Vermund, Sten H. MD, PhD*,†,‡,§,‖; Tique, José A. MD*,‖; Cassell, Holly M. MPH*; Pask, Megan E. MS*; Ciampa, Philip J. MD, MPH*,†,‡; Audet, Carolyn M. PhD*,§
Condom barriers, blood and needle safety, and the prevention of mother-to-child transmission of HIV (PMTCT) were the first biomedical strategies to control HIV that did not focus on behavioral risk reduction alone. In the early 1990s, the hopes for an HIV vaccine led to capacity building in HIV-prevention studies and a boost in large-scale trials for prevention.1,2 The use of antiretroviral therapy (ART) in a pregnant woman for the prevention of infection to her infant was a prescient test of concept for the use of ART as prevention [treatment as prevention (TasP)]. The utility of TasP for preventing sexual transmission was demonstrated by the high efficacy demonstrated by the HIV-Prevention Trials Network (HPTN) 052 protocol. Since 2005, compelling biomedical prevention strategies have been added to the armamentarium for HIV prevention, notably male circumcision and ART for the prevention of sexual transmission. Efficacy of combining several of these biomedical techniques into a synergistic (additive or multiplicative) approach remains to be determined.
The history of disease control and prevention is replete with examples of effective tools that are available for use, but are underutilized in the field or the clinic. HIV/AIDS prevention is a prominent case in point, a challenge that the National HIV/AIDS Strategy for HIV in the United States seeks to address.3 Both journalists and scientists have highlighted the disappointing missed opportunities in the HIV epidemic.4–13 Combination prevention approaches are now available that combine multiple efficacious strategies to block transmission, but all must include behavioral components to avoid risk compensation—the increased risk-taking behavior that may accompany prevention approaches that clients perceive to be more effective than they really are.14 All 3 early approaches (condoms, clean needles/syringes, and PMTCT) also required structural reform and technical capacity building to enable widespread dissemination of the interventions. Widespread condom and needle distribution confronted political opposition that inhibited program scale-up in many venues. Even blood safety measures were resisted in the pre-HIV screening era by many blood-banking authorities for economic reasons.
In this article, we will review key biomedical tools for the prevention of HIV transmission (Table 1) and what the prospects and obstacles are for their further utilization in global HIV control. A recurring theme is that we have technologies that can reduce the epidemic, but we have not deployed them widely or consistently.15–20 Other articles in this JAIDS supplement will address behavioral interventions per se, so we will restrict our discussion to the issues arising in the translation of biomedical tools. We acknowledge the subjective nature of a manuscript such as this one; it is challenging to predict how these tools will have an impact on the global pandemic. However, we believe that speculations regarding the scale-up and application of biomedical prevention can be well informed based on the present knowledge of disease control and prevention for HIV/sexually transmitted infections (STI), tuberculosis, and blood-borne infections such as hepatitis B and C.
Antiretroviral Treatment to Reduce Infectiousness of HIV-Infected Persons
TasP is founded on evidence that persons who are HIV-infected and are on combination ART (cART) are less likely to transmit the virus sexually than those not on cART. Higher viral load has been associated with a higher HIV transmission risk in observational studies.21–30 The use of cART has been associated with reduced risk for sexual transmission. In 2011, the HPTN 052 trial demonstrated definitively the huge benefit of cART use in persons with higher CD4+ T-lymphocyte counts in protecting their sexual partners [hazard ratio of 96% protective efficacy; 95% confidence interval (CI): 73% to 99%].31–33 As this benefit was apparent when cART was offered to persons who would not have qualified for HIV treatment for their own sakes [as per 2009 World Health Organization (WHO) treatment guidelines], WHO issued new guidelines in 2012, suggesting that where possible, more persons should be treated with cART than had been recommended heretofore.34 Although expanding the eligibility of cART with the aim of TasP represents a significant opportunity to prevent new infection, issues of drug resistance, disinhibition, and logistics complexities must be addressed for this approach to be effective in nonclinical trial conditions.35
Efforts in high access cities such as San Francisco and Vancouver have made progress in expanding TasP.36–39 It may be that >30 years of work for HIV risk reduction among men who have sex with men (MSM), with mixed success, has contributed to a higher uptake of HIV therapy in these settings.40,41 In the United States as a whole, however, the overall program coverage with testing, linkage to care, and therapy remains disappointing.42–46 Several new controlled community-randomized studies are being launched to study combination prevention, including implementation of expanded ART coverage, to assess the impact on community-HIV transmission. Four groups intend to launch such studies in 2012 or 2013, some with combinations of TasP, medical male circumcision, and strategic and behavioral intervention innovations. The HPTN 071 POPArt study [Richard Hayes, principal investigator (PI)], the Botswana study (Max Essex, PI), and the ANRS/Africa Center study all intend to address the ART for the prevention question within rigorous community-randomized studies. There are a number of smaller studies that also intend to address the question of reducing HIV at a population level, some of which are in the field for preliminary work.
