Sandra I. McCoy

HIV prevention transformed: the new prevention research agenda

We have entered a new era in HIV prevention whereby priorities have expanded from biomedical discovery to include implementation, effectiveness, and the effect of combination prevention at the population level. However, gaps in knowledge and implementation challenges remain. In this Review we analyse trends in the rapidly changing landscape of HIV prevention, and chart a new path for HIV prevention research that focuses on the implementation of effective and efficient combination prevention strategies to turn the tide on the HIV pandemic.

Weighing the gold in the gold standard: challenges in HIV prevention research.

Objective(s):Few HIV prevention interventions have been evaluated in randomized controlled trials (RCTs). We examined design, implementation, and contextual considerations that may limit detection of a positive or adverse effect in HIV prevention trials. Design:A systematic review of late phase RCTs for prevention of sexual transmission of HIV that randomly allocated intervention and comparison groups; evaluated interventions to prevent sexual transmission in nonpregnant populations; and reported HIV incidence as the primary or secondary outcome. Methods:PubMed/MEDLINE, other electronic databases, and electronic conference proceedings of recent HIV/AIDS-related conferences were searched to identify published or unpublished trials meeting the inclusion criteria. Descriptive, methodological, and contextual factors were abstracted from each trial. Results:The review included 37 HIV prevention RCTs reporting on 39 unique interventions. Only six RCTs, all evaluating biomedical interventions, demonstrated definitive effects on HIV incidence. Five of the six RCTs significantly reduced HIV infection: all three male circumcision trials, one trial of sexually transmitted infection treatment and care, and one vaccine trial. One microbicide trial of nonoxynol-9 gel produced adverse results. Lack of statistical power, poor adherence, and diluted versions of the intervention in comparison groups may have been important issues for the other trials that demonstrated ‘flat’ results. Conclusion:Almost 90% of HIV prevention trials had ‘flat’ results, which may be attributable to trial design and/or implementation. The HIV prevention community must not only examine evidence from significant RCTs, but must also examine flat trials and address design and implementation issues that limit detection of an effect.

Implementation science for the US President's Emergency Plan for AIDS Relief (PEPFAR).

Working with implementing organizations and governments in over 32 countries, the US President’s Emergency Plan for AIDS Relief (PEPFAR) has contributed to the rapid acceleration of HIV treatment access, availability of care and support services, and HIV prevention interventions. In the first phase of PEPFAR, these activities were appropriately carried out in an emergency fashion with the goal of using available interventions to reduce mortality and alleviate suffering from HIV disease as quickly and effectively as possible. Many lessons have been learned through examination of programs, including simple evaluations and operations research. Commensurate with the emergency response, however, state-of-the-art monitoring, evaluation, and research methodologies were not fully integrated or systematically performed. In the second phase of PEPFAR, characterized by an increased emphasis on sustainability, programs must demonstrate value and impact to be prioritized within complex and resource-constrained environments. In this context, there is a greater demand to causally attribute outcomes to programs. Better attribution can be used to inform midcourse corrections in the scale-up of new interventions (eg, male circumcision) or to reevaluate investments in programs for which impact is less clear. To meet these demands, PEPFAR is adopting an implementation science (IS) framework to improve the development and effectiveness of its programs at all levels. IS is the study of methods to improve the uptake, implementation, and translation of research findings into routine and common practices (the ‘‘know-do’’ or ‘‘evidence to program’’ gap). For example, IS was used to evaluate the routine operational effectiveness of the South African National Prevention of Mother-to-Child Transmission Programme. Investigators explored the survival of HIV-free infants across program sites and identified specific sources of variation such as health system factors (eg, limited antenatal visits and lack of syphilis screening) and individual behaviors (eg, breastfeeding practices). By framing the problem through IS, the study revealed opportunities for improving program performance that could be translated into immediate solutions (eg, improving quality of care, infant feeding counseling). In this way, IS proved to be a valuable tool that was used not only to improve program effectiveness, but also to explain what worked, why, and under what circumstances. Although no less rigorous than biomedical research dictated by a static protocol with robust internal validity (ie, ‘‘proof-of-concept’’ research with a precisely defined and narrow objective), an IS approach represents a paradigmatic shift in emphasis to greater external validity. The IS scope is also broader, seeking to improve program effectiveness and optimize efficiency, including the effective transfer of interventions from one setting to another. The methods of IS facilitate making evidence-based choices between competing or combined interventions and improving the delivery of effective and costeffective programs.

