HIV Diagnostics and Vaccines: It Takes Two to Tango.

Current serologic tests for HIV screening and confirmation of infection present challenges to the adoption of HIV vaccines. The detection of vaccine-induced HIV-1 antibodies in the absence of HIV-1 infection, referred to as vaccine-induced seropositivity/seroreactivity, confounds the interpretation of test results, causing misclassification of HIV-1 status with potential affiliated stigmatization. For HIV vaccines to be widely adopted with high community confidence and uptake, tests are needed that are agnostic to the vaccination status of tested individuals (ie, positive only for true HIV-1 infection). Successful development and deployment of such tests will require HIV vaccine developers to work in concert with diagnostic developers. Such tests will need to match today's high-performance standards (accuracy, cost-effectiveness, simplicity) for use in vaccinated and unvaccinated populations, especially in low- and middle-income countries with high HIV burden. Herein, we discuss the challenges and strategies for developing modified serologic HIV tests for concurrent deployment with HIV vaccines.

Call to action: how can the US Ending the HIV Epidemic initiative succeed?

With more than 1·2 million people living with HIV in the USA, a complex epidemic across the large and diverse country, and a fragmented health-care system marked by widening health disparities, the US HIV epidemic requires sustained scientific and public health attention. The epidemic has been stubbornly persistent; high incidence densities have been sustained over decades and the epidemic is increasingly concentrated among racial, ethnic, and sexual and gender minority communities. This fact remains true despite extraordinary scientific advances in prevention, treatment, and care-advances that have been led, to a substantial degree, by US-supported science and researchers. In this watershed year of 2021 and in the face of the COVID-19 pandemic, it is clear that the USA will not meet the stated goals of the National HIV/AIDS Strategy, particularly those goals relating to reductions in new infections, decreases in morbidity, and reductions in HIV stigma. The six papers in the Lancet Series on HIV in the USA have each examined the underlying causes of these challenges and laid out paths forward for an invigorated, sustained, and more equitable response to the US HIV epidemic than has been seen to date. The sciences of HIV surveillance, prevention, treatment, and implementation all suggest that the visionary goals of the Ending the HIV Epidemic initiative in the USA might be achievable. However, fundamental barriers and challenges need to be addressed and the research effort sustained if we are to succeed.

The long wait for long-acting HIV prevention and treatment formulations.

Large randomised studies of new long-acting medications for the prevention and treatment of HIV have shown high effectiveness and acceptability. Although modelling studies indicate these agents could be fundamental in HIV elimination, coordination of their entry into health-care markets is crucial, especially in low-income and middle-income countries with high HIV prevalence, where coordination is low despite UNAIDS flagging that global HIV targets will not be met. Research and implementation projects are tightly controlled by originator pharmaceutical companies, with only a small percentage of eligible people living with or affected by HIV benefiting from these projects. WHO, financial donors, manufacturers, and governments need to consider urgent coordinated action from stakeholders worldwide, akin to the successful introduction of dolutegravir into treatment programmes across low-income and middle-income countries. Without this immediate coordination, large-scale access to long-acting agents for HIV will be delayed, potentially extending into the 2030s. This delay is unacceptable considering the established global HIV targets.

Ethical considerations in determining standard of prevention packages for HIV prevention trials: examining PrEP.

The successful demonstration that antiretroviral (ARV) drugs can be used in diverse ways to reduce HIV acquisition or transmission risks--either taken as pre-exposure prophylaxis (PrEP) by those who are uninfected or as early treatment for prevention (T4P) by those living with HIV--expands the armamentarium of existing HIV prevention tools. These findings have implications for the design of future HIV prevention research trials. With the advent of multiple effective HIV prevention tools, discussions about the ethics and the feasibility of future HIV prevention trial designs have intensified. This article outlines arguments concerning the inclusion of newly established ARV-based HIV prevention interventions as standard of prevention in HIV prevention trials from multiple perspectives. Ultimately, there is a clear need to incorporate stakeholders in a robust discussion to determine the appropriate trial design for each study population.

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.

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of $500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs $150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82% of setting-scenarios at the cost of $144 per year, in 52% at $264, and in 87% at $114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

HIV Prevention in a Time of COVID-19: A Report from the HIVR4P // Virtual Conference 2021.

