The Evidence Project: Protocol for Systematic Reviews of Behavioral Interventions and Behavioral Aspects of Biomedical Interventions for HIV Prevention, Treatment, and Health Service Delivery in Low- and Middle-Income Countries.

The Evidence Project conducts systematic reviews and meta-analyses of HIV behavioral interventions, behavioral aspects of biomedical interventions, combination prevention strategies, modes of service delivery, and integrated programs in low- and middle-income countries. Here, we present the overall protocol for our reviews. For each topic, we conduct a comprehensive search of five online databases, complemented by secondary reference searching. Articles are included if they are published in peer-reviewed journals and present pre/post or multi-arm data on outcomes of interest. Data are extracted from each included article by two trained coders working independently using standardized coding forms, with differences resolved by consensus. Risk of bias is assessed with the Evidence Project tool. Data are synthesized descriptively, and meta-analysis is conducted when there are similarly measured outcomes across studies. For over 20 years, this approach has allowed us to synthesize literature on the effectiveness of interventions and contribute to the global HIV response.

Family Planning Counseling for Women Living with HIV in Low- and Middle-Income Countries: A Systematic Review of the Impact on Contraceptive Uptake, Intention to Use Contraception and Pregnancy Incidence, 2011 to 2022.

Women's ability to control their fertility and have the number of children they want when they want them is an internationally recognized human right. This right has been the driving force behind family planning programs in low- and middle-income countries for more than five decades. The HIV epidemic added greater urgency to those efforts once the risk of vertical transmission of the virus from mothers to their infants was recognized. In 2013, we published a systematic review of the evidence of effectiveness of family planning counseling for women living with HIV, emphasizing HIV related behaviors. In this updated review, we examined 23 studies, primarily from sub-Saharan Africa. The evidence we uncovered reflected efforts to integrate services provided to women. These showed that providing contraceptive services, including intensified counseling and support, in the HIV clinics where women living with HIV received their care increased the likelihood of subsequent use of modern contraception by as much as fourfold. These studies reflected a greater focus on women's family planning decisions and behaviors and less focus on HIV-related behaviors. Among the possible causes of this noted difference we include the widespread coverage of antiretroviral treatment for HIV. This advance has apparently changed the rationale and the approach to integrating family planning and HIV services in ways that may not have been fully appreciated. The results, however, are beneficial: greater coverage of family planning for women who wish to control their fertility and a more equal partnership between family planning services and HIV services in pursuit of the mutual goal of providing integrated services to meet women's needs.

The Impact of Needle and Syringe Exchange Programs on HIV-Related Risk Behaviors in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis Examining Individual- Versus Community-Level Effects.

We conducted a systematic review and meta-analysis of the impact of needle and syringe exchange programs (NSP) on both individual- and community-level needle-sharing behaviors and other HIV-related outcomes in low- and middle-income countries (LMIC). A search of five databases for peer-reviewed trial or quasi-experimental studies reported through July 2021 identified 42 interventions delivered in 35 studies, with a total of 56,751 participants meeting inclusion criteria. Random-effects meta-analysis showed a significant protective association between NSP exposure and needle-sharing behaviors at the individual-level (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.16-0.39, 8 trials, n = 3947) and community-level (OR 0.39, CI 0.22-0.69, 12 trials, n = 6850), although with significant heterogeneity. When stratified by needle-sharing directionality, NSP exposure remained associated with reduced receptive sharing, but not distributive sharing. NSP exposure was also associated with reduced HIV incidence and increased HIV testing but there were no consistent associations with prevalence of bloodborne infections. Current evidence suggests positive impacts of NSPs in LMICs.