TasP for Injection Drug Users
Although much has been achieved among injection drug users in risk reduction using needle and syringe exchange and opiate agonist–based heroin addiction therapy, there are still regions of the world that do not implement these measures. It is plausible that TasP could also be implemented effectively in this population, and such studies are in progress.
Prevention of Mother-to-Child Transmission of HIV
The earliest test of concept for the use of antiretroviral drugs to reduce HIV viral load and infectiousness in one person to protect another was in PMTCT. Evidence from many definitive randomized controlled trial (RCT), for example, the AIDS Clinical Trials Group 076 trial, HPTN's HIVNET 012 trial confirmed that reducing viral loads with ART could reduce transmission markedly to newborn infants. Subsequently, both cART use in HIV-infected pregnant women during the months of breastfeeding and use of preexposure prophylaxis (PrEP) with ART in breastfeeding infants were judged to be safe and effective in reducing transmission in low-income settings where replacement feeding is neither safe nor affordable.47–52
Despite the proven efficacy of antiretroviral prophylaxis or treatment for PMTCT and the high degree of successful implementation in high and middle income countries,53–55 the proportion of women and infants receiving all stages of PMTCT in resource-limited settings has been disappointing.56–64 Failure to engage mothers and/or infants at any step of prevention continuum (Fig. 1) can lead to a failure in preventive efficacy during pregnancy or the postpartum periods. Each of these steps are amenable to clinical and community interventions to improve engagement and coverage. In an effort to document barriers to PMTCT uptake, researchers have often focused on patients, although there is movement toward complementary hospital-based quality improvement approaches.65–70 Well-documented barriers include the lack of PMTCT-related care systems capable of delivering quality service,57,67,71–73 lack of family or community support,65,74,75 stigma,66,67 and concern with confidentiality/treatment at the clinical site.66 Additional barriers include cost/transportation for travel to the clinic,65 cultural pressure to breastfeed (or concern that not breastfeeding would “out” the mother as being HIV positive),66,76 inadequate alternative food sources for infant feeding,64 inadequate knowledge about HIV transmission,65,74 and a desire to deliver at home or with a traditional birth attendant.65 These and other barriers to full coverage of PMTCT represent some of the challenges of translating the benefits of biomedical knowledge effectively into real-world settings56–58,77–82; other prevention strategies such as TasP and adult circumcision will likely face similar challenges, and will benefit from the lessons learned from PMTCT field experience in low-resource settings.
Systems Strengthening for Implementation of PMTCT and TasP
Widespread health-system deficiencies have been identified in a number of low-income countries that lead to a low uptake and adherence to ARV prophylaxis56,61,83 and EID.84 Although socioeconomic factors are often cited as drivers of poor access to PMTCT or EID,85–88 there is increasing attention to the role that strengthening health systems may play in improving access and other program outcomes,89–91 and efforts are underway to strengthen health systems to improve PMTCT-related care.92,93 In 1 study at 2 district hospitals in rural Mozambique, health-system barriers preventing access to EID were addressed using a conceptual framework for quality improvement adapted from Langley et al.92 The process of maternal postpartum care for HIV-infected mothers was analyzed at each hospital; a 2-phase intervention was designed with the help of nursing staff and patients and evaluated using a before/after intervention study design.69,70 Hospital staff were introduced to the Langley model for quality improvement and given the opportunity to participate in the study by describing the process of care, identifying modifiable health system barriers, and designing an intervention aimed at impacting infant retention in EID. The standard process of referral to the EID clinic during maternity discharge was identified as a target for improvement and an intervention was designed that enhanced referral by more tightly linking maternity and EID services through direct accompaniment and by providing privacy for women during counseling. After 2 cycles of intervention, the proportion of mother/infant pairs that succeeded in accessing Early Infant Diagnosis (EID) within 3 months of the child's life improved by 55%. This is but 1 example highlighting the potential benefit of practical site based innovations to improve retention for HIV prevention from mother to child.90,93 Scaling up of quality improvement–based strategies is an essential approach to strengthen health systems and make the best use of available resources in developing countries.
