Shaping and coordinating the implementation science agenda for injectable cabotegravir for PrEP: the role of the Biomedical Prevention Implementation Collaborative (BioPIC).

INTRODUCTION: Data from two randomized controlled trials (RCTs) showed that injectable cabotegravir (CAB) for pre-exposure prophylaxis (PrEP) was efficacious in reducing HIV acquisition. The US Food and Drug Administration approved CAB for PrEP in December 2021; Australia in August 2022; Zimbabwe in October 2022; South Africa in November 2022; Malawi in March 2023; and regulatory approvals are being sought in additional countries. The World Health Organization (WHO) recommended CAB be offered to people at substantial risk of HIV in July 2022. However, implementation experience beyond RCTs is limited. As countries consider CAB implementation, questions remain regarding delivery and involvement of populations excluded from the trials. A coordinated approach is needed to ensure these are addressed and CAB can be introduced in low- and middle-income countries in timely, acceptable and effective ways. DISCUSSION: Beginning in 2018, the Biomedical Prevention Implementation Collaborative (BioPIC) convened over 100 global health experts to develop a comprehensive introduction strategy for CAB. Using this roadmap, country landscaping for CAB introduction and lessons from oral PrEP implementation, AVAC and WHO co-convened 50 researchers, donors, implementers and civil society in September 2021 to: (1) identify questions and evidence gaps related to CAB across contexts and partners; (2) define the implementation science agenda; and (3) agree on mechanism(s) for future coordination. As a result, CAB-related questions were identified, including: defining optimal and feasible HIV testing strategies that expand access; delivery models; integration with a range of services, including family planning and antenatal care; and embedding CAB in demand generation for HIV prevention choices. Through convenings and mapping of implementation research, BioPIC identified gaps in populations, geographies and delivery approaches. CONCLUSIONS: The introduction strategy refined by BioPIC lays the groundwork for future HIV prevention products. Ongoing policy and implementation dialogue is critical to accelerate the design of CAB implementation studies that adequately address priority knowledge gaps. Additional long-acting HIV prevention products may be available over the next 5 years, increasing choice, but potentially making delivery and stakeholder engagement more complex. Ongoing coordination with WHO will accelerate the adoption of evidence-based policies and wide-scale implementation, and lessons from BioPIC can inform introduction processes for long-acting HIV prevention products.

Systematic review of the values and preferences regarding the use of injectable pre-exposure prophylaxis to prevent HIV acquisition.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) is an important HIV prevention option. Two randomized trials have provided efficacy evidence for long-acting injectable cabotegravir (CAB-LA) as PrEP. In considering CAB-LA as an additional PrEP modality for people at substantial risk of HIV, it is important to understand community response to injectable PrEP. We conducted a systematic review of values, preferences and perceptions of acceptability for injectable PrEP to inform global guidance. METHODS: We searched nine databases and conference websites for peer-reviewed and grey literature (January 2010-September 2021). There were no restrictions on location. A two-stage review process assessed references against eligibility criteria. Data from included studies were organized by constructs from the Theoretical Framework of Acceptability. RESULTS: We included 62 unique references. Most studies were observational, cross-sectional and qualitative. Over half of the studies were conducted in North America. Men who have sex with men were the most researched group. Most studies (57/62) examined injectable PrEP, including hypothetical injectables (55/57) or placebo products (2/57). Six studies examined CAB-LA specifically. There was overall interest in and often a preference for injectable PrEP, though there was variation within and across groups and regions. Many stakeholders indicated that injectable PrEP could help address adherence challenges associated with daily or on-demand dosing for oral PrEP and may be a better lifestyle fit for individuals seeking privacy, discretion and infrequent dosing. End-users reported concerns, including fear of needles, injection site pain and body location, logistical challenges and waning or incomplete protection. DISCUSSION: Despite an overall preference for injectable PrEP, heterogeneity across groups and regions highlights the importance of enabling end-users to choose a PrEP modality that supports effective use. Like other products, preference for injectable PrEP may change over time and end-users may switch between prevention options. There will be a greater understanding of enacted preference as more end-users are offered anti-retroviral (ARV)-containing injectables. Future research should focus on equitable implementation, including real-time decision-making and how trained healthcare providers can support choice. CONCLUSIONS: Given overall acceptability, injectable PrEP should be included as part of a menu of prevention options, allowing end-users to select the modality that suits their preferences, needs and lifestyle.

