A Phase III Trial of the Dapivirine Vaginal Ring for HIV-1 Prevention in Women On behalf of The MTN-020/ASPIRE Study Team UZ-UCSF Annual Research Day 8 April 2016

Why was the ASPIRE study done? Women in Africa, especially young women, have been among the hardest hit by HIV. They desperately need HIV prevention tools that are safe, effective and easy to use. More than half of all people currently living with HIV are women. In Africa, young women are the group at greatest risk of becoming infected. Despite great advances in preventing and treating HIV women still face disproportionate risk, and a number of prevention options are not practical or usable by many women.

PrEP: Pre-Exposure Prophylaxis Studies have proven that daily use of an ARV tablet (PrEP) is very effective in preventing HIV. However, PrEP studies among African women did not have similar results due to low adherence to the products (tablets or gels).

MTN-020/ASPIRE MTN-020/ASPIRE was a multi-center, randomized, double-blind, placebo-controlled phase III trial of a silicone elastomer vaginal matrix ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine (25 mg). This vaginal ring was inserted once every 4 weeks in healthy sexually active HIV-1 uninfected women (18-45 years).

ASPIRE Study Questions Will the ring prevent HIV? Is the ring safe? Is the ring acceptable? Will women use the ring (adherence)? If a woman becomes infected with HIV, will drug resistance be a problem?

Trial Design At enrollment, women were randomized 1:1 to dapivirine:placebo. Women were counseled to wear the ring continuously, and a new ring was provided at scheduled monthly visits. Follow-up was for a minimum of 1 year. All received a comprehensive package of HIV-1 prevention services.

Who enrolled in ASPIRE? 2,629 women enrolled at 15 sites in 4 countries: 272 in Malawi (2 sites) 1,426 in South Africa (9 sites) 253 in Uganda ( 1 site) 678 in Zimbabwe (3 sites)

Who enrolled in ASPIRE? Average age 26 (range 18-45) Less than half (41%) were married Nearly all (>99%) reported a primary sex partner & 17% reported more than one partner in the prior 3 months Nearly half did not use a condom with their last sex act Women who enrolled in ASPIRE are truly representative of women at high risk of HIV

How do we know if the ring is effective? We compared the number of HIV infections that occurred in the dapivirine ring group with those in the placebo ring group If effective, we would expect that fewer women in the dapivirine ring group would acquire HIV Placebo Dapivirine Vs.

Primary HIV-1 effectiveness intention-to-treat analysis (15 sites) HIV-1 Protection Overall, women in the dapivirine vaginal ring arm had a 27% reduction in the rate of HIV-1 acquisition, compared to placebo. Primary HIV-1 effectiveness intention-to-treat analysis (15 sites) Dapivirine Placebo # HIV-1 infections 71 97 HIV-1 incidence, per 100 person-years 3.3 4.5 HIV-1 protection effectiveness 95% CI, p-value 27% (1, 46) p=0.046

Primary HIV-1 effectiveness intention-to-treat analysis (13 sites) HIV-1 Protection After excluding data from two sites with lower adherence, the dapivirine ring reduced HIV-1 acquisition by 37%. Primary HIV-1 effectiveness intention-to-treat analysis (13 sites) Dapivirine Placebo # HIV-1 infections 54 85 HIV-1 incidence, per 100 person-years 2.8 4.4 HIV-1 protection effectiveness 95% CI, p-value 37% (12, 56) p=0.007

In other words, the ring prevented about one-third of HIV infections – about one in three women who would have been infected was not. HIV Uninfected For example, if there were 100 women using the dapivirine ring, about 33 infections would be prevented.

HIV protection differed significantly by age Combined, there were 56% fewer HIV infections among women older than age 21. No reduction 56% reduction Results were statistically significant Age 18-21 Older than 21

In other words, among women older than 21, the ring prevented over one half of HIV infections – about one in two women who would have been infected was not. For example, if there were 100 women using the dapivirine ring, 56 infections would be prevented. HIV Uninfected

Adherence was strongly related to age Blood samples and used ring testing showed that younger women were less adherent to the ring Age 27-45 Age 22-26 Age 18-21

Younger Women Both behavioral and biologic effects may have contributed to a lack of HIV protection in women aged 18-21 in ASPIRE. Further research is needed to understand the unique prevention needs of young women.

Safety The dapivirine vaginal ring was shown to be very safe No difference in the number of adverse events (health problems), pregnancies, or HIV drug resistance was observed between study groups

MTN Next Steps… The pathway from demonstration of efficacy to potential large-scale implementation is not instantaneous. An Open Label Extension (OLE) study called “HOPE” is currently proposed to bridge this period.

Open-Label Extension (OLE) of ASPIRE study Primary purpose would be to offer access to dapivirine vaginal ring (active study product) to former ASPIRE participants who are eligible Would also collect data on safety and adherence in the context of open-label use

MTN-020/ASPIRE Summary In MTN-020/ASPIRE, a monthly vaginal ring containing dapivirine safely helped to protect against HIV in African women. Risk was reduced by ~1/3 overall and by >1/2 among those aged ≥22 HIV protection was greater in groups with evidence of better adherence to ring use.

Conclusions Our results, with those of The Ring Study, demonstrate that the dapivirine vaginal ring can protect against HIV.

Conclusions The ring was not protective in young women, who had lower adherence—more research is needed to understand both biologic and behavioral factors in this vulnerable age group.

ASPIRE Team Participants and communities