PrEP studies at AIDS 2016: includes first preclinical data with EFdA

1 August 2016. Related: Conference reports, HIV prevention and transmission, World AIDS 21 Durban 2016.

Simon Collins, HIV i-Base

PrEP was a major theme at the conference with probably more oral presentations and posters than any other subject.

Oral PrEP works. So there was limited new scientific data with the overwhelming majority of studies relating to implementation issues.

A few of the studies with new scientific data are summarised below.

IPERGAY – continued efficacy with longer follow-up

Follow-up of 336 participants in the open label phase of the French/Canadian IPERGAY study (median 18 months, with >500 patient years of follow up) continued to show protection from event-based dosing for PrEP. The single infection was in someone who had not been taking PrEP for several months and who had no detectable drugs levels at diagnosis. [1]

Results from this open label phase were similar to the double-blind phase in terms of partner numbers, frequency of sex and STI rates (which remained high at approximately 40%). One key exception was that when condoms were used less frequently, this was compensated for by higher PrEP use. Also, that participants reported improved pleasure from sex and reduced fear. [2]

A median of 18 pills were taken by participants each month (IQR: 11 to 25), indicating that the overall results related to someone taking approximately 4 pills a week. Modelling data (from the iPrEX study) suggested this level of dosing would provide greater than 95% protection for men.

The single new HIV infection was a man in a stable relationship with a single partner who started ART three days after diagnosis.

The only outstanding scientific questions about the use of oral PrEP using tenofovir DF plus FTC principally relates to the amount of flexibility for timing of event-based dosing, the optimal time for the pre-dose, and whether this strategy provides similar levels of protection for people who have sex less than once a week.

PrEP used by sero-dfferent couples as a bridge to ART

Similarly impressive results were also presented from the Partners Demonstration Project which was an open label study that provided PrEP to the HIV negative partners of HIV positive people as a bridge until the later started ART. [3]

This study enrolled more than 1000 heterosexual couples in four sites (two in Kenya and two in Uganda). In about two-thirds (67%) of the couples the positive partners were women. Random drug level testing suggested high adherence with tenofovir detected in >80% of negative partners that were sampled. During the two years of the study, ART was started by 92% of the positive partners.

Only five incident infections were reported (IR 0.3, 95% CI 0.1-0.7) despite modelling suggesting that more than 60 incident HIV infections would be expected (IR 5.1 per 100 person years, 95% CI 3.9-6.4). These figures showed that PrEP and ART led to reduction in relative risk of 94% (95% CI 85-98, p< 0.001).

Maraviroc for oral PrEP?

Results from a phase 2 study using maraviroc as oral PrEP in women at risk of HIV were presented in as an oral abstract. [4]

This study is a similar design to a study in men presented at CROI in 2016, which although five transmissions were reported, none were in people with detectable drugs. This four-arm randomised study is important for including active drugs for all participants: maraviroc (MVC), MVC + FTC, MVC + tenofovir DF (TDF) or TDF/FTC. All doses were once-daily with matched placebo.

In the women’s study, tolerability was also generally good and comparable between arms, and adherence measured by presence of active drugs levels was about 60%.

No new infections were reported, though, similar to the study in men, the study was not powered to show PrEP efficacy.

Long acting PrEP

Several oral presentations looked at long acting (LA) injectable formulations of rilpivirine and cabotegravir, that were both being studied for use as PrEP (although only cabotegravir studies are continuing).

A delay between the single-dose and multiple-dose clinical studies enabled researchers to look at the long pharmacokinetic tail. Rilpivirine was detectable at sub-therapeutic levels in 7/7 plasma samples collected a mean of 541 days after a single dose exposure to rilpivirine LA. Drug was detectable in vaginal fluid but not in vaginal or rectal tissue. [5]

A qualitative study on acceptability of LA PrEP injections with cabotegravir reported mostly good acceptability. [6]

Slight reprieve for dapivirine

Several new analyses from the MTN-020/ASPIRE study suggested that the dapivirine vaginal ring might have higher efficacy as PrEP (perhaps with risk reduction of 75% [95% CI: 18 to 92], p=0.01) compared to placebo for the highest adherent group. [7]

These analyses used complex ways to correlate adherence with risk and were with small numbers of infections, but results are certainly higher than the initial presentations suggested earlier this year at CROI 2016.

