Because ZDV is cleared primarily through hepatic metabolism (ie, glucuronidation), which is immature in neonates, the half-life and clearance of ZDV are prolonged in neonates compared with those in older infants, thus requiring adjustments in dosing.

Premature infants have even greater immaturity in hepatic metabolic function than do full-term infants, and additional prolongation in clearance has been documented in very premature infants (eg, those born before 34 weeks of gestation).¹¹⁰ Appropriate ZDV dosing for premature infants has not been defined but is being evaluated in a phase I clinical trial in premature infants <34 weeks of gestation (PACTG 331).

The safety and pharmacokinetics of 3TC administered alone or in combination with ZDV in pregnant women and administered for 1 week to their newborns have been evaluated.^111,,112 Clearance was prolonged in these infants. Based on data from this study, the dose recommended for newborns is half the dose recommended for older children (Table 8). No data are available regarding 3TC pharmacokinetics in infants 2 to 6 weeks old, and the exact age at which 3TC clearance begins to resemble that in older children is not known.

NVP administration to HIV-infected pregnant women during labor and as a single dose to their newborns at 2 to 3 days of age has been studied in a phase I trial.¹¹³ The half-life of NVP was prolonged in neonates compared with that in older children, indicating that some modification of NVP dosage is required for administration to neonates.

Although phase I studies of several PI agents (ie, IDV, RTV, NFV, or SQV in combination with ZDV and 3TC) in pregnant HIV-infected women and their infants are ongoing in the United States, no data are available at this time regarding drug dosage, safety, and tolerance of any of the PI agents in neonates.

Application of Data From Clinical Trials of Antiretroviral Agents

Therapy with a single NRTI has been shown to provide substantial benefit to symptomatic infected adults compared with no therapy, despite the limited antiretroviral potency of monotherapy compared with current combination regimens. In initial placebo-controlled antiretroviral clinical trials in HIV-infected adults, ZDV monotherapy decreased disease progression and mortality in patients with AIDS as well as in patients with mild symptoms or those with immune suppression but no clinical symptoms.^114–116 In symptomatic pediatric patients, clinical, immunologic, and virologic benefit has been observed with monotherapy with a variety of NRTI agents, including ZDV, ddI, d4T, and 3TC.^{61,,6267–69,72,79}

Subsequent comparative clinical trials in clinically or immunologically symptomatic infected adults have demonstrated the superior clinical efficacy of initial therapy with dual NRTI combination antiretroviral regimens compared with NRTI monotherapy.^102,,117 Similarly, in pediatric trials in symptomatic, antiretroviral-naive infected children, initial combination therapy with dual NRTI agents (either ZDV and 3TC or ZDV and ddI) was clinically, immunologically, and virologically superior to initial therapy with a single NRTI.^69,,118 More recent studies in antiretroviral-experienced adults have demonstrated that combination therapy that includes a PI (generally with two NRTI agents) is clinically, immunologically, and virologically superior to dual NRTI therapy.^104,,119 Recent data from pediatric trials also indicate that therapy that includes a PI is virologically and immunologically superior to a dual NRTI combination in symptomatic antiretroviral-experienced children.⁷⁷

Data from clinical trials that address the effectiveness of antiretroviral therapy in asymptomatic infants and children with normal immune function are not available. However, initiation of therapy early in the course of HIV infection, including during the period of primary infection in the neonate, is theoretically advantageous. Control of viral replication in perinatally infected infants is inadequate, as demonstrated by the high levels of HIV RNA observed during the first 1 to 2 years of life after perinatal infection. Initiation of aggressive antiretroviral therapy during this early period of viral replication could theoretically preserve immune function, diminish viral dissemination, lower the viral setpoint, and result in improved clinical outcome.

In a preliminary study of early treatment of children, six HIV-infected infants 2 to 4 months of age were placed on a regimen of ZDV, ddI, and NVP; baseline HIV RNA levels were 40 000 to 1 500 000 copies/mL. Five of six infants had an early virologic response with a drop in RNA PCR to <10 000 copies/mL by day 14, and two of the infants maintained undetectable levels of HIV RNA through 168 days of therapy.⁸⁹ These two children had persistently negative HIV cultures and undetectable RNA levels, and became HIV antibody-negative, although HIV DNA PCR remained positive. Clinical trials are ongoing to assess the virologic, immunologic, and clinical response of young infants to early, aggressive antiretroviral therapy with three or four antiretroviral agents.

The theoretic problems with early therapy include the potential for short- and long-term adverse effects, particularly for drugs being administered to infants younger than 6 months, for whom information on pharmacokinetics, drug dosing, and safety is limited. These concerns are particularly relevant because lifelong administration of therapy is likely to be necessary for HIV-infected infants. Additionally, if viral replication is not suppressed, ongoing viral mutation is likely to result in the development of antiretroviral resistance, curtailing the duration of benefit that early therapy might confer and potentially limiting future treatment options. Thus, intensive education of caregivers and patients about the importance of adherence to the prescribed treatment regimen should be provided before therapy is initiated so that 1) potential problems and solutions can be identified, and 2) frequent follow-up can be provided to assess virologic response to therapy, drug tolerance, and adherence.