RESUMEN: Realizamos una revisión sistemática y un metanálisis del impacto de los programas de intercambio de agujas y jeringas (NSP, por sus siglas en inglés) de los comportamientos de uso compartido de agujas tanto a nivel individual como comunitario y otros resultados relacionados con el VIH en países de ingresos bajos y medianos (LMIC, por sus siglas en inglés). Realizamos búsquedas sistemáticas en cinco bases de datos hasta julio de 2021 en busca de ensayos revisados por pares o estudios cuasiexperimentales. En general, 42 intervenciones informadas en 35 estudios entre 56 751 participantes cumplieron los criterios de inclusión. El metanálisis de efectos aleatorios de ocho estudios a nivel individual y 12 a nivel comunitario con 11 075 participantes en total mostró una asociación protectora significativa entre la exposición a NSP y los comportamientos de compartir agujas (individual: OR 0,25, IC95%: 0,16­0,39; comunidad: OR 0,39, IC95%:0,22­0,69), aunque con una heterogeneidad importante. Cuando se estratificó por la direccionalidad del intercambio de agujas, la exposición a NSP permaneció asociada con un intercambio receptivo reducido, pero no con un intercambio distributivo. La exposición a NSP también se asoció con una incidencia reducida del VIH y un aumento de las pruebas del VIH, pero no hubo asociaciones consistentes para la prevalencia de infecciones transmitidas por la sangre. La evidencia actual sugiere impactos positivos de los NSP en los LMIC.

The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial.

BACKGROUND: On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes. METHODS: This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547. FINDINGS: Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline. INTERPRETATION: Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores. FUNDING: None.

The Experiences of Clinical Engineering when Responding to the COVID-19 Pandemic.

The scope of this article is limited to the actions and experiences of the Landstuhl Regional Medical Center (LRMC) Clinical Engineering Branch (CEB) when planning and executing the COVID-19 response at the only US military Role 4 medical treatment facility (MTF) in Europe between 1 February and 1 May 2020. Aspects of the COVID-19 response extended throughout the Regional Health Command; therefore, the full breadth and scope of the total response is far too great to expound within this account alone. The entire medical staff, along with an innumerable number of partners, were immensely engaged in the response and performed remarkably well given the rapidly developing pandemic. It is a testament to the agility of Army Medicine and the robustness of the American and European health systems to develop such a complicated medical response in such a short amount of time.

Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes.

Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-É£ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-É£ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-É£ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

Sexual partner concurrency: is it a useful concept for HIV prevention? A systematic review of the evidence for intervention effectiveness in low- and middle-income countries.

If sexual partner concurrency drives HIV transmission dynamics, shouldn't HIV prevention efforts be addressing this behavior? We systematically reviewed studies evaluating interventions to reduce sexual partner concurrency in low- and middle-income countries using pre/post or multi-arm designs. Only two studies met our inclusion criteria; neither found significant differences by intervention exposure on self-reported concurrency. Overall, very few interventions have specifically targeted concurrency, and those that did have not been rigorously evaluated. In practice, concurrency may be difficult to separate from multiple partnerships more generally.

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility in male, but not female, mice.

Imbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however, the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown. We used a viral-cre approach in male and female mice harboring a "floxed" version of the kcnj3 (Girk1) gene, to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic cortex (PrL). In males, loss of pyramidal GIRK1-dependent signaling differentially impacted measures of affect and impaired working memory and cognitive flexibility. Unexpectedly, ablation of PrL GIRK1-dependent signaling did not impact affect or cognition in female mice. Additional studies used a model of chronic unpredictable stress (CUS) to determine the impact on PrL GIRK-dependent signaling and cognitive function. CUS exposure in male mice produced deficits in cognition that paralleled a reduction in PrL pyramidal GIRK-dependent signaling akin to viral approaches whereas CUS exposure in female mice did not alter cognitive flexibility performance. Stress-induced behavioral deficits in male mice were rescued by systemic injection of a novel, GIRK1-selective agonist, ML297. In conclusion, GIRK1-dependent signaling in male mice, but not females, is critical for maintaining optimal PrL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PrL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.

"We are in this together:" dyadic-level influence and decision-making among HIV serodiscordant couples in Tanzania receiving access to PrEP.