Safety and efficacy of long-acting injectable cabotegravir as preexposure prophylaxis to prevent HIV acquisition.

OBJECTIVE: HIV remains a significant burden, despite expanding HIV prevention tools. Long-acting injectable cabotegravir (CAB-LA) is a new preexposure prophylaxis (PrEP) product. We reviewed existing evidence to determine the efficacy and safety of CAB-LA as PrEP to inform global guidelines. DESIGN: Systematic review and meta-analysis. METHODS: We systematically reviewed electronic databases and conference abstracts for citations on CAB-LA from January 2010 to September 2021. Outcomes included HIV infection, adverse events, drug resistance, pregnancy-related adverse events, and sexual behavior. We calculated pooled effect estimates using random-effects meta-analysis and summarized other results narratively. RESULTS: We identified 12 articles/abstracts representing four multisite randomized controlled trials. Study populations included cisgender men, cisgender women, and transgender women. The pooled relative risk of HIV acquisition comparing CAB-LA to oral PrEP within efficacy studies was 0.21 (95% confidence interval: 0.07-0.61), resulting in a 79% reduction in HIV risk. Rates of adverse events were similar across study groups. Of 19 HIV infections among those randomized to CAB-LA with results available, seven had integrase strand transfer inhibitor (INSTI) resistance. Data on pregnancy-related adverse events were sparse. No studies reported on sexual behavior. CONCLUSIONS: CAB-LA is highly efficacious for HIV prevention with few safety concerns. CAB-LA may lead to an increased risk of INSTI resistance among those who have acute HIV infection at initiation or become infected while taking CAB-LA. However, results are limited to controlled studies; more research is needed on real-world implementation. Additional data are needed on the safety of CAB-LA during pregnancy (for mothers and infants) and among populations not included in the trials.

Pre-exposure prophylaxis (PrEP) for HIV prevention among people who inject drugs: a global mapping of service delivery.

BACKGROUND: The World Health Organization (WHO) recommends oral pre-exposure prophylaxis (PrEP) for all people at substantial risk of HIV as part of combination prevention. The extent to which this recommendation has been implemented globally for people who inject drugs is unclear. This study mapped global service delivery of PrEP for people who inject drugs. METHODS: Between October and December 2021, a desk review was conducted to obtain information on PrEP services for people who inject drugs from drug user-led networks and HIV, harm reduction, and human rights stakeholders. Websites of organizations involved in HIV prevention or services for people who inject drugs were searched. Models of service delivery were described in terms of service location, provider, and package. RESULTS: PrEP services were identified in 27 countries (15 high-income). PrEP delivery models varied within and across countries. In most services, PrEP services were implemented in healthcare clinics without direct links to other harm reduction services. In three countries, PrEP services were also provided at methadone clinics. In 14 countries, PrEP services were provided through community-based models (outside of clinic settings) that commonly involved peer-led outreach activities and integration with harm reduction services. CONCLUSIONS: This study indicates limited PrEP availability for people who inject drugs. There is potential to expand PrEP services for people who inject drugs within harm reduction programs, notably through community-based and peer-led services. PrEP should never be offered instead of evidence-based harm reduction programs for people who inject drugs; however, it could be offered as an additional HIV prevention choice as part of a comprehensive harm reduction program.

Integrating pre-exposure prophylaxis of HIV infection into family planning services: a scoping review.

