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Differences Between Women and Men on Rilpivirine vs Efavirenz for 96 Weeks
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2nd International Workshop on HIV & Women. January 9-10, 2012, Bethesda, Maryland
Mark Mascolini
Rilpivirine plus tenofovir/emtricitabine proved noninferior to efavirenz plus those drugs in both women and men followed for 96 weeks in the ECHO and THRIVE trials, which enrolled antiretroviral-naive people [1]. But certain virologic and safety outcomes differed between women and men in this 96-week pooled analysis.
The THRIVE [2] and ECHO [3] trials established the noninferiority of rilpivirine to efavirenz in previously untreated people through 48 and 96 weeks. Virologic failure rates were higher with rilpivirine in both trials, but rilpivirine had better safety and tolerability profiles than efavirenz. Among people starting treatment with a viral load above 100,000 copies in the two trials, 23% randomized to rilpivirine and 10% randomized to efavirenz had virologic failure at 48 weeks [4]. The higher failure rate with rilpivirine resulted in more nucleoside and nonnucleoside resistance in people taking rilpivirine.
For women, rilpivirine may offer advantages over efavirenz. Efavirenz is a pregnancy category D drug that should not be taken in women intending to become pregnant or in the first trimester, whereas rilpivirine is a pregnancy category B drug that showed no teratogenic potential in animal studies. Also, rilpivirine does not interact with the oral contraceptives norethindrone and ethinyl estradiol, and its better safety profile may be advantageous for some women. (Efavirenz decreases concentrations of norgestimate and etonogestrel, so women should also use barrier contraception with efavirenz.) Like efavirenz, rilpivirine is coformulated with tenofovir/emtricitabine in a single once-daily tablet.
To assess 96-week outcomes in women and men randomized to rilpivirine or efavirenz, ECHO and THRIVE investigators pooled results involving 236 women and 860 men taking one of these nonnucleosides with tenofovir and efavirenz. There were 121 women and 429 men randomized to rilpivirine, and 115 women and 431 men randomized to efavirenz. All four of these study groups had a median age of 34 or 35.
A higher proportion of women than men were black (45% versus 18%), whereas higher proportions of men were white (70% versus 33%) or Hispanic (28% versus 16%). Median pretreatment CD4 counts were similar in women and men (243 and 258), as were median pretreatment viral loads (4.9 and 5.0 log10 copies, or about 79,400 and 100,000 copies).
Overall, at week 96 rilpivirine proved noninferior to efavirenz in people who began treatment with a viral load under 500,000 copies. In people who started treatment with more than 500,000 copies, the sub-50-copy virologic response was lower with rilpivirine than efavirenz, and the difference between rilpivirine and efavirenz was worse for women (30%, 3 of 10 on rilpivirine, versus 57%, 8 of 14 on efavirenz) than in men (67%, 29 of 43 on rilpivirine, versus 79%, 46 of 58 men on efavirenz) (difference -27.1 in women versus -11.9 in men). The results in women, especially, rest on very small numbers.
Among women who began treatment with a viral load between 100,000 and 500,000 copies, the sub-50-copy 96-week response rate was marginally better with rilpivirine (81%, or 30 of 38, versus 73%, or 29 of 40 women). Among men starting treatment in that viral load bracket, 96-week response rates were virtually identical with rilpivirine (72%) and efavirenz (73%). For people starting treatment with a viral load below 100,000 copies, response rates with rilpivirine versus efavirenz did not differ substantially for women or men.
Virologic failure rates were higher with rilpivirine than efavirenz for both women and men at 1 year but not in the second year of treatment:
1-year failure rate in women: 11.6% with rilpivirine versus 3.5% with efavirenz
1-year failure rate in men: 11.4% with rilpivirine versus 5.6% with efavirenz
1-to-2-year failure rate in women: 2.5% with rilpivirine versus 2.6% with efavirenz
1-to-2-year failure rate in men: 2.8% with rilpivirine versus 2.6% with efavirenz
Self-reported adherence correlated with 96-week virologic response. Among women who reported better than 95% adherence, 96-week response rates to rilpivirine (n = 94) and efavirenz (n = 92) were both 78%, while for those who reported less than 95% adherence, rilpivirine and efavirenz response rates were 67% and 64% (n = 18 and n = 14). For men who reported better than 95% adherence, 96-week response rates to rilpivirine (n = 364) and efavirenz (n = 336) were 82% and 85%. Response rates for those reporting under 95% adherence were 52% in the rilpivirine arm (n = 50) and 68% in the efavirenz arm (n = 59). The adherence-related response difference in men may give a better picture of how adherence affects response because the sample size is 3 times larger for men than women (109 versus 32)
A resistance analysis in women involved only 15 women in the rilpivirine arm and 5 in the efavirenz arm who had virologic failure. A higher proportion of women with rilpivirine failure than with efavirenz failure (47% versus none) had new reverse transcriptase mutations at failure, usually E138K (33%) and M184I (27%). E138K is a rilpivirine-associated mutations [5] that restores viral replication capacity in HIV carrying M184I or M184V [6].
