A daily tablet of tenofovir, a drug otherwise used to treat HIV infection, reduced the risk of HIV acquisition among people who inject drugs by 49% in a clinical trial. Those who took the medication most consistently had higher levels of protection, report scientists from the Centers for Disease Prevention and Control (CDC) in The Lancet today.
These findings from Thailand come from the only pre-exposure prophylaxis (PrEP) trial ever conducted with injecting drug users, and show that PrEP can reduce infections associated with sharing injecting equipment as well as sexual transmission among drug users.
Incidence was 0.35 per 100 person-years in the PrEP group and 0.68 per 100 person-years in the placebo group, representing a 48.9% reduction in infections.
The data reinforce previous findings on PrEP’s efficacy in men who have sex with men and heterosexual serodiscordant couples. “This is a significant step forward for HIV prevention,” commented Jonathan Mermin of the CDC. “We now know that PrEP can work for all populations at increased risk for HIV.”
The CDC has issued interim guidance recommending that PrEP is provided to injecting drug users who are at high risk of acquiring HIV, as part of a comprehensive package of prevention services.
Bangkok Tenofovir Study
In order to find out whether a daily tablet of tenofovir (Viread) as PrEP would reduce the risk of HIV infection in this population, American and Thai investigators recruited 2413 people who reported injecting drugs in the previous year. All participants were aged 20 to 60 and were HIV negative at baseline.
Participants were randomised to either receive tenofovir or a placebo (dummy pill).
Of note, the trial drug was tenofovir alone, rather than a combination of tenofovir and FTC (Truvada), as has been used in most other PrEP studies. Participants took 300mg of tenofovir daily, which is the same dose as is contained in Truvada.
Commencing in 2005, this was a controversial study, bitterly opposed by drug user and AIDS activists in Thailand. They felt that PrEP was being offered as a second-best option when needle exchange – a prevention intervention of proven efficacy – was unavailable. The investigators maintain that Thai law prohibits the distribution of needles to inject illegal drugs, but activists blame the US government policy which prohibits federal funding of needle exchange.
They also complained of a lack of meaningful community consultation and limited efforts to make PrEP accessible to injecting drug users in Thailand after the trial has finished.
Nonetheless, the trial ran from 2005 to 2012, with 2413 individuals taking part. Recruitment was slow but retention good – participants stayed in the study an average of four years.
Participants’ average age was 31 years, 80% were male, 48% had primary school education or less, and 79% had previously been incarcerated.
At the beginning of the trial, 63% of the participants had injected drugs in the previous twelve weeks, although only 9% injected daily. One-in-five participants reported sharing needles. Drugs commonly injected were methamphetamine (33%), the tranquilliser midazolam (23%) and heroin (22%).
Drug use dropped dramatically as people took part in the trial (with similar falls in both arms of the study). After one year in the study, only 23% reported injecting drugs and 2% reported sharing needles in the previous twelve weeks.
Self-reports of drug use may underestimate actual use, but the reductions may also be due to the risk-reduction counselling that all participants received and the opioid substitution therapy that some of them took up. Perhaps as a consequence of these prevention interventions, there were far fewer HIV infections in the trial than there had been in previous cohorts of Thai drug users.
At baseline, 22% of participants had had more than one sexual partner in the previous twelve weeks, falling to 11% after one year. Five per cent of the male participants reported sex with another man.
Adherence - directly observed therapy
The study employed directly observed therapy (DOT) and financial incentives. This is likely to have affected the levels of adherence and retention seen in the trial, limiting the extent to which these finding can be generalised across all populations of people who inject drugs.
At the beginning of the trial and at each monthly visit, participants could choose to either take their daily tablets independently at home and record adherence in a daily diary, or to come into the clinic each day and have the pill administered by study staff. For those on DOT, the daily diaries were filled out by study staff.
Participants received 70 baht ($2) each day they came to the clinic for directly observed therapy, potentially earning 2100 baht ($60) a month if their attendance was good. (The official minimum wage in Thailand is 300 baht a day, less than $10). Participants also received 350 baht ($10) for attending monthly study visits, when HIV tests, side-effects monitoring, counselling and behavioural assessments were conducted.
Staff followed up missed appointments with phone calls and home visits.
Participants chose to be on directly observed therapy most (86.9%) of the time.
