Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.
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SUBMITTER: Smith J
PROVIDER: S-EPMC10065903 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.
Smith Jennifer J Bansi-Matharu Loveleen L Cambiano Valentina V Dimitrov Dobromir D Bershteyn Anna A van de Vijver David D Kripke Katharine K Revill Paul P Boily Marie-Claude MC Meyer-Rath Gesine G Taramusi Isaac I Lundgren Jens D JD van Oosterhout Joep J JJ Kuritzkes Daniel D Schaefer Robin R Siedner Mark J MJ Schapiro Jonathan J Delany-Moretlwe Sinead S Landovitz Raphael J RJ Flexner Charles C Jordan Michael M Venter Francois F Radebe Mopo M Ripin David D Jenkins Sarah S Resar Danielle D Amole Carolyn C Shahmanesh Maryam M Gupta Ravindra K RK Raizes Elliot E Johnson Cheryl C Inzaule Seth S Shafer Robert R Warren Mitchell M Stansfield Sarah S Paredes Roger R Phillips Andrew N AN
The lancet. HIV 20230112 4
<h4>Background</h4>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.<h4>Methods</h4>With HIV Synthesis, an indiv ...[more]
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Project description:BackgroundThe use of a combination of the integrase inhibitor, cabotegravir, and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, in a long-acting injectable form is being considered as an antiretroviral treatment option for people with HIV in sub-Saharan Africa. We aimed to model the effects of injectable cabotegravir-rilpivirine to help to inform its potential effectiveness and cost-effectiveness under different possible policies for its introduction.MethodsWe used an existing individual-based model of HIV to predict the effects of introducing monthly injections of cabotegravir-rilpivirine for people with HIV in low-income settings in sub-Saharan Africa. We evaluated policies in the context of 1000 setting scenarios that reflected characteristics of HIV epidemics and programmes in sub-Saharan Africa. We compared three policies for introduction of injectable cabotegravir-rilpivirine with continued use of dolutegravir-based oral regimens for: all individuals on antiretroviral therapy (ART); individuals with a recently measured viral load of more than 1000 copies per mL (signifying poor adherence to oral drugs, and often associated with drug resistance); and individuals with a recently measured viral load of less than 1000 copies per mL (a group with a lower prevalence of pre-existing drug resistance). We also did cost-effectiveness analysis, taking a health system perspective over a 10 year period, with 3% discounting of disability-adjusted life-years (DALYs) and costs. A cost-effectiveness threshold of US$500 per DALY averted was used to establish if a policy was cost-effective.FindingsIn our model, all policies involving the introduction of injectable cabotegravir-rilpivirine were predicted to lead to an increased proportion of people with HIV on ART, increased viral load suppression, and decreased AIDS-related mortality, with lesser benefits in people with a recently measured viral load of less than 1000 copies per mL. Its introduction is also predicted to lead to increases in resistance to integrase inhibitors and non-nucleoside reverse transcriptase inhibitors if introduced in all people with HIV on ART or in those with a recently measured viral load of less than 1000 copies per mL, but to a lesser extent if introduced in people with more than 1000 copies per mL due to concentration of its use in people less adherent to oral therapy. Consistent with the effect on AIDS-related mortality, all approaches to the introduction of injectable cabotegravir-rilpivirine are predicted to avert DALYs. Assuming a cost of $120 per person per year, use of this regimen in people with a recently measured viral load of more than 1000 copies per mL was borderline cost-effective (median cost per DALY averted across setting scenarios $404). The other approaches considered for its use are unlikely to be cost-effective unless the cost per year of injectable cabotegravir-rilpivirine is considerably reduced.InterpretationOur modelling suggests that injectable cabotegravir-rilpivirine offers potential benefits; however, to be a cost-effective option, its introduction might need to be carefully targeted to individuals with HIV who might otherwise have suboptimal adherence to ART. As data accumulate from trials and implementation studies, such findings can be incorporated into the model to better inform on the full consequences of policy alternatives.FundingBill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655).
