HIV Prevention in Clinical Care Settings: 2014 Recommendations of the International Antiviral Society–USA Panel

Importance  Emerging data warrant the integration of biomedical and behavioral recommendations for human immunodeficiency virus (HIV) prevention in clinical care settings.

Objective  To provide current recommendations for the prevention of HIV infection in adults and adolescents for integration in clinical care settings.

Data Sources, Study Selection, and Data Synthesis  Data published or presented as abstracts at scientific conferences (past 17 years) were systematically searched and reviewed by the International Antiviral (formerly AIDS) Society—USA HIV Prevention Recommendations Panel. Panel members supplied additional relevant publications, reviewed available data, and formed recommendations by full-panel consensus.

Results  Testing for HIV is recommended at least once for all adults and adolescents, with repeated testing for those at increased risk of acquiring HIV. Clinicians should be alert to the possibility of acute HIV infection and promptly pursue diagnostic testing if suspected. At diagnosis of HIV, all individuals should be linked to care for timely initiation of antiretroviral therapy (ART). Support for adherence and retention in care, individualized risk assessment and counseling, assistance with partner notification, and periodic screening for common sexually transmitted infections (STIs) is recommended for HIV-infected individuals as part of care. In HIV-uninfected patients, those persons at high risk of HIV infection should be prioritized for delivery of interventions such as preexposure prophylaxis and individualized counseling on risk reduction. Daily emtricitabine/tenofovir disoproxil fumarate is recommended as preexposure prophylaxis for persons at high risk for HIV based on background incidence or recent diagnosis of incident STIs, use of injection drugs or shared needles, or recent use of nonoccupational postexposure prophylaxis; ongoing use of preexposure prophylaxis should be guided by regular risk assessment. For persons who inject drugs, harm reduction services should be provided (needle and syringe exchange programs, supervised injection, and available medically assisted therapies, including opioid agonists and antagonists); low-threshold detoxification and drug cessation programs should be made available. Postexposure prophylaxis is recommended for all persons who have sustained a mucosal or parenteral exposure to HIV from a known infected source and should be initiated as soon as possible.

Conclusions and Relevance  Data support the integration of biomedical and behavioral approaches for prevention of HIV infection in clinical care settings. A concerted effort to implement combination strategies for HIV prevention is needed to realize the goal of an AIDS-free generation.

The availability of combination antiretroviral therapy (ART) has changed the lives of millions of individuals living with human immunodeficiency virus (HIV), transforming HIV from a fatal infection to a manageable chronic disease. Incidence of new HIV-1 infections worldwide has decreased by an estimated 33% since 2001 but remains high at approximately 2.3 million new infections in 2012. In the United States, approximately 50 000 new infections occur each year—a number that has remained largely unchanged since the 1990s.¹

The integration of biomedical and behavioral approaches to HIV prevention, coupled with ART for those infected, represents the cornerstone of efforts to curb the spread of HIV infection.² In an effort to provide practicing clinicians, public health experts, and policy makers with a framework to implement the best HIV prevention interventions, the International Antiviral Society—USA (IAS—USA) Panel has developed recommendations that integrate biomedical and behavioral prevention in the care of people living with or at risk for HIV infection. These recommendations are intended as best practice based on available evidence. Implementing these recommendations may present structural, economic, or political challenges. However, benefits to be derived from their implementation should contribute substantially to preventing disease progression, promoting healthy life years gained, and preventing new HIV infections.

In formulating these recommendations, the panel intentionally avoided distinguishing between behavioral and biomedical interventions, choosing to emphasize that providing prevention in care—for people living with or at risk for HIV infection—requires a combination of activities.

A systematic literature review using Medline and EMBASE was conducted to identify relevant published data. Specific search terms and limits are detailed in the supplemental section on the process of recommendation development (eMethods in the Supplement). Approximately 250 related manuscripts were selected based on scientific evidence or major guidelines. Panel members also conducted hand searches for newly published reports and abstracts from scientific conferences throughout the process. Data not published or presented in a peer-reviewed setting were not considered.

Recommendations were developed by the International Antiviral Society–USA HIV Prevention Recommendations Panel, an international panel of experts in HIV biomedical and behavioral science and practice. The panel convened in person in March 2013 and met regularly by teleconference thereafter. Panel members serve in a volunteer (no financial compensation) capacity and do not participate in industry promotional activities such as speaker bureaus, industry-paid lectures, or other marketing activities during panel membership (details available in the eMethods in the Supplement). Teams evaluated evidence and summarized panel discussions for each section. Prior to convening, members declared and discussed potential conflicts of interest and recused themselves from serving as section leaders or team members accordingly. A description of the panel process is included in the eMethods in the Supplement.

Panel recommendations were limited to HIV prevention for clinical care settings for nonpregnant adults and adolescents. Recommendations for prevention included ART that was available (approved by regulatory bodies or in expanded access [compassionate use]) or in late-stage development (new drug application filed). Recommendations were made by full-panel consensus and rated according to strength of the recommendation and quality of supporting data (Table 1 and Box 1).⁴ Ratings were provided only for recommendations supported by clinical or observational study data. The panel developed these recommendations regardless of clinical setting; thus, they are relevant to the global community. However, most of the cost-effectiveness literature cited is specific to the United States and other well-resourced settings, such as Canada, Western Europe, and Australia. To the extent that resource utilization, care structures, and ART costs vary widely across different settings, the economic discussions should be interpreted accordingly.

