Although the CCR5 inhibitor maraviroc (MVC) is largely underused as an antiretroviral drug it has many properties that support research as a compound for PrEP.
These include high drug levels in vaginal and rectal tissue and a side effect profile that has potential advantages compared to TDF/FTC.
First results from the phase 2 HPTN 069/ACTG 5305 study using maraviroc for oral PrEP were presented at CROI 2016 by Trip Gulick from Weill Cornell Medical College.1
This was a well designed double-blind placebo controlled study that randomised 407 HIV negative adults to one of four active PrEP groups: (i) MVC 300 mg; (ii) MVC + FTC; (iii) MVC + TDF; or (iv) a control group taking TDF/FTC. It is important that all group included active in addition to placebo treatment, even though this involved all participants taking three pills once-daily.
This study enrolled 399 gay men and 7 transgender women at risk of HIV infection, defined by having at least one high level risk during the previous 90 days. Median age was 30 years (range 18 to 70); 62% were white, 28% black and 22% were Latino. Some level of college education (67%) or higher (13%) was reported by 80% of participants.
The primary endpoint was safety and tolerability over 48 weeks, not efficacy. Secondary endpoints included lower grade side effects and acceptability and to characterise the PK and other circumstance if infections occurred.
Most people (84%; 340/406) remained in the study. By week 48, 7% had stopped early and 9% were lost to follow-up, with no differences between groups.
For the primary endpoint of tolerability, there were 67 reports of grade 3/4 side effects, with no significant differences in pairwise comparisons between study groups (all p>0.05). None of the low level grade 2 events were reported by more than 8% in any group, but these were generally higher in groups using two active drugs.
STIs associated with HIV risk were diagnosed in 90 participants (22%) during study follow-up -- and at baseline in 31 participants (8%). These results are important for confirming that this was an appropriately high risk group.
Although this study was not powered for efficacy, there were five new HIV infections all with R5 tropic virus: 4/5 in the MVC alone group and one in the MVC+TDF group. However, all had drug levels that suggested low adherence.
Only one of these cases had significant MVC drug levels but these had been highly variable during the study and might not have been detectable at the time of infection. Two people had no detectable drug levels at any study visit (including person in the MVC+TDF group), and two had MVC levels at the time of diagnosis that were well below that associated with daily dosing.
By comparison, 80% of participants overall had detectable drug concentrations at weeks 24 and 48, showing sufficiently broad use and tolerability to not rule out some level of protective benefit in each group.
However, several other presentations highlighted the complexity of PrEP research given that exact mechanism is not understood, even for TDF/FTC, and that surrogate markers for one compound might not be appropriate for others.
In an oral presentation of a substudy from the HPTN 069/ACTG 5305 study, Ian McGowan from University of Pittsburgh reported that MVC did not increase T cell activation -- a potential concern that could increase the risk of HIV infection. In explant studies where biopsy tissue was exposed to HIV, there were significant levels of suppression in samples from all dual therapy groups at week 24 that was sustained out to week 48, but this was not seen in the MVC monotherapy samples.
A poster from Julie Fox from Guys and St Thomas' Hospital in London reported good PK data in genital fluid and genital/rectal tissue, in both men and women, following a single oral dose of MVC, with higher levels compared to plasma, absorption within a few hours. Concentrations stayed above the MEC target level of 25 ng/mL for 24 hours and remained above the unadjusted IC90 for 72 hours.3
This poster also suggested that interpretation of high drug levels in rectal sample and the urethral might partial reflect excretion of unchanged drug which would limit their use as a surrogate marker for tissue concentrations.
Taken together these limited data suggest that continued research with MVC should likely be in two-drug combinations.
This study was important for several reasons, not least for the choice of study design that included active treatment for all participants.
Although having an active control groups increases the challenge to show efficacy, there is increasing ethical concerns for PrEP studies to now include oral TDF/FTC as the standard of care for the control arm.
Although MVC alone may have had fewer side effects, the concerns from the ex vivo study suggested that there might be important advantage for dual PrEP combinations.
As monotherapy with either TDF or FTC is less effective than TDF/TFC combined, future studies using dual therapy seem appropriate. These will not be decided until results from an ongoing cohort in 188 women using MVC are available.
Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, USA.
- Gulick R et al. HPTN 069/ACTG 5305: phase II study of maraviroc-based regimens for HIV PrEP in MSM. CROI 2016, Boston. Oral abstract 103.
- McGowan I et al. PrEP impact on T-cell activation and explant infection: HPTN 069/ACTG 5305 substudy. Oral abstract 104.
- Fox J et al. Single-dose maraviroc provides high drug levels in all sites: no gender differences. CROI 2016, Boston. Poster abstract 448.
www.croiconference.org/sites/default/files/posters-2016/448.pdf (PDF poster)