Long-acting PrEP; Fem and VOICE PrEP sing same sorrowful song; PrEP not associated with increased risk of future HIV seroconversion
The provision of HIV antiretroviral pre-exposure prophylaxis (PrEP) is one of the four key action items of the ‘Action on HIV- Melbourne Declaration 2012’. PrEP was discussed in several different sessions at CROI 2013. Here are some of the highlights:
In Session 8, ‘HIV prevention: ARV, Counseling, Contraception and Condoms’, Chasity Andrews from David Ho’s group at the Aaron Diamond AIDS Research centre gave an excellent talk on GSK744 which is a new, potent integrase inhibitor (abstract 24LB). GSK744 exists both in an oral and a long acting parenteral formulation. The oral formulation has been evaluated as monotherapy and affords a 2-2.5 log10 decrease in plasma HIV-1 viral load. It’s half-life is approximately 3.71 weeks when given intramuscularly at 800mg.
In Ho’s study 8 Rhesus Macaques were injected with GSK744 twice, at week -1 and week 3+. All animals were intra-rectally challenged from week zero with SHIV 162P3 and received a total of 8 challenges, or until SHIV infection was confirmed.
None of the 8 Macaques receiving GSK744 became infected during the challenge, or during the 10-week follow-up phase whilst all Macaques receiving placebo GSK744 became infected. In follow-up, there was no evidence of DNA in PBMCs nor an antibody response to SHIV in any of the actively treated Macaques.
Further work to be done with GSK744 includes (1) postmortem of the Macaques receiving active GSK744 to determine if there was contained local infection, (2) determining the minimum protective dose for rectal challenge, (3) determining its capacity to protect again HIV vaginal challenge in female macaques.
This drug has the potential to be given monthly or quarterly.
Clinical trials, in addition to determining drug efficacy will need to carefully monitor for both short and longterm toxicity (including for a period of time after injections have ceased). If efficacious, this possible shift in the formulation of PrEP drugs could be remarkably beneficial for people at risk of HIV infection, but will still require appropriate ‘effectiveness’ studies to determine adherence, risk compensation and any informal use of PrEP as an injection. Also in different countries, monthly or quarterly PrEP injections could potentially lead to infringement of human rights for some, including sex workers and people who inject drugs.
In the next talk of session 8, James Smith from the CDC provided further encouraging trial results that showed that a Tenofovir Disoproxil Fumarate (TDF) intravaginal polyurethane ring was able to completely protect 8 female macaques from SHIV vaginal challenge on 16 occasions over 4 months and using 4 ring changes during that time (abstract 25LB). There was no toxicity, no microflora change and Phase 1 Clinical trials will commence in Q3 2013. Very interesting presentation in terms of the machinations of developing the ring so that it effectively delivers the more potent form, TDF which is 500 times more potent than tenofovir and also has activity against HSV-2.
(Note-these two talks complement another session held later on that day “New approaches to HIV drug delivery”, Session 13).
In session 8 Jeanne Marazzo next presented the findings of the VOICE study (Abstract 26LB).
VOICE was a randomised, 5-arm, double-blind, placebo-control trial of PrEP that enrolled5,029 HIV negative women from Zimbabwe, South Africa and Uganda. Most participants were enrolled in South Africa (4,077). Eligible participants had to have had sex in the previous 3 months, be willing to use oral contraception and not be pregnant, or breastfeeding. Participants were randomised to oral tenofovir, oral tenofovir- emtricitabine, oral placebo, 1% tenofovir gel or gel placebo.
An interim DMSB in September 2011 ceased the oral TDF arm because it was safe but not effective. In November 2011 the TFV vaginal gel arm was stopped because it was safe but not effective. In August 2012 follow up of TDF-FTC arm was possible.
The mean age of the participants was 25.3 year. Most women were using injectable contraception. 17% reported anal sex at baseline. 85% reported use of a condom at last vaginal sex. Study retention was excellent with an overall 91% retention rate at study end
Adherence was assessed using monthly count of unused study products (pills or applicators) and quarterly audio-computer assisted self interview (A-CASI). Product return suggested 89% adherence and self-report by A-CASI found an adherence of 90% or above.
There were 334 HIV acquisition events for the intention-to-treat analysis. 22 women were HIV+ by PCR at enrolment. Hence there were 312 HIV acquisitions in the primary analysis, giving an overall HIV incidence of 5.7%. None of the three studied PrEP modalities afforded protection from HIV. The incidence of HIV was highest in women who were less than 25 years old and unmarried. The HIV incidence per 100 person-years in South African women < 25 years of age was 8.7 [7,6-10], > 25 years of age 4.7 [3.8, 5.8], married 0.9 [0.2-2.7] and unmarried 7.5 [6.6, 8,4].
Adherence appears to be the key factor in the observed failure of the study drug as at least 50% of women tested had no TFV found in sampling across the three study arms. These results are consistent with the Fem-PrEP study (Van Damme et al, NEJM 2012), which showed that oral TDF-FTC did not significantly reduce HIV infection compared to placebo and that adherence appeared to be very low in the study.
The disappointing conclusions that the VOICE study team drew were that we need to consider PrEP agents and delivery systems that are long acting and require minimal daily adherence and that a greater understanding of HIV risk perception and biomedical, social and cultural determinants of adherence in these high-risk populations is urgently needed.
In follow-up questions we learned that very few women in the VOICE study reported that they were CSWs and that the study team are doing a separate study, VOICE-D, to explore via in-depth qualitative interviews the issues around risk perception and PrEP adherence.
Finally, to end on a more positive note we learnt from Bob Grant of the iPrEx study team (abstract 27) that during a gap phase that occurred between the iPrEx study ending and an open-label extension of the iPrEx study beginning (where gap times ranged from 7-19 months across the study sites and during which no PrEP was available), that there was no excess incidence of HIV infection observed. Here the theoretical concern was that the use of PrEP during the iPrEx study had simply delayed HIV infection and that when PrEP was ceased during the gap phase that an excess in HIV seroconversions would be observed. This speaks to the notions of biological and behavioural prevention futility where an intervention like PrEP may fail ultimately if it does not alter the conditions that allow transmission. An excellent talk to catch on the webcast.
Dear readers, if you have not already done so please sign the Melbourne Declaration at http://www.melbournedeclaration.com/ as Australia, Asia and the Pacific Region gear up to host World AIDS 2014 next year in Melbourne. Act now and be part of this endeavour!