Box Section Ref ID

Self-knowledge of HIV serostatus is the pivotal step in directing interventions to prevent HIV infection, enabling linkage of newly diagnosed persons to care as well as provision of prevention interventions to those found to be HIV-seronegative but at risk of infection. Despite the importance of this knowledge, approximately 50% of people living with HIV worldwide—and 16% of those in the United States—do not know their serostatus.⁵ Moreover, HIV-infected persons who are unaware of their serostatus may account for as much as 45% of new HIV infections in the United States.⁶ In addition, persons who receive a positive HIV test result often reduce their HIV-related risk behaviors.^6-8

In 2006, the US Centers for Disease Control and Prevention (CDC) issued guidelines recommending routine opt-out HIV testing in health care settings⁹; despite this, many missed opportunities for testing in clinical care continue to occur. Quiz Ref IDIn 2013, the US Preventive Services Task Force recommended routine HIV screening for all persons aged 15 to 65 years.¹⁰ Both of these guidelines note that where prevalence of undiagnosed HIV infection is 0.1% or less, routine screening may be supplanted by screening on the basis of risk assessment.

New developments such as HIV rapid tests, fourth-generation antibody and antigen assays (eTable in the Supplement),¹¹ fewer legal barriers to testing, and integration of screening in diverse settings should facilitate increases in HIV testing and early diagnosis, timely receipt of results, and better linkage to care.¹² Home- and community-based testing strategies, including self-testing, are especially important for populations with unmet health care needs.¹³ Fourth-generation assays allow clinicians to detect some acute and recent HIV infection, narrowing the window between infection and diagnosis to approximately 15 to 20 days, thus allowing diagnosis of persons who are often highly infectious.¹⁴ New diagnostic algorithms also omit the need for routine confirmatory Western blot testing.¹⁵Quiz Ref IDThe CDC Sexually Transmitted Disease Treatment Guidelines recommend that men who have sex with men (MSM) who have multiple or anonymous partners, have sex in conjunction with illicit drug use, use methamphetamine, or who have sex partners who participate in these activities be screened for sexually transmitted infections (STIs) and HIV more frequently (every 3 to 6 months) than MSM without such risk factors.¹⁶

For couples who are or plan to be sexually active, HIV testing is an effective intervention for both heterosexual and same-sex couples.^17,18 With couples HIV testing, participants receive testing and counseling together; individuals learn not only of their own HIV serostatus but also that of their partner(s), which facilitates the delivery of tailored prevention messages and care plans.

Counseling associated with HIV testing is a complex topic. In the United States, state laws vary as to what is required.¹⁹ At a minimum, individuals should know that they are being tested. Some studies have found that counseling conducted at the time of HIV testing serves to reduce HIV-related risk behaviors and subsequent STIs; however, some studies did not demonstrate these effects.^20-31 Counseling should not be an impediment to HIV testing. Indeed, current guidance from the CDC states that prevention counseling should not be required with HIV diagnostic testing or as part of HIV screening programs in health care settings.⁹ Last, the economic value of HIV screening is well substantiated and is enhanced when transmission prevention benefits associated with screening are included.^32-34

Brief risk assessment and brief clinically feasible risk reduction services may be considered for persons at high risk of HIV infection, including those with an incident STI, evidence of injection drug use, or who report sexual or drug using risk. In the sections below, we discuss these services both for persons living with HIV and for persons at increased risk for HIV infection (see Table 2 and 3).

For recommendations regarding HIV testing and knowledge of HIV status, see Box 1.

Suppression of infectious HIV-1 in blood and genital secretions through provision of ART is highly effective in reducing—indeed, largely eliminating—the risk of ongoing HIV transmission. Observational studies of heterosexual couples have confirmed that successful ART reduces probability of HIV transmission.^58,59 In 11 of 13 such studies, almost no HIV transmission was observed when the infected partner was receiving ART.^60,61 In studies in which transmission events occurred despite ART, the HIV-infected participants were likely not reliably adherent to ART.⁶² The PARTNER study, a prospective observational study of 767 serodiscordant couples, 40% of which were same-sex male couples, recently reported no HIV transmission occurring during an estimated 894 couple-years of observation during which the majority of penetrative anal or vaginal sex was condomless, and where the HIV-infected partner was receiving ART.⁶³

The HPTN 052 (HIV Prevention Trials Network 052) study⁶⁴ was a randomized clinical trial (RCT) undertaken to prospectively determine the prevention benefit of ART. Among 1763 HIV serodiscordant couples in 9 countries, HIV transmission was reduced by more than 96% during a period of 18 months by adding ART to standard prevention strategies. The results also demonstrated a clinical benefit (reduction in incident tuberculosis) to individuals offered ART at CD4 cell counts greater than 350/μL compared with ART initiation at CD4 cell counts less than 250/μL.⁶⁵ An ecological study among people who inject drugs in Vancouver, British Columbia, Canada, suggested that ART significantly reduces spread of HIV infection.⁶⁶ In Kwazulu-Natal, South Africa, for every 1% increase in ART use, a 1.4% decrease in HIV incidence was observed.⁶⁷ An association of similar magnitude was established in a population-based analysis in British Columbia.^66,68

