Pre-exposure prophylaxis (PrEP) with tenofovir/FTC reduces sexual transmission of HIV between men at high risk: results from the iPrEx study
1 December 2010. Related: HIV prevention and transmission.
Simon Collins, HIV i-Base
The published results and the supportive supplementary appendix from a large international study (conducted in Peru, Equador, Brazil, US, Thailand and South Africa) provide the first human evidence that daily tenofovir/FTC (Truvada) can reduce the risk of HIV sexual transmission in men who have sex with men (MSM) at a high risk of HIV exposure. [1, 2]
The results should challenge approaches to HIV prevention and they have the potential to drive improved access to tenofovir as an ARV treatment.
The iPrEx study results, together with the full protocol and supplementary information was published online in the New England Journal of Medicine, and are all available without subscription. The top-level results – reducing infection by 44% with minimal safety side effects were widely publicised but the adherence and drug level analyses suggest a far higher potential for protection.
The study randomised just under 2500 men (including 29 transgender women (male-to-female, <1%) to either daily tenofovir/FTC or placebo. As with other prevention studies, iPrEx included intensive risk-reduction counselling, free condoms (monthly), behaviour interview (quarterly) and sexual health monitoring (at least 6-monthly).
Importantly, participants were at high risk of infection due to their behaviour risk. Ten percent of the approximately 5000 people initially screened for the study were already HIV positive and a further 10 became infected between screening and enrolment.
Participants were young (~50% aged 18-24; 20% 25-29 and 20% 30-39 years); sexually active in the previous 12 weeks (18 partners; SD +35); at high risk (~80% having had unprotected anal intercourse (UAI) in the previous 6 months with a partner of unknown HIV status); high STI incidence (13% syphilis, 35% HSV-2 at baseline). Over 40% participants had transactional sex in the previous 6 months, alcohol use was common and high (>4 drinks per drinking day in >50% participants) and HIV awareness/disclosure was low (only 2% had knowingly have sex with an HIV positive person in the previous 6 months). Baseline characteristics were similar between the two arms.
The primary endpoint of at least 85 HIV infections was therefore reached quickly – after a median of 1.2 years (maximum 2.8 years), and total of 3324 patient years of follow-up (PYFU). This was despite a self-reported reduction in risk behaviour (a 50% reduction in the number of partners for receptive intercourse and increasing condom use for receptive intercourse from 50% to 75% of partners) – both potentially the result of a greater focus on HIV risk form the counselling and/or awareness of risk from using a daily prophylaxis.
New infections were reported in 100 participants (36 vs 64 in the active vs placebo group) and demonstrated a crude 44% protection rate (95%CI: 15 to 63; p=0.005) for the active group. Protection was higher in people who reported highest risk sex (recent UAI); 58% protection, 95% CI, 32 to 74). There was no significant between-group difference in protection by geographical region, race or ethnic group, circumcision, level of education, alcohol use, or age.
The analysis of adherence (>95% by self report and 90-95% by pill count; both from week 8 onwards, and slightly lower during the first 8 week) reported higher protection with greater adherence. In a post hoc analyses, pill use on 90% or more of days was recorded at 49% of visits on which efficacy was 73% (95% CI, 41 to 88; p<0.001).
However, results from a small pharmacokinetic sub-study looking at drug levels (both in plasma and intracellular) suggested actual adherence rates could have been dramatically lower. Although the drug level results should be interpreted with caution due to their low number, the associations with infections and suboptimal or undetectable levels were compelling.
Drug levels were only detected in plasma or cells in 3/34 (9%) newly infected people in the active arm. Of the three people with detectable levels, none had cell-associated drug levels higher than median levels in 22 HIV negative controls. Drug level testing was sensitive to one dose of tenofovir and FTC taken within 14 days, though people were tested a median of 35 days (IQR 28 to 56) post-infection.
Conversely, 91% of infections in this sub-group appeared not to be taking tenofovir/FTC on a fortnightlylet alone dailybasis). Rates in an active-arm matched control group of 43 people who were not infected, detected drug levels in approximately 50% of people. Only 8% of this HIV positive group who were considered highly adherent (>50% pills) by self-report were considered on treatment by drug level (compared to 54% of HIV negative controls).