CD4 gains at week 96 were similar in women and men assigned to either rilpivirine or efavirenz (about +225).
At week 96 women had significantly higher nausea rates than men regardless of whether they took rilpivirine (19% versus 11.2%, P < 0.05) or efavirenz (18.3% versus 9.7%, P < 0.05). In contrast, incidence of treatment-related psychiatric adverse events was significantly lower in women than men on rilpivirine (9.1% versus 18.2%, P < 0.05). And these rates were lower than rates in women and men on efavirenz (16.5% versus 29.5%, P < 0.05).
Abnormal dreams and nightmares affected significantly fewer women than men taking rilpivirine (4.1% versus 11.4%, P < 0.05). And again these rates were lower than in women and men taking efavirenz (8.7% versus 17.4%, P < 0.05). Diarrhea rates did not differ significantly in women versus men taking rilpivirine (13.2% versus 16.3%), but diarrhea incidence was significantly lower in women than men taking efavirenz (9.6% versus 18.6%, P < 0.05).
Rates of adverse events leading to discontinuation did not differ significantly between women and men or between rilpivirine and efavirenz. Incidence of grade 2 to 4 treatment-related adverse events was significantly lower with rilpivirine than efavirenz in women (15.7% versus 34.8%, P < 0.001) and men (17.5% versus 32.7%, P < 0.001).
Incidence of treatment-related neurologic problems was significantly lower with rilpivirine than efavirenz in both women and men (P < 0.05 for women and < 0.001 for men), as was incidence of dizziness (P < 0.05 for women and < 0.0001 for men).
Limb fat increased in all treatment arms through week 96. At that point, women taking rilpivirine gained more limb fat than women taking efavirenz (median 1592 g versus 641 g). Median limb fat gains in men at week 96 were 828 g with rilpivirine and 835 g with efavirenz.
Men taking rilpivirine had significantly fewer grade 3 or 4 lab abnormalities than men taking efavirenz (10% versus 18.7%, P < 0.05). Women taking rilpivirine also had fewer grade 3 or 4 lab abnormalities than women taking efavirenz (7.4% versus 11.5%), but that difference was not statistically significant.
Grade 1 to 3 elevations in "bad" low-density lipoprotein cholesterol were significantly less frequent with rilpivirine than efavirenz in women (19.9% versus 49.6%, P < 0.05) and men (19.6% versus 43.1%, P < 0.001).
References
1. Short W, Hodder S, Segal-Maurer S, et al. Sustained efficacy and safety observed in women for RPV vs. EFV plus FTC/TDF & with few gender differences in pooled 96-week ECHO and THRIVE analysis. 2nd International Workshop on HIV & Women. January 9-10, 2012, Bethesda, Maryland. Abstract O_14A.
2. Cohen CJ, Andrade-Villanueva J, Clotet B, et al, THRIVE study group. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378:229-237.
3. Molina JM, Cahn P, Grinsztejn B, et al, ECHO study group. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378:238-246.
4. Rimsky L, Eron J, Clotet B, et al. Characterization of the resistance profile of TMC278: 48-week analysis of the Phase III studies ECHO and THRIVE. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 12-15, 2010. Boston. Abstract H-1810.
5. Rimsky L, Vingerhoets J, Van Eygen V, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis. J Acquir Immune Defic Syndr. 2012;59:39-46. http://www.ncbi.nlm.nih.gov/pubmed/22067667.
6. Xu HT, Asahchop EL, Oliveira M, Quashie PK, Quan Y, Brenner BG, Wainberg MA. Compensation by the E138K mutation in HIV-1 reverse transcriptase for deficits in viral replication capacity and enzyme processivity associated with the M184I/V mutations. J Virol. 2011;85:11300-11308. http://jvi.asm.org/content/85/21/11300.long.
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