The President’s Emergency Plan for AIDS Relief⁶⁹ and the World Health Organization (WHO)⁷⁰ now recommend that HIV-infected persons whose sex partners are HIV-uninfected be offered immediate initiation of ART, irrespective of CD4 cell count. The Internation Antiviral Society–USA⁷¹ and US Department of Health and Human Services⁷² recommend that ART initiation be offered to persons with HIV infection, regardless of CD4 cell count, for both individual health and transmission prevention benefits. Most recently, the WHO has recommended that ART be offered to all persons with CD4 cell counts less than 500/μL regardless of symptoms and with CD4 cell counts greater than 500/μL in a number of specific clinical settings.⁷⁰ Extrapolating from observed individual and population benefits, studies have demonstrated that in the United States, expanded screening (1 time in low-risk and annually in high-risk persons, such as those in serodiscordant partnerships or with multiple sex partners) with immediate ART initiation for individuals who test HIV-seropositive is a cost-effective method of preventing transmission.⁷³ Early ART targeted to HIV-serodiscordant couples has also been projected to be cost-effective in resource-limited settings.⁷⁴

Recent ecological analyses from areas where MSM are most affected by HIV infection have not reported declines in HIV incidence or prevalence as ART use has expanded, despite the encouraging data from the PARTNER study.^63,75 Sustained HIV transmission from untreated (or inconsistently treated) MSM with high levels of plasma and genital HIV RNA is likely driving these epidemics.^75-77

Acute and early HIV infection may limit the effect of ART on the prevention of HIV transmission. During this period, plasma and genital viral loads reach high concentrations and may remain elevated for several months. Very few people learn their serostatus during this period.⁷⁸ Newer HIV tests¹² and testing algorithms that incorporate HIV-1 RNA testing may enhance the likelihood of detection during this time, but the overall effect is likely to be small because the clinical diagnosis of acute HIV infection is frequently not suspected.⁷⁹ Because people with acute and early HIV infection contribute disproportionately to the spread of HIV,^80,81 correct diagnosis and prompt intervention are needed.⁷ Small studies of the sexual behavior of people with early HIV infection do not suggest that behavior change alone will suffice; thus, immediate, lifelong ART is recommended.⁸² Early treatment preserves CD4 cell counts⁸³ and reduces ongoing viral diversification and the size of the viral reservoir.^84,85 Moreover, failure to provide ART during a clinical encounter that occurs early in the disease can result in loss to follow-up with the patient, who may re-engage with care only when they have developed an HIV-related complication.⁸⁶

Adherence to ART is crucial for sustained HIV-1 suppression. Consistent with the current International Association of Physicians in AIDS Care guidelines, once-daily, fixed-dose combination ART is preferred whenever possible.^71,72,87 Even with such regimens, complete adherence can be challenging. Behavioral interventions⁸⁸ that have shown promise include brief psychosocial counseling, such as cognitive behavioral therapy,^89-93 risk-reduction behavioral interventions,⁴⁰ motivational interviewing,^93-95 managed problem-solving counseling,⁹⁶ adverse-effects coping interventions,⁹⁷ peer-led social support groups,^98,99 and counseling interventions for specific populations, including recently released inmates,¹⁰⁰ youth,¹⁰¹ urban-dwelling HIV-seropositive individuals with depression,¹⁰² and persons with low health literacy skills.^103,104 Personalized telephone calls are effective, and computer-administered adherence promotion has shown promise.^105-107 Among people who inject drugs, medication-assisted therapy and directly administered ART have improved adherence.^108,109 For recommendations regarding the preventive benefits of ART, see Box 1.

Behavioral interventions have been shown to reduce sexual risk behaviors, increase condom use, and reduce subsequent STIs among persons living with HIV (Table 3).^{35-51,110-116} The CDC has identified effective, evidence-based behavioral risk-reduction interventions developed for people living with HIV (Table 2).⁵⁰ As seen in Table 3, some of the “best” and “good” evidence (as labeled by the CDC) were developed before ART was widely available. A subset of these interventions has been subjected to economic evaluation and shown to be cost-effective.^115,116 Further, some of the interventions described in Table 2 are brief and could be provided in a clinical setting, whereas others are more intensive and would likely be available only through other resources.

Although implementation of universal ART for HIV-infected persons remains incomplete, expanded use of ART at all stages of HIV infection has changed the dynamic between risk behaviors and how they are perceived. The effect of ART on sexual behavior is likely complex and depends on numerous factors at the individual level.⁵¹ Ongoing behavioral risk assessment is a critical component of care for persons with HIV and should inform a discussion of risk reduction. However, data indicate that despite evidence of benefit, only 61% of people living with HIV who engage in risk behavior with serodiscordant partners receive risk-reduction prevention services.¹¹⁷ Effective behavioral risk-reduction strategies are typically delivered using individualized counseling techniques, including motivational interviewing^118,119 and skills-based counseling.^120,121 In settings where such counseling cannot be delivered, clinicians should at minimum conduct a brief risk assessment^122,123 and refer patients to available relevant health services. Risk screening protocols¹²⁴ may be useful to identify individuals in need of more intensive counseling in busy clinical settings¹²⁵ or to monitor for incident STIs¹²⁶ or clinical indications of injection drug use. Importantly, risks identified during these conversations should facilitate discussion about potential effects of ongoing risk behavior, even in the setting of successfully suppressed plasma HIV viral load. For example, inflammation caused by genital STIs or other inflammatory processes can increase HIV-1 RNA levels in genital secretions even when plasma HIV is suppressed by ART, thus rendering the “fully suppressed” person potentially infectious.¹²⁷ In addition, superinfection (acquisition of a second HIV strain after an immune response to the initial strain has been established) may be relatively frequent in some populations and may be associated with poor clinical outcomes.¹²⁸ Last, treatment for HIV does not affect the risk for acquisition of other STIs.¹²⁹