Further work in an open label extension will focus on why adherence to using the ring was so low overall.

Data in mice for EFdA with potential for yearly slow release implant

Looking further into the future, early data from using the investigational NRTI EFdA, flew under the radar of most PrEP reports.

This small study reported PrEP efficacy against oral and vaginal exposure in humanised BLT mice (bone marrow, liver, thymus).

Although this is early pre-clinical data, the results are important because EFdA is being developed as a slow-release (and removable) implant formulation, that has the potential to provide therapeutic drug levels from a once-yearly implant. [8]

Comment

While PrEP is fast-becoming a new focus for HIV prevention globally, the UK is increasingly isolated for its failure to provide PrEP, even with the recent announcement of EU approval. [9]

Participants in the UK PROUD study, who helped generate data to support broad use are now faced with the imminent prospect of no further access to PrEP. This is one of many shameful UK health disasters.

The poster with early data supporting a potential role for EFdA as PrEP is perhaps a highlight from the conference.

References:

Unless stated otherwise, all references are to the 21st International AIDS Conference (AIDS 2016), 18 – 22 July 2016, Durban, South Africa.

1. Molina JM et al. Efficacy of on demand PrEP with TDF-FTC in the ANRS IPERGAY open-label extension study. AIDS 2016, Durban. Oral abstract WEAC0102.
   http://programme.aids2016.org/Abstract/Abstract/2564 (Abstract)
2. Spire B et al. Reported changes in PrEP and condom use in MSM during the open-label extension of the ANRS IPERGAY study. AIDS 2016, Durban. Poster abstract WEPEC263.
   http://programme.aids2016.org/Abstract/Abstract/9232 (Abstract)
3. Baeten J et al. Integrated delivery of PrEP and ART results in sustained near elimination of HIV transmission in African HIV serodiscordant couples: final results from The Partners Demonstration Project. AIDS 2016, Durban. Oral abstract WEAC0105.
   http://programme.aids2016.org/Abstract/Abstract/3597 (Abstract)
4. Gulick R et al. HPTN 069/ACTG A5305: phase II study of maraviroc-containing regimens for HIV PrEP in United States (U.S.) women. AIDS 2016, Durban. Oral abstract TUAC0102.
   http://programme.aids2016.org/Abstract/Abstract/5346 (Abstract)
   https://www.youtube.com/watch?v=WXxcAF45D_Q (webcast)
5. McGovern I et al. Persistence of rilpivirine following single dose of long-acting injection. AIDS 2016, Durban. Oral abstract TUAC0103
   http://programme.aids2016.org/Abstract/Abstract/4652 (Abstract)
   https://www.youtube.com/watch?v=Wvb1sSZJCFU (Webcast)
6. Kerrigan D et al. Experiences with long acting injectable (LAI) cabotegravir (CAB) as PrEP: a qualitative study among men participating in a phase II study (ECLAIR) in New York and San Francisco. AIDS 2016, Durban. Poster abstract WEPED393
   http://programme.aids2016.org/Abstract/Abstract/5405 (Abstract)
7. Brown E et al. Residual dapivirine ring levels indicate higher adherence to vaginal ring is associated with HIV-1 protection. IDS 2016, Durban. Oral late breaker abstract TUAC0105LB.
   http://programme.aids2016.org/Abstract/Abstract/10376 (Abstract)
   https://www.youtube.com/watch?v=o4r7NZGERHs (Webcast)
8. Wahl A et al. HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a pre-clinical model of HIV infection. AIDS 2016, Durban. Poster abstract TUPEA025.
   http://programme.aids2016.org/Abstract/Abstract/9652 (Abstract)
9. EMA press release. First medicine for HIV pre-exposure prophylaxis recommended for approval in the EU. 22 July 2016.
   http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/07/news_detail_002578.jsp&mid=WC0b01ac058004d5c1