An efficacy study of a new method of HIV prevention has published its first data. ASPIRE is one of two large efficacy trials of a vaginal ring microbicide that have been taking place over the last three years.
The vaginal ring is a soft silicone-rubber ring infused with an anti-HIV drug, which is designed to be inserted into a woman’s vagina once a month and sit on the cervix. The idea of a long-lasting device like the ring is to get round the problem of daily adherence to PrEP (pre-exposure prophylaxis) pills and microbicide gels that is the main reason for the failure to show efficacy of three out of four large studies of these prevention methods conducted in younger women in southern Africa.
ASPIRE (MTN-020), and its companion study, the Ring study (IPM 027) are expected to announce their efficacy results early next year or even at the end of this year. The current paper describes the recruitment and characteristics of ASPIRE participants and sheds some light on the environment in which they live.
Aspire (A Study to Prevent Infection with a Ring for Extended use) was conducted in four African countries at 15 research centres: nine in South Africa, three in Zimbabwe, two in Malawi and one in Uganda. There was a concentration of seven sites in the South African city of Durban which is the capital of KwaZulu Natal province, one of the highest-prevalence places in the world for HIV.
The study enrolled women aged 18-45 between August 2012 and June 2014. Half the women used a vaginal ring containing the antiretroviral drug dapivirine and half a placebo ring not containing the drug. Dapivirine is an antiretroviral drug in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class. It was originally developed by Janssen as a treatment for HIV, but it was dropped from development due to poor bioavailability as an oral drug. Janssen then licensed dapivirine for prevention research to the International Partnership for Microbicides (IPM) and to the Microbicides Trials Network (MTN), who have conducted ASPIRE.
The ring is designed to be inserted monthly (and not taken out during that time, though it can be re-inserted). This means that participant clinic appointments were monthly too. During appointments, participants received tests for HIV and sexually transmitted infections (STIs), adherence counselling, were given condoms and safer sex advice, and had blood samples drawn to determine adherence levels (these will be anonymised and only looked at after the active phase of the trial). Participants were followed-up for a month after last ring use to look at whether the HIV infection rate increased when use stopped.
The women used the ring for at least a year, but ASPIRE was not designed to have a fixed length: instead it stopped when enough data had been accumulated so that there was a 90% chance that, if the vaginal ring stopped 60% of infections, it would have the power to detect this. Some participants used the ring for up to two years. The number of participants planned was originally based on an assumed average background HIV incidence of 3.9% (i.e. the percentage of women who would acquire HIV per year in the absence of using the ring), but this was reduced when it was found that the background rate was more like 5%. This was calculated to be 2600 participants.
Exclusions from the trial
The trial in fact enrolled 2629 women out of 5516 who volunteered for it (48%). The most common reason for being excluded from the trial was that the woman tested HIV-positive on screening. Thirty-five percent of volunteers turned out to have HIV, though this varied significantly by country: it was 15% in Malawi but 46% in Zimbabwe. In South Africa, a third of volunteers (34%) had HIV.
Considerable discretion was also given to researchers to not enrol women whose circumstances might mean they had trouble adhering, such as an unstable living situation. Researcher discretion was responsible for 31% of exclusions, although in Malawi and Uganda it was higher, at 48% and 43% respectively.
The third most common reason, comprising 22% of exclusions, was that the women had one or more of a list of clinical reasons for exclusion ranging from elevated liver enzymes, kidney disease or pelvic inflammatory disease, to recent pregnancy or gynaecological procedures. Having a bacterial STI was not an exclusion criterion as long as it was treated.
The two other significant reasons for exclusion were that the volunteer failed to complete the enrolment procedure (8%) or that she intended to get pregnant (also 8%): to be in the trial, participants had to use a reliable contraception method (other than condoms).
Who were the participants?
Most participants were in their 20s, with an average age of 26 (24 in South Africa). Education level varied significantly by country with 51% of Malawian and 46% of Ugandan participants only having received primary education whereas 87% in South Africa and Zimbabwe had completed secondary school. Six per cent, mostly in South Africa, were college or university graduates.
All participants had a primary sexual partner and for 83% the primary partner was the only partner they had had in the previous three months at the time of enrolment. Having secondary partners was notably more common in Uganda, where 46% of women had had more than one partner and 18% two or more in the last three months. Women in Uganda were also the least likely to say they had used condoms (32%, against an average of 56% and 66% in South Africa) and also the most likely to say they had had transactional sex (sex in exchange for money, gifts, drugs or shelter) in the last year (15% versus an average of 6%).
Female condom use was very rare (1% in the last three months) as was anal sex (2%).
The amount of sex the women had was pretty varied too: on average, women reckoned they had had 20 occasions of vaginal intercourse in the last three months (i.e. once every 4.5 days) but Zimbabwean women had had sex 48 times on average and South African women only ten. This may be explained by the fact that most South African women were single (only 8% married) whereas 83% of Zimbabwean and 85% of Malawian women were married.
Three-quarters of participants and almost all women in Zimbabwe and Malawi had told their primary partners that they were in an HIV prevention study and 64% had talked specifically about the vaginal ring with them (it is designed to be undetectable to a male partner during sex). However, disclosure rates were much lower in Uganda (30% told them they were in a study and 19% talked about the ring).
Very few women (1%) had a partner they knew had HIV: but 43% (67% in Zimbabwe) said they did not know their partner’s HIV status. Fewer women in Malawi did not know (26%) which may reflect widespread HIV testing programmes in that country.
Bacterial STIs were fairly common, with 12% of women having chlamydia, 7% trichomoniasis, 4% gonorrhoea and 1% syphilis.
Cautions and conclusions
As this paper is purely a description of the participants and we will not know if the ring worked till the end of 2016, there are few conclusions to be drawn, but the researchers do sound a note of caution that, owing to quite tight inclusion criteria, women in ASPIRE and the Ring study may not be typical of the women who end up using the ring (if it works) and that, in particular, it is likely to be used by women with poorer sexual health.
There are also unanswered questions about how the ring would be provided in practice. A monthly clinic visit is unlikely to be practical or affordable in most situations, so questions remain about how it would be dispensed.
Nonetheless, the researchers say, it is still important to develop an HIV prevention method which is under the control of women, used before rather than during sex, and which can be concealed.
They comment: "Condom use may be outside the locus of female control, antithetical to constructs of trust and love, and mediated by transactional exchanges of gifts or cash. As female-initiated methods, microbicides are positioned to reduce women’s vulnerability to HIV infection by empowering women to control their use.”
Palanee-Phillips T et al. Characteristics of women enrolled into a randomized clinical trial of dapivirine vaginal ring for HIV-1 prevention. PLOS One DOI: 10.1371/pournal.pone.0128857. June 2015.