INTRODUCTION: The aim of this review was to map evidence of integrating pre-exposure prophylaxis (PrEP) for HIV prevention into family planning services. A comprehensive package, using a combination of PrEP and contraceptive delivery, could reduce the number of new HIV infections and/or unintended pregnancies for at-risk women and adolescent girls. METHODS: A scoping literature search was conducted between August 2020 and October 2020. After developing the review question, electronic databases (MEDLINE, Embase, Cochrane Library, Global Health, Web of Science) were systematically reviewed. All types of articles published from 2012 to August 2020 in English were included. The intended outcome was to identify barriers and enablers of integrating services at the client-level and provider-level. RESULTS: 38 articles met inclusion criteria, with 16 from low-and middle-income countries and 22 from high-income countries. Barriers at the client-level included a lack of risk perception associated with low uptake and continuation of PrEP and pill burden; and at the provider-level, barriers included a lack of studies on cost-effectiveness of integrating services and provider training and knowledge. Facilitators included the initiation of PrEP and contraception at the same time and by the same provider or HIV self-testing. CONCLUSION: Mapping and synthesising current evidence, this review identified key barriers and facilitators for the integration of PrEP into family planning services for women and adolescent girls. In order to address these factors, more implementation research in a variety of settings is needed to meet women's sexual and reproductive health needs globally.

Scaling up access to HIV pre-exposure prophylaxis (PrEP): should nurses do the job?

Task sharing has been one of the most important enabling policies supporting the global expansion of access to HIV testing and treatment. The WHO public health approach, which relies on delivery of antiretroviral therapy (ART) by nurses, has enabled a trebling of the number of people receiving ART during the past decade. WHO recognises that HIV pre-exposure prophylaxis (PrEP) can also be provided by nurses; however, many countries still do not have policies in place that support nurse provision of PrEP. In sub-Saharan Africa, most countries allow nurses to prescribe ART, but only a few countries have policies in place that allow nurses to prescribe PrEP. Nurse-led PrEP delivery is particularly low in the Asia-Pacific region, which has some of the world's fastest growing epidemics. Even in many high-income countries, PrEP scale-up has been limited because policies often require medical doctors or specialists to prescribe. Service providers in many countries are coming to realise that scaling up access to PrEP cannot be achieved by medical doctors alone, and nurse-led PrEP delivery can help to lay the groundwork for supporting uptake of other HIV prevention approaches that will become available in the future. Countries with policies that authorise nurses to prescribe ART could be early adopters and help to pave the way for wider adoption of nurse-led PrEP delivery.

A Landscape Analysis of Offering HIV Testing Services Within Family Planning Service Delivery.

Introduction: Offering HIV testing services (HTS) within sexual and reproductive health (SRH) services is a priority, especially for women who have a substantial risk. To reach women with HIV who do not know their status and prevent mother-to-child HIV transmission, the World Health Organization (WHO) recommends routinely offering HTS as part of family planning (FP) service delivery in high HIV burden settings. We conducted a landscape analysis to assess HTS uptake and HIV positivity in the context of FP/SRH services. Assessment of Research and Programs: We searched records from PubMed, four gray literature databases, and 13 organization websites, and emailed 24 organizations for data on HTS in FP/SRH services. We also obtained data from International Planned Parenthood Federation (IPPF) affiliates in Eswatini, Kenya, Lesotho, Malawi, Namibia, Uganda, Zambia, and Zimbabwe. Unique programs/studies from records were included if they provided data on, or barriers/facilitators to, offering HTS in FP/SRH. Overall, 2,197 records were screened and 12 unique programs/studies were eligible, including 10 from sub-Saharan Africa. Four reported on co-delivery of SRH services (including FP), with reported HTS uptake between 17 and 94%. Six reported data on HTS in FP services: four among general FP clients; one among couples; and one among female sex workers, adolescent girls, and young women. Two of the six reported HTS uptake >50% (51%, 419/814 Kenya; 63%, 5,930/9,439 Uganda), with positivity rates of 2% and 4.1%, respectively. Uptake was low (8%, 74/969 Kenya) in the one FP program offering pre-exposure prophylaxis. In the IPPF program, seven countries reported HTS uptake in FP services and ranged from 4% in Eswatini to 90% in Lesotho; between 0.6% (Uganda) and 8% (Eswatini) of those tested were HIV positive. Implications: Data on providing HTS in FP/SRH service delivery were sparse and HTS uptake varied widely across programs. Actionable Recommendations: As countries expand HTS in FP/SRH appropriate to epidemiology, they should ensure data are reported and monitored for progress and impact.

