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NRTI Backbone Choice Affects Durability of Efavirenz- or Nevirapine-based HAART in Treatment-naive HIV patients

The calendar year in which HIV patients initiated HAART and durability of the nucleoside/nucleotide reverse transcriptase (NRTI) backbone are significant predictors of virological success and treatment failure, according to a study published in the April 6, 2009 early online edition of the Journal of Acquired Immune Deficiency Syndromes.

The 2NN study is the only large, randomized, controlled trial to compare the effectiveness of non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimens containing efavirenz (Sustiva) or nevirapine (Viramune) in treatment-naive HIV patients. This trial did not demonstrate that nevirapine was non-inferior to efavirenz, though other studies have concluded that efavirenz is more effective.

According to the authors of the current study, "important confounding factors [contributing to treatment success or failure] are calendar year of treatment and the NRTIs used," which may help explain the differences between results of cohort studies and the 2NN trial. In the present analysis, the researchers sought to determine the effects of calendar year, NRTI backbone, sex, and race/ethnicity on treatment outcome.

Using a prospective database, the investigators identified treatment-naive HIV patients who had initiated therapy using efavirenz or nevirapine with 2 NRTI backbones.

• stavudine (d4T; Zerit) plus lamivudine (3TC; Epivir)
• tenofovir (Viread) plus didanosine (ddI; Videx)

Among 994 participants in the cohort, 73% started therapy with an efavirenz-based regimen while 27% commenced therapy with a nevirapine-based regimen. 

Successful virological suppression was defined as HIV viral load less than 500 copies/mL. Treatment failure was defined as switching or discontinuing a NNRTI or 2 viral load measurements greater than 500 copies/mL.

Results

• There were no differences between efavirenz and nevirapine with regard to virological success or treatment failure:
  • 71% of patients receiving efavirenz and 72% receiving nevirapine achieved virological success (P = 0.77, not a significant difference);
  • 23% receiving efavirenz and 26% receiving nevirapine experienced treatment failure (P = 0.58, also not significant).
• Calendar year of commencing HAART had a significant effect on time to virological success and treatment failure (P < 0.001).
• The likelihood of virological success for regimens containing stavudine/lamivudine as the NRTI backbone was 52%.
• Non-thymidine analog backbones, as a group, seemed least likely to be associated with virological success (relative hazard [RH] 0.62). 
• This was largely due to the fact that the tenofovir/didanosine backbone was significantly associated with treatment failure (RH 6.48; P < 0.001).
• Sex and race/ethnicity were not significantly associated with treatment outcome.

In conclusion, the study authors wrote, "These data demonstrate that efavirenz- and nevirapine-containing HAART regimens are equivalent in terms of virologic success and that the backbone remains a critical determinant."

"Calendar year of commencing HAART and NRTI backbones were significant predictors of virological success and treatment failure, explaining differences in data to the 2NN study," they continued. "The weaker the NNRTI (or the protease inhibitor) the more important the NRTI backbone becomes."

Finally, the authors stated, "Cohort studies are however difficult to analyze due to inherent biases, and physicians should individualize their choice of drugs for patients, using controlled data."

Since the 2NN study was started, stavudine, didanosine, and zidovudine (AZT; Retrovir) have fallen out of favor in industrialized countries as preferred NRTIs for first-line HAART due to concerns about their toxicities.

Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; Imperial College School of Medicine, London, UK.

4/14/08

Reference

NT Annan, M Nelson, S Mandalia, and others. The Nucleoside Backbone Affects Durability of Efavirenz- or Nevirapine-Based Highly Active Antiretroviral Therapy in Antiretroviral-Naive Individuals. Journal of Acquired Immune Deficiency Syndromes. April 6, 2009 [Epub ahead of print].