Table 2.
Inclusion of women in pivotal antiretroviral clinical trials
| Trial | Design | Investigational drug(s) | Total enrolment | Proportion of women | Overall findings | Sex-based analysis | Results of subgroup analysis |
|---|---|---|---|---|---|---|---|
| HEAT [13] | Double-blind, placebo-matched, randomised, non-inferiority trial
Third agent: LPV/r |
ABC/3TC vs TDF/FTC | 694 | 16% in ABC/3TC arm
20% in TDF/FTC arm |
No difference in proportion with virological suppression at week 48
No difference in safety endpoints |
No | |
| ASSERT [14] | Randomised, open-label trial
Third agent: EFV |
ABC/3TC vs TDF/FTC | 385 | 17% in ABC/3TC arm
20% in TDF/FTC arm |
No difference in change from baseline renal function or drug-related AEs
Greater proportion achieved virological suppression in TDF/FTC arms in those with VL <100,000 and those with VL ≥100,000 |
No | |
| ACTG A5202 [15] | Phase III, partially blind, randomised clinical trial
Four study arms: ABC/3TC + EFV ABC/3TC + ATV/r TDF/FTC + EFV TDF/FTC + ATV/r |
ABC/3TC vs TDF/FTC | 797 with baseline VL ≥100, 000 | 15% in stratum with viral load ≥100, 000 | In high VL stratum, shorter time to virological failure with ABC/3TC (HR 2.33) | Yes | Higher virological failure with ABC/3TC in men (HR 3.00, 95% CI 1.74–5.17) but not women (HR 0.85, 95% CI 0.30–2.89) |
| ACTG A5202 [16] | ABC/3TC vs TDF/FTC | 1857 (total population) | 17% | No difference in time to virological failure between two NRTI backbones at 96 weeks | No | ||
| ACTG A5202 [17] | ATV/r vs EFV | 1857 | 17% | Yes | For women, higher risk of virological failure with ATV/r vs EFV in both ABC/3TC backbone (HR 2.55, 95% CI 1.20–5.41) and TDF/FTC backbone (HR 2.16, 95% CI 0.97–4.80)
With ATV/r, higher risk of virological failure for women vs men (HR 1.72, 95% CI 0.99–2.99) |
||
| SINGLE [18,19] | Phase III, double-blind, placebo-matched, non-inferiority RCT
Two study arms: ABC/3TC/DTG vs TDF/FTC/EFV |
DTG | 833 | 16% | DTG-regimen both inferior and superior to EFV-regimen in achievement of virological suppression at week 48
|
Yes | In women, 57/67 (85%) achieved virological suppression with DTG vs 47/63 (75%) with EFV (non-significant trend appears to favour DTG arm) |
| SPRING-2 [19,20] | Phase III, double-blind RCT
DTG vs RAL; NRTI backbone at investigator's discretion |
DTG | 822 | 15% in DTG group
14% in RAL group |
DTG non-inferior to RAL in achievement of virological suppression | Yes | In women, 162/186 (87%) achieved virological suppression with DTG vs 18/291 (83%) with RAL (non-significant trend appears to favour DTG group) |
| FLAMINGO [19,21] | Open-label RCT
DTG vs DRV/r NRTI backbone at investigator's discretion |
DTG | 484 | 15% | DTG both non-inferior and superior to DRV/r in achievement of virological suppression | Yes | In women, 26/31 (84%) achieved virological suppression in DTG group vs 30/41 (73%) in DRV/r group (non-significant trend appears to favour DTG group) |
| GS-US-236-0102 [22,23] | Phase III, double-blind, placebo-matched RCT
Study arms: TDF/FTC/EVG/c vs TDF/FTC/EFV |
EVG/c | 700 | 11% | No difference in achievement of virological suppression between EVG/c (87.6%) and EFV (84.1%) at week 48
Higher mean increase in CD4 cell count with EVG/c vs EFV At week 144, virological suppression was 80.2% with EVG/c and 75.3% with EFV; lower drug discontinuation with EVG/c |
Yes | No difference between men and women in proportion achieving virological suppression at week 48
At week 144, 78% of women in EFV and EVG/c groups had virological suppression; for men, 80.2% suppressed with EVG/c vs 75.3% with EFV (appears to favour EVG/c) |