Complementary Strategies to PMTCT
Implementing an intervention designed to create and sustain behavior change is another alternative to increasing access to biomedical interventions, but this may be a gradual process of education and culture change.94 Attempting to change maternal birthing practices and early child-rearing behavior can be especially challenging, as target behavior may conflict with culturally accepted practices and beliefs. Traditionally, interventions to improve uptake have been targeted at pregnant women.95–97 Recently, the importance of support from husbands in ensuring the uptake of PMTCT has been addressed through the engagement of men in antenatal HIV counseling65,98 and changes to hospital or clinical systems.58,59,68,93,99
Many HIV-infected women who would like to plan their family size do not have access to contraception; it has been estimated that filling the unmet need for contraception among all the HIV-infected women who need it would result in a huge decline in mother-to-child transmissions.100–121 Although this is not TasP, it is another PMTCT intervention that depends on capacity building and broadening of the HIV-prevention mandate to include other primary health care needs in afflicted communities. Concerns that hormonal contraception use in seronegative women may result in a higher risk of acquisition do not apply in the case of seropositive women.122,123 Furthermore, there are alternative approaches to hormonal use that are being underutilized, including the intrauterine device.124–127
Antiretroviral Prophylaxis to Reduce Susceptibility of HIV-Uninfected Persons
At a May 10, 2012, meeting, the US Food and Drug Administration's Antiviral Drugs Advisory Committee recommended the approval of a drug labeled “efficacy supplement” for the use of Truvada tablets [each tablet has 200 mg of emtricitabine (FTC) and 300 mg of tenofovir disoproxil fumarate (TDF), made by Gilead Sciences, Inc.] for PrEP, namely, oral tablet use for the prevention of HIV transmission in HIV-uninfected persons. Oral PrEP has been consistently effective in successive trials in men, ranging from 44% to 68% efficacy in clinical trials such as iPrEx, Partners PrEP, and TDF-2.128–132 In women, the Partners PrEP and TDF-2 studies suggested oral PrEP efficacy, but the FEMPrEP133 and Vaginal and Oral Interventions to Control the Epidemic (VOICE)134,135 trials did not, though the FTC/TDF oral PrEP arm of the VOICE trial continues as of this writing (June 2012). Similarly, the use of a topical 1% tenofovir microbicide intravaginally worked to protect against HIV in women in the CAPRISA 004 trial,136 but it did not work in the VOICE trial.137,138 Hence, the evidence is more consistent that oral PrEP works well in men but is less consistent for oral and for topical PrEP in women (Table 1). Rectal microbicides (also topical PrEP, but designed for anal sex protection) are theoretically useful for women and men practicing anal sex, but they have not yet been tested in phase 3 clinical efficacy trials. Topical PrEP remains an area of intense current investigation.139–144 Opinions differ as to the likely utility of PrEP as a substantial public health tool for HIV prevention, though a female-controlled product could be a valuable addition to women's options.145–148
Occupational exposure to needle stick injuries, surgical instruments, or other substantial medical injuries within the context of caring for an HIV-infected person can expose health care workers (or even sanitation workers) to HIV.149–151 Postexposure prophylaxis (PEP) with cART is now standard practice for many high-risk exposures (with a higher volume in persons who are not viral load suppressed, to give 1 example) and is an option for prophylaxis even in lower risk exposures.152,153 Again, implementation issues loom large: successful PEP requires reducing the risk of the needle exposure to begin with, prompt reporting of needle stick injuries, and successful adherence of exposed staff to the cART PEP regimen.154
