Control of HIV will require integrating a combination of evidence-based HIV prevention interventions, developed based on the understanding of local epidemic patterns, including local HIV prevalence, incidence, and epidemic factors and important risk factors among key populations. A growing number of interventions have shown partial efficacy in reducing HIV infectiousness and susceptibility, including knowledge of HIV serostatus, which leads to behavioral risk reduction particularly among those learning HIV-infected persons, condom use, medical male circumcision (MC) for HIV-uninfected men, and antiretrovirals when used as therapy (ART) by HIV-infected persons and preexposure prophylaxis (PrEP) by HIV-uninfected persons. However, no single HIV prevention strategy will have complete uptake or perfect adherence, thus will have <100% effectiveness, making the rational packaging of partially effective interventions into integrated programs one of the most critical research and implementation questions for HIV prevention for the near future.
THINKING ABOUT COMBINATION HIV PREVENTION
Making combination prevention work requires careful selection of component interventions and objectivity in reviewing data about key risk factors, most affected populations, and efficacy of individual interventions. Parsimony in selecting possible interventions is important because scale, coverage, affordability, and impact could be compromised with more complex combination packages. Pilot work is important to determine the acceptability and feasibility of scaling these interventions to achieve high coverage by prioritizing the subset of the population at high risk of HIV transmission or acquisition, and acceptability of interventions to those populations.
A key first principle for choosing the components of a combination intervention package is synergy—ideally that the effect of a combination of interventions is at least the sum of the parts, if not greater. Just like combination ART is most effective when the components are active against different parts of the viral life cycle, a combination of prevention interventions directed at different risk factors and avenues of HIV transmission may have the greatest combined impact. An example of targeting different paths for transmission among heterosexuals in a generalized heterosexual epidemic would be a combination strategy that includes (1) MC for HIV-uninfected men, (2) ART roll out in HIV-infected persons, and (3) behavior change interventions that reduce risk and increase uptake and adherence to these interventions. Interventions that seek to reduce infectivity in HIV-infected individuals are likely to be most synergistic with interventions that reduce susceptibility among HIV-uninfected individuals.1 Mathematical models can be used to identify situations where interventions may have a “superadditive” effect by reducing the basic reproductive number (Ro) of an infection below a critical threshold.2
A second principle of combination HIV prevention is coverage, which is a function of access to the interventions and willingness of persons prioritized based on the risk to utilize the interventions. A fundamental initial step toward achieving high coverage of HIV prevention interventions is HIV testing and knowledge of HIV serostatus, which is needed for targeting interventions to reduce HIV susceptibility or infectiousness. For HIV-infected persons, in order to have high coverage of ART for HIV prevention benefits, prevention coverage entails breaking down the multiple steps in the cascade from HIV testing to linkage to care: clinic referral, ART eligibility assessment, pre-ART retention, ART initiation for those who are eligible, and sufficient adherence to achieve sustained viral suppression,3 particularly among those most likely to transmit. Similarly, there is a cascade for “HIV prevention” for persons who are HIV uninfected: learning one's HIV status, uptake, and adherence to evidence-based prevention services (such as MC) and more user-dependent interventions such as PrEP, coupled with prevention counseling. Achieving high coverage requires addressing the multiple steps in these “cascades” beginning with the knowledge of serostatus, demand stimulation (to increase awareness of HIV risk, benefits of, and access to interventions), linkage, adherence, and retention.
Economic analyses are important for estimating the cost–benefit of intervention packages in terms of HIV infections averted and lives saved. As an example, economic analyses of the impact of scaling up ART showed that at high ART coverage, over time, the intervention costs incurred are balanced by reduced costs of HIV-associated morbidity, mortality, and incident HIV cases averted.4,5 Economic analyses can estimate the initial cost outlay and time to “break even” in costs based on infections prevented with a universal “test-and-treat” scenario,4 or scaling up ART coverage at different CD4 levels.5 In assessing the health economic impact of combination prevention, the principles of synergy and coverage also apply. Interventions that reduce susceptibility, such as PrEP and MC, are cost-effective additions to ART for the prevention through the synergistic effect of reducing HIV incidence at costs that, relative to lifelong ART, are less.6,7 Nonetheless, costs for prevention can plateau over time. If strategies to reduce infectiousness and susceptibility are not adequately scaled up, then the number of new infections may remain constant rather than decreasing, thus increasing the overall costs in the long term.4 One challenge for health economic analyses is to incorporate heterogeneity in costs, in addition to heterogeneity in disease modeling because as programs are scaled up, smaller programs may have increased costs.8 For HIV prevention interventions to be cost-effective over time, economic analyses support combining highly effective strategies, widespread coverage for ART, synergistic interventions that reduce susceptibility, and identification of efficiencies in the delivery of services throughout the cascade from testing, linkages to, and retention in care.6
We describe 3 populations and relevant considerations in developing and testing possible strategies for combination HIV prevention in these populations to illustrate the differences in the populations to be reached, risk factors for new HIV infections, and interventions to be considered for combination HIV prevention packages.
