June 27, 2013
People who use injection drugs are disproportionately affected by HIV. In Canada, it is estimated that up to 16% of new HIV infections in 2011 may have been due to injection drug use and up to 14,200 people living with HIV in 2011 may have become infected this way. Although many interventions are known to be effective at preventing HIV among people who use injection drugs -- such as methadone treatment programs, needle exchanges and supervised injection sites -- additional strategies could play an important role in reducing the spread of HIV in this population.
Pre-exposure prophylaxis, or PrEP, is a new HIV prevention tool recently found to be effective at reducing the rate of new HIV infections among some populations of HIV-negative individuals. It involves taking anti-HIV medications on a regular basis, starting before an exposure and continuing afterwards.
Several types of PrEP have been investigated, including the daily use of pills taken orally (oral PrEP) and the application of a gel into the vagina (topical PrEP). These types of PrEP contain the antiretroviral drug tenofovir (called Viread when used in pill form) or combinations of tenofovir and emtricitabine (sold as a fixed-dose co-formulation pill called Truvada).
Several trials have found that oral PrEP taken daily can reduce the risk of HIV transmission among populations whose main risk of HIV transmission is through sex, including heterosexual people and men who have sex with men (MSM). As a result, the US Food and Drug Administration (FDA) approved the use of Truvada as PrEP to prevent the sexual transmission of HIV. Also, the Centers for Disease Control and Prevention (CDC) in the US released guidelines for healthcare providers on the prescription of Truvada for heterosexual men and women and MSM.
Until recently, no studies had investigated the effectiveness of PrEP for populations whose main risk of infection is through injection drug use.
Started in 2005, the primary aim of the Bangkok Tenofovir Study was to determine if oral tenofovir taken daily could reduce the risk of HIV infection among people who use injection drugs. The study was a collaborative project involving the CDC in the US, the Bangkok Metropolitan Administration and Thailand's Ministry of Public Health.
HIV-negative men and women between 20 and 60 years of age who reported injecting drugs in the previous year were eligible to participate in this study. Participants were recruited through 17 drug treatment clinics in urban Bangkok, Thailand and then randomized to take either a daily pill containing tenofovir or a daily pill that did not contain tenofovir (a placebo). Participants did not know which group they were randomized to.
Once enrolled in the study, participants could choose to visit the drug treatment clinic every day and take their pills under the direct observation of study staff (also known as directly observed therapy, or DOT) or visit the clinic once a month, receive a 28-day supply of pills and take the pills on their own. Participants were allowed to switch between these two options throughout the study and were compensated financially for each visit to the drug treatment clinic.
Previous studies show that adherence is critical for PrEP to work. Therefore, drug diaries were used to track participants' adherence to their daily pill-taking schedules and were filled out either by the study staff (if the participant was on DOT) or by the participant themselves (if not on DOT). Drug levels in the blood were also measured to determine if people were taking their pills.
All participants -- regardless of whether they were randomized to take daily tenofovir or placebo pills -- had access to additional services offered by the drug treatment clinics. These services included:
As it is illegal in Thailand to provide sterile needles for the purpose of injecting drugs, needles were not provided at the clinics. However, low-cost sterile needles are readily available in Thailand pharmacies without a doctor's prescription.
Once every month study participants were assessed for side-effects and toxicity, received adherence and risk-reduction counselling and were tested for HIV.
Between 2005 and 2012, more than 2,400 HIV-negative men and women were enrolled in the study and approximately half were assigned to take PrEP and half to take a placebo. The majority of the participants were male (80%) and the average age was 31 years. At the time they entered the study, 63% of participants reported injecting drugs and 18% reported sharing needles in the past 12 weeks. Participants were followed for an average of four years.
A total of 50 HIV infections occurred during the study. The rate of HIV infection was lower among those assigned to take PrEP, with the number of new HIV infections in each group as follows:
Overall, the relative risk of acquiring HIV was 49% lower among participants assigned to take daily tenofovir pills and this difference was statistically significant.
Participants generally preferred to visit the clinic daily and take their pills under direct observation rather than visiting the clinic monthly and taking the pills on their own. Those enrolled in the study were on DOT an average of 87% of the time and, according to the drug diaries, participants (including those on DOT and not on DOT) took their pills an average (median) of 94% of the time.