Persons with HIV should receive guidance and support in disclosing infection status to sex and drug injection partners. In some jurisdictions, legislation that criminalizes HIV exposure may discourage HIV-infected persons from disclosure; thus, it is important to know the relevant legal context and to be aware of resources that may facilitate this process.¹³⁰ Some care settings have formalized HIV partner management programs and demonstrated enhanced effectiveness of partner elicitation and notification.^131,132 If self-disclosure is used, factors to discuss are how to prepare for disclosure, to whom it will be made, when and how it will take place, how it can affect the client and persons to whom disclosure is made, and the stressful nature of the process.¹³³

For recommendations regarding risk reduction counseling, status disclosure, and partner notification, see Box 1.

Simultaneous scale-up of combining access to ART, opioid substitution therapy, and harm reduction services can greatly reduce the incidence of HIV infection among people who inject drugs, and is supported by technical guidelines from the WHO, United Nations Office on Drugs and Crime, and the Joint United Nations Programme on HIV/AIDS.^134-136 In an ecological study in Vancouver, British Columbia, Canada, increased ART coverage corresponded with reduction in “community median plasma viral” load and an approximately 50% reduction in new HIV diagnoses, including those among people who inject drugs.⁶⁶ More recently, a population-based analysis in British Columbia demonstrated a greater than 90% province-wide decline in new diagnoses of HIV infection, which was largely attributed to the expansion of harm-reduction programs coupled with enhanced ART coverage among people who inject drugs.⁶⁸ Unfortunately, people who use drugs face widespread barriers to accessing ART in many settings.¹³⁷

Quiz Ref IDTreatment for opiate addiction with opioid substitution therapies, especially methadone, increases the likelihood that people who inject drugs will initiate ART.¹³⁸ Once initiated, methadone maintenance increases ART adherence, including among homeless persons.¹³⁹ Opioid substitution therapies likely reduce HIV transmission by reducing illicit opioid use, sharing of injection equipment, numbers of sex partners, and exchange of sex for drugs or money.¹⁴⁰ In addition, there is no evidence of increased sexual risk behavior after initiating ART among people who inject drugs.^141,142 Of note, use of opioid substitution therapies should be voluntary; coercive treatment does not prevent HIV transmission and does not treat addiction.¹⁴³

Needle and syringe exchange programs link individuals to health care services and provide sterile injection equipment and supplies, reducing associated transmission risks. No RCTs document efficacy for these programs, although observational reports support their use. Health outcomes among people who inject drugs living in New York City when syringe exchange was legal were compared with those among people who inject drugs living in Newark, New Jersey, when exchange was illegal. People who inject drugs living in Newark had substantially higher prevalence rates of HIV, hepatitis C virus, and hepatitis B virus infections and more frequent self-reported needle reuse and sharing.¹⁴⁴ Access to a supervised injection facility is associated with improved individual health outcomes,^145-147 risk behaviors,^148,149 and societal outcomes.¹⁵⁰ Moreover, the use of medicalized heroin in a supervised injection facility has clinical benefit¹⁵¹ and is cost-effective.¹⁵²

In contrast, although most persons who use drugs take them by mouth, insufflation, smoking, or anal or vaginal insertion rather than injection, data that might inform HIV prevention strategies targeted at such noninjection drug use are limited. Approaches to HIV prevention for substance users are consistent with those used among non–substance users and should emphasize prevention of sexual transmission. Emerging data support novel strategies, including medications to treat stimulant dependence in MSM¹⁵³ and reduce risk behaviors in active stimulant users.¹⁵⁴ For recommendations regarding prevention in people who inject drugs, see Box 1.

The HIV care continuum provides a representation of the steps necessary to take HIV-infected persons from diagnosis to suppression of plasma HIV-1 viral load. The value of investing in linkage to care after a new HIV diagnosis has been demonstrated.^155,156 A model-based study demonstrated that investments along the most distal part of the care continuum (ensuring adherence, linkage, and retention) were more economically efficient than those devoted to increase HIV screening.¹⁵⁷

Moving individuals across the HIV care continuum can be arduous for those on the margins of the health care delivery system.^158,159 Interventions that consider the individual’s social environment and attendant structural factors produce more positive and sustainable outcomes compared with those that do not.¹⁶⁰ Commonly cited community or structural barriers include fear of being stigmatized because of an HIV diagnosis; joblessness resulting from disclosure; inability to afford health care; homelessness or unstable housing; incarceration; lack of a supportive social network; food insecurity; and legal, legislative, and policy factors that pose obstacles to addressing these concerns.^161,162

For these reasons, structural and community-level interventions (broadly defined as those that build on the awareness that environmental, social, political, and economic factors are potential sources of HIV risk and vulnerability) are increasingly important.¹⁶²

The period after a person is initially diagnosed with HIV represents a critical opportunity to establish linkage to care. Failure to do so reduces the opportunity to address current health issues, access preventive services, and initiate timely ART. However, data to inform interventions to ensure that this linkage is made are sparse. One RCT evaluated a brief (up to 5 sessions) case management intervention focused on identifying individual strengths, reducing barriers to obtaining care, and accompanying persons to appointments. Compared with passive referral, the intervention was more effective in creating linkage to care.¹⁶³ Use of outreach efforts, financial incentives, navigation assistance, partner services, and social marketing have successfully engaged individuals from underserved and marginalized populations, including persons of color and MSM.^164-166 Further research is needed to identify barriers to care and optimal strategies for increasing linkage to care. New approaches to program science should inform this process and are especially important in resource-limited settings.