When to Initiate Therapy

Antiretroviral therapy is recommended for HIV-infected children with clinical symptoms of HIV infection (ie, clinical category A, B, or C) (Table 3) or evidence of immune suppression (ie, immune category 2 or 3) (Table 2), regardless of the age of the child or viral load. Clinical trial data from adults and children have demonstrated that antiretroviral therapy in symptomatic patients slows clinical and immunologic disease progression and reduces mortality.^69,,118,120

Ideally, antiretroviral therapy should be initiated in all HIV-infected infants younger than 12 months as soon as a confirmed diagnosis is established, regardless of clinical status, immunologic status, or viral load. HIV-infected infants younger than 12 months are considered at high risk for disease progression, and the predictive value of immunologic and virologic parameters to identify those who will have rapid progression is less than that for older children. Identification of infection during the first few weeks of life permits clinicians to initiate antiretroviral therapy or to intensify ongoing antiretroviral therapy used for chemoprophylaxis of perinatal transmission during the initial phases of primary infection. However, clinical trial data documenting therapeutic benefit from this approach are not currently available, and information on drug dosing in neonates is limited. Because resistance to antiretroviral drugs (particularly PI agents) can develop rapidly when drug concentrations fall below therapeutic levels (either as a result of inadequate dosage or incomplete adherence), issues associated with adherence should be fully assessed and discussed with the HIV-infected infant's caregivers before the decision to initiate therapy is made.

Two general approaches were outlined by the Working Group for initiating therapy in asymptomatic children older than 1 year. The first approach would be to initiate therapy in all HIV-infected children, regardless of age or symptom status. Such an approach would ensure 1) treatment of infected children as early as possible in the course of disease, and 2) intervention before immunologic deterioration. Data from prospective cohort studies indicate that most HIV-infected infants will have clinical symptoms of infection by 1 year of age.^121,,122 Additionally, most asymptomatic infected children older than 1 year have CD4+ T-lymphocyte percentages of <25%,¹²² which is indicative of immunosuppression and therefore warrants antiretroviral therapy.

An alternative approach would be to defer treatment in asymptomatic children older than 1 year with normal immune status in situations in which the risk of clinically significant disease progression is low (eg, low viral load) and when other factors (eg, concern for adherence, safety, and persistence of antiretroviral response) favor postponing treatment. In such cases, the health care provider should monitor virologic, immunologic, and clinical status carefully. Factors that should be considered in deciding when to initiate therapy include 1) high or increasing HIV RNA levels, 2) rapidly declining CD4+ T-cell lymphocyte number or percentage to values approaching those indicative of moderate immune suppression (ie, immune category 2 [Table 2]), and 3) development of clinical symptoms. The level of HIV RNA considered indicative of increased risk for disease progression is not well defined for young children. Regardless of age, any child with HIV RNA levels of >100 000 copies/mL is at high risk for mortality (Tables 5,6), and antiretroviral therapy should be initiated regardless of clinical or immune status. HIV RNA levels consistent with the current treatment recommendations for HIV-infected adults (ie, >10 000–20 000 copies/mL) also may be indicative of the need for treatment for asymptomatic children 30 months of age and older (Table 7). Additionally, any child with HIV RNA levels that demonstrate a substantial increase (more than a 0.7 log₁₀ [fivefold] increase for children younger than age 2 and more than 0.5 log₁₀ [threefold] increase for those 2 years of age and older) on repeated testing should be offered therapy, regardless of clinical or immunologic status or absolute level of viral load. These recommendations are based on limited data and may need revision as more information becomes available (Table 9).

Issues associated with adherence to treatment are especially important in considering whether and when to initiate therapy. Antiretroviral therapy is most effective in patients who have never received therapy and who therefore are less likely to have antiretroviral-resistant viral strains. Lack of adherence to prescribed regimens and subtherapeutic levels of antiretroviral medications, particularly PI agents, may enhance the development of drug resistance. Participation by the caregivers and child in the decision-making process is crucial, especially in situations for which definitive data concerning efficacy are not available.

Choice of Initial Antiretroviral Therapy

Combination therapy is recommended for all infants, children, and adolescents treated with antiretroviral agents. Compared with monotherapy, combination therapy 1) slows disease progression and improves survival, 2) results in a greater and more sustained virologic response, and 3) delays development of resistant mutations. Monotherapy with the antiretroviral drugs currently available is no longer recommended to treat HIV infection. (ZDV monotherapy is appropriate, however, when used in infants of indeterminate HIV status during the first 6 weeks of life to prevent perinatal HIV transmission. Infants identified as being HIV-infected while receiving ZDV chemoprophylaxis should be changed to a combination antiretroviral drug regimen; ZDV therapy should be interrupted if combination therapy is not initiated immediately and should not be resumed until/unless it is part of a combination regimen.)

Aggressive antiretroviral therapy for primary perinatal infection with three drugs provides the best opportunity to preserve immune function and delay disease progression and thus is recommended. The goal of antiretroviral therapy is to suppress viral replication maximally, preferably to undetectable levels. Based on clinical trials in infected adults, the preferred regimen to accomplish this goal is combination therapy with two NRTI agents and one PI. Although these combinations have had limited evaluation in clinical trials in children, they can reduce HIV RNA to undetectable levels in some children.^{77,,101,123,124} An interim analysis from a clinical trial of children (ie, PACTG 338) has demonstrated that therapy with drug combinations that include a PI is more effective than therapy with two NRTI antiretroviral drugs in reducing viral load to undetectable levels and increasing CD4+ T-lymphocyte number.⁷⁷ New antiretroviral drugs and combinations are being studied in infected adults and children. Other drug combinations that demonstrate sustainable viral load suppression and acceptable toxicity and dosing profiles likely will become available, which will increase treatment options for children in the future.

PI agents with formulations appropriate for infants and children who cannot swallow pills include NFV, available in a powder formulation that can be mixed with water or food, and RTV, available in liquid formulation. Optimal dosing of these drugs in children younger than 2 years is not known but is being evaluated in clinical trials. IDV and SQV are not available in liquid formulations. IDV or soft gel SQV capsules are recommended for consideration as second-line agent for children who can tolerate swallowing capsules. Optimal dosing of these drugs in infants and children is not known but is being evaluated in clinical trials. The original hard gel capsule formulation of SQV has limited bioavailability and thus is not recommended for use with two NRTI agents. Some studies have indicated substantial increases in SQV drug levels when co-administered with other PI agents (eg, RTV) or with other drugs that inhibit the cytochrome P450 enzyme system. However, data regarding such combinations in children are not available.