| S-EPMC8050198 | biostudies-literature
Project description:Cabotegravir is an integrase strand transfer inhibitor (INSTI) for HIV treatment and prevention. Cabotegravir-based long-acting pre-exposure prophylaxis (PrEP) presents an emerging paradigm for infectious disease control. In this scheme, a combination of a high efficacy and low solubility of anti-infection drugs permits the establishment of a pharmaceutical firewall in HIV-vulnerable groups over a long period. Although the structure-activity-relationship (SAR) of cabotegravir as an INSTI is known, the structural determinants of its low solubility have not been identified. In this work, we have integrated multiple experimental and computational methods, namely X-ray diffraction, solid-state NMR (SSNMR) spectroscopy, solution NMR spectroscopy, automated fragmentation (AF)-QM/MM and density functional theory (DFT) calculations, to address this question. The molecular organization of cabotegravir in crystal lattice has been determined. The combination of very-fast magic-angle-sample-spinning (VF MAS) SSNMR and solution NMR, as supported by AF-QM/MM and DFT calculations, permits the identification of structural factors that contribute to the low aqueous solubility of cabotegravir. Our study reveals the multitasking nature of pharmacophores in cabotegravir, which controls the drug solubility and, meanwhile, the biological activity. By unraveling these function-defining molecular features, our work could inspire further development of long-acting HIV PrEP drugs.
| S-EPMC10819392 | biostudies-literature
Project description:ObjectiveHIV 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.DesignSystematic review and meta-analysis.MethodsWe 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.ResultsWe 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.ConclusionsCAB-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.
| S-EPMC10090368 | biostudies-literature
Project description:IntroductionAlthough pre-exposure prophylaxis (PrEP.) is an efficacious HIV prevention strategy, its preventive benefit has not been shown among young women in sub-Saharan Africa, likely due to non-adherence. Adherence may be improved with the use of injectable long-acting PrEP methods currently being developed. We hypothesize that providing long-acting PrEP to women using injectable contraceptives, the most frequently used contraceptive method in South Africa, could improve adherence to PrEP, result in a reduction of new HIV infections, and be a relatively easy-to-reach target population. In this modelling study, we assessed the epidemiological impact and cost-effectiveness of providing long-acting PrEP to injectable contraceptive users in Limpopo, South Africa.MethodsWe developed a deterministic mathematical model calibrated to the HIV epidemic in Limpopo. Long-acting PrEP was provided to 50% of HIV negative injectable contraceptive users in 2018 and scaled-up over two years. We estimated the number of HIV infections that could be averted by 2030 and the drug price of long-acting PrEP for which this intervention would be cost-effective over a time horizon of 40 years, from a healthcare payer perspective. In the base-case scenario we assumed long-acting PrEP is 75% effective in preventing HIV infections and 85% of infected individuals are on antiretroviral drug therapy (ART) by 2030. In sensitivity analyses we adjusted PrEP effectiveness and ART coverage. Costs between $519 and $1119 per disability-adjusted life-year (DALY) averted were considered potentially cost-effective, and <$519 as cost-effective.ResultsWithout long-acting injectable PrEP, 224,000 (interquartile range 176,000 to 271,000) new infections will occur by 2030; use of long-acting injectable PrEP could prevent 21,000 (17,000 to 26,000) or 9.8% (8.9% to 10.6%) new HIV infections by 2030 (including 6000 (4000 to 7000) in men). Long-acting PrEP would prevent 34,000 (29,000 to 39,000) or 12,000 (8000 to 15,000) at 75% and 95% ART coverage by 2030 respectively. To be considered potentially cost-effective the annual long-acting PrEP drug price should be <$16, and/or ART coverage remains at <85% in 2030.ConclusionsProviding long-acting PrEP to injectable contraceptive users in Limpopo is only potentially cost-effective when long-acting PrEP drug prices are low. If low prices are not feasible, providing long-acting PrEP only to women at high risk of HIV infection will become important.
