On August 26, Nora Volkow, M.D., director of the National Institute on Drug Abuse (NIDA), published a blog promoting the use of pre-exposure prophylaxis, known as PrEP, in preventing the spread of human immunodeficiency virus (HIV). She cited the clinical trial sponsored by the Centers for Disease Control and Prevention (CDC) and the Thailand Ministry of Health conducted from 2005 to 2012 in which injecting drug users were given the PrEP medications in a randomized, controlled, double-blind trial. The trial results, published in The Lancet in June, showed that PrEP reduced HIV infection among drug users by more than 50 percent compared to patients taking placebo. In addition, the results showed observing patients taking the medication daily was even more effective: their risk of contracting HIV was 56 percent less than it was in the group that got take-homes of the study drug.
The medication, an antiretroviral called tenofovir, like other antiretrovirals has side effects, such as upset stomach, that may discourage patients who otherwise feel well from taking it. However, those side effects go away after several weeks. There can be other serious side effects as well. It is contraindicated for people who are HIV-positive.
Last year, the Food and Drug Administration (FDA) approved tenofovir in combination with emtricitabine (Truvada) as a prophylactic intervention for contracting HIV sexually. The CDC, based on the Bangkok study, is now recommending that injecting drug users take Truvada.
Patients in the Bangkok trial received a daily oral dose of 300 milligrams of tenofovir disoproxil fumarate (TDF), or tenofovir. As a result of the trial, the CDC recommended that PrEP be considered as a prevention option for people who inject illegal drugs and are at very high risk for HIV infection.
For the Bangkok Tenofovir Study, as the phase-III trial is called, patients who were not infected with HIV and who reported injecting illegal drugs in the past year were enrolled in a double-blind, controlled trial to determine the safety and efficacy of daily oral TDF to reduce the risk for HIV infection. There were 2,413 men and women randomized to receive either daily TDF or placebo. They could choose to either receive tablets daily under observation or receive 28 daily take-home doses. They could switch the supply method at 28-day follow-up visits, at which they were given counseling on medication adherence and risk reduction, an HIV test, and a pregnancy test, and assessed for adverse events. Risk behaviors were assessed every three months. At study clinics, which are operated by the Bangkok Metropolitan Administration, social services, primary medical care, methadone, condoms and bleach (for cleaning injection equipment) were provided free of charge.
The study was conducted from 2005 to 2012. Nearly a quarter of the patients were lost to follow-up, almost the same number in the TDF group as in the placebo group.
After enrollment, 50 patients were infected with HIV: 17 in the TDF group and 33 in the placebo group. However, two participants in the TDF group were found to have been infected with HIV at enrollment. Excluding these two participants, HIV incidence was 0.35 per 100 person-years in the TDF group and 0.68 in the placebo group — a 48.9 percent reduction in HIV infection in the TDF group.
Participants in the TDF group reported more nausea and vomiting than the control group during the first two months of medication use, but after that, there were no differences.
At the one-year follow-up, risk behaviors decreased significantly for both the TDF and the placebo groups; this reduction lasted throughout the study. Injecting drugs dropped from 62.7 percent to 22.7 percent, needle sharing dropped from 18.1 percent to 2.3 percent and reporting multiple sexual partners dropped from 21.7 percent to 11.0 percent.
Parenteral or sexual transmission?
Last year the FDA approved Truvada (emtricitabine plus tenofovir) to reduce the risk of HIV infection by men having sex with men and heterosexually active men and women. The trials leading to this indication did not evaluate either safety or efficacy among injecting drug users.
PrEP with tenofovir has already been shown to reduce sexual transmission of HIV. While this was the first study to show that it is effective in people who inject drugs, the study authors also said that they could not say with certainty that the intervention prevented parenterally transmitted HIV. Since injection drug users are also at heightened risk for contracting HIV sexually, the tenofovir could have reduced sexually transmitted HIV.
Using the combination to prevent parenteral (infection via needle) HIV infection in people not at risk for sexual infection is “off-label.” What places injection drug users at risk for HIV is needle sharing, injecting at least once a day, and injection of cocaine or methamphetamine. The CDC recommends that injection drug users receiving PrEP receive interventions targeting both injection and sexual risk behaviors.
PrEP is contraindicated in people with unknown or positive HIV status. The authors of the Lancet study said it should be delivered as part of a comprehensive set of prevention services. In particular, adherence to daily PrEP is critical.
Integrating PrEP to injection drug users who are at the highest risk for HIV infection with prevention and clinical care for hepatitis B and C, abscesses and overdoses, as well as social services, could benefit a population with many challenges, the CDC said.
Critics of the study argue that opioid treatment programs (OTPs), instead of requiring patients who test negative for HIV and have recently used injecting drugs, should focus on harm reduction. They note that the Bangkok clinics did not provide clean syringes. “My initial reaction is the first thing OTPs should do to reduce the risk of HIV acquisition among patients is provide sterile syringes and injecting equipment, along with condom promotion,” Sean Barry of VOCAL NY, an advocacy group for methadone patients and active drug users that has been focusing on HIV and hepatitis, told ADAW. “We know that works in the real world,” said Barry. “I'd say the biggest ethical consideration is ensuring OTP patients have access to the full standard of care in terms of harm-reduction services, not necessarily directly observed therapy for PrEP.”
And he said the Bangkok study had “serious problems with the design, including denying participants the standard of care in HIV prevention for people who inject drugs (e.g., syringe exchange), and questions about its real-world applicability.”
NIDA and the CDC are promoting PrEP among injection drug users as part of President Obama’s goal of an “AIDS-free generation.” Truvada is made by Gilead Sciences. Its cost to patients has been estimated at between $11,000 and $14,000 a year.
Taking HIV medication prophylactically reduces the risk of HIV infection among injecting drug users, the CDC and NIDA say, based on a study conducted in Bangkok and funded by the CDC.