Although not ideal, alternative regimens may be considered for initial therapy in circumstances in which the caregiver has concerns regarding the feasibility of adherence to a complex drug regimen or when the patient and caregivers prefer an alternative regimen. Alternative regimens have demonstrated clinical benefit in adult and pediatric patients, although these regimens may not suppress viral load to below-detectable levels as consistently as does combination therapy with two NRTI agents and a PI. Such alternative regimens include combination regimens of two NRTI agents, with NVP substituted for the PI, or two NRTI agents alone. However, drug regimens that do not result in sustained viral suppression may result in the development of viral resistance to the drugs being used.

Table 10 lists the recommended antiretroviral drug regimens for initiation of therapy in a previously untreated child. Table 8 lists the antiretroviral drugs currently available and dosing for infected infants, children, and adolescents, and provides detailed information on toxicities and special instructions for use in children.

The initial antiretroviral regimen chosen for infected infants theoretically could be influenced by the antiretroviral regimen their mothers may have received during pregnancy. However, data from PACTG 076 indicate that ZDV resistance did not account for most infants who became infected despite maternal ZDV treatment,¹²⁵ and data from PACTG 185 indicate that duration of previous ZDV therapy in women with advanced HIV disease, many of whom received prolonged ZDV before pregnancy, was not associated with diminished ZDV efficacy for reduction of transmission.¹²⁶ Data do not suggest that the antiretroviral regimen for an infected infant should be chosen on the basis of maternal antiretroviral use. However, continuing to monitor the frequency of perinatal transmission of antiretroviral-resistant HIV isolates is crucial, because maternal therapy with multiple antiretroviral agents is becoming more common and the prevalence of resistant viral strains in the HIV-infected population may increase over time.

When to Change Antiretroviral Therapy

Each of the following three circumstances warrants a change in antiretroviral therapy: 1) failure of the current regimen with evidence of disease progression based on virologic, immunologic, or clinical parameters (Table 11); 2) toxicity or intolerance of the current regimen; or 3) new data demonstrating that a drug or regimen is superior to the current regimen.

When therapy must be changed because of treatment failure or suboptimal response to treatment, clinicians should work with families to assess the possible contribution of adherence problems to the failure of the current regimen. Issues regarding adherence should be addressed to increase the likelihood of a successful outcome when initiating a new therapy. These issues are best addressed before therapy is instituted and need to be reinforced during therapy.

Intensive family education, training in the administration of prescribed medications, and discussion of the importance of adherence to the drug regimen should be completed before initiation of new treatment. In addition, frequent patient visits and intensive follow-up during the initial months after a new antiretroviral regimen is started are needed to support and educate the family and to monitor adherence, tolerance, and virologic response to the new regimen.

Virologic Considerations for Changing Therapy

Information is limited regarding HIV RNA response to antiretroviral therapy in infants and young children. However, the general virologic principles underlying the use of antiretroviral therapy are similar for all persons with HIV infection. Because HIV RNA monitoring is critical for the management of infected children, Working Group members used the available data and clinical experience when definitive data were not available to make the following recommendations. These recommendations may require modification as new information becomes available.

Ideally, antiretroviral therapy should maximally suppress viral replication to below levels capable of being detected with currently available HIV RNA assays, which may not always be achievable in children with HIV infection. Perinatally infected children generally have high HIV RNA levels, and clinical benefit may be observed with decrements in HIV RNA levels that do not result in undetectable levels. However, failure to maximally suppress replication may be associated with increased probability of viral mutations and the emergence of drug resistance. Consideration of the implications of changing regimens and the choice of new drugs should include an acknowledgment of the potential for limiting the patient's future options for potent therapy.

Consensus recommendations have been developed using plasma HIV RNA measurements to guide changes in antiretroviral therapy for adults with HIV infection.⁶ The recommendations for adults indicate that health care providers should consider changing therapy if 1) HIV RNA levels drop less than threefold (0.5 log₁₀) after 4 weeks of therapy and less than 10-fold (1.0 log₁₀) after 8 weeks of therapy, or 2) HIV RNA has not decreased to undetectable levels after 4 to 6 months of therapy. Because HIV RNA levels in perinatally infected infants are high compared with levels observed when therapy is initiated in most infected adults, the initial virologic response of infected infants and young children to initiation of antiretroviral therapy may take longer than that observed in adults (ie, 8–12 weeks). In addition, suppression of HIV RNA to undetectable levels may be achieved less often than has been reported for infected adults, despite potent combination therapy with two NRTI agents and a PI. Therefore, virologic indications for changing therapy in infected children differ slightly from those recommended for infected adults. Adult guidelines should be followed for infected adolescents.⁶

Virologic response should be initially assessed 4 weeks after therapy is initiated. However, the time required to achieve maximal virologic response to therapy may vary depending on the specific baseline HIV RNA value at the onset of therapy. If baseline HIV RNA levels are high (ie, >1 000 000 copies/mL), virologic response may not be observed until 8 to 12 weeks after initiating antiretroviral therapy. However, if baseline HIV RNA levels are similar to those observed in untreated infected adults (ie, <100 000 copies/mL), initial response should be observed within 4 weeks after initiating therapy. After a maximal virologic response is achieved, HIV RNA levels should be measured at least every 3 months to monitor continued response to therapy. At least two measurements (taken at least 1 week apart) should be performed before considering a change in therapy.

The following situations may indicate a need for change in therapy in infected children.

• Less than a minimally acceptable virologic response after 8 to 12 weeks of therapy. For children receiving antiretroviral therapy with two NRTI agents and one PI, such a response is defined as a less than 10-fold (1.0 log₁₀) decrease from baseline HIV RNA levels. For children who are receiving less potent antiretroviral therapy (ie, dual NRTI combinations), an insufficient response is defined as a less than fivefold (0.7 log₁₀) decrease in HIV RNA levels from baseline.