| S-EPMC6922023 | biostudies-literature
Project description:The retrovirus HIV-1 is the etiological agent of the decades-long AIDS pandemic. Although vaccination is the most common preexposure route to prevent acquisition of viral disease, scalable efficacious vaccination strategies have yet to be developed for HIV-1. By contrast, small molecule inhibitors of the HIV-1 enzymes reverse transcriptase, integrase, and protease have been developed that effectively block virus replication. Three different drug compounds are commonly prescribed for people living with HIV as once-daily oral tablets. Once-daily pills composed of two different reverse transcriptase inhibitors are moreover approved as preexposure prophylaxis (PrEP) treatment for virus naïve individuals who may partake in behaviors associated with increased risk of HIV-1 acquisition such as unprotected sex or injection drug use. Long-acting (LA) injectable HIV-1 enzyme inhibitors are at the same time being developed to sidestep adherence noncompliance issues that can arise from self-administered once-daily oral dosing regimens. Cabotegravir (CAB)-LA, which inhibits integrase strand transfer activity, has in recent clinical trials been shown to prevent HIV-1 acquisition more effectively than once-daily oral dosed reverse transcriptase inhibitors. In this Perspective, we examine bench to bedside aspects of CAB-LA treatment and development, starting from the biochemical basis of HIV-1 integration and pharmacological inhibition of integrase catalysis. We also review the results of recent clinical trials that evaluated CAB-LA, as well as the promises and challenges that surround its use for HIV/AIDS PrEP.
| S-EPMC8515172 | biostudies-literature
Project description:BackgroundLong-acting injectable cabotegravir, a drug taken every 2 months, has been shown to be more effective at preventing HIV infection than daily oral tenofovir disoproxil fumarate and emtricitabine, but its cost-effectiveness in a high-prevalence setting is not known. We aimed to estimate the incremental cost-effectiveness of long-acting injectable cabotegravir compared with tenofovir disoproxil fumarate and emtricitabine in South Africa, using methods standard to government planning, and to determine the threshold price at which long-acting injectable cabotegravir is as cost-effective as tenofovir disoproxil fumarate and emtricitabine.MethodsIn this modelled economic evaluation and threshold analysis, we updated a deterministic model of the South African HIV epidemic with data from the HPTN 083 and HPTN 084 trials to evaluate the effect of tenofovir disoproxil fumarate and emtricitabine and long-acting injectable cabotegravir provision to heterosexual adolescents and young women and men aged 15-24 years, female sex workers, and men who have sex with men. We estimated the average intervention cost, in 2021 US$, using ingredients-based costing, and modelled the cost-effectiveness of two coverage scenarios (medium or high, assuming higher uptake of long-acting injectable cabotegravir than tenofovir disoproxil fumarate and emtricitabine throughout) and, for long-acting injectable cabotegravir, two duration subscenarios (minimum: same pre-exposure prophylaxis duration as for tenofovir disoproxil fumarate and emtricitabine; maximum: longer duration than tenofovir disoproxil fumarate and emtricitabine) over 2022-41.FindingsAcross long-acting injectable cabotegravir scenarios, 15-28% more new HIV infections were averted compared with the baseline scenario (current tenofovir disoproxil fumarate and emtricitabine roll-out). In scenarios with increased coverage with oral tenofovir disoproxil fumarate and emtricitabine, 4-8% more new HIV infections were averted compared with the baseline scenario. If long-acting injectable cabotegravir drug costs were equal to those of tenofovir disoproxil fumarate and emtricitabine for the same 2-month period, the incremental cost of long-acting injectable cabotegravir to the HIV programme was higher than that of tenofovir disoproxil fumarate and emtricitabine (5-10% vs 2-4%) due to higher assumed uptake of long-acting injectable cabotegravir. The cost per infection averted was $6053-6610 (tenofovir disoproxil fumarate and emtricitabine) and $4471-6785 (long-acting injectable cabotegravir). The cost per long-acting cabotegravir injection needed to be less than twice that of a 2-month supply of tenofovir disoproxil fumarate and emtricitabine to remain as cost-effective, with threshold prices ranging between $9·03 per injection (high coverage; maximum duration) and $14·47 per injection (medium coverage; minimum duration).InterpretationLong-acting injectable cabotegravir could potentially substantially change HIV prevention. However, for its implementation to be financially feasible across low-income and middle-income countries with high HIV incidence, long-acting injectable cabotegravir must be reasonably priced.FundingUnited States Agency for International Development, The Bill & Melinda Gates Foundation.
