HIV-prevention research on substance-using populations has focused primarily on people who inject drugs (PWIDs). Scale-up of proven combination HIV-prevention strategies that include syringe exchange programs (SEPs) and opioid substitution therapies (OSTs) effectively and significantly curtail HIV incidence among PWIDs. Around the world, however, most substances of use and abuse (eg, cocaine/crack, heroin, prescription medications, amphetamine-like stimulants, amyl nitrites, cannabis, alcohol, and tobacco) are administered through routes of administration other than injection (eg, snorting, smoking, inhaling, ingesting, and rectal insertion). These forms of substance use apply to a much larger proportion of the general population than injection drug use does, affecting virtually all HIV-risk groups and all regions of the world. These licit and illicit substances of use and abuse make up a dynamic part of the world economy and are available in even the most conservative societies.
NOT JUST THE NEEDLE
Strategies for HIV prevention among PWIDs do not translate well to noninjectors. First, the most important HIV transmission route among noninjectors is sexual and is not linked to the route of drug administration. Second, because the nature and the frequency of substance use among noninjectors vary widely (eg, sporadic use, binging, and daily use), they may not identify as “substance users” and may not be reached by venue-based HIV-prevention interventions that typically target PWIDs, such as SEPs and OST. Moreover, noninjection substance use occurs in various contexts that confer HIV transmission risks and involves unique subgroups (eg, lesbian, gay, bisexual, or transgender; street youth; sex workers; and low-income migrant workers), which complicates omnibus prevention efforts. Adding complexity, both injection and noninjection substance users who are HIV positive can transmit infection, which among nonsubstance users can be prevented using antiretroviral therapy (ART).1 Data are needed to inform whether this strategy is viable for active substance users who may have a difficulty in adhering to ART regimens. Finally, policymakers, leaders in civil societies, and even some substance users debate whether noninjection substance use warrants focus in HIV prevention above and beyond evidence-based interventions used by all persons at risk. We present the literature regarding this issue and advocate for a research agenda to guide HIV-prevention efforts among all populations of substance users, including noninjectors.
NONINJECTION SUBSTANCE USE AND TRANSMISSION OF HIV AND OTHER SEXUALLY TRANSMITTED INFECTION
Some forms of noninjection substance use, particularly stimulant use, confer elevated rates of HIV transmission, due to their association with high-risk sexual behaviors.2 Cocaine and amphetamine-like stimulants can increase sexual arousal3,4 and promote high-risk sexual behaviors among users.3 Stimulants are frequently a drug of choice among men who have sex with men (MSM)5 and female sex workers. Other noninjected substances also associated with sexual HIV transmission include alcohol,6 volatile nitrates, and some prescription drugs.7 Due to its worldwide availability, alcohol misuse is increasingly recognized as a significant factor associated with HIV sexual risk behaviors in both MSM8 and heterosexuals.9 There are no studies showing independent associations between cannabis use and elevated HIV transmission risks.10
TOOLS FOR PREVENTING HIV TRANSMISSION IN NONINJECTING SUBSTANCE USE
Epidemiology and Surveillance
There is a compelling need for better data on HIV incidence attributable to noninjection substance use. Substance use often involves ≥2 substances that may be coadministered (ie, polypharmacy)11 or used within the same time frame, which complicates measurement and an understanding of contextual influences of substance-related HIV risks. These realities underscore the need for event-level data and surveillance approaches that are flexible and time sensitive. Studies that focus on HIV risks related to noninjection substance use often rely on estimates of relative risks. By contrast, little attention has been focused on attributable risks at the individual and population levels, which would yield the number of HIV infections that could be averted if specific forms of substance use were reduced or eliminated (ie, etiologic fractions). Such studies require prospective data collected from large samples reporting varying levels and types of substance use. For example, in Project EXPLORE and the Multisite AIDS Cohort Study, both large studies of MSM, substance use, particularly stimulant use, was shown to account for 28% and 33%12,13 of new HIV infections, respectively.
