Capravirine, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), failed to control HIV better than placebo in a 48-week study of people with resistance to NNRTIs, according to a report at the Twelfth Conference on Retroviruses and Opportunistic Infections held in Boston, Massachusetts. However, a subgroup analysis suggested that a regimen including capravirine, nelfinavir, and two nucleoside reverse transcriptase inhibitors (NRTIs) had some activity against virus resistant to both zidovudine and lamivudine.
In vitro studies indicate that capravirine is able to inhibit some HIV strains resistant to current NNRTIs. Laboratory work also suggests that resistance to capravirine evolves more slowly than to other NNRTIs, Rick Pesano, MD, PhD reported.
The current trial randomised people taking a failing NNRTI regimen to receive 700mg or 1400mg of capravirine twice daily or placebo. All participants also received twice-daily nelfinavir and two NRTIs picked on the basis of treatment history and genotype. None of the 179 study participants had been previously treated with a protease inhibitor.
Trial enrollees had moderately advanced disease, with an average viral load around 4.4 log copies/mL and median CD4 counts of 206 cells/mm3 in the placebo group, 248 cells/mm3 in the 700-mg capravirine group, and 249 cells/mm3 in the 1400-mg capravirine group. Resistance to NRTIs and NNRTIs was similar across the study arms.
Pesano reported 48-week failure rates—defined as failure to reduce the viral load by 0.5 log by Week 4, or rebounding after a 0.5 log reduction—of 24% with placebo, 15% with 700 mg of capravirine, and 13% with 1400 mg, differences that were not statistically significant. The reductions in viral load from baseline to Week 48 also did not differ significantly: 2.1 logs, 2.3 logs, and 2.4 logs, respectively.
A 48-week noncompleter-equals-failure analysis determined that 58% of patients taking 1400 mg of capravirine twice daily had a viral load below 400 copies/ml, compared with 43% taking 700mg twice daily, and 46% taking placebo. These differences also fell short of statistical significance.
In a preplanned analysis of nonrandomised subgroups who began treatment with virus resistant to zidovudine and lamivudine, 54% in the 1400mg group had a viral load under 400 copies/ml at Week 48, compared with 36% taking 700mg, and 31% taking placebo. This trend was not statistically significant, however.
The better noncompleter response with 1400mg of capravirine partly reflects the high dropout rates in the other 2 arms—44% with placebo, 42% with 700mg capravirine, and 30% with 1400mg capravirine. Whereas 15% of patients stopped the 700mg dose because of side effects, 7% stopped the 1400-mg dose for that reason.
Diarrhoea affected 65% in the 1400mg group and 53% in the 700mg group. However, diarrhoea also was reported by 49% given placebo, and the incidence of diarrhea in all treatment arms may have been due to nelfinavir therapy. Rates of nausea were 35% with 1400mg, 27% with 700mg, and 20% with placebo.
Dr. Pesano noted that the high failure rates in all three study arms came as a surprise, since people started nelfinavir with no protease inhibitor experience and also began carefully chosen NRTIs. The study outcomes will be further scrutinized as the development of capravirine continues.
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Pesano R et al. 24-week safety, tolerability, and efficacy of capravirine as add-on therapy to nelfinavir and 2 nucleoside reverse transcriptase inhibitors in patients failing a nonnucleoside reverse transcriptase inhibitor-based regimen. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 555, 2005.