• HIV RNA not suppressed to undetectable levels after 4 to 6 months of antiretroviral therapy. However, although suppression of HIV RNA to undetectable levels and maintenance for prolonged periods is desirable, few data in children indicate that such suppression is always achievable. In addition, the number of alternative therapeutic regimens for children is limited. The initial HIV RNA level of the child at the start of therapy and the level achieved with therapy should be considered when contemplating potential drug changes. For example, an immediate change in therapy may not be warranted if there is a sustained 1.5 to 2.0 log₁₀ reduction in HIV RNA copy number, even if RNA remains detectable at low levels.

• Repeated detection of HIV RNA in children who had initially had undetectable levels in response to antiretroviral therapy. The presence of repeatedly detectable RNA suggests the development of resistance or problems with adherence or drug bioavailability. More frequent evaluation of HIV RNA levels should be considered if the HIV RNA increase is limited (eg, if using an HIV RNA assay with a lower limit of detection of 1000 copies/mL, there is a ≤0.7 log₁₀increase from undetectable to ≃5000 copies/mL in an infant younger than age 2). If adherence to therapy has been inconsistent, renewed efforts to educate the caregivers and patient and closer follow-up from members of a multidisciplinary care team may improve adherence.

• A reproducible increase in HIV RNA copy number in children who have had a substantial HIV RNA response but who still have low levels of detectable HIV RNA. Such an increase would warrant a change in therapy if, after initiation of the therapeutic regimen, a greater than threefold (>0.5 log₁₀) increase in copy number is observed for children 2 years and older and a greater than fivefold (>0.7 log₁₀) increase is observed for children younger than 2 because of the greater biologic variability in RNA in young children.

Immunologic Considerations for Changing Therapy

CD4+ T-lymphocyte count and percentage are independent predictors of disease progression and mortality in HIV-infected children.^38,,39 The association of HIV RNA and CD4+ percentage with long-term mortality risk in HIV-infected children has been evaluated; for each absolute decline of five percentiles in CD4+ percentage at baseline or during follow-up, the mortality risk ratio increased by 1.3 (95% CI = 1.2–1.5), independent of the child's HIV RNA level.³⁸ Additionally, for children with CD4+ percentages <15% (ie, those in immune category 3), prognosis was correlated with the degree of depression of CD4+ percentage (ie, life expectancy was lower for children with CD4+ percentages <5% compared with children with CD4+ percentages 10%-14%) (Table 4).

Before considering changing antiretroviral therapy because of decline in CD4+ lymphocyte values, a minimum of one repeated measurement of CD4+ values should be obtained at least 1 week after the initial test. The following are immunologic indications that may warrant a change in antiretroviral therapy for HIV-infected children.

• Change in immune classification (Table 2). However, minimal changes in CD4+ percentile that may result in a change in immune category (eg, from 26% to 24% or from 16% to 14%) may not be as critical as a rapid substantial change in CD4+ percentile within the same immune category (eg, a decrease from 35% to 25%).

• For children with CD4+ percentages <15% (ie, those in immune category 3), a persistent decline of five or more percentiles in CD4+ cell percentage (eg, from 15% to 10% or from 10% to 5%).

• A rapid and extensive decrease in absolute CD4+ T-lymphocyte count (eg, a >30% decline in <6 months).

Clinical Considerations for Changing Therapy

The occurrence of certain clinical events while receiving antiretroviral therapy is evidence of HIV disease progression and/or a poor prognosis for infants and children. The following clinical criteria warrant consideration of a change in antiretroviral therapy.

• Progressive neurodevelopmental deterioration (ie, persistence or progression of deterioration documented on repeated testing as demonstrated by the presence of two or more of the following findings: impairment in brain growth, decline of cognitive function documented by psychometric testing, or clinical motor dysfunction) (Table 12). In such cases, the new treatment regimen should optimally include at least one antiretroviral drug with substantial CNS penetration (eg, ZDV or NVP, which have CSF/plasma ratios >0.2).

• Growth failure (ie, persistent decline in weight-growth velocity despite adequate nutritional support and without other explanation).

• Disease progression (ie, advancement from one pediatric clinical category to another [Table 2]). Prognosis is poorer as patients progress to more advanced clinical categories.⁶²However, in patients with stable immunologic and virologic parameters, progression from one clinical category to another (eg, from clinical category A to category B) may not represent an indication to change therapy. For example, development of new OI, particularly in patients who have severe immunosuppression at the time therapy was initiated, may not reflect a failure of antiretroviral therapy but rather persistence of immunologic dysfunction despite adequate antiviral response. Thus, in patients whose disease progression is not associated with neurologic deterioration or growth failure, virologic and immunologic parameters should be considered when deciding whether to change therapy.

Choice of a New Antiretroviral Regimen

The choice of a new antiretroviral regimen is dictated by the indications that warranted the change in therapy and the limited numbers of available alternative antiretroviral agents. Although the efficacy of different combination antiretroviral regimens in children can likely be extrapolated from clinical trial data obtained for adults, data are limited concerning the pharmacokinetics, appropriate dosing, and short- and long-term safety of various combinations in infected children. New regimens should be chosen partly on the basis of the impact of the changes on future treatment options.

The following principles should be followed when choosing a new antiretroviral regimen in children who have received previous treatment.

• When therapy is changed because of toxicity or intolerance, agents with different toxicity and side effect profiles should be chosen, when possible. Health care providers should have comprehensive knowledge of the toxicity profile of each agent before selecting a new regimen. In the event of drug intolerance, change of a single drug in a multidrug regimen and, in certain circumstances, dose reduction are permissible options. However, antiretroviral drugs should only be reduced to the lower end of the therapeutic range for which an effective dosing range is known, and adequacy of antiretroviral activity should be confirmed by the monitoring of HIV RNA levels.

