Similar efficacy and a few gender related differences in side effects with rilpivirine vs efavirenz at 96-weeks
Polly Clayden, HIV i-Base
Rilpivirine (RPV) did not show teratogenicity risk in pre-clinical studies and is therefore FDA pregnancy category B, nor does it interact with the oral contraceptives norethindrone and ethinyl estradiol. For these reasons, it could be a useful option for women of child bearing potential.
RPV was non-inferior to efavirenz (EFV) when combined with a nucleos(ti)de backbone in the pooled 96-week analysis of the phase 3 ECHO and THRIVE trials but only for baseline viral load strata <500,000 copies/mL. The primary endpoint was viral suppression to <50 copies/mL at week 48 by TLOVR analysis, with non inferiority defined by 95% CI compared to control not crossing the lower margin of -12%.
An investigation was conducted to look at safety and efficacy outcomes in women participating in these trials specifically and in comparison to men. This analysis included data from 236 (22%) women and 860 men, of these, 121 women and 429 men were randomised to RPV, and 115 women and 431 men to EFV. The women and men had similar median age of about 35 years, baseline CD4 counts of 243 and 258 cells/mm3 and viral loads of 4.9 and 5.0 log10 copies/mL respectively. Of the participants, a greater proportion of women than men (45% vs 18%) were black, and a smaller proportion (33% vs 70%) were white and Latina/o (16% vs 28%).
At 96 weeks, CD4 increases were similar in women and men in the RPV and EFV groups (approximately 225 cells/mm3).
Overall, 14% vs 6.1% of women failed virologically and/or discontinued treatment in the RPV and EFV arms respectively. The difference between the two arms was greater in the first year of treatment with 11.6% vs 3.5% failing compared to 2.5% vs 2.6% in the second year. These proportions were similar for men participating in the study: overall 14.2% vs 7%, year one 11.4% vs 4.4%, and year two 2.8% vs 2.6%, in the RPV and EFV arms respectively.
Stratification by baseline viral load showed similar rates of virological suppression for women and men with <100, 000 copies/mL receiving RPV or EFV (approximately 80%). Between >100,000 and 500,000 copies/mL, women in the RPV arm did slightly better than those receiving EFV, respectively 81% and 73% had viral loads <50 copies/mL at 96 weeks. The results for men in this viral load stratum were similar across the two arms, 72% and 73% for RPV and EFV. Above 500,000 copies/mL only 30% of women in the RPV arm had viral loads <50 copies/mL but this percentage relied on results for 3/10 women. For women receiving EFV the proportion was 57% (8/140). Of the men 67% (29/43) and 79% (46/58) in the RPV and EFV arms had viral loads <50 copies/mL at 96 weeks.
Of women who reported adherence >95%, both those receiving RPV (n=94) and EFV (n=92) had 78% rates of virological suppression <50 copies/mL. For those reporting <95% adherence suppression rates were lower, 67% and 64% for RPV (n=18) and EFV (n=14) respectively.
For men who reported >95% adherence, 96-week suppression rates with RPV (n=364) and EFV (n= 336) were 82% and 85%. Rates for those reporting <95% adherence were 52% with RPV (n=50) and 68% with EFV (n=59).
Resistance was analysed in a very small subset of women, RPV (n=15) and EFV (n=5). This revealed 20% of virologic failures with wild-type virus and 60% of with NNRTI resistance. There were more NRTI mutations in the women receiving RPV than EFV, 47% vs 0% and the most common were E138K (33%) and M184I (27%).
At week 96, rates of adverse events (AEs) leading to discontinuation of treatment were similar across treatment arms and genders. Incidence of grade 2 to 4 adverse events was significantly lower with RPV than EFV in women, 15.7% vs 34.8% and men, 17.5% vs 32.7%, both p<0.001.
Nausea occurred more frequently in women than men receiving both RPV and EFV, 19% vs 11.2%, 18.3% vs 9.7%, both p<0.05. But the incidence of treatment-related psychiatric adverse events was significantly lower in women than men receiving RPV, 9.1% vs 18.2%, p<0.05). Both these rates were lower than those in women and men receiving efavirenz, 16.5% vs 29.5%, p<0.05).
There were lower rates of abnormal dreams and nightmares in women than men receiving RPV 4.1% versus 11.4%, p<0.05. Women also experienced less of these events than men with EFV, 8.7% vs 17.4%, p<0.05. Rates of diarrhoea were similar in women and men receiving RPV, 13.2% versus 16.3%, but lower in women than men receiving efavirenz, 9.6% vs 18.6%, p< 0.05.
Women and men receiving RPV reported lower incidence of neurologic AEs compared to those receiving EFV, 15.7% vs 34.8%, p<0.05, and 17.5% vs 32.7%, p<0.001, for men and women respectively. There was also lower incidence of dizziness, 12.4% vs 27.8%, p<0.05 and 8.8% vs 28.8%, p<0.0001; and rash, 5.8% vs 16.5%, p<0.05 and 6.8% vs 12.5%, p<0.05.
Women and men receiving RPV had less grade 3 or 4 laboratory abnormalities 7.4% vs 11.5% and 10% vs 18.7% but this only reached statistical significance in men, p<0.05.
There were less grade 1 to 3 elevations in LDL cholesterol with RPV than EFV in women 19.9% vs 49.6%, p< 0.05, and men 19.6% vs 43.1%, p<0.001.
For all groups, there were significant increases from baseline in limb fat at week 96 with no statistical differences between treatment groups. Women receiving RPV appeared to have greater increase than the EFV group, median 1592g vs 641g. For men the two groups had similar median increases 828g vs 835g.
There was a trend towards greater BMD changes in women for both arms, but this was in a small sample size (n=30).
Short W et al. Sustained efficacy and safety observed for RPV vs EFV plus FTC/TF and with a few gender differences in pooled 96-week ECHO and THRIVE analysis. 2nd International Workshop on HIV and Women. 9-10 January 2012, Bethesda, MD. Oral abstract O_14A.