This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACT HYPOTHESIS Intuitively one would suspect that a once-daily regimen would be better than a twice-daily regimen, but currently no such regimen exists. There are once-daily dosing drugs such as efavirenz (Sustiva ), but they still require the addition of drugs that are administered twice daily. In choosing lopinavir/ritonavir (Kaletra ) as the protease inhibitor and efavirenz (Sustiva ) as the non-nucleoside reverse transcriptase inhibitor (NNRTI), a regimen that would be more forgiving of missed doses was intentionally chosen. Both of these drugs have long half-lives that make them the ideal drugs to be used in the adolescent population. But within the REACH cohort, those adolescents who were reported non-adherent, the most frequent reasons cited were forgetting medication, not having their medication with them, experiencing a change in daily routine, and sleeping through their dose.Efavirenz (Sustiva ) is available as one 600mg capsule. The lopinavir/ritonavir (Kaletra ) dose is 3 capsules twice-daily. These regimens have minimized the burden of pill taking for adolescents.The rationale for using therapeutic drug monitoring (TDM) with efavirenz (Sustiva ) and lopinavir/ritonavir (Kaletra ) is based on the observation of inter-individual variability in drug plasma levels. In a study conducted in Switzerland (Marzolini et. al., 2001), 226 efavirenz (Sustiva ) plasma levels were obtained from 130 HIV-infected individuals who had been on an efavirenz (Sustiva ) containing regimen for at least 3 months. The blood samples were obtained 14 hours (on average) after drug intake. There was marked inter-patient variability in the efavirenz (Sustiva ) plasma levels. Virologic failure was observed in 50% of patients with low efavirenz (Sustiva ) levels (<1000 micrograms/l) and CNS toxicity was approximately three times more frequent in patients with high efavirenz (Sustiva ) levels (>4000 micrograms/l) compared with patients with 1000-4000 micrograms/l. Measuring efavirenz (Sustiva ) and lopinavir/ritonavir (Kaletra ) plasma levels and adjusting the doses accordingly should lead to a better virological outcome.
SPECIFIC AIMS Primary ObjectivesTo compare the effectiveness of a PI-containing (2 NRTIs + lopinavir/ritonavir (Kaletra)) and a PI-sparing (2 NRTIs + efavirenz (Sustiva)) HAART regimen in adolescents.To determine if therapeutic drug monitoring (TDM) of either lopinavir/ritonavir (Kaletra) or efavirenz (Sustiva) with dose adjustment of either of these two drugs improves virologic response.Secondary ObjectivesTo measure adherence by MEMS caps, subject self-report, trough concentrations and pill count, and to compare these measures.To compare adherence to therapy in the two HAART treatment arms and to correlate adherence with the virologic outcome.To determine the frequency and severity of symptoms of psychological distress and CNS side effects in all treatment arms.To determine the safety profiles of the study medications and the TDM strategy.To determine time to virologic failure for each of the study arms.To determine the prevalence of HIV resistance mutations at baseline among subjects who fail therapy.To determine the relative contribution of viral resistance, inadequate drug dosage, symptoms of psychological distress and CNS side effects, and poor adherence to the failure of HAART in adolescents.To determine the prognostic significance of pre-therapy immune status in predicting response to therapy.To define unique aspects of immune reconstitution in HIV-infected adolescents.
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