BACKGROUND: A substantial number of new HIV infections in sub-Saharan Africa occur within stable couples. Biomedical prevention (pre-exposure prophylaxis, PrEP) and treatment (antiretroviral therapy, ART) can provide benefits to sexual partners and can be used to prevent infection within HIV serodiscordant couples. However, research is typically focused on individuals, not dyads, even when the intervention may directly or indirectly impact sexual partners. Gaps remain in understanding best practices for recruitment, informed consent, and intervention implementation in studies involving HIV prevention and treatment among heterosexual serodiscordant couples. This qualitative study was undertaken to understand and describe decision-making and dyadic-level influence among members of serodiscordant couples regarding (1) participation in a dyadic-based research study involving HIV self-testing and access to PrEP, and (2) utilization of PrEP and ART. METHODS: This qualitative study was nested within an observational cohort study assessing the acceptability of home-based couples' HIV self-testing and uptake of dyadic care for serodiscordant couples involving facilitated referral for HIV-positive partners and access to PrEP for HIV-negative partners. Semi-structured in-depth interviews were conducted among a subset of study participants (n = 22) as well as individuals involved in serodiscordant relationships who chose not to participate (n = 9). Interviews focused on couples' decision-making regarding study participation and dyadic-level influence on medication use. Interviews were transcribed verbatim and translated from Kiswahili into English. Data were analyzed using thematic analysis. RESULTS: Three major themes were identified: (1) HIV as "two people's secret" and the elevated role of partner support in serodiscordant relationships; (2) the intersectional role of HIV-status and gender on decision-making; (3) the relational benefits of PrEP, including psychosocial benefits for the couple that extend beyond prevention. CONCLUSIONS: The study found that couples made joint decisions regarding study participation and uptake of HIV-related medication. Relational autonomy and dyadic-level influence should be considered within research and programs involving HIV serodiscordant couples.

Does Capacity Development Increase Demand for Health Services and Rights Among Key Populations Affected by HIV? A Systematic Review of Evidence from Low and Middle-Income Countries.

Capacity development is a process by which individuals, organizations and societies develop abilities to perform functions, solve problems and achieve objectives. This systematic review sought to document capacity development interventions, the associated outcomes and its effectiveness in increasing demand for rights and health services among key populations (KP) in low and middle-income countries. Twenty papers met our review's selection criteria. Significant improvements in health service utilization were achieved in most community mobilization and peer-led interventions. Whilst we found ample evidence linking capacity development to uptake of services, there was a striking dearth of research examining the impact of capacity development on demand for rights among KP. There was inadequate contextual data to explain variations in intervention effectiveness across different projects. More evidence is needed on the impact of capacity development on demand for health services and rights among KP. Consensus on parameters of capacity development and priority outcomes is required.

Economic compensation interventions to increase uptake of voluntary medical male circumcision for HIV prevention: A systematic review and meta-analysis.

BACKGROUND: Economic compensation interventions may help support higher voluntary medical male circumcision (VMMC) coverage in priority sub-Saharan African countries. To inform World Health Organization guidelines, we conducted a systematic review of economic compensation interventions to increase VMMC uptake. METHODS: Economic compensation interventions were defined as providing money or in-kind compensation, reimbursement for associated costs (e.g. travel, lost wages), or lottery entry. We searched five electronic databases and four scientific conferences for studies examining the impact of such interventions on VMMC uptake, HIV testing and safer-sex/risk-reduction counseling uptake within VMMC, community expectations about compensation, and potential coercion. We screened citations, extracted data, and assessed risk of bias in duplicate. We conducted random-effects meta-analysis. We also reviewed studies examining acceptability, values/preferences, costs, and feasibility. RESULTS: Of 2484 citations identified, five randomized controlled trials (RCTs) and three non-randomized controlled trials met our eligibility criteria. Studies took place in Kenya, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. Meta-analysis of four RCTs showed significant impact of any economic compensation on VMMC uptake (relative risk: 5.23, 95% CI: 3.13 to 8.76). RCTs of food/transport vouchers and conditional cash transfers generally showed increases in VMMC uptake, but lotteries, subsidized VMMC, and receiving a gift appeared somewhat less effective. Three non-randomized trials showed mixed impact. Six additional studies suggested economic compensation interventions were generally acceptable, valued for addressing key barriers, and motivating to men. However, some participants felt they were insufficiently motivating or necessary; one study suggested they might raise community suspicions. One study from South Africa found a program cost of US$91 per additional circumcision and US$450-$1350 per HIV infection averted. CONCLUSIONS: Economic compensation interventions, particularly transport/food vouchers, positively impacted VMMC uptake among adult men and were generally acceptable to potential clients. Carefully selected economic interventions may be a useful targeted strategy to enhance VMMC coverage.