PEP is also an alternative for inadvertent sexual exposure, as with condom breakage or nonuse, or with rape. RCT evidence is lacking for both occupational and nonoccupational PEP, but epidemiology suggests cART to be possibly effective for reducing transmission risk.155,156 Again, the translation of PEP efficacy to population effectiveness depends on working systems of surveillance, availability of expertise and cART, willingness of the exposed person to uptake the PEP intervention, and their success in adherence to PEP. The HPTN 040 study demonstrated in an RCT that PEP given to infants born to mothers who had not received ART worked to prevent infant infection.157–160 Intrapartum transmission occurred in 3.2% (47) of the infants studied. Transmission rates were significantly lower in the Zidovudine + Nevirapine arm 2.2% (11) (95% CI: 1.2 to 4.0, P = 0.045) and the ZDV + NFV + 3 TC 2.5% (12) (95% CI: 1.4% to 4.3%, P = 0.045) compared with the ZDV arm.157–159
MEDICAL MALE CIRCUMCISION TO REDUCE SUSCEPTIBILITY
Ecological and epidemiological evidence has suggested that infant or later circumcision might reduce HIV transmission risk.161–165 Voluntary medical male circumcision in adults was tested in 3 RCTs in sub-Saharan Africa, and their results were remarkably consistent.166–168 Hence, when the cheaper, simpler, and safer infant circumcision had not been performed previously, adult male circumcision is deemed advisable in high HIV prevalence settings. There are obstacles to uptake: cultural acceptability, fear of pain and/or surgical mistakes, and poor understanding about the risks and benefits of circumcision.169–183 The decision to circumcise or not is often based more on social acceptability than on medical evidence. In sub-Saharan Africa, rites of passage for men often include circumcision (traditionally conducted outside of a clinical setting) presenting an opportunity for health workers to incorporate safe surgical practices into traditional rituals. Education campaigns and improved access to safe surgical services have led to an increased uptake among communities where circumcision was uncommon.184,185 Western countries are experiencing the opposite trend. The belief that male circumcision is akin to genital mutilation is becoming more widespread. Some researchers and laypeople argue that it leads to long-term psychological trauma in the male infant, impacting everything from mother–son bonding to future sexual relationships, although there is no scientific evidence to support this belief.
Male circumcision of either HIV-infected men or HIV-uninfected men who later seroconvert may reduce their infectiousness to others through reduction of STIs (such as the very common human papillomavirus) among other potential mechanisms.186–199 However, if men have sex before their wounds are healed, after surgery, the risk could rise as has been observed in Uganda.200 Also, risk compensation is a concern if men increase high-risk behavior because they have been circumcised and no longer perceive personal risk.201,202 If proper technical procedures, risk reduction counseling, and community consultations are adhered to, male circumcision is a theoretically powerful tool, especially when incorporated into a combination prevention strategy designed to reduce the risk through behavioral modification and biological interventions.164,203–207
Evidence that circumcision will prevent HIV acquisition or transmission among MSM is not consistent and is less likely to be as strong in its association as with heterosexual transmission.195,208–211 For example, being circumcised may not help much if one is the receptive partner in MSM sexual relations. Infant circumcision is cheaper, easier, and less risky than is adult circumcision. An excellent long-term investment is to seek universal male infant circumcision in high prevalence regions to nurture a new generation of lower risk men.169,212–219
HIV VACCINES TO REDUCE SUSCEPTIBILITY (PREVENTIVE VACCINES)
In a huge RCT in Thailand (n = 16,402), a 4-dose priming live vector canarypox vaccine [ALVAC-HIV (vCP1521)] vaccine followed by 2-dose gp120 subunit bivalent (AIDSVAX B/E) booster regimen proved to be somewhat efficacious in preventing HIV infection.220 The modified intention-to-treat analysis excluded 7 participants who had acute HIV-1 infection at baseline unbeknownst to the investigators, finding a vaccine efficacy of 31% (95% CI: 1% to 52%).221 The vaccine regimen did not reduce the viral set point in participants who seroconverted despite being in the vaccine group. Despite this success, neither product is being carried forward into production nor is the trial being confirmed to propose licensure. This illustrates the global economic dynamics of vaccine development; only a more efficacious product is likely to inspire the private sector to license and market the vaccine.
