Journal Club Alcohol, Other Drugs, and Health: Current Evidence July–August 2013

Featured Article 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 Choopanya K, et al. Lancet. 2013;381(9883):2083–2090.

Study Objective To assess whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission (acquisition) in people with injection drug use.

4 Study Design Randomized, double-blind, placebo-controlled trial. Population was 2413 volunteers from 17 drug-treatment clinics in Bangkok, Thailand who were eligible if they were aged 20–60 years, were HIV-negative, and reported injecting drugs during the previous year. Participants were assigned to either tenofovir (N=1204) or placebo (N=1209). They were enrolled between 2005 and Subjects chose either daily directly observed treatment or monthly visits and could switch at monthly visits. All subjects received monthly HIV testing, individualized risk- reduction and adherence counseling, blood “safety assessments” every 3 months, and were offered condoms and methadone treatment (if indicated).

5 Assessing Validity of an Article about Therapy Are the results valid? What are the results? How can I apply the results to patient care?

Are the Results Valid? Were patients randomized? Was randomization concealed? Were patients analyzed in the groups to which they were randomized? Were patients in the treatment and control groups similar with respect to known prognostic variables?

Are the Results Valid? (cont‘d) Were patients aware of group allocation? Were clinicians aware of group allocation? Were outcome assessors aware of group allocation? Was follow-up complete?

Were patients randomized? Yes. –Participants were randomized in blocks of 4 to either tenofovir or placebo.

Was randomization concealed? Yes. –Subjects were randomized using a computer-generated randomization sequence.

Were patients analyzed in the groups to which they were randomized? Yes (intention-to-treat analysis).

Were the patients in the treatment and control groups similar? No. –Baseline characteristics differed on sexual intercourse with a casual partner in the past 12 weeks and men having sex with men in the past 12 weeks, both of which were more common in the placebo group (40% versus 36% and 6% versus 4%, respectively).

Were patients aware of group allocation? No. –Participants were masked to treatment group assignment. –Tenofovir and placebo tablets were similar in shape, color, and taste.

Were clinicians aware of group allocation? No. –Study staff were masked to treatment group assignment.

Were outcome assessors aware of group allocation? No. –Two researchers were unmasked after the data were locked.

Was follow-up complete? No. –The authors followed-up participants for 9665 person-years. There were no differences in follow- up time, withdrawal, or loss to follow-up between treatment groups. –Of the tenofovir group, 409 of 1204 participants did not provide complete follow-up. –Of the placebo group, 410 of 1209 participants did not provide complete follow-up.

What Are the Results? How large was the treatment effect? How precise was the estimate of the treatment effect?

How large was the treatment effect? The authors confirmed HIV infection in 52 participants total: 17 (33%) in the tenofovir group. 35 (67%) in the placebo group. There was a 48.9% reduction in HIV incidence in the tenofovir group compared with the placebo group in the intention-to-treat analysis (an incidence of 0.35 per 100 person-years versus 0.68 per 100 person-years). The cumulative probability of HIV infection in the two groups separated consistently after 36 months.

How Can I Apply the Results to Patient Care? Were the study patients similar to the patients in my practice? Were all clinically important outcomes considered? Are the likely treatment benefits worth the potential harm and costs?

Were the study patients similar to those in my practice? The study took place in Bangkok, Thailand. Demographics included: –% Male: 80 –Education level of primary school or less: mean 48% –Largest age group represented: 20–29 (mean 43%) Clinical characteristics –63% of subjects injected drugs in the 12 weeks prior to study enrollment –Largest percentage of subjects reported injecting less frequently than every week (mean 32%)

Were all clinically important outcomes considered? Yes. -The trial was not powered to assess efficacy by subgroup, but tenofovir showed statistically significant reductions in HIV incidence among women (79%,P=0.03) and participants aged ≥40 years (89%, P=0.01).

Are the likely treatment benefits worth the potential harm and costs? Yes. –This study is the first to show that daily oral pre- exposure prophylaxis with tenofovir, used in combination with other HIV prevention strategies, reduces the risk of HIV infection among people with injection drug use. –Prevalence of nausea and/or vomiting was slightly higher in tenofovir group over placebo (8% versus 5%). –Costs were not reported.