Consistent retention in care has been associated with shorter time to viral load suppression, lower cumulative viral load burden, improved immune function, decreased mortality, and decreased engagement in HIV transmission behaviors.^167,168 A large observational study found that retention increased substantially after the implementation of clinic-wide interventions, including print reminders and brief verbal messages used by all clinic staff.¹⁶⁹ Patient navigation interventions, community and peer outreach, print media, verbal messages from clinic staff, financial incentives, and youth-focused case management and support have been associated with increased retention in care.^107,170-173 For HIV-infected, opioid-dependent individuals, 1 RCT demonstrated that medication-assisted drug treatment (buprenorphine and naloxone) was associated with increased retention in care.¹⁷⁴ For recommendations regarding clinic-wide interventions, see Box 1.

Until recently, the prevention of HIV infection for uninfected individuals was focused only on behavioral interventions. Although these continue to be important, effective biomedical approaches are now available (see Table 4 and Table 5). Importantly, all biomedical prevention trials have also included state-of-the-art behavioral counseling as part of the approach. Thus, HIV prevention should not be considered as either behavioral or biomedical but rather as a combination intervention.

Quiz Ref IDThere is strong evidence that brief behavioral counseling delivered to persons at risk for HIV infection reduces sexual risk behaviors, increases condom use, and reduces subsequent STIs including HIV.^{50,110-114,184-188} The EXPLORE Study, a multicity, randomized trial of a 10-session counseling intervention among MSM, demonstrated a 39% reduction in HIV incidence during a 12- to 18-month period after counseling and an 18% reduction in incidence during a 48-month period.^189,190These findings are bolstered by a meta-analysis of randomized trials that tested much briefer, single-session sexual risk reduction counseling interventions that embodied similar principles of behavior change.¹⁹¹ Reductions in incident STIs have been demonstrated to result from brief interventions of skills-based individualized counseling in trials with high-risk men and women, and a number have been labeled as “best” or “good” evidence-based interventions by CDC (Table 3).^29,50,52-57 Not surprisingly, interventions that involved a longer duration of a single counseling session were more effective than those of briefer duration. Face-to-face counseling interventions also had greater effects than media-delivered messages. Risk reduction counseling can be delivered alone or ideally in combination with biomedical prevention strategies targeting HIV-uninfected persons.^6,50,192,193

The most effective individualized counseling provides patients with self-management skills and condoms.^110,194,195 In addition, content analyses of effective counseling have identified common principles that promote preventive behaviors: fostering a sense of self-belief and self-worth, distinguishing fact from myth, evaluating options and consequences, formulating commitment to change, planning skills, promoting self-control, establishing pleasurable alternatives to high-risk sexual activity, negotiating safer behaviors, setting limits, and acting to help others protect themselves.¹⁹⁶ Although various counseling approaches have nuances tailored to particular populations and service settings, most are well suited for use in combination with biomedical prevention technologies. For recommendations regarding risk reduction counseling for HIV-uninfected persons, see Box 1.

Preexposure prophylaxis (PrEP) with daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a fixed-dose combination decreases HIV-1 acquisition among MSM,¹⁸¹ serodiscordant heterosexual couples,¹⁷⁸ and heterosexual adults¹⁷⁹ (Table 5). Daily oral TDF alone was effective for preexposure prophylaxis in heterosexual couples¹⁷⁸ and people who inject drugs.¹⁸⁰ The US Food and Drug Administration approved daily oral FTC/TDF for HIV prevention in 2013, and the CDC has issued guidance for its use.¹⁹⁷

The key determinant of preexposure prophylaxis efficacy is medication adherence. Detection of TDF in plasma has been associated with reduction in HIV acquisition by approximately 90% among MSM and heterosexual adults.^178,179,181 Detection of TDF in peripheral blood mononuclear cells commensurate with daily use was associated with an estimated 99% reduction in HIV risk (95% CI, 96% to >99%).¹⁹⁸ In contrast, no efficacy was discerned in 2 trials in which TDF was generally detected in less than 30% of female participants.^182,183

Clinical trial findings highlight important considerations for preexposure prophylaxis implementation, including the development of drug resistance among participants experiencing acute retroviral infection at enrollment, underscoring the need to rule out acute infection prior to starting preexposure prophylaxis. Resistance to TDF/FTC was not observed^178,179,181 or was rare¹⁸² in infections that developed after starting preexposure prophylaxis.^178-183 Importantly, trial participants who received regular risk assessment and counseling did not exhibit an increase in risk behaviors.^178,179,181 Observational cohort studies of persons receiving open-label preexposure prophylaxis are under way and should provide important information about risk compensation now that preexposure prophylaxis efficacy is known.

Despite these encouraging results, unanswered questions remain. Although daily oral FTC/TDF is the only preexposure prophylaxis regimen that is approved by the Food and Drug Administration, oral TDF alone is effective and does not confer a risk of resistance to FTC.^178,179 New CDC preexposure prophylaxis guidelines suggest the potential for “off-label” use of TDF alone in serodiscordant couples and people who inject drugs, based on trial data.¹⁹⁷ Nondaily use of oral FTC/TDF was efficacious in nonhuman primates but has not been fully evaluated in humans.¹⁹⁹ Daily use of preexposure prophylaxis has advantages over nondaily dosing, including achievement of consistently higher levels of drug, greater tolerance of occasional missed doses, and establishment of a pill-taking routine.²⁰⁰ Although oral FTC/TDF is active against hepatitis B virus, there is a risk of hepatitis flare if active agents are stopped, especially in persons with cirrhosis. Thus, hepatitis B virus–uninfected persons should ideally begin vaccination prior to preexposure prophylaxis initiation.

