Bangkok Tenofovir Study: US CDC recommends oral PrEP for injecting drug users – based on 16 fewer infections over 5 years

25 July 2013. Related: HIV prevention and transmission.

Simon Collins, HIV i-Base

On 13 June 2013, the US CDC recommended that Pre-Exposure Prophylaxis (PrEP) should be considered as an option for people who inject drugs in order to prevent HIV transmission. [1]

The recommendation was based on the results of a randomised, double-blind, placebo controlled phase 3 study that was published in the Lancet on the same day. [2]

The Bangkok Tenofovir Study enrolled more than 2,400 HIV negative adults (aged 20-60 years) who inject drugs. Participants were randomised (1:1) to either daily oral tenofovir (300 mg) or placebo. Mean duration of follow-up was 4.6 years (maximum 6.9 years) with approximately 24% loss to follow-up in each arm. Adherence was high (>85% of daily pills taken by patient diaries) and directly observed therapy was an option in the study.

During the study (run from 2005 to 2012), 50 people became HIV positive: 17 in the tenofovir group and 33 in the placebo group, indicating a 48.9% reduction in HIV incidence (95% CI 9.6 to 72.2; p=0·01). Side effects and complications were similar in each group, although nausea and vomiting were higher in the tenofovir group in the first two months. No tenofovir resistance was detected in participants who became HIV positive in the active arm.

Risk behaviors for injecting drugs decreased significantly over the first year (from 62.7% to 22.7%), sharing needles (18.1% to 2.3%), and reporting multiple sexual partners (21.7% to 11.0%), and these risk behaviors remained below baseline throughout the entire period of the trial (all three comparisons, p<0.001). These rates were similar in the TDF and placebo groups.

Although this study used daily tenofovir, the US CDC recommended that the fixed-dose dual combination of tenofovir/FTC be used as this formulation has FDA approval for use as PrEP.

The CDC press release commented: “Providing PrEP to IDUs at very high risk for HIV acquisition could contribute to the reduction of HIV incidence in the US. In addition, if PrEP delivery is integrated with prevention and clinical care for the additional health concerns faced by IDUs (e.g., hepatitis B and C infection, abscesses, and overdose), substance abuse treatment and behavioral health care, and social services, PrEP will contribute additional benefits…”.

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The CDC statement is important for raising treatment access and rights for people who inject drugs but the Lancet study on which it was based raises many questions.

One of these is that after three years of follow-up there was no difference between arms in the rate of infections and that if the study had ended then – or been stopped due to futility – then this would have joined the other studies where PrEP showed no benefit.

Although the reduction in relative risk between arms was halved after five years – and reduced by 70% in people whose drugs levels showed adherence – this represented very few averted infections: 16 more people became HIV positive in the placebo group after following 1200 people at high risk for five years. This required a large intervention for what could arguably modest outcomes.

The incidence of HIV reported in the placebo arm (0.68/100 patient years) was significantly lower than historical data suggested for a similar group (3.4/100 patient years during the AIDSVAX vaccine study). This suggests that the increased care and counselling within the study could have had a more significant impact on reducing infections (perhaps by 500%) than the impact of receiving either active drug or placebo.

The differences in events between arms may therefore be related to the impact of counselling wearing off after three years, though this is not specifically discussed in the paper.

Rates of risky drug use were also significantly reduced during the first three years of the study, so tenofovir may have been reducing risks from sexual transmission – at least in part. PrEP should not therefore be seen as a substitution for needle-exchange and other prevention programmes that have already been proven to reduce risks of HIV transmission among people who inject drugs.

References:

1. US CDC Morbidity and Mortality Weekly Report (MMWR). Update to interim guidance for PreExposure Prophylaxis (PrEP) for the prevention of HIV infection: PrEP for injecting drug users (13 June 2013)
   http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6223a2.htm
2. 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, Volume 381, Issue 9883, Pages 2083 – 2090, 15 June 2013. doi:10.1016/S0140-6736(13)61127-7.
   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61127-7/abstract