The HIV Research for Prevention (HIVR4P) conference catalyzes knowledge sharing on biomedical HIV prevention interventions such as HIV vaccines, antibody infusions, pre-exposure prophylaxis, and microbicides in totality-from the molecular details and delivery formulations to the behavioral, social, and structural underpinnings. HIVR4P // Virtual was held over the course of 2 weeks on January 27-28 and February 3-4, 2021 as the coronavirus disease 2019 (COVID-19) pandemic continued to inflict unprecedented harm globally. The HIVR4P community came together with 1,802 researchers, care providers, policymakers, implementers, and advocates from 92 countries whose expertise spanned the breadth of the HIV prevention pipeline from preclinical to implementation. The program included 113 oral and 266 poster presentations. This article presents a brief summary of the conference highlights. Complete abstracts, webcasts, and daily rapporteur summaries may be found on the conference website (https://www.hivr4p.org/).

The case for an HIV cure and how to get there.

In light of the increasing global burden of new HIV infections, growing financial requirements, and shifting funding landscape, the global health community must accelerate the development and delivery of an HIV cure to complement existing prevention modalities. An effective curative intervention could prevent new infections, overcome the limitations of antiretroviral treatment, combat stigma and discrimination, and provide a sustainable financial solution for pandemic control. We propose steps to plan for an HIV cure now, including defining a target product profile and establishing the HIV Cure Africa Acceleration Partnership (HCAAP), a multidisciplinary public-private partnership that will catalyse and promote HIV cure research through diverse stakeholder engagement. HCAAP will convene stakeholders, including people living with HIV, at an early stage to accelerate the design, social acceptability, and rapid adoption of HIV-cure products.

Multi-stakeholder consensus on a target product profile for an HIV cure.

Developing a cure for HIV is a global priority. Target product profiles are a tool commonly used throughout the drug development process to align interested parties around a clear set of goals or requirements for a potential product. Three distinct therapeutic modalities (combination therapies, ex-vivo gene therapy, and in-vivo gene therapy) for a target product profile for an HIV cure were identified. Using a process of expert face-to-face consultation and an online Delphi consultation, we found a high degree of agreement regarding the criteria for the optimum target product profile. Although the minimum attributes for a cure were debated, the broad consensus was that an acceptable cure need not be as safe and effective as optimally delivered antiretroviral therapy. An intervention that successfully cured a reasonable fraction of adults would be sufficient to advance to the clinic. These target product profiles will require further discussion and ongoing revisions as the field matures.

HIV Research for Prevention 2018: From Research to Impact Conference Summary and Highlights.

The HIV Research for Prevention (HIVR4P) conference is dedicated to advancing HIV prevention research, responding to a growing consensus that effective and durable prevention will require a combination of approaches as well as unprecedented collaboration among scientists, practitioners, and community workers from different fields and geographic areas. The conference theme in 2018, "From Research to Impact," acknowledged an increasing focus on translation of promising research findings into practical, accessible, and affordable HIV prevention options for those who need them worldwide. HIVR4P 2018 was held in Madrid, Spain, on 21-25 October, with >1,400 participants from 52 countries around the globe, representing all aspects of HIV prevention research and implementation. The program included 137 oral and 610 poster presentations. This article presents a brief summary of highlights from the conference. More detailed information, complete abstracts as well as webcasts and daily Rapporteur summaries may be found on the conference website.

Understanding and measuring uptake and coverage of oral pre-exposure prophylaxis delivery among adolescent girls and young women in sub-Saharan Africa.