Service delivery interventions to increase uptake of voluntary medical male circumcision for HIV prevention: A systematic review.

BACKGROUND: Voluntary medical male circumcision (VMMC) remains an essential component of combination HIV prevention services, particularly in priority countries in sub-Saharan Africa. As VMMC programs seek to maximize impact and efficiency, and to support World Health Organization guidance, specific uptake-enhancing strategies are critical to identify. METHODS: We systematically reviewed the literature to evaluate the impact of service delivery interventions (e.g., facility layout, service co-location, mobile outreach) on VMMC uptake among adolescent and adult men. For the main effectiveness review, we searched for publications or conference abstracts that measured VMMC uptake or uptake of HIV testing or risk reduction counselling within VMMC services. We synthesized data by coding categories and outcomes. We also reviewed studies assessing acceptability, values/preferences, costs, and feasibility. RESULTS: Four randomized controlled trials and five observational studies were included in the effectiveness review. Studies took place in South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. They assessed a range of service delivery innovations, including community-, school-, and facility-based interventions. Overall, interventions increased VMMC uptake; some successfully improved uptake among age-specific subpopulations, but urban-rural stratification showed no clear trends. Interventions that increased adult men's uptake included mobile services (compared to static facilities), home-based testing with active referral follow-up, and facility-based HIV testing with enhanced comprehensive sexual education. Six acceptability studies suggested interventions were generally perceived to help men choose to get circumcised. Eleven cost studies suggested interventions create economies-of-scale and efficiencies. Three studies suggested such interventions were feasible, improving facility preparedness, service quality and quantity, and efficiencies. CONCLUSIONS: Innovative changes in male-centered VMMC services can improve adult men's and adolescent boys' VMMC uptake. Limited evidence on interventions that enhance access and acceptability show promising results, but evidence gaps persist due to inconsistent intervention definition and delivery, due in part to contextual relevance and limited age disaggregation.

Condom Social Marketing Effects in Low- and Middle-Income Countries: A Systematic Review Update, 1990 to 2019.

OBJECTIVE: To update the prior systematic review from studies published in the past 9 years that examine the effects of condom social marketing (CSM) programs on condom use in low- and middle-income countries. DATA SOURCES: PubMed, CINAHL, PsycINFO, Sociological Abstracts, and EMBASE. Hand searching of AIDS, AIDS and Behavior, AIDS Care, and AIDS Education and Prevention. STUDY INCLUSION AND EXCLUSION CRITERIA: (a) Published from 1990 to January 16, 2019, (b) low- or middle-income country, (c) evaluated CSM, (d) analyses across preintervention to postintervention exposure or across multiple study arms, (e) measured condom use behavior, and (f) sought to prevent HIV transmission. DATA EXTRACTION: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 2 reviewers extracted citation, inclusion criteria, methods, study population, setting, sampling, study design, unit of analysis, loss to follow-up, comparison group characteristics, intervention characteristics, and eligible outcome results. DATA SYNTHESIS: The 2012 review found 6 studies (combined N = 23 048). In a meta-analysis, the pooled odds ratio for condom use was 2.01 (95% confidence interval [CI]: 1.42-2.84) for the most recent sexual encounter and 2.10 (95% CI: 1.51-2.91) for a composite of all condom use outcomes. Studies had significant methodological limitations. Of 518 possible new citations identified in the update, no new articles met our inclusion criteria. CONCLUSIONS: More studies are needed with stronger methodological rigor to help provide evidence for the continued use of this approach globally. There is a dearth of studies over the past decade on the effectiveness of CSM in increasing condom use in low- and middle-income countries (LMIC).

The Evidence Project risk of bias tool: assessing study rigor for both randomized and non-randomized intervention studies.