• When changing therapy because of treatment failure, adherence to therapy should be assessed as a potential cause of failure.

• If the patient is adherent to the prescribed drug regimen, assume the development of drug resistance and, if possible, change to at least two new antiretroviral agents. Change in one drug or addition of a drug to a failing regimen is suboptimal. The new regimen should include at least three drugs, if possible. The potential for cross-resistance between antiretroviral drugs should be considered in choosing new drugs.

• When considering changing to a new regimen, all other medications taken by the patient should be reviewed for possible drug interactions.

• A change to a new regimen, especially to one containing PI agents, must include a discussion of treatment adherence issues between the caregivers of the infected child and the health care provider. The health care provider must recognize that certain medications are difficult to take in combination because of exacting and often conflicting requirements such as whether they can be taken with food, other antiretrovirals, and other medications.

• When considering changing therapy because of disease progression in a patient with advanced disease, the patient's quality of life must be considered.

Table 13 provides specific drug choices for changing a failing regimen. Because these issues are similar for all HIV-infected patients regardless of age, Table 13 is duplicated from the Guidelines for Use of Antiretroviral Therapy in HIV-Infected Adults and Adolescents.⁶

Principles of Management of Adverse Drug Reactions

1.  Try to determine whether the adverse event is attributable to antiretroviral agents, to other medications, to progressive HIV infection itself, or to other infections that may complicate the course of HIV.

 The clinical and laboratory manifestations of disease progression may mimic toxicities associated with some of the antiretroviral agents and other medications that the child is taking. Many HIV-infected children receive PCP prophylaxis with TMP/SMX concurrently with antiretroviral therapies. In such instances, the development of neutropenia may be attributable to TMP/SMX, to antiretroviral agents (eg, ZDV), or to HIV infection itself. Examples of infections that may cause signs and symptoms suggestive of drug toxicities include 1) Mycobacterium avium complex (MAC)¹²⁸: bone marrow suppression, hepatic dysfunction, abdominal pain, and diarrhea; 2) cytomegalovirus (CMV)¹²⁹: bone marrow suppression, hepatic dysfunction, bloody diarrhea, alteration in CNS; 3) Parvovirus¹³⁰: anemia, rash; and 4) Epstein–Barr virus (EBV)¹³¹: hepatic dysfunction, bone marrow suppression, lymphadenopathy.

2.  Continue therapy in the presence of nonlife-threatening toxicities.

 Determination of the nature and severity of toxicity as well as the relative importance of each medication that the child is receiving is essential in developing a safe and effective treatment strategy. Table 14 depicts grades of severity of abnormal laboratory tests and adverse clinical events that may reflect common and potentially severe drug toxicities. As a rule, attempts should be made to continue antiretroviral therapy at effective doses except in the presence of severe (grade 4) or life-threatening toxicities, in which circumstances therapy should be stopped. Severe and possibly rapidly fatal complications including pancreatitis, hepatic failure, or severe skin rashes (with risk of progression to Stevens–Johnson syndrome) require discontinuation of the most suspect medication(s) and often at least temporary interruption of all medications possibly implicated. Lower-grade toxicities (grades 1 and 2) should prompt increased and more frequent observation, monitoring, and evaluation. Moderately severe toxicities (grades 2 and 3) may require consideration of specific interventions such as 1) the use of specific pharmacologic modulating therapies such as erythropoietin for the treatment of anemia¹³² and granulocyte colony stimulating factor (G-CSF) for the treatment of neutropenia¹³³; or 2) dose reduction of agents for which a range of effective dosages has been documented (eg, ZDV and ddI). Consultation with a clinician experienced in the care of HIV-infected children is recommended in these circumstances.

3.  If there is a need to discontinue antiretroviral therapy for an extended period, many Working Group participants recommend stopping all antiretroviral agents simultaneously rather than continuing one or two agents alone. This is recommended in an attempt to minimize the risk of developing drug resistance in the face of potential increased viral replication.

 Subtherapeutic drug levels and continued viral replication, as may be seen with intermittent use of antiretroviral drugs, is associated with increased risk of the development of genetic mutations associated with drug resistance. This has been shown to be especially true with PI agents. When toxicity considerations require interruption of treatment, it is preferable to discontinue all antiretroviral agents simultaneously. Likewise, during temporary disruptions of therapy, it is advisable to withhold all doses of the agent(s) throughout the period required to clarify and to ameliorate the problem rather than to sporadically withhold and administer individual doses. In circumstances where prolonged discontinuation of therapy is anticipated, it is recommended to change to a new agent(s) rather than to continue withholding one or more drugs. Finally, it is recommended that after resolution or improvement of the toxicity, all of the interrupted antiretroviral agents be simultaneously reinstituted or a partially or completely new regimen be initiated.

Common Adverse Drug Reactions

Drug Interactions Involving Agents Used in the Management of HIV Infection

Appropriate management of HIV-infected children frequently involves the use of multiple drug regimens that place these children at high risk for drug interactions. Children with advanced HIV disease frequently receive more than 15 different medications, some of which are investigational and many associated with limited published experience in children.¹⁴⁴ Lack of information about drug interactions of newly approved antiretroviral agents and other medications makes it difficult to predict the likelihood and consequences of these interactions.

Types of drug interactions include additive toxicity and pharmacokinetic interactions. In general, drug interactions that alter the pharmacologic effects can increase or decrease serum levels of drugs by changing absorption, distribution, metabolism, or elimination. The risk of such drug interactions increases with the number of medications taken, the use of experimental or new drugs, and when drugs used in combination share similar pharmacodynamics or toxicities. In combination regimens, drug interactions can result in effects that are additive, synergistic, or antagonistic. Table 8 provides detailed information on the most common known drug interactions of many of the medications used commonly in pediatric HIV disease. Table 15 provides a list of medications that share toxicities, thus enhancing the potential for adverse drug interactions.