In response to World Health Organization (WHO) guidance recommending oral pre-exposure prophylaxis (PrEP) for all individuals at substantial risk for HIV infection, significant investments are being made to expand access to oral PrEP globally, particularly in sub-Saharan Africa. Some have interpreted early monitoring reports from new programs delivering oral PrEP to adolescent girls and young women (AGYW) as suggestive of low uptake. However, a lack of common definitions complicates interpretation of oral PrEP uptake and coverage measures, because various indicators with different meanings and uses are used interchangeably. Furthermore, operationalising these measures in real-world settings is challenged by the difficulties in defining the denominator for measuring uptake and coverage among AGYW, due to the lack of data and experience required to identify the subset of AGYW at substantial risk of HIV infection. This paper proposes an intervention-centric cascade as a framework for developing a common lexicon of metrics for uptake and coverage of oral PrEP among AGYW. In codifying these indicators, approaches to clearly define metrics for uptake and coverage are outlined, and the discussion on 'low' uptake is reframed to focus on achieving the highest possible proportion of AGYW using oral PrEP when they need and want it Recommendations are also provided for making increased investments in implementation research to better quantify the sub-group of AGYW in potential need of oral PrEP.and for improving monitoring systems to more efficiently address bottlenecks in the service delivery of oral PrEP to AGYW so that implementation can be taken to scale.

An Unexpected Case of Scurvy in a Peritoneal Dialysis Patient.

This case describes an obese adult male peritoneal dialysis patient who presented with a pruritic follicular rash. Nutrient deficiency was not suspected initially in this case because there was no history of protein-calorie malnutrition, but the patient reported a diet devoid of fruits and vegetables and had not been taking his dialysis vitamin as prescribed. Skin biopsy showed follicular hyperkeratosis with fragmented hair shafts and corkscrew hairs consistent with scurvy. After supplementation with ascorbic acid 500 mg twice daily for 2 weeks, the rash resolved completely. Dialysis patients are at increased risk for vitamin C deficiency due to indiscriminant clearance of the nutrient with dialysis, but scurvy is rarely seen.

The science of Durban, AIDS 2016.

INTRODUCTION: The science presented at the 21st International AIDS Conference in Durban, South Africa, in July 2016, addressed the state of the field across basic, clinical, prevention, law and policy and implementation science. METHODS AND RESULTS: The AIDS response has seen remarkable achievements in scientific advances, in translation of those advances into prevention, treatment and care for affected individuals and communities, and in large scale implementation - reaching 18 million people with antiviral therapy by mid-year 2016. Yet incident HIV infections in adults remain stubbornly stable and are increasing in some regions and among adolescents and adults in some key populations, challenging current science, policy and programming. There have been important advances in both preventive vaccines and in cure research, but both areas require ongoing investment and innovation. Clinical research has flourished with new agents, regimens, delivery modes and diagnostics but has been challenged by aging and increasingly complex patient populations, long-term adherence challenges, co-infections and co-morbidities, and unresolved issues in TB management and epidemic control. It is an extraordinary period of innovation in prevention, yet the promise of new tools and combination approaches have yet to deliver epidemic HIV control. CONCLUSIONS: Proven interventions, most notably pre-exposure prophylaxis, PrEP, have been limited in rollout and impact. Treatment as prevention has the promise to improve clinical outcomes but remains uncertain as a prevention tool to reduce population-level HIV incidence. The improvement of legal, policy and human rights environments for those most at risk for HIV acquisition and most at risk for lack of access to essential services; sexual and gender minorities, sex workers of all genders, people who inject drugs, and prisoners and detainees remain among the greatest unmet needs in HIV/AIDS. Failure to do better for these individuals and communities could undermine the HIV response.

HIVR4P 2016, Partnering for Prevention: Conference Summary and Highlights.

HIV Research for Prevention: AIDS Vaccine, Microbicide, and ARV-based Prevention Science (HIVR4P) was built on a growing consensus that effective HIV prevention requires a combination of approaches and that understanding, analyzing, and debating the cross-cutting issues that impact prevention research are all essential to combat the global HIV/AIDS epidemic. To that end, the biennial HIVR4P conference is dedicated to all biomedical HIV prevention research approaches, including HIV vaccines, microbicides, pre-exposure prophylaxis, and treatment as prevention. The HIVR4P 2016 conference was held in Chicago, Illinois (USA), on October 17-21, and included more than 700 scientific presentations and 21 satellite sessions covering the latest and most promising advances across the HIV prevention research field. The theme "Partnering for Prevention" represented the conference's commitment to breaking down silos between research disciplines as well as between researchers, program developers, care providers, advocates, communities, and funders. Delegates spanning 42 countries attended the conference. One-third of those in attendance were early career investigators, which reflects a firm commitment to emerging researchers and ultimately to the goal of developing a sustainable scientific enterprise well into the future. This article presents a concise summary of highlights from the conference. For a more detailed account, one may find full abstracts, daily summaries, and webcasts on the conference website at hivr4p.org.