HIV-prevention science has overwhelmingly focused on behavioral interventions to reduce HIV-transmission behaviors. Behavioral interventions, often consisting of brief individual or multisession group interventions, have shown efficacy in reducing drug and/or sexual transmission behaviors compared with the standard of care or to baseline risk behaviors.14 Substance users are less likely, however, to reduce sexual risk behaviors compared with drug risk behaviors.14 The lack of evidence-based programs for sexual behaviors related to noninjection substance use is striking. Notable exceptions exist for female crack cocaine users,15 or heterosexual16 and MSM methamphetamine users.17 Interventions are especially needed that reduce substance use–related HIV risks in groups that have high HIV prevalence (eg, MSM, sex workers, street youth, and migrant workers).
Behavioral drug treatments including contingency management and cognitive behavioral therapies have shown reductions in sexual risks and methamphetamine use among MSM in outpatient treatment.18 No medications are approved to treat stimulant dependence, which is unfortunate. Among individuals who inject opioids, treatment using OST can reduce HIV incidence.19 Although medications are approved for alcohol dependence, none show efficacy in reducing sexual HIV risk behaviors. Future HIV-prevention strategies should consider Screening, Brief interventions, and Referral to drug Treatment in venues that high-risk substance users frequently attend, such as sexually transmitted disease clinics.20
Recent advances offer new biomedical approaches to HIV prevention, such as HIV treatment as prevention (TasP) and as a prevention strategy for HIV-uninfected populations as preexposure prophylaxis (PrEP)21 or postexposure prophylaxis (PEP). With the potential use of these new therapies, there are concerns about adherence to ART,5,22 engagement in care, and continued risk behaviors among substance users that dampen the political will for assessing these strategies. Yet the effect of stigma is significant and measurable: in the United States and Canada, injection and noninjection drug users were less likely than were nondrug users to have access to ART.23 One recent study found that offering PEP in combination with contingency management was feasible and acceptable among methamphetamine-using MSM.24 Overall, little research has evaluated acceptability, feasibility, and efficacy of TasP, PrEP, or PEP with substances users, independent of needle use. Surveillance studies rarely include biomarkers of HIV disease status or substance use among substance users, which leads to underestimates of prevalence.
Noninjection substance users, particularly stimulant users, often encounter multilevel risk environments that prevent access to HIV and drug treatment. These include gender inequalities, intimate partner violence,25 stigma, discrimination, incarceration, homelessness, lack of health insurance, and coerced treatment. Effective structural interventions are also needed to address these substance-related HIV risks that range in scope and unit of analysis. These include changes in drug possession laws, increased access to drug treatment, and interventions at the venue-level (eg, safer inhalation facilities, prison settings) and community-level (eg, school-based interventions). The need for research on the influence of regional drug policies (eg, supply control efforts, criminal sanctions on drug possession and use, and prescription monitoring systems) is palpable. Drug policies differ according to the needs, resources, and culture of the region, whereas most were created with the intention of enhancing public good26; these often carry major unintended consequences to the public health.27 Research into structural level changes within the health care system also is of high priority. In the US President's National HIV/AIDS Strategy, HIV prevention is organized at the system level to optimally influence the outcomes toward HIV prevention among HIV-positive individuals, including substance users (seek, test, treat, and retain).
NEW SUBSTANCES AND EMERGING GROUPS AT RISK
Shifting patterns of substance use and the ways and contexts in which they are used present a moving target for HIV prevention. In countries where the HIV incidence among PWIDs has declined, HIV transmissions among substance users have shifted from injection to sexual behaviors. In Brazil and the southern cone of Latin America, cocaine injection was prevalent in the late 1980s and in the early 1990s but subsequently declined with a rise in crack use.28 In Thailand, since the late 1990s, declining heroin injection has been replaced by widespread methamphetamine smoking.29 South Africa is also experiencing a methamphetamine epidemic, with most users reporting noninjection routes of administration.30 Other countries in sub-Saharan Africa have witnessed emerging epidemics of heroin and cocaine use, and their impact on HIV incidence within the context of high HIV prevalence in the general population is unknown.31 Changes in the ways in which substance use influences HIV transmission behaviors across broad geographic areas underscore the vital need for rapid surveillance assessment and response, with an increased use of biomarkers that target HIV subtypes and medication resistance.
