By Dr. Geoffrey Modest
A British open-labeled study looked at the effectiveness of pre-exposure prophylaxis (PrEP) to prevent HIV-1 infection in high risk patients (see doi.org/10.1016/S0140-6736(15)00056-2) — the PROUD trial, a partially drug-company funded. Details of study:
- 544 patients enrolled (median age 35, 81% white, 5% asian, 4% black; 59% with university degree; 63% with sexually-transmitted infection (STI) diagnosed in prior year, 3 negative tests in past year), all HIV-1 negative men who had sex with men (MSM) and had anal intercourse without a condom in the previous 90 days, recruited from 13 sexual health clinics in England
- Patients were assigned either to immediate treatment with daily tenofovir disoproxil fumarate (TDF) 245mg plus emtricitabine (FTC) 200mg, or the same treatment delayed for 1 year
- Results:
- 3 HIV infection in the immediate group, (1.2/100 person-years)
- 20 HIV infections in the deferred group (9.0/100 person-years), despite being given counseling, condoms, and even 174 prescriptions for post-exposure prophylaxis (recommended dose: 28 days of TDF-FTC plus lopinivir)
- So, relative risk reduction of 86% (64-96%, p=0.0001), absolute difference 7.8/100 person-yrs (4.3-11.3), which translates to treating 13 men for 1 year to avert 1 HIV infection
- 21 (8%) of patients on the meds interrupted or missed doses because of 28 adverse events, 13 considered related to the study drug, almost all of which were considered mild to moderate. 3 had high creatinine levels.
- No difference in other STIs, including rectal gonorrhea or chlamydia (which suggests that there is not much risk compensation: i.e., when those on meds think they are protected and engage in even riskier sexual practices. Also there were no reported differences in numbers of different anal sex partners between the groups, though there was more receptive anal sex without a condom in the immediate treatment group)
- Study was stopped early because of the increase in HIV infections, and all in the deferred group were offered PrEP
- Tenofovir was detected in the plasma of all 52 sampled participants who reported they were taking the drug.
The perspective here is that HIV infections have been increasing in the MSM community in the UK, despite increased HIV testing and earlier treatment (which decreases transmission). The PROUD trial was actually a pilot trial designed to look at recruitment and retention of patients to test the feasibility of a larger trial, but there were so many HIV infections that they could assess the effectiveness of PrEP (as a secondary outcome). Of note, the 3 cases of HIV in the PrEP group were: one with a reactive HIV test at the 4-week visit, with infection likely to have predated the PrEP; one had HIV detected at the 61st week visit but had no prescribed drug after the first 30-day supply; one seroconverted at 53 weeks, with his last clinic attendance at the 12-week visit where he got 90 days of drugs — so, all 3 were not on meds when they got HIV (meaning that no infections happened in those actually taking the PrEP). And, not surprisingly, none developed any HIV mutations (since they were not taking the drugs). 2 patients who had likely prior HIV infection did develop the codon 184 mutation, likely related to exposure to FTC. No TDF mutations were found. One interesting side issue in a non-placebo controlled trial is that patients may be more adherent to the meds, since they know they are real meds and not potentially placebo, and in that way may actually simulate the real-world clinical situation better. Also, though this should not be an issue, the formulation of TDF/FTC they used is a little different from ours, where there are 300mg of TDF.
So, a pretty remarkable study, finding that in a “real-world setting”, not in a controlled clinical trial, there was overall remarkably good medication adherence and it really worked in preventing HIV infection in this very high-risk cohort (with numbers surpassing some studies done in the ivory towers – e.g. the much larger IPrEX trial with 2499 people randomized to TDF-FTC or placebo, found a 44% reduction in HIV infections (New Engl J Med 2010; 363:2587-2599). Another option remains intermittent PrEP. The IPERGAY study (see http://www.cdc.gov/nchhstp/newsroom/2015/IPERGAY-2015-Media-Statement.html ) also found an 86% HIV risk reduction in MSM using on-demand TDF-FTC with 2 tablets taken 2-24 h prior to sex, one 24 h later and one 48 h later. It would be useful to assess the effectiveness of PrEP in other high-risk groups (e.g., drug users) in poorer communities and in other countries.