Other antiretroviral drugs are theoretically well suited for preexposure prophylaxis, and long-acting preparations or sustained delivery systems administered parenterally or topically (eg, in a vaginal ring) may address the challenge of daily adherence. The efficacy of directly applied topical agents was supported by the results of the CAPRISA (Centre for the AIDS Programme of Research in South Africa) 004 trial, which showed benefit from use of vaginal 1% tenofovir gel before and after sex.²⁰¹ However, daily use of this regimen was not successful in the VOICE (Vaginal and Oral Interventions to Control the Epidemic) trial, likely because of low rates of adherence to the product.¹⁸³ A major challenge is to identify research and regulatory pathways for evaluating preexposure prophylaxis regimens. A surrogate marker for prophylactic efficacy is not yet available, although drug concentrations and tissue culture systems to assess viral replication appear promising.

Economic evaluations generally suggest that preexposure prophylaxis could be cost-effective in the United States but only if used among MSM at highest risk (annual incidences >2%).^202,203 Shorter durations of use, improved adherence and efficacy, and decreased drug costs would enhance the economic attractiveness of preexposure prophylaxis for MSM. Even so, studies generally indicate that although cost-effective, the financial burden of a preexposure prophylaxis program could be substantial. For example, use of preexposure prophylaxis among high-risk MSM for 20-year duration could lead to an incremental increase in US health care costs of up to $75 billion.²⁰³ For recommendations regarding preexposure prophylaxis, see Box 1.

Nonhuman primate models suggest that antiretroviral postexposure prophylaxis (PEP) is highly effective in preventing infection after retroviral challenge.²⁰⁴ Although RCTs evaluating efficacy of postexposure prophylaxis have not been feasible, a retrospective case-control study of health care workers found that those who used zidovudine after an occupational exposure were 81% less likely to become HIV-infected than those who did not.²⁰⁵ The CDC subsequently developed guidelines for use of postexposure prophylaxis in occupational²⁰⁶ and nonoccupational²⁰⁷ settings. Postexposure prophylaxis is generally safe, and its use was associated with decreased HIV acquisition in a study comparing MSM in Brazil who used postexposure prophylaxis compared with those who did not.²⁰⁸ However, studies among MSM in America and Australia²⁰⁹ have suggested that some individuals may not accurately estimate their risk, leading to HIV acquisition despite availability of postexposure prophylaxis. Given the challenge of obtaining postexposure prophylaxis quickly and because animal studies suggest greater protection if postexposure prophylaxis is administered prior to retroviral challenge, individuals at repeated risk for HIV acquisition may benefit from postexposure prophylaxis.

Nonoccupational postexposure prophylaxis should only be administered to individuals who have had mucosal contact with infected blood or genital secretions or to health care workers who have needle stick exposures to HIV-infected source patients.²¹⁰ Clinicians should determine whether a given exposure could result in HIV transmission and whether the source partner was HIV-infected or of unknown serostatus but at high risk of being infected. If the source is known to be HIV-infected, ascertainment of specific ART use and HIV drug resistance in the index case should inform selection of ART for postexposure prophylaxis. Postexposure treatment should include 3 medications that are least likely to be affected by drug resistance.

The US Public Health Service currently recommends initiation of a 3-drug regimen for occupational postexposure prophylaxis,²⁰⁶ and this should be considered for sexual and parenteral exposures. Postexposure prophylaxis should be initiated as soon as possible, not more than 72 hours after a high-risk exposure.^206,211 Animal studies support the use of postexposure prophylaxis for a duration of 28 days.²¹¹

The updated guidelines for postexposure prophylaxis recommend FTC/TDF and raltegravir as the initial regimen.²⁰⁶ TDF-based postexposure prophylaxis regimens are better tolerated than those containing zidovudine.^212,213 A recent study of FTC/TDF and raltegravir as postexposure prophylaxis found that the most common adverse effects included nausea or vomiting (27%), diarrhea (21%), and headache (15%).²¹³ When choosing postexposure prophylaxis regimens, tolerability must be considered to ensure regimen adherence.²¹⁴ However, with access to newer antiretroviral drugs that are better tolerated, and with increased potential resistance in the community, adding a third drug is reasonable. The inclusion of an HIV protease inhibitor increases the likelihood of adverse effects.²¹⁵

Postexposure prophylaxis provides an opportunity to engage persons who have recurring high-risk exposure and to offer appropriate risk-reduction strategies.²¹⁶ These may include referrals to address patterns of sexual risk and substance use. In addition, clinicians should consider risk-based screening for concomitant STIs and the need for emergency contraception. Persons who initiate postexposure prophylaxis should be followed up for 6 months after completion of the regimen if conventional antibody testing is used and for 4 months if newer fourth-generation assays containing p24 antigen are used.²⁰⁶ For recommendations regarding postexposure prophylaxis, see Box 1.