BACKGROUND: Different tools exist for assessing risk of bias of intervention studies for systematic reviews. We present a tool for assessing risk of bias across both randomized and non-randomized study designs. The tool was developed by the Evidence Project, which conducts systematic reviews and meta-analyses of behavioral interventions for HIV in low- and middle-income countries. METHODS: We present the eight items of the tool and describe considerations for each and for the tool as a whole. We then evaluate reliability of the tool by presenting inter-rater reliability for 125 selected studies from seven published reviews, calculating a kappa for each individual item and a weighted kappa for the total count of items. RESULTS: The tool includes eight items, each of which is rated as being present (yes) or not present (no) and, for some items, not applicable or not reported. The items include (1) cohort, (2) control or comparison group, (3) pre-post intervention data, (4) random assignment of participants to the intervention, (5) random selection of participants for assessment, (6) follow-up rate of 80% or more, (7) comparison groups equivalent on sociodemographics, and (8) comparison groups equivalent at baseline on outcome measures. Together, items (1)-(3) summarize the study design, while the remaining items consider other common elements of study rigor. Inter-rater reliability was moderate to substantial for all items, ranging from 0.41 to 0.80 (median κ = 0.66). Agreement between raters on the total count of items endorsed was also substantial (κw = 0.66). CONCLUSIONS: Strengths of the tool include its applicability to a range of study designs, from randomized trials to various types of observational and quasi-experimental studies. It is relatively easy to use and interpret and can be applied to a range of review topics without adaptation, facilitating comparability across reviews. Limitations include the lack of potentially relevant items measured in other tools and potential threats to validity of some items. To date, the tool has been applied in over 30 reviews. We believe it is a practical option for assessing risk of bias in systematic reviews of interventions that include a range of study designs.

Willingness to use short-term oral pre-exposure prophylaxis (PrEP) by migrant miners and female partners of migrant miners in Mozambique.

Migrant miners from Mozambique who work in South Africa and their partners are at substantial risk for HIV infection. We conducted a cross-sectional study to assess the willingness of migrant miners and female partners of miners to take short-term pre-exposure prophylaxis (PrEP) for prevention of HIV acquisition. The study was conducted in Gaza Province, Mozambique, between September and October 2015. A total of 131 male miners and female partners of male miners completed a questionnaire. Subsequently, 48 in-depth interviews among male miners and female partners of miners and 3 focus-group discussions (6 participants each) among female partners of miners were conducted. Quantitative data were tabulated using Stata. A structured coding scheme was developed and qualitative data were analysed using Atlas.ti. Most participants (94%) were willing to take PrEP for short-term use. Facilitating factors for willingness to use PrEP were concerns about partner's sexual behaviour, desire for pregnancy and one's own sexual behaviour. The main barriers to PrEP use were concerns regarding side-effects, perceived difficulty adhering to daily pill taking and concern about partner/family disapproval. Overall, participants saw potential barriers for PrEP as minor obstacles that could be overcome. The male partner's influence on PrEP use was significant.

Can Policy Interventions Affect HIV-Related Behaviors? A Systematic Review of the Evidence from Low- and Middle-Income Countries.

In their response to HIV, many countries have adopted and enacted policies to reduce transmission and increase HIV-related service use. Theoretically, policy-level interventions for HIV prevention have the potential to improve health behavior outcomes. These policy interventions vary in their scale, from relatively minor changes in clinical policy to major national legal initiatives. Assessing the effectiveness of HIV policy interventions is a challenging undertaking. While many policies exist and guide HIV programmes, relatively few have specifically been evaluated for their effects on reducing HIV risk taking or increasing HIV health-seeking behaviors. Thus, questions on the effectiveness of policy interventions to prevent HIV and change HIV-related risk behaviors remain largely unanswered. To address this current gap in the literature, we systematically reviewed the existing evidence on the effect of HIV policy interventions on changing HIV-related behaviors in low-and middle-income countries.

Values and Preferences on the Use of Oral Pre-exposure Prophylaxis (PrEP) for HIV Prevention Among Multiple Populations: A Systematic Review of the Literature.

