Final results of a major international comparative study of nevirapine or efavirenz-based triple antiretroviral therapy suggest that nevirapine-based HAART may have proved inferior to efavirenz-based therapy over 48 weeks of follow-up, contrary to initial headline findings presented at the Tenth Conference on Retroviruses and Opportunistic Infections in Boston in 2003. The full results are published in the April 17th edition of The Lancet.
However, in an accompanying commentary, Dr Andrew Carr of Sydney’s St Vincent’s Hospital warns that an inferior virological result at 48 weeks may not translate into an inferior clinical outcome in the longer term, and that the study results lack information on drug resistance patterns after treatment failure that might help clinicians make better-informed decisions about the optimal first-line regimen for patients.
The study, called 2NN, compared four regimens using a nucleoside analogue backbone of stavudine and lamivudine (d4T/3TC), and randomised participants to receive either nevirapine twice daily (200mg), nevirapine once daily (400mg), efavirenz once daily (600mg) or efavirenz (800mg) plus nevirapine (400mg) once daily. The study was open label, which means that all participants knew which drugs they were taking.
The study recruited 1216 treatment-naïve participants with HIV-1 RNA above 5,000 copies/ml, with no CD4 cell count restrictions. Patients were followed for 48 weeks. The primary endpoints of the study (each described as `treatment failure`) were failure to achieve a viral load reduction of at least -1 log10 copies/ml by week 12, or two viral load measurements above 50 copies/ml after initial suppression below this level, or clinical disease progression, or a change of treatment due to intolerance.
Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz.
The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI –0.9 to 12.8). This difference was not statistically significant but the upper limit of the confidence interval was greater than 10%, indicating that the difference between the two doses could have been as great as 12.8%, and if so, this difference would have been statistically significant. Dr Andrew Carr noted in his commentary: “2NN found that nevirapine twice daily was not equivalent to efavirenz at week 48.”
However, there were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per ml at week 48 (p=0.193).
“These results provide physicians with key scientific information necessary to confidently choose an NNRTI based on the individual needs of each of their patients,” according to lead 2NN investigator Professor Joep Lange of the Academic Medical Center in Amsterdam.
The authors note that, across the board, well known side-effects of efavirenz or nevirapine tended to occur at the lower end of the range previously reported in clinical studies of the drugs, although two deaths due to drug-related adverse events did occur in nevirapine recipients (one due to Stevens-Johnson syndrome and one due to fulminant hepatitis).
The full text of the paper reporting the 2NN study results and an accompanying commentary are available for free download from The Lancet website. Registration is required.