Going global: the adoption of the World Health Organization's enabling recommendation on oral pre-exposure prophylaxis for HIV.

In September 2015, the World Health Organization (WHO) launched evidence-based guidelines by recommending that any person at substantial HIV risk should be offered oral pre-exposure prophylaxis (PrEP) containing tenofovir disoproxil fumarate (TDF) as an additional prevention choice. Since 2017, PrEP medicines have also been listed in the WHO's Essential Medicines List, including TDF/emtricitabine (FTC) and TDF in combination with lamivudine (3TC). A descriptive policy review and analysis of countries adopting WHO's 2015 recommendation on oral PrEP was conducted. As of June 2018, we identified 35 countries that had some type of policy on oral PrEP, and an additional five countries where a specific policy on PrEP is currently pending. A total of 19 high-income countries (HICs) and 21 low- and middle-income countries (LMICs) have adopted or have a pending policy. Most countries that have adopted or pending PrEP are in the European (42.9%) or African (30.0%) region. TDF/FTC is the most commonly recommended PrEP drug in the guidelines reviewed, although seven countries, namely in sub-Saharan Africa (6/7), are also recommending the use of TDF/3TC for PrEP. In sum, by the end of 2018, at least 40 countries (20.6%) are anticipated to have adopted WHO's oral PrEP recommendation. Nonetheless, policy uptake does not reflect broader programmatic coverage of PrEP services, which remain limited across all settings, irrespective of income status. Enhancing global partnerships is needed to support and track ongoing policy adoption and to ensure that policy is translated into meaningful implementation of PrEP services.

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.

Beyond the 90-90-90: refocusing HIV prevention as part of the global HIV response.

INTRODUCTION: The remarkable expansion in availability of antiretroviral therapy (ART) over the past two decades has transformed HIV infection into a manageable chronic condition. People with HIV infection now live long and healthy lives on treatment that is simpler, safer and cheaper. According to UNAIDS estimates, the global coverage of ART reached 46% in 2015, resulting in a 26% decrease in annual HIV-related deaths since 2010. Such success has positioned treatment access at the centre of the global HIV response as a way to prevent mortality, morbidity and HIV transmission through a "Treat All" approach. Continuing expansion of treatment is needed to further reduce HIV-related mortality. This progress with treatment, however, masks a stagnation in the estimated annual number of new HIV infections. Continuing levels of HIV incidence despite treatment scale-up stem from several factors, which should be addressed in order to prevent new infections and decrease the numbers of people requiring treatment in the future. DISCUSSION: ART can only reach those already diagnosed, and although it is unclear what proportion of new infections occur during acute and early infection prior to treatment initiation, phylogenetic studies suggest that it might be substantial. Thus, better testing approaches to reach the 40% of people with undiagnosed HIV infection as early as possible are critical. New approaches to reach men, young people and key populations, where HIV risk is highest and HIV prevention, testing and treatment coverage is lowest, are also needed. Overall coverage of effective prevention interventions remains low, enabling HIV transmission to occur, or time is required to show population-level effects. For example, the full impact of the medical male circumcision intervention will be seen once a larger proportion of men in age cohorts with high incidence are circumcised. Finally, strategically focused pre-exposure prophylaxis interventions have the potential to prevent HIV acquisition among populations at substantial risk, averting treatment costs in coming years. CONCLUSIONS: The United Nations (UN) targets to end AIDS include the "90-90-90" targets for HIV diagnosis, treatment and viral suppression. While 90-90-90 has been widely emphasized and adopted by countries and international funders, the focus thus far has largely been on increasing access to ART - the second "90." A similar emphasis on achieving UN HIV prevention targets and adequate funding for meeting these is essential, alongside treatment, in order to reduce population-level incidence and change the trajectory of the HIV epidemic over the long term.

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.

WHO guidance on the prevention of viral hepatitis B and C among people who inject drugs.

