The non-nucleoside reverse transcriptase inhibitors (NNRTIs), Sustiva (efavirenz) and Viramune (nevaripine), are now very commonly used as part of first-line HAART regimens. Previously, there was no data directly comparing the two NNRTIs nor the combination of the two. The eagerly awaited 2NN study, presented by the International Antiviral Therapy Evaluation Center (IATEC) at the 10th CROI, compared the efficacy and safety of Sustiva and Viramune in a open-label large-scale, randomized multicenter head-to-head trial. In this 48-week analysis, 1,216 people were randomized to either Viramune 400mg once daily, Viramune 200mg twice daily, Sustiva 600mg once daily, or Sustiva 800mg + Viramune 400mg once daily. All persons received a HAART backbone of Epivir + Zerit (d4T), but this was altered if necessary due to toxicity. Eighty-four percent of participants completed the 48 weeks of the study.
This study compared the percentage of people who developed treatment failure, the number of people who attained viral suppression, the increase in the number of CD4 cells, and the incidence of adverse events. The participants in all the groups were similar at baseline (median CD4 cell count 190 cells/mm3, median viral load (VL) of 4.7 log copies/ml). There were no significant differences in treatment success (viral suppression or change in the CD4 count) among all four treatment arms. The proportion of individuals who were considered a treatment success at 48 weeks was 56 percent in the once-daily and twice-daily Viramune group, 62 percent in the Sustiva group, and 47 percent in the dual-NNRTI group. The only statistical difference in efficacy was seen between the Sustiva and the dual-NNRTI group. Surprisingly, Viramune and Sustiva alone were clinically better than the combination mainly because there was less toxicity and therefore fewer dropouts.
Since all the treatment arms had similar efficacy, the focus turned to the number of adverse events in each group. The two Viramune arms had more liver toxicity and rash, but a better lipid profile and less central nervous system effects (CNS effects include sleep disturbance, abnormal dreams, and anxiety) than Sustiva. It appears that once-a-day Viramune is as effective as twice-a-day, but may have more side effects. Twenty-five participants died during the study, and two were attributable to Viramune (one liver toxicity, one severe rash). In conclusion, two NNRTIs are not better than one. The decision to use Viramune or Sustiva as part of a first-line regimen, given their similar efficacy, should be based upon the acceptability of the adverse event profile to the physician and HIV-positive individual.
| ||Viramune Once a Day|
(N = 220)
|Viramune Twice a Day|
(N = 387)
(N = 400)
|Viramune + Sustiva|
(N = 209)
|Patients who changed tx (%)||29||22||20||34.5|
|Treatment failure (%)||44||44||38||53|
|Suppressed VL (%)||70||65||70||63|
|CD4 increase (cells/mm3)||170||160||160||150|
|Total clinical adverse events (%)||28||27||22||35|
|CNS side effects (%)||2||5||6.5||8|
|Grade 3-4 liver lab abnormalities (%)||13||8||4.5||9|
|Other lab abnormalities (%)||8||13||9||10|