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.

www.aodhealth.org 3

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 2010.

• 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).www.aodhealth.org

www.aodhealth.org 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?

www.aodhealth.org 6

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?

www.aodhealth.org 7

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?

www.aodhealth.org 8

Were patients randomized?

• Yes.

– Participants were randomized in blocks of 4 to either tenofovir or placebo.

www.aodhealth.org 9

Was randomization concealed?

• Yes.

– Subjects were randomized using a computer-generated randomization sequence.

www.aodhealth.org 10

Were patients analyzed in the groups to which they were

randomized?

• Yes (intention-to-treat analysis).

www.aodhealth.org 11

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).

www.aodhealth.org 12

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.

www.aodhealth.org 13

Were clinicians aware of group allocation?

• No.

– Study staff were masked to treatment group assignment.

www.aodhealth.org 14

Were outcome assessors aware of group allocation?

• No.

– Two researchers were unmasked after the data were locked.

www.aodhealth.org 15

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.

www.aodhealth.org 16

What Are the Results?

• How large was the treatment effect?

• How precise was the estimate of the treatment effect?

www.aodhealth.org 17

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.

www.aodhealth.org 18

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?

www.aodhealth.org 19

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%)

www.aodhealth.org 20

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).

www.aodhealth.org 21

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.