According to daily diaries, participants took the study drug on 83.8% of days. This didn’t differ between the PrEP arm and the placebo arm. However, older people and women had better adherence.
Consistent with other PrEP studies, the trial did not identify any significant safety concerns associated with daily oral use of tenofovir. Those taking tenofovir were more likely to experience nausea or vomiting (8%) than those in the placebo group (5%), but this was largely during the first two months of treatment.
The amount and severity of other adverse events reported were similar among participants in both the treatment and control groups. There was no indication of elevated creatinine or renal failure among participants in the tenofovir group.
No tenofovir resistance was found among participants who became infected during the trial.
Fifty of the 2413 participants became HIV positive during the study – 17 were in the PrEP group, and 33 were in the placebo group. Incidence was 0.35 per 100 person-years in the PrEP group and 0.68 per 100 person-years in the placebo group.
This amounts to a 48.9% reduction in HIV incidence, in an intent-to-treat analysis (95% confidence interval 9.6 – 72.2%).
For reasons that remain unclear, infection rates did not differ for the first three years that participants stayed in the trial, but diverged strongly afterwards.
Efficacy was stronger in women and in people over the age of 40.
Drug concentration testing on blood samples of 13 people in the PrEP group who seroconverted showed that 39% of them had detectable tenofovir in their blood.
An analysis that was not originally planned, and which excluded individuals with poor adherence and without detectable drug in their blood, suggested that PrEP reduced infections by 73.5%.
It is impossible to know how many of the HIV infections which occurred are linked to drug use, and how many to sexual transmission. Some argue that the decreasing rates of drug use in the cohort point to a role for sexual transmission, while the authors note that those who seroconverted reported more ongoing injecting than those who did not. Further behavioural analyses will be published at a later date.
The authors note the high burden of HIV infection attributable to injecting drug use in many parts of the world and suggest that regulators and public health bodies can now consider adding PrEP to HIV prevention programmes for people who inject drugs.
For the United States, the CDC has already issued interim guidance suggesting that injecting drug users at high risk of infection should be offered Truvada (not tenofovir) as PrEP, “as part of a comprehensive set of prevention services”.
However, at present in the United States, Thailand and numerous other countries, that package of services only occasionally includes needle exchange. The effectiveness of this intervention was proven many years ago, it also protects against hepatitis C, is acceptable to people who inject drugs, and is cheap.
“PrEP is not a replacement for politically sensitive needle exchange programmes,” commented Salim Abdool Karim in a commentary accompanying the Lancet article. He called for it to be included as part of a combination prevention programme for injecting drug users.
Similarly, Michel Sidibé of UNAIDS noted that this combination should include provision of clean needles and syringes, opioid substitution therapy, accessible health care services, the removal of punitive laws, and work with police and law enforcement bodies.
“We now need to get serious about making PrEP available to those who can benefit,” said Mitchell Warren of AVAC, noting the lack of demonstration projects to answer critical questions about how best to deliver PrEP.
In relation to people who inject drugs, considerable work needs to be done on how acceptable the strategy is in different communities and how it can be delivered in ‘real world’ settings without the resources of a clinical trial. Effective ways to support individuals with adherence need to be identified, perhaps not requiring directly observed therapy and financial incentives.
Moreover, realistic prices for PrEP drugs need to be negotiated, otherwise marginalised people in low- and middle-income countries are unlikely to benefit.
Choopanya K et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet, doi:10.1016/S0140-6736(13)61127-7, 2013. (Abstract here.)
Martin M et al. Enrollment Characteristics and Risk Behaviors of Injection Drug Users Participating in the Bangkok Tenofovir Study, Thailand. PLoS ONE 6(9): e25127. (Full text here.)
Chua A et al. The Tenofovir Pre-Exposure Prophylaxis Trial in Thailand: Researchers Should Show More Openness in Their Engagement with the Community. PLoS Med 2(10): e346, 2005. (Full text here.)
Abdool Karim SS HIV pre-exposure prophylaxis in injecting drug users. The Lancet, doi:10.1016/S0140-6736(13)61140-X, 2013.
Smith DK et al. Update to Interim Guidance for Preexposure Prophylaxis (PrEP) for the Prevention of HIV Infection: PrEP for Injecting Drug Users. Morbidity and Mortality Weekly Report 62(23); 463-465, 2013. (Full text here.)