Efavirenz (Sustiva, Du Pont Pharmaceuticals), a non-nucleoside reverse transcriptase inhibitor (NNRTI), may be substituted for a protease inhibitor as part of a triple-drug regimen for children with HIV, according to changes in the pediatric AIDS treatment guidelines.
"Recent data, primarily from adults, with the use of efavirenz in place of the protease inhibitor, may support the substitution of efavirenz," said the guidelines, which recommended combination therapy for all infants, children and adolescents who are treated with antiretroviral agents.
"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 guidelines state.
When the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection were first released in April 1998 they recommended a preferred regimen of combination therapy of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and a protease inhibitor. When the guidelines were updated in February, the recommendation included an alternative: to substitute efavirenz for the protease inhibitor with two NRTIs.
The change is based on new data regarding safety, dosing, and virologic and immunologic efficacy of efavirenz. The new data comes primarily from testing in adults, however, there is one study of children as young as 3 years old. The Ped iatric Aids Clinical Trials Group study number 382 (PACTG 382) was an open-label study of efavirenz with nelfinavir (Viracept, Agouron) and NRTIs in 57 children with HIV.
In a preliminary intent-to-treat analysis, after 20 weeks of therapy, 65% of the children had plasma HIV RNA levels of < 400 copies/mL, and 52% had viral loads levels of < 50 copies/mL.
However, using this drug in pediatrics will be difficult, the guidelines cautioned. "There are currently no pharmacokinetic data available on appropriate dosage of efavirenz in children under age 3 years, and although a liquid preparation is currently under study, only a capsular formulation is available," they said.
The only hard and fast rule of the pediatric HIV treatment guidelines is that treatment regimen is patient specific. In other words, that there are no hard and fast rules. Instead, the guidelines serve as just that - guidelines - to help pediatricians choose from among various treatment options. "Because the standard of care for HIV children is not as well defined as it is for HIV adults, the guidelines give pediatricians a range of options," said Ram Yogev, MD, of Children's Memorial Hospital in Chicago, and a member of the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, which produced the guidelines. "Slowly, we are shifting to a more aggressive treatment regimen, but the guidelines are still a con sensus of the Working Group, and they only recommend"; they don't dictate.
The guidelines help physicians decide when to initiate therapy, what drug regimen to initiate and when to change therapy; they help pediatricians make some sense of the confusion in dealing with multiple drugs and the myriad situations that may confront them in trying to deal with these complicated cases.
Antiretroviral therapy is recommended for HIV-positive children with clinical symptoms of HIV infection or evidence of immune suppression regardless of the child's age or viral load. Antiretroviral therapy in symptomatic patients slows clinical and immunologic disease progression and reduces mortality, according to the guidelines.
"HIV-infected infants aged less than 12 months are considered at high risk for disease progression," the guidelines said "and the predictive value of immunologic and virologic parameters to identify infants who will have rapid progression is less than that for older children."
Identifying infection during the first few weeks of life permits physicians to initiate antiretroviral therapy or intensify chemoprophylaxis if that child was on a zidovudine (AZT, Retrovir, Glaxo Wellcome) regimen to prevent perinatal transmission, the guidelines said.
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), physicians should determine whether adherence to the regimen will be an issue. It may be better, in some cases, to delay treatment if compliance is an issue. Whether or not a very young child will be compliant often depends on the caregiver; often a parent who has HIV is unable to comply to both his or her regimen and the child's.
In one extreme example, Yogev told of a young patient who died. After the funeral, the family returned bags of unused medication that were prescribed for that child.
Also, characteristics of the medications can be a factor in adherence. Some medications do not come in a liquid form, which make them difficult for children to take. Some just taste terrible, and anyone who has tried to give a 2-year-old a nasty tasting medication, knows the inherent problem with taste.
Two general approaches for initiating therapy in asymptomatic children 1 year and older were outlined by the Working Group. The first approach would be to initiate therapy in all HIV-infected children, regardless of age or symptoms. This approach would ensure treatment of infected children as early as possible and intervention before immunologic deterioration. Data from prospective cohort studies indicate that most infants with HIV will have HIV symptoms by age 1 year. Most asymptomatic children older than 1 year also have CD4 T-lymphocyte percentages of < 25%, which is indicative of immunosuppression and warrants antiretroviral therapy.
An alternative approach, according to the guidelines, would be to defer treatment in asymptomatic children 1 year and older with normal immune status when the risk for clinical disease progression is low (for instance, the child has a low viral load) and when other factors, such as compliance and safety, favor postponing treatment. If treatment is deferred, the physician should regularly monitor virologic, immunologic and clinical status.
The guidelines said factors to consider in deciding when to initiate therapy include high or increasing HIV RNA levels, rapidly declining CD4+ T-lymphocyte number or percentage to values approaching those that indicate moderate immune suppression, or development of clinical symptoms. Viral loads, which indicate an increased risk for disease progression, are 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, and antiretroviral therapy should be initiated - regardless of clinical or immune status. HIV RNA levels in asymptomatic children 30 months or older 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. In addition, any child with viral loads that demonstrate a substantial increase (> 0.7 log10 increase for children aged younger than 2 years and > 0.5 log10 increase for those 2 years and older) after 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," the guidelines said.
The guidelines spend a considerable amount of time addressing issues associated with adherence to treatment, which 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," the guidelines said. "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."
The guidelines clearly recommended combination therapy for all infants, children, and adolescents who are treated with antiretroviral agents. "When compared with monotherapy, combination therapy slows disease progression and improves survival, results in a greater and more sustained virologic response, and 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," the guidelines said.
"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 guidelines said. "The goal of antiretroviral therapy is to maximally suppress viral replication, preferably to undetectable levels."
"We understand better now to keep the child at a lower number of virus. The benchmark was 100,000, now it's down to 10,000 to 20,000," Yogev explained.
Because the treatment regimens are so complex, a patient has a better chance of survival if the physician has many HIV patients. Yogev recommended that pediatricians treating children with HIV consult the guidelines on the Internet at www.cdc.gov and confer with members of the working group before initiating or changing treatment. "Call the experts. Check the Internet, we will keep trying to update you. The knowledge of HIV in children is changing so fast, there is no way we can have hard and fast rules to treat the disease. The more we learn about it, the more we have to change the rules," Yogev said.
You can express your views on this article, or other relevant themes, in the Infectious Diseases in Children Specialty Forums.