An updated adherence analysis from the ASPIRE study indicates that consistent users of a vaginal ring containing dapivirine experienced 65% fewer infections, the 21st International AIDS Conference (AIDS 2016) in Durban, South Africa heard in July. Some additional analyses suggested a higher level of effectiveness. Moreover, African women who took part in the study told researchers that they liked the product, found it easy to use and preferred it to possible alternatives such as tablets or vaginal gels.
The ASPIRE study evaluated the effectiveness of a vaginal ring impregnated with the anti-HIV drug dapivirine. The ring, which is similar to devices used for contraception, is designed to be worn inside the vagina for a month at a time; women can insert and remove it themselves. The study recruited 2629 women in Malawi, South Africa, Uganda and Zimbabwe.
The headline findings, released in February, were somewhat disappointing – an overall reduction in infections of 27%. But this masked a higher level of effectiveness for the older study participants, who may have had higher levels of adherence than the younger participants. Stratified by age, the vaginal ring had zero effectiveness for women aged 18-21; reduced infections by 56% in women aged over 22-26; and reduced infections by 51% in women aged 27 and over.
In Durban, Elizabeth Brown of the University of Washington presented a new analysis which attempted to correlate effectiveness with different levels of adherence. Whereas previous analyses have evaluated adherence by measuring levels of dapivirine in the blood, this could reflect the ring only being inserted the day before a clinic visit. The new analysis looked at the level of drug left behind in rings that were returned to the researchers after use, giving a better indication of adherence throughout the month.
Before use, the rings contain 25mg of dapivirine. As a ring that has been worn for a full month should have 20-21mg of drug remaining, any level below 22mg was treated as indicating medium to high adherence. A ring with 23.5mg or more of drug indicated non-adherence.
- Periods of time with non-adherence represented 33% of follow-up. As could be expected, there was not a statistically significant reduction in HIV infections during these periods.
- Periods of time with medium to high adherence represented 42% of follow-up. Rings used this much reduced HIV infections by 65%, compared to placebo.
The researchers also conducted additional analyses, which attempted to adjust for the actual length of time between study visits and examined adherence two or three months prior to HIV infection (rather than just one month prior). These suggested that effectiveness for women with the highest level of adherence might be 75% or 92%. Moreover, periods of non-adherence appeared to represent a smaller proportion (20%) of time.
“Across multiple analyses, there is a statistically significant relationship between ring use and HIV protection,” the researchers concluded. “These analyses provide evidence suggesting a dose-response relationship between ring use and HIV acquisition.”
Acceptability: the importance of education and partner attitudes
A qualitative component of the study, interviewing 214 study participants, provides insight into women’s experience using the vaginal rings and their appreciation of the product’s qualities. Elizabeth Montgomery and Ariane van der Straten of RTI International presented results in two posters.
The women who were interviewed (either in an in-depth interview, a series of in-depth interviews or as part of a focus group) were recruited from 6 of the 15 study sites. Their demographics broadly reflected those of the larger study: average age of 26, 45% were married, and 73% had completed secondary school.
The ring was felt to be simple and discreet, as this woman explained:
“I like them because once you wear it, you don’t feel it, and nobody can suspect you are wearing something. I like it because nothing changes regarding how we live as women.”
While some women had initial concerns about the appearance of the ring and potential side-effects, these were generally overcome through group discussion, counselling and increasing familiarity with the product. Continuing to provide this kind of support may be important if vaginal rings are rolled out.
“When you are seeing the ring for the first time you get shocked. I was too and almost quit because of the size of the ring… During education I learned that the ring was soft, I thought the ring was hard and painful. They showed that to insert the ring you need to twist it like 8 and when I tried it, it was easy and doable.”
The researchers asked some women to compare vaginal rings with other ways in which prevention drugs could be delivered – oral tablets, injections, implants, vaginal suppositories, vaginal films and vaginal gels. Women often preferred methods that were familiar to them – the vaginal rings they had been using as part of ASPIRE or products similar to contraceptives they knew about.
They tended to appreciate long-acting products rather than those which needed to be remembered daily or applied at the time of sex.
“The ring is better than a condom because when you are going to have sex the ring is already inside you, unlike the condom that you have to wear before every sex act.”
Nonetheless, there could be some anxiety about the side-effects, invasiveness and lack of reversibility of long-acting products.
“I am afraid… I don’t know how it [the injection] is going to be like inside my body, I don’t know if it going to affect my health.”
Such concerns in relation to vaginal rings diminished with education and through experience.
Several potential products (including rings, gels, suppositories and films) need to be applied inside the vagina and this was off-putting for some participants, especially those under the age of 25. Some women removed the vaginal ring during menstruation.
Women described negotiating use of the vaginal ring with male partners. Partners often had an influence (either positive or negative) on women’s attitudes to and use of the ring.
“No, I told him to take the ring as the condom. I said: ‘Because you do not want the condom, this is now our condom, just ignore it, it’s inside my body and it’s mine. Because you don’t want the condom so pretend as if this is my condom because you don’t want to wear a condom I am wearing mine.’ We never had problems about it and we never spoke about it again.”
Women could be concerned that a partner would feel the ring during sex.
“Sometimes you find your partner is fingering you and finds a ring, then that’s followed by 21 questions.”
Elizabeth Montgomery told aidsmap.com that some participants’ misgivings about the research process could have contributed to lower adherence. Women expressed concerns about not knowing if they had received an active or placebo ring, the unknown efficacy and unproven safety of the ring, and the idea of being ‘researched on’. Therefore the fact of taking part in a placebo-controlled study may have had an impact on non-use of the ring.
Nonetheless, many women said they liked taking part in the study. They felt that they were part of a ‘team’ and were doing something for a broader, communal good. They valued the free healthcare and other study benefits that were provided. Of course, this could have influenced some of the women's responses during interviews.
In studies of oral PrEP, adherence has tended to be better in open-label studies than in the original placebo-controlled trials. The context of these studies can address some of the concerns about the research process mentioned above – participants know they are receiving an active product and that it has proven to be effective and safe. The studies are closer to ‘real world’ conditions than placebo-controlled trials. In the case of oral PrEP, higher levels of effectiveness were demonstrated.
Given this, participants of the ASPIRE study are now being invited to enrol in an open-label follow-up study of the dapivirine vaginal ring. Women who took part in the Ring Study (another randomised study of the same product) will also be asked to join an open-label study. The International Partnership for Microbicides hopes that regulators may approve the dapivirine vaginal ring in 2018.
Brown E et al. Residual dapivirine ring levels indicate higher adherence to vaginal ring is associated with HIV-1 protection. 21st International AIDS Conference, Durban, abstract TUAC0105LB, 2016.
Montgomery M et al. Key insights into acceptability and use of the vaginal ring: results of the MTN-020 ASPIRE trial qualitative component. 21st International AIDS Conference, Durban, abstract WEPEC265, 2016.
van der Straten A et al. HIV pre-exposure prophylaxis (PrEP) formulation preference among women participating in the qualitative component of the ASPIRE (MTN-020) study. 21st International AIDS Conference, Durban, abstract WEPDC0203.