Several classes of medications often prescribed for adolescents, notably oral contraceptives and antidepressants/anxiolytics, have important interactions with antiretroviral drugs. In the case of contraceptives, RTV and NFV decrease estradiol levels, potentially reducing their efficacy. Clinicians may consider switching to progestin-only formulations of oral or injectable contraceptives. NVP may have the same effect on estradiol levels, although there is less information about this medication interaction. IDV modestly increases Ortho Novum levels, but no dosage or medication changes are recommended. With respect to psychotropics, RTV should not be used with the antidepressant bupropion and many benzodiazepines (anxiolytics). RTV also significantly increases levels of the antidepressant desipramine (and other tricyclics) and fluoxetine (serotonin reuptake inhibitor). If these agents are used concomitantly, toxicity should be anticipated and close monitoring is essential. IDV may have the same effects, although there is less information available.

Clinicians should be aware of the following serious, potentially life-threatening drug interactions when taking care of HIV-infected patients: 1) the use of astemizole/terfenadine, cisapride, triazolam, or midazolam in combination with macrolides, azoles, or PI agents may result in cardiac arrhythmias; 2) the use of foscarnet in combination with pentamidine may result in hypocalcemia; 3) the use of ganciclovir in combination with aminoglycosides or amphotericin B may result in renal failure; 4) the use of ganciclovir in combination with imipenem-cilastatin may result in seizures; 5) the use of ddC or ddI in combination with pentamidine increases the risk for life-threatening pancreatitis; and 6) PI agents should not be used with meperidine (Demerol) and propoxyphene (Darvon), and concurrent administration with alfentanil (Alfenta), fentanyl (Sublimaze), and methadone results in increased levels of these narcotics, which can depress respiration. All of the above drug combinations should be avoided.

Infectious Complications

As a group, the infectious complications of HIV infection comprise the most frequent AIDS-defining conditions in children with AIDS in the United States. These include opportunistic protozoan, fungal, and viral infections as well as recurrent episodes of bacterial infection of varying severity. In 1996, 678 cases of AIDS were reported in US infants and children younger than age 13, with 578 AIDS-indicator OI reported in these children. Pneumonia caused by P carinii, esophageal candidiasis, and recurrent serious bacterial infections alone accounted for 70% of OI and 43% of all AIDS-indicator conditions. By comparison, the most common noninfectious AIDS-indicator conditions reported in 1996 were lymphoid interstitial pneumonia (or pulmonary lymphoid hyperplasia), which occurred in 20% of newly reported cases of AIDS in children, HIV encephalopathy in 17%, and HIV wasting syndrome in 15% of cases. Relative frequencies of individual infections and noninfectious AIDS-indicator conditions observed in 1996 data were similar to those in previous years (Table 16).^145,,146

Considerations Regarding the Prevention of
Secondary Infections

A comprehensive approach to the prevention of opportunistic and recurrent serious bacterial infections in HIV-infected children requires both systematic monitoring of immunologic and virologic status and the administration of immunizations and prophylactic antimicrobials, and the selective use of immunoglobulin replacement therapy. Defining optimal guidelines for preventive treatment (whom to treat, when to start, what to use) is a challenging task, given the vast array of opportunistic pathogens, the limited number of available effective prophylactic agents, and the need to balance the risk of incurring infection against the expense, inconvenience, and potential for developing toxicity, resistance, and drug interactions inherent in preventive therapies. Acute episodes of infection may be life-threatening. For those conditions in which a given preventive treatment has been shown safe and effective, primary prophylaxis can reduce the likelihood of occurrence of certain OI. In contrast to recurrent serious bacterial infections, few of the protozoan, fungal, or viral infections complicating HIV are curable with currently available treatments. For many of these conditions, after the initial infectious episode, secondary prophylaxis in the form of lifelong suppressive therapy is indicated to prevent recurrent clinical diseases.

Guidelines for the prevention of OI in both children and adults infected with HIV have been developed jointly by the USPHS and the IDSA and were published recently.¹⁰ These guidelines are republished as a companion document in this supplement to which readers are referred for guidance on preventing OI in children with HIV infection. (See the “Pediatric Note” sections included in the discussion of each opportunistic organism, as well as the pediatric-specific tables and figure.) In general, adolescents with HIV infection should be managed according to the guidelines for prevention of OI in adults.

The remainder of this article addresses the treatment of specific infectious and noninfectious complications of HIV infection in children, as well as additional important management issues respecting pediatric HIV/AIDS.

Treatment of Specific Secondary Infections

Sexually Transmitted Diseases (STD)

Most adolescents with HIV infection have been infected sexually rather than through injection or by perinatal mechanisms. Therefore, it is important to evaluate thoroughly adolescents for other STDs.¹⁹⁵ This evaluation includes an annual anogenital examination and, for all sexually experienced females, a pelvic examination. Routine screening for STDs should include testing for syphilis, gonorrhea, chlamydia, hepatitis A and B viruses, and human papilloma virus (HPV). Cervical and anal dysplasia (and neoplasia) are significant consequences of HPV infection. Chronic and recurrent vaginal candidiasis are also complications of HIV infection in adolescent females, as is HSV infection in both males and females. Published CDC guidelines should be consulted for recommendations regarding diagnosis and treatment.¹⁹⁶

Management of Other Complications

Childhood Immunizations

HIV-infected and HIV-exposed children should be immunized according to the Immunization Schedule for HIV-Infected Children included in the 1997 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected With Human Immunodeficiency Virus,¹⁰ and subject to routine precautions and some additional HIV-specific considerations.²⁰⁸ Suboptimal responses to several vaccines has been demonstrated in HIV-infected children, particularly those with advanced immunosuppression.^209–213 However, routine serologic testing for antibody response is not recommended after any of the childhood vaccines. In regions experiencing a measles outbreak, serologic testing for measles immunity may be considered to identify susceptible children who would benefit from immune globulin prophylaxis.^213–215 Some pediatric HIV centers routinely assess for the presence of measles antibodies as a test of functional antibody status.