Daily oral pre-exposure prophylaxis (PrEP) is the use of antiretroviral drugs by HIV-negative people to prevent HIV infection. WHO released new guidelines in 2015 recommending PrEP for all populations at substantial risk of HIV infection. To prepare these guidelines, we conducted a systematic review of values and preferences among populations that might benefit from PrEP, women, heterosexual men, young women and adolescent girls, female sex workers, serodiscordant couples, transgender people and people who inject drugs, and among healthcare providers who may prescribe PrEP. A comprehensive search strategy reviewed three electronic databases of articles and HIV-related conference abstracts (January 1990-April 2015). Data abstraction used standardised forms to categorise by population groups and relevant themes. Of 3068 citations screened, 76 peer-reviewed articles and 28 conference abstracts were included. Geographic coverage was global. Most studies (N = 78) evaluated hypothetical use of PrEP, while 26 studies included individuals who actually took PrEP or placebo. Awareness of PrEP was low, but once participants were presented with information about PrEP, the majority said they would consider using it. Concerns about safety, side effects, cost and effectiveness were the most frequently cited barriers to use. There was little indication of risk compensation. Healthcare providers would consider prescribing PrEP, but need more information before doing so. Findings from a rapidly expanding evidence base suggest that the majority of populations most likely to benefit from PrEP feel positively towards it. These same populations would benefit from overcoming current implementation challenges with the shortest possible delay.

Effectiveness and safety of oral HIV preexposure prophylaxis for all populations.

OBJECTIVE: Preexposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes. DESIGN: Rigorous systematic review and meta-analysis. METHODS: A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis. RESULTS: Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared with placebo. Trials with PrEP use more than 70% demonstrated the highest PrEP effectiveness (risk ratio = 0.30, 95% confidence interval: 0.21-0.45, P < 0.001) compared with placebo. Trials with low PrEP use did not show a significantly protective effect. Adverse events were similar between PrEP and placebo groups. More cases of drug-resistant HIV infection were found among PrEP users who initiated PrEP while acutely HIV-infected, but incidence of acquiring drug-resistant HIV during PrEP use was low. Studies consistently found no association between PrEP use and changes in sexual risk behavior. PrEP was not associated with increased pregnancy-related adverse events or hormonal contraception effectiveness. CONCLUSION: PrEP is protective against HIV infection across populations, presents few significant safety risks, and there is no evidence of behavioral risk compensation. The effective and cost-effective use of PrEP will require development of best practices for fostering uptake and adherence among people at substantial HIV risk.

Seasonal PrEP for partners of migrant miners in southern Mozambique: a highly focused PrEP intervention.

INTRODUCTION: To be used most effectively, pre-exposure prophylaxis (PrEP) should be prioritized to those at high risk of acquisition and would ideally be aligned with time periods of increased exposure. Identifying such time periods is not always straightforward, however. Gaza Province in southern Mozambique is characterized by high levels of HIV transmission and circular labour migration to mines in South Africa. A strong seasonal pattern in births is observable, reflecting an increase in conception in December. Given the potential for increased HIV transmission between miners returning in December and their partners in Gaza Province, PrEP use by the latter would be a useful means of HIV prevention, especially for couples who wish to conceive. METHODS: A mathematical model was used to represent population-level adult heterosexual HIV transmission in Gaza Province. Increased HIV acquisition among partners of miners in December, coinciding with the miners' return from South Africa, is represented. In addition to a PrEP intervention, the scale-up of treatment and recent scale-up of male circumcision that have occurred in Gaza are represented. RESULTS: Providing time-limited PrEP to the partners of migrant miners, as opposed to providing PrEP all year, would improve the cost per infection averted by 7.5-fold. For the cost per infection averted to be below US$3000, at least 85% of PrEP users would need to be good adherers and PrEP would need to be cheaper than US$115 per person per year. Uncertainty regarding incidence of HIV transmission among partners of miners each year in December has a strong influence on estimates of cost per infection averted. CONCLUSIONS: Providing time-limited PrEP to partners of migrant miners in Gaza Province during periods of increased exposure would be a novel strategy for providing PrEP. This strategy would allow for a better prioritized intervention, with the potential to improve the efficiency of a PrEP intervention considerably, as well as providing important reproductive health benefits.