HIV treatment as prevention : models, data, and questions-towards evidence-based decision-making

Antiretroviral therapy (ART) for those infected with HIV can prevent onward transmission of infection, but biological efficacy alone is not enough to guide policy decisions about the role of ART in reducing HIV incidence. Epidemiology, economics, demography, statistics, biology, and mathematical modelling will be central in framing key decisions in the optimal use of ART. PLoS Medicine, with the HIV Modelling Consortium, has commissioned a set of articles that examine different aspects of HIV treatment as prevention with a forward-looking research agenda. Interlocking themes across these articles are discussed in this introduction. We hope that this article, and others in the collection, will provide a foundation upon which greater collaborations between disciplines will be formed, and will afford deeper insights into the key factors involved, to help strengthen the support for evidence-based decision-making in HIV prevention

HIV treatment as prevention: models, data, and questions--towards evidence-based decision-making.

Antiretroviral therapy (ART) for those infected with HIV can prevent onward transmission of infection, but biological efficacy alone is not enough to guide policy decisions about the role of ART in reducing HIV incidence. Epidemiology, economics, demography, statistics, biology, and mathematical modelling will be central in framing key decisions in the optimal use of ART. PLoS Medicine, with the HIV Modelling Consortium, has commissioned a set of articles that examine different aspects of HIV treatment as prevention with a forward-looking research agenda. Interlocking themes across these articles are discussed in this introduction. We hope that this article, and others in the collection, will provide a foundation upon which greater collaborations between disciplines will be formed, and will afford deeper insights into the key factors involved, to help strengthen the support for evidence-based decision-making in HIV prevention

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$144 per year, in 52% at $264, and in 87$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

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$144 per year, in 52% at $264, and in 87$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

Cost-effectiveness of easy-access, risk-informed oral pre-exposure prophylaxis in HIV epidemics in sub-Saharan Africa: a modelling study.

BACKGROUND: Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS: We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug$11, HIV test $4, and$14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3$100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS: In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION: Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING: US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation

A framework for understanding the epidemiological impact of HIV treatment.

<p>The published results of models <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001259#pmed.1001259-Montaner1" target="_blank">[38]</a>,<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001259#pmed.1001259-AbuRaddad1" target="_blank">[53]</a>–<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001259#pmed.1001259-Goodreau1" target="_blank">[55]</a> that have estimated the contribution of different stages of HIV infection to onward transmission are compiled in a median cumulative distribution of infections generated by one infected person over the course of his/her infection in the absence of treatment (red line). The horizontal axis shows time from the time of infection to 12 years, which is the mean survival time for those with untreated HIV infection <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001259#pmed.1001259-Todd1" target="_blank">[56]</a>. The vertical axis shows the cumulative transmission, from 0% (no new infections generated yet) to 100% (all onward transmission completed). (Note that the uncertainty in this distribution is not indicated.) The shading indicates the approximate CD4 cell count category at each time point <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001259#pmed.1001259-Eligibility1" target="_blank">[25]</a>,<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001259#pmed.1001259-Lodi1" target="_blank">[26]</a>. Currently, treatment tends to be initiated well below a CD4 cell count of 200 cells/μl <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001259#pmed.1001259-Cornell1" target="_blank">[32]</a>, meaning that the contribution of treatment to prevention is minimal because most of the transmission from that person has already occurred before treatment starts. If increased testing and improved linkages to care enabled individuals to start treatment at a CD4 cell count very close to 200 cells/μl, this could result in a substantial reduction in HIV incidence, because ∼25%–30% of transmission normally arises from individuals after that point. The prevention impact would be expected to be even greater with initiation close to a CD4 cell count of 350 cells/μl. If the average number of new infections arising from an infected person in a susceptible population exceeds one before treatment could be feasibility initiated, then treatment could not eliminate the HIV epidemic. In this framework, the influence of other forms of prevention will be to change the shape of the graph. For instance, if many men are circumcised or individuals have fewer new sexual partners per time unit, then new infections arising from an infected person will grow more slowly over time, so that on average one new infection might be generated only after the point at which a feasible programme could have initiated treatment.</p