Measuring drug levels in the blood has been used in previous PrEP studies as a more accurate measure of whether participants are taking their pills. This method was also used in the Bangkok Tenofovir Study: In a random sample of 138 HIV-negative participants assigned to take PrEP, only 67% had a detectable level of drug in their blood. This suggests that many participants were not taking their medications daily and that the information in the drug diaries may have overestimated adherence.
Similar to other studies, PrEP was more effective in preventing HIV infection among the participants who had higher rates of adherence. In one analysis, "high" adherence was defined as being on DOT, taking the medications at least 71% of the time, not missing more than two consecutive days of pill-taking, and having detectable levels of drug in the blood. Individuals who met these criteria were 74% less likely to become infected with HIV.
The tenofovir pills were generally well tolerated and safe. However, there were higher reports of nausea and vomiting among those in the tenofovir group but only during the first two months after starting the drug. Also, more participants in the tenofovir group (53%) than in the placebo group (49%) had slightly elevated levels of an enzyme produced by the liver known as alanine aminotransferase. This suggests that tenofovir may have negatively impacted liver function in a small proportion of participants. No drug resistance was detected among those in the tenofovir group who became infected during the study.
We know from previous studies that the daily use of tenofovir can prevent the sexual transmission of HIV; however, researchers of the Bangkok Tenofovir Study wanted to determine if it can also reduce the risk of HIV transmission through injection drug use. Unfortunately -- since participants in the study were at risk of HIV transmission through both routes of HIV transmission -- it was not possible to definitively conclude whether PrEP reduced the risk through sex, injection drug use or both. However, analysis suggests that participants in the study were mostly at risk through injection drug use. Overall, 45% of participants reported injecting drugs during the study, and injection risk behaviour (not sexual risk behaviour) was associated with becoming infected with HIV. Therefore, the study investigators believe this trial likely demonstrated that daily tenofovir can reduce the risk of HIV transmission through injection drug use.
While establishing the effectiveness of PrEP, the study also emphasized the importance of using a combination of prevention strategies (a combination approach to HIV prevention) with people who use injection drugs. Risk behaviours decreased throughout the study, likely as a result of the other services provided at the drug treatment clinics, with the proportion of people reporting injecting drugs in the past three months decreasing from 63% to 23% and needle sharing from 18% to 2%. As a result, the rate of HIV infection among those in the placebo group was much lower than the investigators expected when planning the study.
Interventions to prevent infections other than HIV are also important for a combination approach. Although PrEP may reduce the risk of HIV transmission through sex and injection drug use, it does not reduce the transmission of other infections that are transmitted in the same way, such as other STIs and hepatitis C. Hepatitis C, in particular, is highly prevalent among people who use injection drugs and is generally transmitted more easily than HIV. Interventions such as sterile needles and condoms are effective at reducing the risk of HIV, STI and hepatitis C transmission.
Authors of the study state that "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."
However, questions remain regarding the impact that PrEP could have among people who use injection drugs outside of a clinical trial. The Bangkok Tenofovir Study took place under tightly controlled conditions, and ongoing services were provided to participants, which may have improved the prevention impact of PrEP. In particular, participants were on DOT most of the time (perhaps because of the financial compensation provided at each daily visit), and this likely played a role in supporting adherence and ensuring that PrEP worked. The impact of PrEP may be lower among people who use injection drugs who are not on DOT and have trouble adhering to regular PrEP use. In fact, PrEP was not effective in some previous clinical trials done with heterosexual women because of low adherence rates among study participants.
Further research is needed to better understand the potential role of PrEP within a combination approach to improving the health and well-being of people who use injection drugs.
The CDC have updated their interim PrEP guidelines to include recommendations for people who use injection drugs. These recommend that people who use injection drugs and are at high risk of HIV infection be prescribed Truvada (not tenofovir) as PrEP. The guidelines state that "providing PrEP to IDUs [injection drug users] at very high risk for HIV acquisition could contribute to the reduction of HIV incidence in the United States. 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 healthcare, and social services, PrEP will contribute additional benefits to a population with multiple life-threatening physical, mental, and social health challenges."
Pre-exposure prophylaxis (PrEP) -- CATIE Fact Sheet
Choopanya K, Martin M, Suntharasamai P, 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. 2013 Jun;381(9883):2083-90.
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