HIV AMONG MEN WHO HAVE SEX WITH MEN AND TRANSGENDER WOMEN
Men who have sex with men (MSM) account for the majority of new HIV infections throughout North and South America. In the United States, MSM comprised nearly two thirds of new HIV infections in 2010; they are the only group in whom new infections are increasing. Black MSM aged 13–24 years had more than 3-fold the number of new HIV infections as white and Latino MSM and increased the most from 2007 to 2010. Transgender women (people assigned “male” at birth but identify as female and/or transgender) have extremely elevated infection rates in both North and South America.9–12 Although HIV infection rates are high in Asia and Africa as well, less is known about drivers of infection in these populations; research is ongoing to determine the feasibility of reaching MSM in Asia and Africa,13 which will guide future HIV prevention efforts.
Recent modeling on the epidemiology of new infections in MSM in the Americans suggests that more than one third of new infections occur within main partnerships, and approximately two thirds of those infections occur within partnerships that are not known to be serodiscordant.14 To address the major risk factors of HIV infection in MSM populations in the America, several approaches are being currently piloted individually; those with high uptake and adherence will be combined to test their ability to achieve synergistic reductions in infections (Table 1).
1. Personalized risk calculators can reduce risk behaviors and improve outcomes including HIV risk behaviors,15 control of dyslipidemia,16 bone mineral density,17,18 dietary behavior,18 and alcohol abuse.19,20 Online tools, including education and videos can reduce risk, lower delivery costs, increase intervention fidelity, and maximize dissemination.21 An online tool is being piloted to determine if it is useful for MSM to assess their risk and set goals for improving sexual health, similar to diet and exercise Web sites. This Web site will then direct men to interventions, described below.
2. Daily oral emtricitabine (FTC)-tenofovir (TDF) PrEP significantly reduces the risk of HIV in MSM22; efficacy is related to adherence.23 Interventions shown to be effective in increasing adherence to ART in HIV-positive persons or preventive medications in healthy individuals (eg, malaria prophylaxis, HIV postexposure prophylaxis, osteoporosis prevention) include SMS strategies,24,25 client-centered counseling,26 cognitive behavioral therapy,27 and providing clinical feedback28; these approaches have been utilized to support PrEP adherence and are currently being piloted in PrEP studies and demonstration projects.29,30
3. HIV testing in sexual partnerships with emphasis on linkages to HIV care for HIV-infected men. A substantial proportion of transmissions are occurring from MSM who are unaware of their HIV infection, including those in relationships that are believed to be seroconcordant negative. Rates of HIV testing and the proportion of HIV-infected persons identified31 are significantly higher when “recruitment” occurs through social and sexual networks, particularly in young and African American MSM32; these approaches are being piloted in combination with home self-testing. SMS reminders also increase testing rates.33
4. Brief couples HIV testing34 and online strategies are being piloted, given data that indicate a substantial minority of infections occur in stable partnerships.
5. Strategies to increase linkage to care for HIV-infected MSM are being evaluated in a number of programs to reduce the drop-off in the HIV care cascade and to achieve viral suppression in the majority.35
Synergies for prevention in this population could be achieved by (1) addressing multiple components of the “transmission chain” (eg, reducing per-act risk transmission through PrEP and reducing partner change rate through behavioral interventions) and (2) targeting populations with minimal overlap (eg, PrEP for HIV-uninfected men, HIV testing, and linkage to ART to suppress viral load in HIV-infected partners). The individual components of the proposed package are being piloted (Table 1) to determine which are desirable, scalable, culturally appropriate, potentially cost-effective, and have plausibility for having an impact on HIV seroincidence in both North and South America. Once the package is finalized, the integrated strategy will be tested in a 2-stage process: a “vanguard” pilot study of the entire package and if the combination impacts intermediate measures (eg, uptake of and adherence to components and synergistic combinations), an efficacy trial.