Correction: Voluntary Medical Male Circumcision for HIV Prevention: New Mathematical Models for Strategic Demand Creation Prioritizing Subpopulations by Age and Geography.

[This corrects the article DOI: 10.1371/journal.pone.0160699.].

Voluntary Medical Male Circumcision for HIV Prevention: New Mathematical Models for Strategic Demand Creation Prioritizing Subpopulations by Age and Geography.

Over 11 million voluntary medical male circumcisions (VMMC) have been performed of the projected 20.3 million needed to reach 80% adult male circumcision prevalence in priority sub-Saharan African countries. Striking numbers of adolescent males, outside the 15-49-year-old age target, have been accessing VMMC services. What are the implications of overall progress in scale-up to date? Can mathematical modeling provide further insights on how to efficiently reach the male circumcision coverage levels needed to create and sustain further reductions in HIV incidence to make AIDS no longer a public health threat by 2030? Considering ease of implementation and cultural acceptability, decision makers may also value the estimates that mathematical models can generate of immediacy of impact, cost-effectiveness, and magnitude of impact resulting from different policy choices. This supplement presents the results of mathematical modeling using the Decision Makers' Program Planning Tool Version 2.0 (DMPPT 2.0), the Actuarial Society of South Africa (ASSA2008) model, and the age structured mathematical (ASM) model. These models are helping countries examine the potential effects on program impact and cost-effectiveness of prioritizing specific subpopulations for VMMC services, for example, by client age, HIV-positive status, risk group, and geographical location. The modeling also examines long-term sustainability strategies, such as adolescent and/or early infant male circumcision, to preserve VMMC coverage gains achieved during rapid scale-up. The 2016-2021 UNAIDS strategy target for VMMC is an additional 27 million VMMC in high HIV-prevalence settings by 2020, as part of access to integrated sexual and reproductive health services for men. To achieve further scale-up, a combination of evidence, analysis, and impact estimates can usefully guide strategic planning and funding of VMMC services and related demand-creation strategies in priority countries. Mid-course corrections now can improve cost-effectiveness and scale to achieve the impact needed to help turn the HIV pandemic on its head within 15 years.

Exploring the Potential Health Impact and Cost-Effectiveness of AIDS Vaccine within a Comprehensive HIV/AIDS Response in Low- and Middle-Income Countries.

BACKGROUND: The Investment Framework Enhanced (IFE) proposed in 2013 by the Joint United Nations Programme on HIV/AIDS (UNAIDS) explored how maximizing existing interventions and adding emerging prevention options, including a vaccine, could further reduce new HIV infections and AIDS-related deaths in low- and middle-income countries (LMICs). This article describes additional modeling which looks more closely at the potential health impact and cost-effectiveness of AIDS vaccination in LMICs as part of UNAIDS IFE. METHODS: An epidemiological model was used to explore the potential impact of AIDS vaccination in LMICs in combination with other interventions through 2070. Assumptions were based on perspectives from research, vaccination and public health experts, as well as observations from other HIV/AIDS interventions and vaccination programs. Sensitivity analyses varied vaccine efficacy, duration of protection, coverage, and cost. RESULTS: If UNAIDS IFE goals were fully achieved, new annual HIV infections in LMICs would decline from 2.0 million in 2014 to 550,000 in 2070. A 70% efficacious vaccine introduced in 2027 with three doses, strong uptake and five years of protection would reduce annual new infections by 44% over the first decade, by 65% the first 25 years and by 78% to 122,000 in 2070. Vaccine impact would be much greater if the assumptions in UNAIDS IFE were not fully achieved. An AIDS vaccine would be cost-effective within a wide range of scenarios. INTERPRETATION: Even a modestly effective vaccine could contribute strongly to a sustainable response to HIV/AIDS and be cost-effective, even with optimistic assumptions about other interventions. Higher efficacy would provide even greater impact and cost-effectiveness, and would support broader access. Vaccine efficacy and cost per regimen are critical in achieving cost-effectiveness, with cost per regimen being particularly critical in low-income countries and at lower efficacy levels.