New compounds are being derived from parent substances of abuse, altered sufficiently to avoid laws on drug possession and distribution.32 Their use is on the rise.33 These include synthetic cannabinoids, cathinones (eg, “bath salts”), and other amphetamine analogs, which are marketed to the youth. Whether these substances are associated with elevated HIV transmission risks is unknown. Among noninjection substance–using youth, engagement in HIV-risk behaviors is high, especially among those who are MSM and street involved.34 Evidence is accruing that shows school attendance is protective against HIV35 and substance use.36 Little is known about substance-related risks or their mitigation in youth who drop out of school, are orphaned, or who do not work.
GAPS IN KNOWLEDGE
* Can HIV-positive substance users adhere to ART and experience the TasP benefit? When offered as part of HIV prevention, ART can prevent HIV transmission in HIV serodiscordant couples when started early1 and reduces HIV transmission in HIV-negative MSM.21 Yet, substance users were systematically excluded from “proof-of-concept” trials that established the initial efficacy of combination HIV-prevention strategies due to concerns over potential medication adherence problems.
* What data exist on HIV in high-risk subgroups of substance users, including users of noninjection substances, from racial/ethnic groups and in regions where substance use, homosexuality, or sex-work are illegal that can guide high-impact prevention studies? There is a compelling need for data from low- and middle-income countries that have ongoing generalized HIV epidemics (eg, Sub-Saharan Africa and South and Southeast Asia) or emerging epidemics (eg, Central Asia).
* What medications or behavioral therapies are effective for treating substance use that might reduce HIV-related transmission behaviors? In contrast to OST, effective medications for alcoholism have modest effect sizes, and there are no medications for stimulant drugs. As more effective medications are developed, efforts to assess these for reducing drug-related sexual risk behaviors should be prioritized.37
* What structural interventions can be implemented to reduce HIV transmissions among users of injection and noninjection substances within settings of criminal justice or of primary care services?
THE WAY FORWARD
An evidence-informed strategy to guide HIV prevention in noninjection substance users draws heavily from the successes of combination HIV prevention in nonsubstance users and from declines in HIV transmission among PWIDs from using the combination of SEPs, OSTs, and ART.
We propose a rational plan of HIV-prevention research for substance users addressing the following:
In most high-income countries, links between noninjection substance use and HIV transmission behaviors are well described. There is a need for evidence describing associations between these factors, particularly in regions where cultural and religious sanctions exist against substance use, homosexual behaviors, street youth, and women. An increased emphasis on biomarkers of HIV incidence and substance use is vital.
Combination Prevention Approaches in Noninjection Substance Users
There is a crucial need to conduct studies that advise implementation of combination prevention approaches (eg, PrEP, TasP, and PEP) in substance users. Strategies of TasP remain unproven among injection and noninjection substance users who are HIV positive, which is of the highest priority. Combination HIV-prevention strategies of PrEP and PEP in HIV-negative substance users at high risk also merit consideration. Recognizing that no medication can be effective if it remains in the bottle, efforts to quantify and address potential problems with medication adherence in substance users, including structural and behavioral approaches, are important. Testing of depot formulations of ART medications specifically in noninjection substance use would carry a high impact. There is a concomitant need for combination HIV-prevention research that addresses co-occurring infections in substance users, particularly hepatitis C, tuberculosis, and sexually transmitted infections.
Substance Use–Related Risk Reduction Strategies
Sexual behaviors are the principal risk for HIV transmission among noninjection substance users, and studies that develop potent substance-use reduction tools, including medication and behavioral approaches, can reduce risk behavior. However, it is unknown as to what extent HIV incidence can be reduced.
To significantly reduce HIV incidence among individuals who engage in noninjection substance use and sexual risk behaviors, scientists and policymakers need to set aside personal biases about substance use, sexual behaviors, and cultural attitudes that promote abstinence as the only goal, recognizing that even modest decreases in substance use and related sexual risks may reduce harms and hence be associated with impressive etiologic fractions. Although condoms are effective against HIV transmission, rising HIV incidence in high-risk subgroups of substance users are unlikely to be reversed without additional prevention strategies, such as combination prevention, structural interventions, and interventions to reduce substance use. In prior work,38 we noted the need to overcome “addictophobia” to continue gains in HIV prevention with PWIDs. Future success in HIV prevention for noninjection substance users will rely on the ability to marshal the scientific and political will to allocate resources to reduce HIV transmissions in groups whose sexual risk behaviors are associated with substance use—and not just with the needle.
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