Successful vaccine development is no longer just a theoretical possibility; having succeeded in primate animal models and now in a human RCT, investigators will not rest until a viable and more efficacious product is developed.222,223 This suggests a host of challenges from which we can learn from other vaccine experiences. HIV is an STI, so suboptimal coverage with hepatitis B vaccine and human papillomavirus vaccine (the only licensed STI vaccines) in adolescents and adults suggests that HIV vaccine deployment would run into the same problems.224–229 We have no good global vaccine infrastructures or routine health care engagement for adult vaccination. There is some reticence to agree to STI vaccines given stigma, including among parents for their children.230 Continued challenges in global vaccine coverage, even for childhood vaccines, are to be expected to be relevant for HIV vaccines, once available.231 This includes antivaccine forces claiming the lack of cost–benefit evidence for vaccines, spurious toxicities attributed falsely to vaccines, and arguments about immunological overload that have no evidence to support them.232,233
One of the principal objections voiced to STI vaccines is that of disinhibition or risk compensation, the possibility that if someone is protected against an STI, then they might be more likely to engage in risky behavior. In the early hepatitis B virus (HBV) vaccine RCTs, there was a rise in HBV incidence after the first dose of HBV vaccine, attributed to the disinhibition among MSM who were in the trial.234,235 Hence, this potential risk must be taken seriously and studied alongside prevention technology benefits.
HIV VACCINES TO REDUCE TRANSMISSIBILITY (THERAPEUTIC VACCINES)
An effective vaccine given to HIV-infected persons could theoretically reduce the viral load in the infected person by enhancing or complementing natural imperfect immune responses. Animal models have suggested feasibility of such approaches in idealized experiments, but no human data have been convincing enough to suggest that any tested products have been effective.236
TREATMENT OF COINFECTIONS TO REDUCE HIV VIRAL LOAD AND TRANSMISSION RISK
Coinfection with such infectious agents as Mycobacterium tuberculosis, helminthes, herpesviruses, and syphilis can cause immune activation and upmodulate HIV expression.27,237–239 Coinfection with Schistosoma haematobium is associated with increased HIV risk, as was seen previously for STIs, perhaps related to the disruption of integumentary integrity and/or local inflammation.240–243 Rhesus macaques infected with Schistosoma mansoni are more susceptible to HIV and shed more HIV once infected.244–247 Treatment or suppression of the coinfections can reduce plasma and presumably genital viral load, as suggested in genital herpesvirus–suppression studies.248–255 Thus, excellent primary care for HIV-infected persons that involves coinfection treatment or suppression could reduce the transmissibility of HIV by reducing HIV viral load and transmissibility.
CLEAN NEEDLES AND SYRINGES FOR INJECTION
Despite global reductions in HIV infection, substance use specifically injection drug use (IDU) continues to be a significant driver of the epidemic.256 IDU has been estimated to be responsible for about 9% (3 million) of the 34 million persons of persons living with HIV globally, including about 17% of the prevalent HIV cases in the United States.257,258 The WHO estimates that 1 out of 10 new HIV infections globally is attributed to IDU, and CDC suggests IDU to be associated with 9% of new HIV infections in the United States.258,259 Eastern Europe and Central Asia continue to incur high rates due to IDU; the numbers infected with HIV in these regions have tripled over the past decade.259–261 To stem the impending surge in new cases in regions not yet saturated and/or effectively implemented control measures, multiple prevention strategies have been implemented with various degrees of success. Harm-reduction efforts such as opioid substitution therapy (OST) and needle and syringe programs (NSPs) have shown to be effective at reducing HIV in IDUs.9,262–264 Needle exchange was one of the first methods used in the public health arsenal to control the epidemic. NSPs not only provide sterile needles and equipment but they also provide an avenue for HIV, STI, substance abuse, and mental health care and treatment to a marginalized risk group. Since the mid-1980s, NSPs have emerged around the world with great success, most notably in Canada, Western Europe, and Australia.260 However coverage has been stymied by controversy, government-imposed regulations, and lack of available resources. Out of the 151 countries where IDU is prevalent, only 82 countries have implemented NSPs, and OST is provided in 71 countries; however, coverage is variable across programs and regions.260 Low- and middle-income countries countries have been unable to meet the WHO distribution guidelines of 200 syringes per IDU per year.265 In the United States, NSP support is wrought by politics and regulation. In 2009, the ban on using US federal funds for NSPs was lifted by the Executive Branch of government only to be reinstated by the Congress in the 2012 federal budget.266,267
The peril of extensive nosocomial HIV transmission has been demonstrated in major outbreaks in Russia, Libya, Romania, and other countries.268–271 Medical injections were implicated in each of these outbreaks. The importance attributed to unsafe medical injections in the transmission of HIV in sub-Saharan Africa has been minimized by the enormous attentions given to sexually transmitted HIV.272,273 The perception that unsafe medical injections are rare in sub-Saharan Africa rests on the assurance in health workers' training and supervision, and compliance with existing safety guidelines. In Cameroon, health workers admit to selling syringes and needles for extra income and then reusing syringes and needles.274 These workers were often unhappy with their own behaviors, suggesting that education and efforts to improve working conditions might reduce the practice.274 Programs to improve provider practices; reduce community demand for injections; support the procurement of appropriate injection commodities to eliminate reuse of syringes and needles and improve safety are still needed in these settings.
