OCTANE 2: nevirapine and lopinavir/r are similar when used with tenofovir and FTC in treatment-naive women

2 April 2010. Related: Conference reports, Pregnancy, CROI 17 (Retrovirus) 2010.

Polly Clayden, HIV i-Base

In an oral presentation, James McIntyre showed data from the OCTANE/A5208 trial.

This trial, conducted in seven African countries, was designed to evaluate which of two antiretroviral regimens is more effective in women previously exposed to single dose NVP and whether single dose NVP compromises subsequent NVP-containing HAART. [1]

OCTANE was composed of Trial 1 and Trial 2. Trial 1 women (n=243) were NVP exposed at least six months prior to the study and those in Trial 2 (n=502) were unexposed. Women in each trial were randomised to receive either NVP or lopinavir/ritonavir (LPV/r) in regimens with tenofovir (TDF) and emtricitabine (FTC). Women with CD4 <200 cells/mm3 were eligible.

The time from randomisation to death or virologic failure (defined as plasma viral load <1 log copies/mL below baseline 12 weeks after treatment initiation, or >400 copies/mL at or after 24 weeks) was the primary endpoint in both studies.

Trial 1 was stopped by the DSMB in October 2008 at a median of 66 weeks, after an interim analysis, which found LPV/r to be significantly more effective than NVP and associated with fewer side effects. We reported this data in previously in HTB. [2, 3]

It is notable that in this study the LPV/r arm performed extremely well with only 8% of women meeting an endpoint vs 26% in the NVP arm (adjusted HR 3.6; 95% CI 1.7–7.5).

Trial 2 was designed to assess equivalence (defined as 95% CI for the HR: 0.5–2.0) between the two treatment arms. As in Trial 1, women were followed for >48 weeks. This was an intent-to-treat analysis of 500 women (2 excluded): 249 in the NVP arm and 251 in the LPV arm.

Baseline characteristics were similar in both arms, median: age 34 years, CD4 121 cells/mm3 and viral load 5.15 log copies/mL. One woman in the LPV/r arm had received single dose NVP but was included in the analysis. In a random sample of 119 women, baseline NVP resistance was detected in 1% of women. The median duration of follow-up was 118 weeks; 14 women in the NVP and 6 in the LPV/r arms were lost to follow-up.

Dr McIntyre reported that 42 (17%) women in the NVP arm and 50 (20%) in the LPV/r arm reached the primary endpoint (HR 0.85; 95%CI 0.56–1.29). These results met the criteria for equivalence. The as-treated analysis results were similar (HR 0.71; 95%CI 0.45–1.13).

When the investigators broke down the composite endpoint to look at virologic failure and death separately, they found 15% vs 17% experienced virologic failure and 2% vs 3% died in the NVP and LPV/r arms respectively.

Overall, 93 women discontinued NVP or LPV/r permanently, 70 (28%) in the NVP arm and 23 (9%) in the LPV/r arm, HR 3.4 (95% CI 2.2-5.5). Of these, 35 (14%) in the NVP arm and 0 in the LPV/r arm discontinued due to adverse events, p<0.0001.

Grade 3 or 4 signs/symptoms while receiving NVP or LPV/r were reported in 75 (15%) women (14% in NVP, 16% in LPV/r arm), and 26% and 22% (respectively) had grade 3/4 laboratory test abnormalities. Dr McIntyre noted that the protocol took a conservative approach to adverse events for women receiving NVP but events in the LPV/r arm could be managed without a protocol-mandated switch in therapy.

In conclusion, the study reported that NVP+TDF+FTC and LPV/r+TDF+FTC were equivalent in treatment-naïve women. This suggests that the previously reported inferiority of NVP in Trial 1 was related to NVP resistance from single dose NVP exposure.

comment

James McIntyre remarked that these data are reassuring for programmes using nevirapine, particularly in Africa where it is a mainstay of antiretroviral regimens.

What remains unexplained is why the LPV/r arm in Trial 1 performed so well whereas in Trial 2 what we are seeing is similar to general experience.

When this was questioned after the presentation Dr McIntyre remarked that this raises “intriguing possibilities” and there may be some plausibility that nevirapine-induced mutations could have some effect on gag/pol cleavage causing conformational changes which may make protease enzymes less effective. If so, protease inhibitors would have less to inhibit, so would work better. He added that he knew of no evidence to support this!  

It is perhaps worth noting that equivalence in this study is powered with an equivalence range from 0.5 to 2 – ie requiring a doubling or halving of the risk is still defined as ‘equivalent’. 

When looking at absolute rates at other studies that use a tighter range, differences of up to 12% are typically viewed as being ‘non-inferior’. Using a doubling/halving in risk is stretching this even further.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections. 16-10 February 2010, San Francisco. All oral abstracts are available as webcasts.
http://www.retroconference.org

1. McIntyre J et al. Efficacy of ART with NVP+TDF/FTC vs LPV/r+TDF/FTC among antiretroviral-naive women in Africa: OCTANE Trial 2/ACTG A5208. 17th CROI, 2010. Oral abstract  153 LB.
   http://www.retroconference.org/2010/Abstracts/39798.htm
   Webcast: Treatment outcomes in women and children. Friday 9.30am.
   http://www.retroconference.org/2010/data/files/webcast_2010.htm
2. OCTANE Trial DSMB finds ritonavir-boosted lopinavir superior to nevirapine in HIV-positive women previously exposed to single dose nevirapine. HTB, December 2008.
   https://i-base.info/htb/261
3. Lopinavir/r containing regimen superior to nevirapine containing regimen in women previously exposed to single dose nevirapine. HTB, April 2009.
   https://i-base.info/htb/1449