A Review of the Role of Food Insecurity in Adherence to Care and Treatment Among Adult and Pediatric Populations Living with HIV and AIDS

Adherence to antiretroviral therapy (ART) is critical for reducing HIV/AIDS morbidity and mortality. Food insecurity (FI) is emerging as an important barrier to adherence to care and treatment recommendations for people living with HIV (PLHIV), but this relationship has not been comprehensively examined. Therefore, we reviewed the literature to explore how FI may impact ART adherence, retention in medical care, and adherence to health care recommendations among PLHIV. We found data to support FI as a critical barrier to adherence to ART and to other health care recommendations among HIV-infected adults, HIV-infected pregnant women and their HIV-exposed infants, and child and adolescent populations of PLHIV. Associations between FI and ART non-adherence were seen in qualitative and quantitative studies. We identified a number of mechanisms to explain how food insecurity and ART non-adherence may be causally linked, including the exacerbation of hunger or ART side effects in the absence of adequate food and competing resource demands. Interventions that address FI may improve adherence to care and treatment recommendations for PLHIV.

Does Food Insecurity Undermine Adherence to Antiretroviral Therapy? A Systematic Review

A growing body of research has identified food insecurity as a barrier to antiretroviral therapy (ART) adherence. We systematically reviewed and summarized the quantitative literature on food insecurity or food assistance and ART adherence. We identified nineteen analyses from eighteen distinct studies examining food insecurity and ART adherence. Of the thirteen studies that presented an adjusted effect estimate for the relationship between food insecurity and ART adherence, nine found a statistically significant association between food insecurity and sub-optimal ART adherence. Four studies examined the association between food assistance and ART adherence, and three found that ART adherence was significantly better among food assistance recipients than non-recipients. Across diverse populations, food insecurity is an important barrier to ART adherence, and food assistance appears to be a promising intervention strategy to improve ART adherence among persons living with HIV. Additional research is needed to determine the effectiveness and cost-effectiveness of food assistance in improving ART adherence and other clinical outcomes among people living with HIV in the era of widespread and long-term treatment.

Evaluation of Large-Scale Combination HIV Prevention Programs : Essential Issues

HIV prevention research has shifted to the evaluation of combination prevention programs whereby biomedical, behavioral, and structural interventions are implemented concurrently to maximize synergies among interventions. However, these kinds of combination prevention packages, particularly when implemented at scale, pose significant evaluation challenges, including how best to determine impact and how and whether to measure the effectiveness of component strategies. In addition, methodological challenges unique to HIV infection such as the absence of a reliable incidence assay, the lack of naive control groups, and no suitable surrogates further complicate rigorous evaluation. In this commentary, we discuss the key considerations for planning impact evaluations of combination HIV prevention programs in light of these challenges, including defining the evaluable package, determining which component programs require independent assessment of impact, choosing study designs with valid counterfactuals, selecting appropriate outcomes of interest, and the importance of mid-course program corrections.

Unmet Need for Family Planning, Contraceptive Failure, and Unintended Pregnancy among HIV-Infected and HIV-Uninfected Women in Zimbabwe