YOUNG WOMEN IN SUB-SAHARAN AFRICA
One of the highest priorities for delivery and evaluation of integrated strategies for HIV prevention is young women in sub-Saharan Africa.36 The magnitude of the HIV epidemic in heavily impacted areas such as KwaZulu-Natal province in South Africa is staggering, where a study of women attending family planning and sexually transmitted disease clinics from 2004 to 2007 found an HIV prevalence of 35.7% among young women whose median age was 22 years and an HIV incidence of 6.5/100 person-years.37 Data from the Africa Center in KwaZulu-Natal showed highest HIV incidence (6.6/100 person-years) among women at 24 years of age and a peak HIV incidence of 4.1% among men 5 years later (ie, age 29).38
Drivers of HIV risk among young African women include unprotected sex, sexually transmitted infections in some populations, and age differences. Older partners have higher HIV prevalence, and gender power disparities are greater, making it harder for women to negotiate safer sex.39–41 Gender-based violence may be an important driver in these settings, as indicated by the alarming rape statistics from parts of Africa. However, evidence-based interventions are not available for some of the social and behavioral drivers of infection among young women in Africa. Young African women also are at risk for unwanted pregnancy42,43 among HIV-infected and HIV-uninfected women and require addressing cultural underpinnings and system access.44,45 Social norms often dictate that young women should not engage in sex and thus influence provider attitudes about contraception can be a barrier to young women's access to prevention services, condoms, contraceptive services, sexual and reproductive health services, treatment of sexually transmitted infections, and HIV testing,46 thus increasing their risk when they are sexually active. There is a tremendous unmet need for contraception worldwide47; the incidence of unplanned pregnancies among young women in Africa ranges from 4% to 16% in microbicide and HIV prevention trials,48–50 and the risk of HIV acquisition and transmission has been found to be 2-fold higher during pregnancy.51–53 A complicating factor is that some observational data indicate a 1.4-fold to 2.0-fold increased risk of HIV acquisition among women who use injectable hormonal contraceptives, particularly among depot medroxyprogesterone acetate (DMPA) users.54,55 However, the observational data are inconsistent and must be balanced by the safety, reversibility, contraceptive effectiveness, and widespread availability and acceptance of DMPA among providers and women.56,57
Given the overlapping risks for HIV acquisition, pregnancy, and the need for both HIV prevention and reproductive health services, combination prevention for young African women could be delivered through integrated reproductive health and HIV prevention services, which include behavioral, biomedical, and structural interventions (Table 2). It will be important to pilot different program models for providing youth-friendly integrated reproductive health and HIV prevention interventions to achieve high uptake of HIV testing, PrEP, and long-acting, reversible contraception options, as described below.
1. HIV testing and counseling strategies shown to be effective in reaching adolescents and young adults need to be implemented. Effective approaches include community mobilization and mobile vans, including peer-based outreach, and school-based HIV testing.58,59
2. Linkages to HIV care. Young women and men found to be HIV infected will be referred for HIV care to provide clinical benefits and reduce secondary transmissions, using evidence for strategies that effectively link HIV-infected persons into care.60
3. Reproductive health services and contraceptive planning: The same population of young women at high risk of HIV is at high risk of unwanted pregnancies and need user-friendly services with expanded contraception and counseling about the observational data on hormonal contraceptives and HIV risk.61
4. PrEP with adherence support is an evidence-based intervention to reduce HIV susceptibility among young HIV-uninfected women in some populations. Daily oral FTC/TDF PrEP significantly reduces the risk of sexual HIV acquisition; efficacy rates among heterosexuals range from no efficacy in studies with low adherence to 62% and 75% among young heterosexuals in Botswana in the TDF-2 trial and HIV serodiscordant couples in the Partners PrEP Study.62–64 Gender-specific and age-specific subgroup results from Partners PrEP (>70% efficacy in women <30 years),65 and the TDF-2 trial in Botswana, found that PrEP provides high protection from HIV infection for women.62 FTC/TDF as PrEP works when taken; adherence is strongly related to efficacy, as demonstrated by retrospective testing of plasma tenofovir levels in the trials with efficacy66,67 and lack of efficacy.63,68 PrEP would be offered to young women with a partner who is HIV-infected or of unknown serostatus and could offset increased risk from DMPA, until additional data are available about HIV risk due to long-acting progestins and other contraception modalities. Thus, in a combination prevention package that includes PrEP for young women will require assessment of risk assessment and motivations, as well as adherence monitoring and support, particularly in the first few months after PrEP initiation, through SMS support, and where feasible, real-time drug levels.