Voluntary male circumcision reduces the risk of heterosexual HIV acquisition by 53% to 60%,^175-177 an effect that is durable,²¹⁷ measurable at population level,²¹⁸ and cost-effective.^219,220 The procedure also decreases transmission of genital human papilloma virus²²¹ and herpes simplex virus type 2.²²² Adult male circumcision has not been associated with direct protection of female partners,²²³ but with wider implementation, whole populations will likely benefit.²²⁴ Observational studies in Africa involving large numbers of neonates have also found male circumcision to be safe.^225,226

The WHO and Joint United Nations Programme in HIV/AIDS recommend voluntary male circumcision for HIV prevention in priority countries in sub-Saharan Africa with generalized epidemics and low prevalence of male circumcision. More than 1 million men have undergone this procedure as part of HIV prevention programs.²²⁷ Despite the recommendations, efforts to promote male circumcision in priority countries have had mixed results, likely because of limited health care resources and cultural attitudes toward circumcision. The need to simplify the procedure in resource-limited settings has led to development of medical devices that require minimal or no surgery, introduction of new, more efficient procedures that increase productivity by task shifting (a process of delegation whereby tasks are moved, when appropriate, to less specialized health workers), use of diathermy^228,229 for hemostasis, and use of prepackaged surgical instruments. In some countries, demand from men has been low, and changes in the delivery system alone will not achieve the levels targeted. Political leadership has been critical to expansion efforts.²³⁰

Although no trials of adult male circumcision have been conducted among MSM, some epidemiologic data suggest that the procedure might be protective for MSM who engage in primarily insertive anal sex.²³¹ For recommendations regarding male circumcision, see Box 1.

Genital STIs facilitate transmission and acquisition of new HIV infection. Among HIV-uninfected partners in serodiscordant heterosexual couples, the presence of herpes simplex virus type 2 seropositivity, trichomoniasis, genital ulcer disease, cervicitis, or vaginitis substantially increased risk of HIV-1 acquisition, irrespective of the infected partner’s plasma viral load.²³² Early syphilis and anorectal STIs are associated with high risk for concurrent or subsequent HIV acquisition.^126,233

Interventions to detect and treat STIs identify persons at highest risk for sexual acquisition and transmission of HIV and can prioritize delivery of risk-reduction interventions, especially preexposure prophylaxis. The CDC and the HIV Medicine Association recommend routine screening for common STIs, including syphilis, gonorrhea, and chlamydia infections, for persons at high risk for HIV acquisition, particularly MSM.^16,234 A relevant sexual history should, in turn, direct STI screening toward specific anatomical sites and screening for sexual acquisition of hepatitis C virus, which is associated with high-risk anal sex practices.²³⁵ Routine laboratory screening for common STIs among MSM is summarized in Box 2.

Box Section Ref ID

For people living with HIV, sexual health, including prevention and detection of STIs, has become an important component of primary care.²³⁴ Recent trends indicate an increase in syphilis and gonorrhea among some HIV-infected persons, particularly MSM, and that incident hepatitis C is increasing in this group as well.^129,236-239 Despite this, routine screening for STIs in the HIV care setting is low.²⁴⁰ Behavioral assessments should direct appropriate screening for common STIs, including syphilis, gonorrhea, and chlamydia, at exposed anatomical sites (pharynx, rectum, and urethra).¹⁶ Because many syphilis cases are latent (positive serology in the absence of clinical signs), serologic screening is crucial. Last, the quadrivalent human papillomavirus vaccine is safe and immunogenic in HIV-infected persons and should be offered routinely.^241-243 For recommendations regarding STI screening and prevention, see Box 1 and Box 2.

Quiz Ref IDUnintended pregnancy is a considerable burden for many women and their families, and access to safe, effective, and acceptable contraception is critical. For reproductive-aged women living with HIV, it is especially important as a means to plan pregnancy with intent to prevent vertical HIV-1 transmission and ensure maternal health. Use of hormonal contraception does not affect HIV disease progression among HIV-infected women or the likelihood of HIV transmission to male partners, nor is there an increase in the recognized adverse effects of use of hormonal contraception in women with HIV relative to those without HIV.^244,245

Some observational studies have raised concern about a potentially increased risk of HIV acquisition among users of specific hormonal contraception methods, primarily depot-medroxyprogesterone acetate (DMPA), but results overall are inconsistent and study quality varies.²⁴⁶ In studies that reported an association, the relative risk was generally in the 1.5 to 2 range. A recent modeling analysis concluded that unless the true effect size approaches more than double the risk, it is unlikely that reductions in injectable hormonal contraceptives could result in a public health benefit, except possibly in those countries in southern Africa with the largest HIV epidemics.²⁴⁷ A systematic review recently summarized available analyses of various methods of hormonal contraception in terms of the risk of HIV acquisition.²⁴⁶ The authors concluded that data do not suggest that hormonal contraceptive pills are associated with an increased risk of HIV acquisition. For injectable hormonal contraceptives, no data suggest a close association between norethisterone enanthate (NET-EN) and HIV acquisition, although data are limited.²⁴⁸ Some observational data raise concern about a potential association between use of depot-medroxyprogesterone acetate and risk of HIV acquisition. There are almost no data on whether methods such as contraceptive implants, patches, rings, or hormonal intrauterine devices may impact risk of HIV acquisition.

During a 2012 WHO technical consultation, experts reviewed all available biological, epidemiologic, and modeling data and recommended that the WHO continue to suggest no restriction on use of any method of hormonal contraception; however, they noted that for women at high risk of HIV infection, condom use and other HIV preventive measures should be strongly emphasized for those using progestogen-only injectable contraception.²⁴⁹ The CDC subsequently updated its medical eligibility criteria for contraceptive use to reflect this stance for women in the United States.²⁵⁰ For recommendations regarding hormonal contraception, see Box 1.

