TREATMENT RECOMMENDATIONS
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Initiation of Antiretroviral Therapy
General Considerations
Antiretroviral therapy has provided substantial clinical benefit to HIV-infected children with immunologic or clinical symptoms of HIV infection. Studies have demonstrated substantial improvements in neurodevelopment, growth, and immunologic and/or virologic status with initiation of ZDV, didanosine (ddI), lamivudine (3TC), or stavudine monotherapy (48-53). More recent pediatric trials of symptomatic children who have not previously received antiretrovirals have demonstrated that combination therapy with either ZDV and 3TC or ZDV and ddI is clinically, immunologically, and virologically superior to monotherapy with ddI or ZDV as initial therapy (36, 54, 55). A trial involving children who have previously received antiretrovirals has demonstrated that combination therapy that includes a protease inhibitor is virologically and immunologically superior to dual nucleoside combination therapy (56).
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 that are observed during the first 1-2 years of life following 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 set point, and result in improved clinical outcome.
In a preliminary study of early treatment of children, six HIV-infected infants aged 2-4 months were placed on a regimen of ZDV, ddI, and nevirapine; baseline HIV RNA levels were 40,000-1,500,000 copies per 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 (57). These two children had persistently negative HIV cultures, 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 theoretical problems with early therapy include the potential for short- and long-term adverse effects -- particularly for drugs being administered to infants aged <6 months, for whom information on pharmacokinetics, drug dosing, and safety is limited. These concerns are particularly relevant because life-long administration of therapy is likely to be necessary for HIV-infected infants. 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. Therefore, 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 a) potential problems and solutions can be identified and b) 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 (i.e., those in clinical categories A, B, or C) (Table 2) or evidence of immune suppression (i.e., those in immune categories 2 or 3) (Table 1) --regardless of the age of the child or viral load (Table 7). Clinical trial data from both adults and children have demonstrated that antiretroviral therapy in symptomatic patients slows clinical and immunologic disease progression and reduces mortality (54, 55, 58).
Ideally, antiretroviral therapy should be initiated in all HIV-infected infants aged <12 months as soon as a confirmed diagnosis is established -- regardless of clinical or immunologic status or viral load. HIV-infected infants aged <12 months are considered at high risk for disease progression, and the predictive value of immunologic and virologic parameters to identify infants 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 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 available, and information on drug dosing in neonates is limited. Because resistance to antiretroviral drugs (particularly protease inhibitors) 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 infants caregivers before the decision to initiate therapy is made.
Two general approaches for initiating therapy in asymptomatic children aged >1 year were outlined by the Working Group. The first approach would be to initiate therapy in all HIV-infected children, regardless of age or symptom status. Such an approach would ensure a) treatment of infected children as early as possible in the course of disease and b) intervention before immunologic deterioration. Data from prospective cohort studies indicate that most HIV-infected infants will have clinical symptoms of infection by age 1 year (59,60). Most asymptomatic infected children aged >1 year also have CD4+ T-lymphocyte percentages of <25% (60), which is indicative of immunosuppression (Table 1) and warrants antiretroviral therapy.
An alternative approach would be to defer treatment in asymptomatic children aged >1 year with normal immune status in situations in which the risk for clinical disease progression is low (e.g., low viral load) and when other factors (e.g., concern for adherence, safety, and persistence of antiretroviral response) favor postponing treatment. In such cases, the healthcare provider should regularly monitor virologic, immunologic, and clinical status. Factors to be considered in deciding when to initiate therapy include a) high or increasing HIV RNA levels, b) rapidly declining CD4+ T-lymphocyte number or percentage to values approaching those indicative of moderate immune suppression (i.e., immune category 2 [Table 1]), or c) 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 (Table 4), and antiretroviral therapy should be initiated -- regardless of clinical or immune status. HIV RNA levels in asymptomatic children aged >30 months that are the same as levels for which there are treatment recommendations for HIV-infected adults (e.g., >10,000- 20,000 copies/mL) also may indicate the need to initiate treatment (Table 6). In addition, any child with HIV RNA levels that demonstrate a substantial increase (more than a 0.7 log10 [fivefold] increase for children aged <2 years and more than a 0.5 log10 [threefold] increase for those aged >2 years) 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.
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 protease inhibitors, 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 who are treated with antiretroviral agents (Table 8). When compared with monotherapy, combination therapy a) slows disease progression and improves survival, b) results in a greater and more sustained virologic response, and c) delays development of virus mutations resistant to the drugs being used. Monotherapy with the currently available antiretroviral drugs 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 who are identified as being HIV-infected while receiving ZDV chemoprophylaxis should be changed to a combination antiretroviral drug regimen.
Aggressive antiretroviral therapy for primary perinatal infection with three drugs is recommended because it provides the best opportunity to preserve immune function and delay disease progression. The goal of antiretroviral therapy is to maximally suppress viral replication, preferably to undetectable levels. Based on clinical trials involving infected adults, the preferred regimen is combination therapy with two NRTIs and one protease inhibitor. Although these combinations have had limited evaluation in clinical trials involving children, they can reduce HIV RNA to undetectable levels in some children (61, 62). An interim analysis from a clinical trial of children (i.e., PACTG protocol 338) has demonstrated that therapy with drug combinations that include a protease inhibitor is more effective than therapy with two NRTI antiretroviral drugs in reducing viral load to undetectable levels and increasing CD4+ T-lymphocyte number (56). 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 most likely will become available, which will increase treatment options for children in the future.