| GS-236-0103 [24,25] | Phase III, double-blind, placebo-matched, non-inferiority RCT
Study arms: TDF/FTC/EVG/c vs TDF/FTC/ATV/r |
EVG/c | 708 | 8% in EVG/c group
11% in ATV/r group |
No difference in achievement of virological suppression between EVG/c (89.5%) and ATV/r (86.8%) at week 48
At week 144, no difference in rates of virological suppression between two groups |
Yes | No difference between men and women in proportion achieving virological suppression at week 48
At week 144, 62% of women in EFV group and 52% of women in EVG/c had virological suppression; wide CI but trend to favouring ATV/r |
| WAVES [26] | Phase III, double-blind RCT
Study arms: TDF/FTC/EVG/c vs TDF/FTC/ATV/r |
EVG/c | 575 | 100% | At week 48, 87.2% of women in EVG/c group and 80.8% of women in ATV/r group had virological suppression (difference 6.5%; 95% CI 0.4–12.6%) confirming non-inferiority
Similar mean increase in CD4 cell count (221 cells/mm3 with EVG/c and 212 cells/mm3 with ATVr/) |
N/A | |
| STARTMRK [27,28] | Phase III, double-blind, non-inferiority RCT
Study arms: TDF/FTC/RAL vs TDF/FTC/EFV |
RAL | 563 | 19% | At 48 weeks, virological suppression achieved in 86.1% in RAL group vs 81.9% in EFV group, confirming non-inferiority | No (48 weeks) | |
| Yes (5 years) | At 5 years (n=43 women), 90% of women in RAL group and 85% of women in EFV group had virological suppression (trend to favouring RAL)
Trend to higher mean change in CD4 for women on RAL vs EFV (383 cells/mm3 vs 327 cells/mm3) |
||||||
| ACTG 5257 [29] | Phase III, open-label RCT
NRTI backbone: TDF/FTC |
RAL vs ATV/r vs DRV/r | 1809 | 24% | No difference in proportion of patients with virological failure at 96 weeks between the three regimens | Yes | In women, no difference in rate of virological failure between three regimens at 96 weeks (23.8% for ATV/r, 23.8% for DRV/r and 24.5% for RAL |
| ARTEMIS [30,31] | Phase III, open-label RCT
Study arms: TDF/FTC/DRV/r vs TDF/FTC/LPV/r |
DRV/r | 689 | 30% | Virological suppression achieved by 84% of those on DRV/r vs 78% of those on LPV/r, confirming non-inferiority of DRV/r | No (48 weeks) | |
| At week 192, DRV/r was both non-inferior and superior in clinical efficacy compared to LPV/r | Yes (192 weeks) | At week 192, 71.2% of women in DRV/r group and 56.2% of women in LPV/r group had virological suppression, favours DRV/r | |||||
| Pooled ECHO and THRIVE [32–34] | Phase III, double-blind RCTs
ECHO: RPV vs EFV (both with TDF/FTC) THRIVE: RPV vs EFV (with ABC/3TC, TDF/FTC or ZDV/3TC) |
RPV | 1368 | 24% | RPV non-inferior to EFV for virological suppression at 48 weeks; in ECHO, higher risk of virological failure with RPV when baseline VL≥100,000 copies/mL | Yes | At week 48, no differences between men and women with virological suppression with either RPV (85% men and 83% women suppressed) or EFV (82% men and 83% women suppressed) |
| STaR [35] | Phase IIIb, open-label RCT comparing two STRs
TDF/FTC/EFV vs TDF/FTC/RPV |
RPV | 786 | 7% | RPV non-inferior to EFV for virological suppression and mean change in CD4 cell count
Post hoc analysis: trend to reduced response for RPV when baseline VL >500,000 copies/mL |
No |
ABC: abacavir; 3TC: lamivudine; TDF: tenofovir disoproxil fumarate; FTC: emtricitabine; LPV/r: ritonavir-boosted-lopinavir; EFV: efavirenz; AE: adverse event; VL: viral load; ATV/r: ritonavir-boosted-atazanavir; HR: hazard ratio; CI: confidence interval; vs: versus; DTG: dolutegravir; ITT: intention-to-treat; NRTI: nucleoside reverse transcriptase inhibitor; RAL: raltegravir; DRV/r: ritonavir-boosted-darunavir; EVG/c: cobicistat-boosted-elvitegravir; RPV: rilpivirine; BMD: bone mineral density; ZDV: zidovudine; STR: single-tablet regimen.