Viral hepatitis B and C (HBV, HCV) disproportionately affect people who inject drugs (PWID) across the world. To date there has been little global action focusing on prevention, care and treatment of HBV and HCV among PWID. Here we report on the development process and discuss the implications of evidence informed WHO Guidelines for the Prevention of HBV and HCV in PWID. The World Health Organization (WHO) convened a Guideline Development Panel to develop recommendations on the prevention of HBV and HCV among PWID. The process followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It included the development of PICO (Population, Interventions, Comparator, Outcomes) questions and conducting systematic reviews. Quality of evidence was classified into 4 levels: high, moderate, low, and very low. In the process of moving from evidence to recommendations, the following were considered: quality of evidence, balance of benefits and harms, community values and preferences and resource use. The WHO recommendations include the following for working with PWID: offer the rapid HBV vaccination regimen; offer incentives to increase uptake and completion of the HBV vaccine schedule; needle and syringe programs should also provide low dead-space syringes for distribution; and offer peer interventions to reduce the incidence of viral hepatitis. This guideline complements other WHO documents regarding PWID, including HIV prevention initiatives such as needle and syringe programs and opioid substitution therapy. This guidance offers a first step in the prevention of HBV and HCV among PWID. However, the lack of high quality evidence in this area necessitates further research and resources for implementation.

HIV prevalence among injection drug users in rural Guangxi China.

AIMS: To determine the HIV-1 seroprevalence, risk behaviors and demographic characteristics associated with HIV-1 infection among injection drug users (IDU) in rural Guangxi, China. DESIGN AND SETTING: Between July and November 2002, 702 IDU were screened for HIV-1 antibody through community outreach in rural Guangxi, China for enrollment in an HIV sero-incidence study. PARTICIPANTS: A total of 702 active high-risk IDU were screened. High-risk injection was defined as anyone who reported injecting drugs at least three times per week in the last month or injected drugs with shared equipment on at least three occasions in the last 3 months. MEASUREMENTS: HIV-1 antibody testing with confirmation by Western blot was performed on all subjects. Demographic and risk assessment survey data were collected at screening from everyone whose baseline HIV antibody status was known. FINDINGS: HIV-1 antibody prevalence among 702 IDU at baseline was 25% with a median age of 26.7 years (18.2-43.2). Based on a multivariate logistic regression model using risk factors identified in univariate analyses, the following risk factors were associated significantly with an increase in risk for HIV seropositivity: age > 26 years (OR 1.50; 95% CI 1.04, 2.17), sharing of rinse water (OR = 1.24; 95% CI 1.09, 1.40), not having sex in the last 6 months (OR = 1.62; 95% CI 1.08, 2.43). CONCLUSIONS: HIV infection among IDU in Guangxi, one of China's major HIV epidemic regions, is high and the infection occurs predominantly among older IDU males who share rinse water.

HIV incidence, retention, and changes of high-risk behaviors among rural injection drug users in Guangxi, China.

BACKGROUND: A prospective observational study of HIV seroincidence among high-risk injection drug users (IDU) was carried out in Guangxi, China. The primary objectives of this study were (1) to estimate HIV seroincidence (2) to estimate participant retention rate and (3) to evaluate changes in drug use and sexual behavior over a one year period. METHODS: Five hundred HIV seronegative IDU were enrolled. HIV-1 incidence and retention rates were analyzed as a function of sociodemographic, behavioral, and recruitment variables. Changes in drug use and sexual behavior were analyzed at the baseline, 6-month and 12-month follow- up visits. RESULTS: At 12 months of follow-up, the HIV-1 incidence rate was 3.1 per 100 person years, [95% CI: (1.6%; 5.2%)] and participant retention rate was 87%. Reported changes in high-risk behaviors over 12-months included significant decreases in the frequency of heroin injection, in direct or indirect sharing of injection equipment, and in the number of sexual partners. CONCLUSIONS: HIV incidence is high among IDU in Guangxi, China despite a self-reported decrease in some high risk behaviors over the course of the study.