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.The current most recommended management of HIV-infected pediatric subjects and adults dictates the use of combination therapies, generally consisting of two nucleoside reverse transcriptor inhibitors (NRTI) and one protease inhibitor (PI). However, the available treatment regimens for pediatric subjects are limited. There are few PIs available in formulations appropriate for young pediatric subjects. Many pediatric subjects are beginning to experience virologic failure on their present PI containing regimens due to incomplete virologic suppression, which invariably leads to drug resistance and virologic rebound. Furthermore, poor adherence to complicated treatment regimens is an important factor that significantly affects the choice of drug combinations, as well as subsequent virologic response. The development of potent combination therapies with proven efficacy but less complicated dosing schedules and/or alternative drugs to PIs, such as non- nucleoside reverse transcriptase inhibitor (NNRTI), is critical to improving the outcome for HIV-infected pediatric subjects. Thus, this study will assess the safety, tolerance, antiviral activity and pharmacokinetics of a once-daily regimen containing two NRTIs, emtricitabine (FTC) (Coviracil) and didanosine (ddI) (VIDEX), and one NNRTI, efavirenz (EFV) (Sustiva) as an effective alternative to PI containing regimens. A pilot study of FTC + ddI + EFV in treatment-naive HIV-infected adults as once-daily dose regimen has been conducted to assess the efficacy and safety of this regimen (The ANRS 091 Trial). The study was originally designed as a 24-week open-label protocol in 40-antiretroviral naive HIV-1 infected adults. However, subjects are still on study treatment and recently completed 64 weeks of treatment. Eligible subjects had a CD4 cell count >100/mm3 and a plasma HIV-RNA >5000 copies/mL at baseline. All three drugs were taken once-a-day at bedtime, FTC (200 mg), ddl (400 mg if >60 Kg; 250 mg if <60 Kg) and EFV (600 mg). The baseline characteristics of the study population were as follows: the mean age was 33 years, 88% men, 92% classified as CDC disease stage A, and a median CD4 count of 373 cells/mm3. Subjects were seen at weeks 2, 4 and every 4 weeks of treatment. The study results show that at week 12, 39 of 40 subjects who started treatment had a viral load (VL) <400 copies/mL, and 20 (50%) had a VL <20 copies/mL. Mean decrease in plasma HIV-RNA was 3.14 log10copies/mL. Mean increase in CD4 count was 120 cells/mm3. At week 24, a sustained decrease in VL was noted, with 37/40 (93%) subjects achieving < 50 copies/mL. At week 48, 95% of subjects (38/40) maintained a plasma HIV-RNA below 400 copies/mL. No subject was lost to follow-up. One subject was off therapy, and one subject experienced a virologic failure and switched to a PI containing regimen. The analysis of the data up to week 48 of treatment shows no Grade 3 or 4 adverse events were reported, and the most common treatment related adverse events occurred during the first 24 weeks of treatment. These reported events were, twenty-nine subjects (73%) experienced transient central nervous system adverse events, four subjects (10%) experienced rash, and 13 subjects (33%) reported mild diarrhea. The FTC-EFV-ddI combination regimen provides strong HIV-1 RNA suppression by 48 weeks in treatment naive adult subjects as shown by 95% of the subjects reaching <400 copies/mL. In comparison, data from an open-label study of once-a-day lamivudine (3TC) + EFV + ddI in treatment naive adults showed that 60% of the subjects had viral loads under 50 copies/mL at 48 weeks of treatment. The latest update for ANRS 091 trial presented at the 8th Conference of Retrovirus and Opportunistic Infectious in Chicago, showed that at week 64, 90% of subjects (36/40) maintained a plasma HIV RNA below 400 copies/mL. One subject was lost to follow-up, two subjects were off therapy, and one subject experienced a virological failure. Median baseline CD4 count was 373 cells/mL, increasing by a median of 159 and 219 cells/mL at weeks 24 and 64, respectively. This pilot study concludes that FTC + EFV + ddI is a potent and well tolerated once-a-day highly active antiretroviral therapy (HAART) regimen that deserves further evaluation not only in naive adults but also in naive pediatric subjects.

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General Clinical Research Centers Program (M01)
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Baylor College of Medicine
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