After more than 30 years, we are at a potential turning point in the control of the global HIV epidemic. With enhanced access to effective ART and durable viral suppression, nearly all persons living with HIV could be rendered noninfectious. Those without HIV but at risk for infection can access prevention interventions ranging from ART-based preexposure prophylaxis to voluntary medical male circumcision. These biomedical interventions can be productively complemented by appropriate behavioral and structural interventions and support services. Clinicians are crucial in implementing these interventions, and should use evidence-based HIV prevention tools.

Corresponding Author: Jeanne M. Marrazzo, MD, MPH, Box 359932, Harborview Medical Center, 325 9th Ave, Seattle, WA 98104 (jmm2@uw.edu).

AuthorContributions: Drs Marrazzo and del Rio had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Marrazzo, del Rio, Holtgrave, Cohen, Kalichman, Montaner, Wheeler, Grant, Kumarasamy, Shoptaw, Dabis, Benson.

Acquisition, analysis, or interpretation of data: Marrazzo, Holtgrave, Mayer, Montaner, Grant, Grinsztejn, Walensky, Dabis, Sugarman, Benson.

Drafting of the manuscript: Marrazzo, del Rio, Holtgrave, Kalichman, Mayer, Montaner, Wheeler, Grant, Grinsztejn, Shoptaw, Dabis, Benson.

Critical revision of the manuscript for important intellectual content: Marrazzo, del Rio, Holtgrave, Cohen, Kalichman, Montaner, Wheeler, Grant, Kumarasamy, Shoptaw, Walensky, Dabis, Sugarman, Benson.

Statistical analysis: Holtgrave.

Administrative, technical, or material support: Marrazzo, Holtgrave, Grinsztejn, Kumarasamy, Benson.

Study supervision: Marrazzo, del Rio, Holtgrave, Cohen, Montaner, Benson.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Disclosure information represents the previous 3 years (updated May 20, 2014). Dr Marrazzo has served as a consultant to Merck and Astra-Zeneca; Dr del Rio has no conflicts to disclose; Dr Holtgrave’s institution, The Johns Hopkins Bloomberg School of Public Health, has received research funds from Johnson and Johnson and Female Health Company; Dr Cohen has served as a consultant to Janssen Global Services and Roche Molecular Systems, Inc; Dr Mayer’s institution, Fenway Health, has received research grants from Gilead Sciences and Merck; Dr Montaner’s institution, BC-Centre for Excellence in HIV/AIDS at Providence Health Care and the University of British Columbia, has received research grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare; Dr Kalichman has no conflicts to disclose; Dr Wheeler has no conflicts to disclose; Dr Grant has served as a consultant to Siemens Healthcare and ViiV Healthcare, and his institution, the University of California San Francisco, has received support from Gilead Sciences for travel, accommodation, and meeting expenses; Dr Grinsztejn has no conflicts to disclose; Dr Kumarasamy has no conflicts to disclose; Dr Shoptaw has no conflicts to disclose; Dr Walensky has no conflicts to disclose; Dr Dabis has no conflicts to disclose; Dr Sugarman has no conflicts to disclose; Dr Benson’s spouse has received research support from Bristol-Myers Squibb and Boehringer Ingelheim Pharmaceuticals, Inc, and has served as a scientific advisor to CytoDyn and Merck & Co, Inc, as a scientific advisory board member for Gilead Sciences, Inc, GlobeImmune, Inc, and Monogram Biosciences, and as a member of data monitoring committees for Axio and Gilead Sciences, Inc. He has stock in GlobeImmune, Inc.

Funding/Support: This work is supported and funded by the International Antiviral (formerly AIDS) Society–USA (IAS-USA), a mission-based, nonmembership, 501(c)(3) not-for-profit organization. The IAS−USA appointed members to the IAS−USA HIV Prevention Recommendations Panel to develop the recommendations and provided staff support. In the last 5 years, IAS−USA has received commercial support (grants) for selected continuing medical education (CME) activities that are pooled (ie, no single company supports any single effort) from Abbott Laboratories, AbbVie, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Therapeutics, Merck & Co, Mylan, Pfizer, Salix Pharmaceuticals, Tibotec Therapeutics, Vertex Pharmaceuticals, and ViiV Healthcare. The designation of selected CME activities refers to the IAS−USA structure of accepting commercial support only if there are enough companies with competing products to meet the criteria for independence and only on programs appropriate for support by commercial sources (eg, recommendations are not supported by industry grants). No private sector funding was used to support the effort. Panel members are not compensated for participation in the effort.

Role of the Sponsor: The IAS–USA determined the need for updated recommendations, selected the panel members based on expertise in biomedical and behavioral HIV care and research, and provided administrative oversight and financial support. The panel is responsible for the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication.

Additional Contributions: The authors thank Jennifer R. Ham, MPH, IAS-USA, for administrative management of the development of the recommendations; Ms Ham was compensated as part of her employment. The authors also thank Margaret A. Fischl, MD, University of Miami, for initiating this effort and for her helpful review of the manuscript, and Chelsea B. Polis, PhD, US Agency for International Development, for her helpful review of the section on hormonal contraception.

Correction: This article was corrected online on July 19, 2014, to correct the group name and typographical errors.