5. HIV testing of male partners. Young African women often do not know the status of their partners. To reduce HIV exposure, women will be encouraged to have their male partners tested for HIV, which will be facilitated by community mobilization and mobile HIV testing. Male partner involvement may increase contraception and PrEP uptake and adherence. Higher coverage of HIV testing among young men facilitates promotion of medical MC for HIV-uninfected men and increases uptake of ART for HIV-infected male partners, which each have indirect and direct benefits to young women.
HETEROSEXUAL HIV SERODISCORDANT COUPLES IN SUB-SAHARAN AFRICA
Population data from Africa suggest that a substantial fraction of new infections may occur within stable serodiscordant marital or cohabiting heterosexual relationships, with the majority of transmissions from the HIV-infected partner in the serodiscordant partnership and a substantial minority from an outside partner.69–73 Understanding HIV prevention choices and targeting prevention strategies to this group are public health priorities. A number of countries have identified HIV serodiscordant couples as a priority population for the implementation of novel HIV prevention strategies, given their high risk, smaller number for targeting relative to the general population, ability to be targeted for prevention efforts through promotion of couples HIV counseling and testing, and clear advantage to the partnership to avert HIV transmission. Importantly, during the past 2 years, 2 pivotal novel prevention interventions—ART (through HPTN 052) and PrEP (through the Partners PrEP Study)—demonstrated high efficacy for HIV protection in clinical trials conducted among HIV serodiscordant couples and are the core of a potential integrated strategy for combination prevention in couples. World Health Organization (WHO) has released guidelines for counseling and HIV-1 prevention for HIV serodiscordant couples, which emphasize the centrality of ART and PrEP, along with the attention to other HIV prevention interventions including MC.74,75 Determining how these efficacious interventions can effectively be delivered in real-world settings is the priority for combination prevention for this population.
HPTN 052 and Partners PrEP delivered their intervention strategies in the context of a combination package of HIV preventions, including frequent HIV counseling and testing, risk-reduction counseling (including as a couple), and access to condoms, MC, ART according to national guidelines, and other prevention strategies (eg, screening and treatment for sexually transmitted infections). The impact of these integrated services is reflected in substantially diminished HIV risk even in the delayed treatment or placebo arms of those trials. Thus, these clinical trials offer a model of combination HIV prevention for couples in the unique context of randomized clinical trials with intensive interventions and follow-up.
Recent WHO recommendations for earlier initiation of ART for HIV-infected members of HIV serodiscordant couples require translation into programmatic contexts.75 WHO guidelines are evolving in some settings to include lifelong ART for HIV-infected mothers regardless of CD4 count for the prevention of mother-to-child transmission (PMTCT) Option B+.76 Similarly, optimal strategies for PrEP delivery are yet to be defined and require demonstration projects and use of implementation science methods including demonstration of effectiveness among couples in which an HIV-infected partner is not yet on ART, due to refusal or other reasons (ie, PrEP as a bridge until ART is started and viral suppression achieved).77,78 Indeed, neither ART nor PrEP use was associated with 100% protective efficacy, indicating a need for examining the effect of strategic integration of these 2 efficacious interventions, against a background of an effective prevention package. Thus, implementation science is needed to define the following:
1. Integration of testing and ongoing prevention and care for couples into routine service delivery74–76
2. Choices couples make for HIV prevention and the messages needed regarding different prevention strategies
3. Uptake and sustained adherence to HIV prevention interventions whether ART or PrEP79
4. Uptake and retention for new ways of delivering ART (eg, Option B+ for PMTCT with lifelong ART after pregnancy for HIV-positive women, early ART at high CD4 counts)76 and
5. Uptake of MC among HIV-uninfected uncircumcised men in couples.
A potential package of combination services to evaluate using implementation science is presented in Table 3.
Combination HIV prevention requires rigorous review of the epidemiology of HIV infection to identify populations most impacted and at high risk, drivers of HIV infection, and efficacy of the available interventions to address these risk factors. Interventions should be considered in terms of potential synergies, feasibility of delivery at scale, and acceptability to populations. Evaluation of combination prevention packages requires a staged approach to evaluate acceptability, feasibility of delivery, and integration with other services, which should be followed by an evaluation of impact with outcome measurements, ideally based on HIV viral suppression in HIV-infected persons and HIV incidence in uninfected persons. Economic evaluation is important for costing delivery components and to estimate the cost per HIV infection averted and lives saved.
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