In higher income countries, public concern has obliged blood-collection agencies and policy makers to continue to search for more sensitive HIV screening tests, despite a dramatic decrease in the transmission of HIV infection through blood transfusions.275–278 The availability of HIV-1 p24 antigenic testing and state-of-the art genomic amplification techniques, although expensive, allow for the identification of the vast majority of window-phase donations.277,279 The impact of other less-expensive strategies on HIV transmission risk reduction, such as donor deferral and the nonuse of donations from higher-risk subpopulations has been highlighted in low-income countries.280–284 Unfortunately, these cost-effective strategies are not being applied consistently.280,281,285–287 Although progress toward improving safe and adequate supplies of blood is being made,285 continued government commitment is critical for ensuring quality, safety, and adequacy of the blood supply, particularly in lower-income nations where challenges in capacity, logistics, and infrastructure are common.
PHYSICAL BARRIERS TO VIRUS–CELL CONTACT
Consistent and correct condom use is estimated to provide an 80% reduction in HIV seroconversion.288 Male condoms are inexpensive, widely accessible, have few side effects, and (among many populations) are a culturally acceptable HIV-prevention intervention. The number of condoms used worldwide is increasing, possibly due to increased social marketing campaigns to increase social acceptability in casual and committed relationships.289 Although condoms reduce the risk of HIV transmission, evidence suggests they are used inconsistently.289–291 Negotiating condom use can be difficult for women as the decision to use a condom often rests with her partner.
Female condoms were designed to provide women with more control over their sexual safety, but uptake has been low.292,293 Women needed considerable training and motivation to use the first generation products successfully.294–297 New generation products are better designed and may be more appealing; studies are in progress.298 Among couples where both partners actively participate in the decision-making process, condoms may be eschewed for other reasons: cost, feel, availability, desire for pregnancy, the belief that they are unnecessary in a “serious” relationship, or religious beliefs may sway partners to have unprotected sex.299–301
The finding of an efficacious intervention in one venue does not guarantee success in a different cultural context. A prime example is the control of the HIV epidemic among IDUs in Australia vs. the continuing spread in Russia; lack of political support for universal NSP and a ban on OST in Russia fuel their IDU-related HIV epidemic.260,302,303 A second example is the success in the 1990s with HIV prevention in Uganda, contrasted to that seen in its neighboring nations.304–307 Standardized approaches for adapting interventions to new contexts have been developed, including RE-AIM308,309 and ADAPT-ITT,94,310 but adaption of behavioral interventions is time consuming and fraught with potential challenges. The tailoring of a given epidemic response to local drivers of transmission is needed for both effectiveness and efficiency. Combination prevention approaches are most promising, but they require substantial success in achieving coverage metrics beyond those achieved in most global programs.311–313 The good news is that the myriad of biomedical intervention strategies now demonstrated to be effective in reducing HIV transmission can be combined to make major inroads into the global pandemic.314,315 Even as we research new approaches, the scientific community shares an urgent obligation to communicate current opportunities to policy makers, funders, and communities to motivate HIV control and prevention.316
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