Understanding the modes of transmission model of new HIV infection and its use in prevention planning

The modes of transmission model has been widely used to help decision-makers target measures for preventing human immunodeficiency virus (HIV) infection. The model estimates the number of new HIV infections that will be acquired over the ensuing year by individuals in identified risk groups in a given population using data on the size of the groups, the aggregate risk behaviour in each group, the current prevalence of HIV infection among the sexual or injecting drug partners of individuals in each group, and the probability of HIV transmission associated with different risk behaviours. The strength of the model is its simplicity, which enables data from a variety of sources to be synthesized, resulting in better characterization of HIV epidemics in some settings. However, concerns have been raised about the assumptions underlying the model structure, about limitations in the data available for deriving input parameters and about interpretation and communication of the model results. The aim of this review was to improve the use of the model by reassessing its paradigm, structure and data requirements. We identified key questions to be asked when conducting an analysis and when interpreting the model results and make recommendations for strengthening the model’s application in the future

Potential effects of disruption to HIV programmes in sub-Saharan Africa caused by COVID-19: results from multiple mathematical models

Background: The COVID-19 epidemic could lead to the disruptions to provision of HIV services for people living with HIV and those at risk of acquiring HIV in sub-Saharan Africa, where UNAIDS estimates that more than two thirds of the 37.9 million (32.7-44.0 million) people living with HIV reside in 2018. We set out to predict the potential effects of such disruptions on HIV-related deaths and new infections. Methods: Five well-described models of HIV epidemics (Goals, Optima HIV, HIV Synthesis, Imperial College model, EMOD) were each used to estimate the effect of various potential disruptions to HIV prevention, testing and treatment services on HIV-related deaths and new infections in sub-Saharan Africa lasting 6 months from 1 April 2020. Disruptions affecting 20%, 50% and 100% of the population were considered. In further analyses shorter term disruptions and the possibility of reductions in sexual activity during disruptions were considered. Findings: A six-month interruption of supply of antiretroviral (ARV) drugs across 50% of the population of people living with HIV on treatment would be expected to lead to a 1.63-fold (median across models; range 1.39 to 1.87) increase in HIV-related deaths over a one year period compared to with no disruption. In sub-Saharan Africa this amounts to an excess of 296,000 (median over model estimates, range 229,000 – 420,000) HIV deaths should such a high level of disruption occur. There would also be an approximately 1.6-fold increase in mother to child transmission of HIV. While an interruption of supply of ARV drug would have by far the largest impact of any potential disruptions, effects of poorer clinical care due to over-stretched health facilities, interruptions of supply of other drugs such as cotrimoxazole and suspension of HIV testing would all have significant population-level impact on mortality. Interruption to condom supplies and peer education would make populations more vulnerable to increases in HIV incidence, although physical distancing measures could lead to reductions in risky sex. Interpretation: During the COVID-19 pandemic the primary priority for governments, donors, suppliers and communities should focus on maintaining uninterrupted supply of ARV drugs for people with HIV to avoid additional HIV-related deaths. The provision of other HIV prevention measures is also important to prevent any increase in HIV incidence

Modeling Scenarios for the End of AIDS

At the end of 2012, 3 decades after the human immunodeficiency virus (HIV) was first identified, neither a cure nor a fully preventive vaccine was available. Despite multiple efforts, the epidemic remains an exceptional public health challenge. At the end of 2012, it was estimated that, globally, 35 million people were living with HIV, 2.3 million had become newly infected, and 1.6 million had died from AIDS-related causes. Despite substantial prevention efforts and increases in the number of individuals on highly active antiretroviral therapy (HAART), the epidemic burden continues to be high. Here, we provide a brief overview of the epidemiology of HIV transmission, the work that has been done to date regarding HIV modeling in different settings around the world, and how to finance the response to the HIV epidemic. In addition, we suggest discussion topics on how to move forward with the prevention agenda and highlight the role of treatment as prevention (TasP) in curbing the epidemic