Background Prevention of unintended pregnancies among women living with HIV infection is a strategy recommended by the World Health Organization for prevention of mother-to-child transmission of HIV (PMTCT). We assessed pregnancy intentions and contraceptive use among HIV-positive and HIV-negative women with a recent pregnancy in Zimbabwe. Methods We analyzed baseline data from the evaluation of Zimbabwe’s Accelerated National PMTCT Program. Eligible women were randomly sampled from the catchment areas of 157 health facilities offering PMTCT services in five provinces. Eligible women were ≥16 years old and mothers of infants (alive or deceased) born 9 to 18 months prior to the interview. Participants were interviewed about their HIV status, intendedness of the birth, and contraceptive use. Results Of 8,797 women, the mean age was 26.7 years, 92.8% were married or had a regular sexual partner, and they had an average of 2.7 lifetime births. Overall, 3,090 (35.1%) reported that their births were unintended; of these women, 1,477 (47.8%) and 1,613 (52.2%) were and were not using a contraceptive method prior to learning that they were pregnant, respectively. Twelve percent of women reported that they were HIV-positive at the time of the survey; women who reported that they were HIV-infected were significantly more likely to report that their pregnancy was unintended compared to women who reported that they were HIV-uninfected (44.9% vs. 33.8%, p<0.01). After adjustment for covariates, among women with unintended births, there was no association between self-reported HIV status and lack of contraception use prior to pregnancy. Conclusions Unmet need for family planning and contraceptive failure contribute to unintended pregnancies among women in Zimbabwe. Both HIV-infected and HIV-uninfected women reported unintended pregnancies despite intending to avoid or delay pregnancy, highlighting the need for effective contraceptive methods that align with pregnancy intentions.

Poor diet quality is associated with low CD4 count and anemia and predicts mortality among antiretroviral therapy-naive HIV-positive adults in Uganda.

Background:We assessed the association between dietary diversity and CD4 count, moderate anemia, and mortality among 876 antiretroviral therapy–naive people living with HIV/AIDS infection (PLHIV) in Uganda. Methods:Participants were interviewed and followed for an average of 21.6 months. Dietary diversity was measured using the Individual Dietary Diversity Score (IDDS) (range, 0–12) and summarized into an overall measure and disaggregated into nutrient-rich food groups (range, 0–7), cereals, roots, and tubers (range, 0\x{2013} 2); and oils, fats, sugars, and condiments (range, 0\x{2013} 3). We determined the cross-sectional associations between dietary diversity and (1) immunosuppression (CD4 count ⩽ 350 cells/&mgr;L) and (2) moderate anemia (hemoglobin < 10 g/dL) at baseline with logistic regression. We assessed the association between IDDS and mortality using Cox proportional hazards regression. Results:The mean IDDS score was 6.3 (SD 1.7) food groups per day, with a mean of 2.7 (SD 1.1) nutrient-rich food groups per day. Each additional nutrient-rich food group consumed was associated with a 16% reduction in the likelihood of having a CD4 count ⩽350 cells/&mgr;L [adjusted odds ratio, 0.84; 95% confidence interval (CI): 0.72 to 0.97] at baseline. Among those with >350 CD4 cells per microliter, but not those with CD4 count ⩽350 cells per microliter, consumption of nutrient-rich food groups was associated with a lower odds of moderate anemia (adjusted odds ratio, 0.57; 95% CI: 0.34 to 0.96). During follow-up, 48 participants (5.6%) died (mortality rate of 3.1 per 100 person-years). IDDS was inversely associated with mortality [adjusted hazard ratio, 0.76; 95% CI: 0.63 to 0.91]. Conclusion:These results suggest that diet quality is an important determinant of HIV disease severity and mortality in antiretroviral therapy–naive PLHIV.

Improving the efficiency of HIV testing with peer recruitment, financial incentives, and the involvement of persons living with HIV infection.

Background:The authors piloted an HIV testing and counseling (HTC) approach using respondent-driven sampling (RDS), financial incentives, and persons living with HIV infection (PLHIV). Methods:Eligible participants were aged 30–60 years, African American or black, and residents of Oakland, CA. Participants were tested for HIV infection and asked to refer up to 3 others. The authors compared the efficiency of RDS to conventional outreach-based HTC with the number needed to screen (NNS). They evaluated the effect of 2 randomly allocated recruitment incentives on the enrollment of high-risk or HIV-positive network associates: a flat incentive (

Next steps for research on hormonal contraception and HIV

20) for eligible recruits or a conditional incentive (