Nutrition in HIV Infection

Worldwide, malnutrition is the most common cause of immunodeficiency and a leading contributor to childhood mortality. In children whose weight for height is normal, mortality is 0.5%, whereas in those children whose weight for height is decreased, mortality increases to >18%.²¹⁶ When malnutrition accompanies the immunodeficiency of HIV disease, immune function is impaired additionally. In the United States, survival in patients with HIV disease, as well as with other chronic diseases such as cystic fibrosis and cancer, is related directly to nutritional status.

In children with HIV disease, severe wasting is an AIDS-defining illness and was reported as an AIDS-indicator condition in 17% of children with AIDS in 1996.¹⁴⁶ In a multicenter trial evaluating the effects of ZDV on childhood HIV, 80% of the children with HIV infection had weight-for-age less than the 25th percentile.⁶² Other studies have demonstrated that decreases in weight and height percentiles begin within the first 6 months of life.²¹⁷ Therefore, impaired nutritional status may reflect viral activity early in life, before more obvious sequelae of HIV disease develop. Recognition by health care providers of the importance of nurturing and nutrition should increase awareness and anticipation of clinical situations that may potentially impair availability, absorption, or utilization of sufficient nutrients.

Appropriate nutrition is a fundamental and necessary part of a child's medical therapy. Nutrition impacts on the management of children with HIV infection by affecting gastrointestinal tract function, CNS development, immune function, recovery from infection, bioavailability of therapeutic agents, growth, and quality of life. Because of these multiple effects, nutritional support should be an integral part of any therapeutic intervention for mothers and children with HIV disease. A team of providers with multidisciplinary skills is required for optimal management. For HIV-infected children whose parents (virtually all living biological mothers) may have chronic disease, the nutritional status of the nurturing parent impacts on family health and cannot be ignored when developing a care plan for a child. Families affected by HIV may experience chronic and recurrent stress related to deaths of family members, poverty, social isolation, substance abuse, and discrimination. Instead of being the recipient of support and nurturing, children with HIV-infected parents may find that they are these parents' prime source of support.²¹⁸

Diagnosis of Altered Nutritional Status, Malnutrition, and Wasting Syndrome

Growth delay affecting both height and weight is one of the earliest effects of HIV disease in infants and children. Serial measurements of height, weight, and head circumference are an essential component of diagnosis. Nutrition intervention should begin before a child is malnourished. Preventive measures should be taken at the onset of alterations in nutritional status. Altered nutritional status for children with HIV infection is defined by 1) weight growth velocity that is <5% for >2 months; 2) a decrease in one major growth percentile channel for weight; 3) weight percent standard or weight-for-height percent standard that is <90%; 4) weight for height that is <5%; 5) a loss of >5% of lean body mass; or 6) serum albumin that is <3 g/dL.²¹⁹

The diagnosis of malnutrition can be made simply by determining accurately weight and height and weight-for-height percentile. Malnutrition is classified as mild, moderate, or severe based on height and weight parameters for age as described by Waterlow.²²⁰Children who are 90% to 100% of standard (50th percentile) weight-for-height are normal; children who are 80% to 90% of standard weight-for-height are mildly malnourished; children who are 70% to 80% of standard weight-for-height are moderately malnourished; and children <70% of standard weight-for-height are severely malnourished.

Wasting syndrome is defined by the CDC as 1) persistent weight loss >10% of baseline; 2) downward crossing of at least two of the following percentile lines on the weight-for-age chart (eg, 95th, 75th, 50th, 25th, 5th) in a child 1 year of age or older; or 3) <5th percentile on weight-for-height chart on two consecutive measurements ≥30 days apart, in addition to chronic diarrhea (ie, at least two stools per day for ≥30 days) and documented intermittent or consistent fever for ≥30 days. These signs and symptoms should not be attributable to any concurrent illness.²²¹

Guidelines for Evaluation of Nutritional Status

Estimating Energy Requirements

Asymptomatic adults with HIV infection have increased resting energy expenditure and total energy expenditure,²²²but preliminary data in children with HIV infection suggest that resting energy expenditure is not increased in those children with failure to thrive.²²³ Clinical experience suggests that energy requirements are normal during times of well-being, but that the child with HIV infection may not compensate for periods of stress (eg, infection) when energy requirements are increased.

The Recommended Daily Allowance (RDA) is the most convenient standard for determining caloric needs. Alternatively, resting energy expenditure plus activity or stress factors (eg, febrile illness) could be used to estimate energy requirements, although the specific energy requirements, engendered by HIV infection itself, are not yet known. During times of stress, caloric requirements may increase to 150% of the RDA.

• Download figure
• Open in new tab
• Download powerpoint

Treatment of Nutritional Deficiency

The approach to maximizing nutritional support and avoiding malnutrition in children with HIV infection is accomplished by attention to the following goals of nutritional management: 1) treat underlying gastrointestinal or infectious diseases that interfere with nutrient intake, absorption, or increase nutrient loss; and 2) provide sufficient nutrition for catch-up growth.

Summary

Nutritional intervention should be integrated into the care plan for all HIV-exposed and -infected children. Because nutritional issues affect the entire family, to have an impact, therapy must be directed at the family unit. Efficacy of medical treatment and quality of life are improved by developing a nutritional strategy that maintains appropriate growth and physical activity. These guidelines are intended to provide a basis for intervention; however, for implementation, they require the participation of a multidisciplinary team including nurses, nutritionists, pharmacists, physicians, and social workers.