The odds of HIV infection in people in the active arm with detectable drug levels were 12.9-fold lower (95%CI: 1.7 to 99.3; p<0.001), corresponding to a relative reduction in HIV risk of 92% (95%CI: 40 to 99; p<0.001). After adjustment for reported unprotected receptive anal intercourse, the relative risk reduction was 95% (95%CI: 70 to 99; p<0.001).
There was a reassuringly high concordance (>95%) between both plasma and their respective intracellular active moieties and between each drug (both drug were similarly detected in each compartment).
Side effects and tolerability
Although side effects were frequently reported, these were similar between active and placebo groups (70% each, p=0.50) and a similar incidence of serious adverse events (5% each group, p=0.57; NS). Moderate nausea (Grade 2 or higher) was reported more frequently in the active group during the first four weeks (p=0.04)). Unexplained weight loss (>5% weight) occurred more frequently in the active arm (34 vs 19 events, p=0.04).
Creatinine levels were raised (1.1 x ULN or 1.5 x baseline) for 26 measurements in the active arm vs 15 times in the placebo group (2% vs 1% respectively, p=0.08), with 44% remaining in the normal range and 88% of elevated levels not confirmed on the subsequent test. Seven people in the active arm and three in the placebo arm discontinued due to elevated creatinine.
While correlation between protection and active drug levels suggests that pre- and post-exposure dosing may be more critical than daily dosing, the risk of resistance in people who become infected is more complicated. Although resistance was not detected in any of the 34 people in the active arm who became infected – potentially exposed to intermittent or continuous dual-therapy – the lack of difference between viral load in infected people in the active and placebo arms (5.15 vs 5.10 log copies/mL in the tenofovir/FTC and placebo groups respectively, p=0.72) suggests low or non-adherence.
However, in 2/10 people in the active arm who were subsequently found to be HIV positive at baseline, were found to have M184 mutations that could have potentially developed during early exposure to dual tenofovir/FTC therapy. While this could also be explained by infection with drug-resistant HIV (a third person had broad NNRTI and RTI resistance). Further studies, supported by modelling, would help determine whether a higher risk of resistance would be likely to come from daily PrEP (exposure to dual therapy during seroconversion) or intermittent PrEP (exposure to suboptimal drug levels between drug use).
These results are overwhelmingly supportive for a potent new prevention option to reduce the risk of sexual acquisition of HIV in gay men. On an individual risk with good drug levels (PK supports this being taken 24 hours before and within 2 hours after exposure) the reduction in single exposure risk may be as significant as that conferred by an undetectable viral load (<50 copies/mL) in reducing infectiousness of an HIV positive partner (each >90% reductions). Nevertheless, results from ongoing studies of intermittent PrEP will inform this assumption.
These data do not address the practicality of daily PrEP as a population intervention to reduce infection but they do strongly inform individual protection in the context of high adherence prior to and after exposure risk.
Concerns about the practicality of PrEP as a population-based intervention were quickly raised to challenge the optimism of these positive results: and the efficacy levels in iPrEx clearly dont support policy changes. Three of these concerns focus on i) 44% efficacy being too low to support population-based widespread use, ii) the ethics of using a lifesaving treatment that is currently accessed by less than 20% of people on treatment in resource-limited settings and iii) implementation. distribution and access.
The first issue may change significantly given positive impact that use of PrEP has now shown, especially if PrEP is combined with other risk reduction options. The second may determine that PrEP will initially be an option used more in Western countries – as with condoms, or antiretroviral treatment. If PrEP safely reduces he risk of sexual transmission then it should be an option that people can chose, whether through private or public health care – as with condoms. If PrEP really works (with careful adherence) the global demand should theoretically drive greater demand, lower prices and more rapid access within ARV treatment programmes.
- Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010
(10.1056/NEJMoa1011205). Free access: http://www.nejm.org/doi/full/10.1056/NEJMoa1011205
Direct PDF download: http://www.nejm.org/doi/pdf/10.1https://i-base.info/htb/14191056/NEJMoa1011205
- Supplementary appendix: http://www.nejm.org/doi/suppl/10.1056/NEJMoa1011205/suppl_file/nejmoa1011205_appendix.pdf
iPrEx Study press release and fact sheets: http://www.iprexnews.com
iPrEx study materials NIAID: Press Release: http://www.niaid.nih.gov/news/newsreleases/2010/Pages/iPrEx.aspx