Summary

Background

Antiretroviral pre-exposure prophylaxis reduces sexual transmission of HIV. We assessed whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission in injecting drug users.

Methods

In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment clinics in Bangkok, Thailand. Participants were eligible if they were aged 20—60 years, were HIV-negative, and reported injecting drugs during the previous year. We randomly assigned participants (1:1; blocks of four) to either tenofovir or placebo using a computer-generated randomisation sequence. Participants chose either daily directly observed treatment or monthly visits and could switch at monthly visits. Participants received monthly HIV testing and individualised risk-reduction and adherence counselling, blood safety assessments every 3 months, and were offered condoms and methadone treatment. The primary efficacy endpoint was HIV infection, analysed by modified intention-to-treat analysis. This trial is registered withClinicalTrials.gov, number NCT00119106.

Findings

Between June 9, 2005, and July 22, 2010, we enrolled 2413 participants, assigning 1204 to tenofovir and 1209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0·35 per 100 person-years) and 33 in the placebo group (0·68 per 100 person-years), indicating a 48·9% reduction in HIV incidence (95% CI 9·6—72·2; p=0·01). The occurrence of serious adverse events was much the same between the two groups (p=0·35). Nausea was more common in participants in the tenofovir group than in the placebo group (p=0·002).

Interpretation

In this study, daily oral tenofovir reduced the risk of HIV infection in people who inject drugs. Pre-exposure prophylaxis with tenofovir can now be considered for use as part of an HIV prevention package for people who inject drugs.

Once-daily oral tenofovir decreased the risk of HIV infection by 48·9% in injecting drug users when provided with other HIV prevention services at drug-treatment clinics in Bangkok. Findings from other pre-exposure prophylaxis trials showed that adherence had an important effect on efficacy.11, 12 In this study, efficacy increased from 46% to 56% in the per-protocol analysis based on observed adherence and to 74% when limited to participants with detectable tenofovir concentrations. Although the trial was not powered to assess efficacy in subgroups, we saw higher efficacy in women (79%) and in participants aged 40 years or older (89%)—two subgroups with high levels of adherence. The modified intention-to-treat efficacy result did not rule out tenofovir efficacy at less than 10% as specified in the protocol.

We do not know why HIV incidence in the two groups did not differ consistently until after 36 months (figure 2). Low levels of adherence or low risk behaviour during the first 36 months could have masked the effect of tenofovir, but adherence did not change by time on study and risk behaviour decreased during follow-up. The low HIV incidence and slow accrual of infections might be why no between-group difference was seen before 36 months. At 36 months, there were 27 infections and, assuming 49% efficacy, the distribution should have been nine with tenofovir and 18 with placebo. However, there were 13 with tenofovir and 14 with placebo, a difference of only four events.

As has been reported in other trials,11, 12 participants in the tenofovir group reported more nausea and vomiting in the first couple of months of follow-up than did those in the placebo group. When used for treatment of HIV, tenofovir is associated with small decreases in renal function.26, 27 We did not find higher rates of increased creatinine or renal disease in participants randomly allocated to tenofovir.

Other pre-exposure prophylaxis trials have described antiretroviral-resistance mutations in HIV-positive participants, especially in those with unrecognised HIV infection at enrolment.11—13 We did not detect tenofovir resistance in HIV-positive participants in this study. The two participants with unrecognised HIV infection at enrolment were randomly allocated to placebo, limiting the possibility that acquired resistance would occur.

Participant reports of injecting drugs and sharing needles decreased during follow-up, consistent with previous trials in people who inject drugs in Bangkok.28, 29 The HIV incidence in placebo recipients in our study was 0·68 per 100 person-years. This incidence compares with an incidence of 5·8 per 100 person-years in a preparatory trial done in the same clinics in 1995—99 and of 3·4 per 100 person-years during the 1999—2003 AIDSVAX B/E HIV vaccine trial.22, 28 This decrease over time is probably due to many factors, including monthly HIV risk-reduction counselling, decreased needle sharing, and monthly HIV testing speeding up the diagnosis of HIV and limiting the number of people with unrecognised acute HIV infection able to transmit HIV to others.

Our study had several limitations. Participants could have under-reported stigmatised and illegal behaviours such as injecting drugs.30 However, the illegality and stigma attached to these activities did not change during the trial, meaning that rates of under-reporting should have remained constant. The study aimed to establish whether tenofovir would reduce parenteral HIV transmission, but participants might have become infected sexually. Previous studies in people who inject drugs in the same clinics in Bangkok have shown strong associations between injecting drugs and HIV infection, but no association between sexual activity and HIV infection.28, 29 In this study, although reports of injecting drug use decreased, 1018 (45%) participants reported injecting drugs during follow-up, including 35 (70%) of those who contracted HIV during the course of the study. Furthermore, similar to the previous studies in the drug-treatment clinics, drug overdose, traffic accidents, and sepsis were the most common causes of death, and participants were frequently incarcerated. Together these data suggest that participants were actively injecting drugs and that parenteral HIV transmission, not sex, was the primary route of HIV infection. Additional risk behaviour analyses are underway. The study was done in drug-treatment clinics offering a package of HIV prevention interventions and DOT; tenofovir effectiveness might differ in other settings.

Findings from three randomised, placebo-controlled trials have shown that a daily dose of tenofovir or tenofovir-emtricitabine can reduce sexual HIV transmission.11—13 Findings from two other studies showed that tenofovir and tenofovir-emtricitabine did not reduce sexual HIV transmission.31, 32 Adherence seems to be the key factor determining efficacy.33These trials draw attention to the need for methods to help people using pre-exposure prophylaxis achieve effective levels of adherence.

To our knowledge, this study is the first to show that daily oral pre-exposure prophylaxis with tenofovir, when used in combination with other HIV prevention strategies, reduces the risk of HIV infection among people who inject drugs (panel). The US Food and Drug Administration has approved the use of tenofovir-emtricitabine to prevent sexual acquisition of HIV in high-risk individuals.34 On the basis of the results of this study, regulatory and public health authorities can now consider whether pre-exposure prophylaxis with tenofovir should be part of an HIV prevention package to reduce the risk of HIV infection in people who inject drugs.

Panel

Research in context

Systematic review

We searched PubMed for phase 1, 2, and 3 randomised clinical trials in human beings assessing tenofovir for the treatment of HIV infection and animal trials using tenofovir to prevent HIV infection. We used the search terms “HIV”, “tenofovir”, “treatment”, “prevention”, and “clinical trials”, restricting our search to studies published in English through December, 2004. The study was launched in 2005 and, at the time, no phase 3 clinical trials using tenofovir in human beings for HIV pre-exposure prophylaxis had published results.

Interpretation

To our knowledge, this is the first study to show that daily oral pre-exposure prophylaxis with tenofovir, when used in combination with other HIV prevention strategies, reduces the risk of HIV infection in people who inject drugs. Much like findings from other pre-exposure prophylaxis trials, our findings showed that adherence had an important effect on efficacy. On the basis of these findings regulatory and public health authorities can now consider whether pre-exposure prophylaxis with tenofovir should be part of an HIV prevention package to reduce the risk of HIV infection in people who inject drugs.

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