Protease inhibitors with formulations appropriate for infants and children who cannot swallow pills include nelfinavir (Viracept ® , manufactured by Agouron Pharmaceuticals, Inc., La Jolla, California), available in a powder formulation that can be mixed with water or food, and ritonavir (Norvir ® , manufactured by Abbott Laboratories, North Chicago, Illinois), available in a liquid formulation. Optimal dosing of these drugs in children aged <2 years is not known but is being evaluated in clinical trials (See Appendix). Indinavir (Crixivan ® , manufactured by Merck and Company, Inc., West Point, Pennsylvania) and saquinavir (hard gel capsule, Invirase, and soft gel capsule, Fortovase, manufactured by Hoffmann-LaRoche, Inc., Nutley, New Jersey) are not available in liquid formulations. Indinavir is recommended for consideration 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 (See Appendix).
The hard-gel capsule formulation of saquinavir (Invirase) has limited bioavailability and thus is not recommended for use with two NRTIs. Some studies have indicated substantial increases in saquinavir drug levels when coadministered with other protease inhibitors (e.g., ritonavir) or other drugs that inhibit the cytochrome P450 enzyme system. However, data regarding such combinations in children are not available. The soft-gel formulation of saquinavir (Fortovase) with enhanced bioavailability has been approved by the Food and Drug Administration (FDA) for treatment of HIV infection in adults; however, data regarding appropriate dosing of this formulation in pediatric patients are not available.
Alternative regimens, although not ideal, 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 been clinically beneficial in adult and pediatric patients, but these regimens may not suppress viral load to below detectable levels as consistently as does combination therapy with two NRTIs and a protease inhibitor. Such alternative regimens include combination regimens of two NRTIs with nevirapine substituted for the protease inhibitor or two NRTIs 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.
The initial antiretroviral regimen chosen for infected infants theoretically could be influenced by the antiretroviral regimen their mother may have received during pregnancy. However, data from PACTG protocol 076 indicate that ZDV resistance did not account for most infants who became infected despite maternal ZDV treatment (63), and data from PACTG protocol 185 indicate that duration of prior 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 (64). Data do not suggest that the antiretroviral regimen for infected infants 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.
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 pharmacokinetics studies performed in full term infants (65). Because ZDV is primarily cleared through hepatic metabolism (i.e., glucuronidation), which is immature in neonates, the half-life and clearance of ZDV are prolonged in neonates compared with older infants, thus requiring adjustments in dosing (See Appendix).
Premature infants have even greater immaturity in hepatic metabolic function than do full-term infants, and further prolongation in clearance has been documented in very premature infants (e.g., those born before 34 weeks gestation) (66). Appropriate ZDV dosing for premature infants has not been defined but is being evaluated in a phase I clinical trial of premature infants born before 34 weeks gestation (i.e., PACTG protocol 331) (See Appendix).
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 (67, 68). Clearance was prolonged in these infants. On the basis of data from this study, the dose recommended for use in newborns is half the dose recommended in older children (See Appendix). No data are available regarding 3TC pharmacokinetics among infants aged 2-6 weeks, and the exact age at which 3TC clearance begins to approximate that in older children is not known.
Nevirapine administration to HIV-infected pregnant women during labor and as a single dose to their newborns at age 2-3 days has been studied in a phase I trial (69). The half-life of nevirapine was prolonged in neonates compared with that in older children, indicating that some modification of nevirapine dosage is required for administration to neonates (See Appendix).
Although phase I studies of several protease inhibitors (i.e., indinavir, ritonavir, nelfinavir, or saquinavir in combination with ZDV and 3TC) in pregnant infected women and their infants are ongoing in the United States, no data are available regarding drug dosage, safety, and tolerance of any of the protease inhibitors in neonates.
Changing Antiretroviral Therapy
When to Change Antiretroviral Therapy
The following three reasons warrant a change in antiretroviral therapy: a) failure of the current regimen with evidence of disease progression based on virologic, immunologic, or clinical parameters; b) toxicity or intolerance to the current regimen; and c) new data demonstrating that a drug or regimen is superior to the current regimen (Table 9). 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 HIV-infected persons. 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 HIV RNA assays -- which may not always be achievable in HIV-infected children. 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 patients future options for potent therapy.
Consensus recommendations have been developed using plasma HIV RNA measurements to guide changes in antiretroviral therapy for HIV-infected adults (5). The recommendations for adults state that healthcare providers should consider changing therapy if a) 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 b) HIV RNA has not decreased to undetectable levels after 4-6 months of therapy. Because HIV RNA levels in infants who are perinatally infected 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 observed in adults (i.e., 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 NRTIs and a protease inhibitor. 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.
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 time of starting therapy. If baseline HIV RNA levels are high (i.e., >1,000,000 copies/mL), virologic response may not be observed until 8-12 weeks after initiating antiretroviral therapy. However, if baseline HIV RNA levels are more similar to those observed in untreated infected adults (i.e., <100,000 copies/mL), initial response should be observed within 4 weeks following initiation of 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 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:
Immunologic Considerations for Changing Therapy
CD4+ T-lymphocyte count and percentage are independent predictors of disease progression and mortality in HIV-infected children (35, 36). 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 childs HIV RNA level (35). For children with CD4+ percentages of <15% (i.e., those in immune category 3), prognosis also was correlated with the degree of depression of CD4+ percentage (i.e., life expectancy was less for children with CD4+ percentages of <5% compared with children with CD4+ percentages of 10%-14%) (Table 3).
Before considering changing antiretroviral therapy because of a 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:
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:
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 available alternative antiretroviral agents. Although the efficacy of different combination antiretroviral regimens in children probably can be extrapolated from clinical trial data obtained for adults, data are limited regarding 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 prior treatment.
Detailed information regarding issues associated with specific drug choices for changing a failing regimen and potential cross resistance between various antiretroviral drugs is available elsewhere (5). Because these issues are similar for all HIV-infected persons (regardless of age) they are not addressed specifically in this document.
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