Viramune in combination with nucleoside analogues has been approved by the FDA under its accelerated approval program.
In the first major study presented, ACTG 241, a randomized, double blind, placebo-controlled trial, researchers followed 398 subjects for 48 weeks at 16 participating investigational sites. All subjects entering the study had advanced HIV infection with CD4 cell counts of less than or equal to 350 (mean CD4 cell count for these patients was 153). The study compared the combination of AZT, ddI, and viramune to the combination of AZT, ddI, and placebo. Subjects in this trial had received extensive prior nucleoside therapy. The ACTG 241 study found that the combination of AZT, ddI, and viramune increased CD4 cell count significantly more than AZT, ddI, and placebo combination. In a substudy, viral markers were followed. In these subjects the combination of AZT, ddI, and viramune, reduced the viral load significantly more than AZT, ddI, and placebo, throughout the 48 weeks of the trial. The clinical significance of changes in viral RNA has not been established.
The second major study presented, BI 1046, an international randomized, double blind, placebo-controlled trial, investigated viramune in previously untreated subjects. The six-month results from this twelve-month study compared the combinations of AZT, ddI, and viramune; AZTand ddI; and viramune and AZT in 151 HIV-1 infected subjects with CD4 counts between 200 and 600. Changes in CD4 counts through 28 weeks: levels of CD4 in those randomized to AZT plus ddI plus viramune, and AZT plus ddI remained significantly above baseline; however there was no significant difference between these arms. The triple drug regimen containing viramune decreased the viral load below the limit of detection in about two-thirds of the subjects, which was significantly greater than either double therapy regimen.
In controlled clinical trials, the most common viramune side effect was rash, which in 7.6% of subjects was considered severe. Increases in the liver enzymes occurred in 5-10% of subjects compared with 2-5% in controls. No data are available on disease progression or survival, however clinical endpoint studies are underway.
Viramune is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which has a different mechanism of action and a distinct side effect profile from other classes of currently approved antiretrovirals. While the nucleoside analogues prevent the growth of the DNA chain, non-nucleoside drugs directly inactivate the enzyme.