Neuropsychological Complications of HIV Infection

Neurologic/Psychometric Testing

Psychometric/neurodevelopmental/neurobehavioral testing of infants and children should be correlated with clinical neurologic, neuroimaging, and laboratory assessments. Periodic evaluations are integral to the care of pediatric patients with HIV infection, especially those with neurologic abnormalities or developmental delays, or those receiving antiretroviral therapy. Psychometric evaluations should be performed or supervised by a licensed psychologist, preferably one with experience in the social and medical confounders often present in this population, using standardized tests of global mental abilities with reliable age norms. Scheduling follow-up testing will require adaptation to the particular circumstances of the patient and resources available in a particular geographic region. However, because neurologic surrogate markers are important for treatment decisions, ideally the schedule outlined inTable 17 should be considered. To reduce the burden of testing, there can be some consideration for using more abbreviated testing tools, such as screening devices, and more extensive assessments if a problem is identified. If PE is suspected, confirmatory adjunctive testing should be considered (Tables 12, 17).

Other Neurologic Disorders

There are other noteworthy neurologic disorders that occur in association with HIV infection. It is imperative to differentiate those resulting from HIV infection or associated immune deficiency from secondary opportunistic infection (OI), other organ system dysfunction, or etiologies unrelated to HIV infection.

Psychiatric and Behavioral Manifestations

There is increasing evidence of significant neurobehavioral aberrations in HIV-infected children.²⁴⁸ As in adults, overt symptoms are likely attributable to organic pathology of the CNS, particularly if associated with clinically diagnosed PE or a concomitant CNS OI. However, a significant portion of overt psychiatric symptoms in children likely results from reaction to chronic illness, environmental and social issues, familial or genetic predisposition, SE, or drug toxicities. Frank psychosis or primary depression is rarely reported in children but may be underrecognized. Autistic symptomatology in children with PE also has been described. Emotional and behavioral manifestations of HIV in preschool and school children are predominantly disorders of attention, particularly attention deficit/hyperactivity disorder (ADHD), but also may include depression, anxiety, adjustment disorders, and learning disabilities.²⁴⁸ Coping with their own chronic illness, and often that of other family members as well, adds emotional and behavioral stress to the lives of children with HIV infection.

Treatment of Neuropsychological Complications of HIV Infections

As it has become clear that a significant number of children with HIV/AIDS develop clinical neurologic and behavioral difficulties, it has become necessary to develop treatment regimens that are effective and safe in the CNS/peripheral nervous system, as well as are effective prophylactic regimens. Antiretroviral drugs are also essential in reversing the ravages of PE, but other adjunctive nonpharmacologic and nutritional therapies are important in improving the quality of life of these children.

Treatment of CNS/PNS Complications

Treatment of Psychiatric and Neurobehavioral Complications

The treatment of psychiatric and neurobehavioral problems represents a difficult but essential task. In addition to improving a child or adolescent's overall quality of life, when effective, such treatments afford additional benefits including those that accrue to improved compliance with treatment regimens and better adherence to reducing high-risk transmission behaviors.

Psychoactive Medications

Summary

In addition to severe immune deficiency and multiorgan dysfunction, CNS impairment is a major consequence of HIV infection; infants and children are uniquely at risk for the encephalopathic effects of HIV, particularly if infection occurs during early stages of fetal or neonatal brain development. There is a wide spectrum of neurologic and behavioral manifestations of PE, but alternative underlying non-HIV conditions must be considered in the differential diagnosis. Although rare in infants and young children, CNS OI also can precipitate neurologic or psychiatric dysfunction or may mimic or confuse the diagnosis of PE. PE is a clinical diagnosis established by serial psychometric testing and clinical neurologic examinations and may be supported by neuroimaging, immunologic, and virologic studies; such tests and evaluations also are important surrogate markers for antiretroviral drug efficacy. Table 17 summarizes the recommended schedule for psychometric and neurologic studies.

Antiretroviral therapies available currently have proven efficacy in improving neurologic manifestations of HIV. However, some debilitating neuromuscular toxicities have been reported. As antiretroviral therapies improve, the CNS may become an important harbor for HIV viral particles that elude elimination or suppression. Such scenarios will only add to the growing need for developing innovative adjunctive therapies directed at specific neuropathogenic pathways. There has been a gratifying overlap in preventing certain CNS OI with systemic OI prophylaxis; however, individual cases may need specific CNS OI prophylaxis/treatment.

In addition to implementing antiretroviral therapy and OI prophylaxis/treatment, attention should be given to maximizing motor and language function, alleviating pain, integrating in the educational setting when possible, and instituting psychotherapy and/or psychoactive medications when needed. Adverse behavioral patterns may respond to combinations of behavioral modification regimens and drug therapies; underlying treatable causes should be explored. Correction of nutritional deficiencies and, in certain cases, supplementation, is essential. As the pendulum of the epidemic has swung from dying with AIDS to living with HIV infection, diagnostic studies and therapeutic interventions must be tempered carefully with maximizing quality of life.

Palliative Care and Pain Management in HIV Infection

Children who have HIV infection, regardless of the stage of illness, complications, or goals of care, often are highly symptomatic. An evolving discipline, pediatric palliative medicine is focused on the management of the physical, psychological, and spiritual problems inherent in life-threatening illnesses regardless of these variables. Pain management for children with HIV infection is one component of a comprehensive program providing palliative care for these children.

Summary

Table 19 provides a summary of the major issues raised in this discussion of palliative care and pain management in infants, children, and adolescents with HIV infection. Appropriate attention to palliative care and pain management has a profound and direct impact on quality of life and should be part of the overall management plan for all children with HIV infection.