| S-EPMC9708606 | biostudies-literature
Project description:BackgroundHeterosexual men in South Africa are a large key population to exposure to HIV, yet preferences for HIV pre-exposure prophylaxis (PrEP) among this population have not, to date, been investigated in the literature. This paper aims to explore HIV prevention preferences among heterosexual men in urban South Africa, as well as to examine the demand and characteristics of men who favour long-acting injectable (LAI) PrEP over condoms and oral PrEP.MethodsData were collected among 178 self-reported HIV-negative heterosexual men, who were given example products and information before being asked which they preferred. Multivariate logistic regression was used to analyse which characteristics were associated with product choice.Results48% (n = 85) of participants preferred LAI PrEP, while 33% (n = 58) and 20% (n = 35) chose oral PrEP and condoms respectively. Having children (marginal effect = 0.22; 95% CI [0.01, 0.44]) or having higher risk attitude scores (marginal effect = 0.03; 95% CI [0.01, 0.06]) was significantly associated with a choice of LAI PrEP, while those who had unprotected anal intercourse (marginal effect = - 0.42; 95% CI [- 0.57, - 0.27]) and those who were concerned with protection against other sexually transmitted infections over HIV (marginal effect = - 0.42; 95% CI [- 0.60, - 0.24]) appeared less likely to prefer LAI PrEP.ConclusionsThe results suggested a relatively high demand and theoretical acceptability for LAI PrEP among heterosexual men in urban South Africa, but there appeared to be fewer distinct predictors for the willingness to use LAI PrEP compared to studies conducted among gay and bisexual men and women. Nevertheless, the findings contribute to the mapping of the demand and determinants of heterosexual men's preferences for novel antiretroviral-based prevention in sub-Saharan Africa, and the data could aid in the differentiated design of future HIV prevention strategies using LAI PrEP in conjunction with other methods.
| S-EPMC6657137 | biostudies-literature
Project description:BackgroundLong-acting injectable cabotegravir (CAB-LA) for preexposure prophylaxis (PrEP) has proven efficacious in randomized controlled trials. Further research is critical to evaluate its effectiveness in real-world settings and identify effective implementation approaches, especially among young sexual and gender minorities (SGMs).ObjectiveImPrEP CAB Brasil is an implementation study aiming to generate critical evidence on the feasibility, acceptability, and effectiveness of incorporating CAB-LA into the existing public health oral PrEP services in 6 Brazilian cities. It will also evaluate a mobile health (mHealth) education and decision support tool, digital injection appointment reminders, and the facilitators of and barriers to integrating CAB-LA into the existing services.MethodsThis type-2 hybrid implementation-effectiveness study includes formative work, qualitative assessments, and clinical steps 1 to 4. For formative work, we will use participatory design methods to develop an initial CAB-LA implementation package and process mapping at each site to facilitate optimal client flow. SGMs aged 18 to 30 years arriving at a study clinic interested in PrEP (naive) will be invited for step 1. Individuals who tested HIV negative will receive mHealth intervention and standard of care (SOC) counseling or SOC for PrEP choice (oral or CAB-LA). Participants interested in CAB-LA will be invited for step 2, and those with undetectable HIV viral load will receive same-day CAB-LA injection and will be randomized to receive digital appointment reminders or SOC. Clinical appointments and CAB-LA injection are scheduled after 1 month and every 2 months thereafter (25-month follow-up). Participants will be invited to a 1-year follow-up to step 3 if they decide to change to oral PrEP or discontinue CAB-LA and to step 4 if diagnosed with HIV during the study. Outcomes of interest include PrEP acceptability, choice, effectiveness, implementation, and feasibility. HIV incidence in the CAB-LA cohort (n=1200) will be compared with that in a similar oral PrEP cohort from the public health system. The effectiveness of the mHealth and digital interventions will be assessed using interrupted time series analysis and logistic mixed models, respectively.ResultsDuring the third and fourth quarters of 2022, we obtained regulatory approvals; programmed data entry and management systems; trained sites; and performed community consultancy and formative work. Study enrollment is programmed for the second quarter of 2023.ConclusionsImPrEP CAB Brasil is the first study to evaluate CAB-LA PrEP implementation in Latin America, one of the regions where PrEP scale-up is most needed. This study will be fundamental to designing programmatic strategies for implementing and scaling up feasible, equitable, cost-effective, sustainable, and comprehensive alternatives for PrEP programs. It will also contribute to maximizing the impact of a public health approach to reducing HIV incidence among SGMs in Brazil and other countries in the Global South.Trial registrationClinicaltrials.gov NCT05515770; https://clinicaltrials.gov/ct2/show/NCT05515770.International registered report identifier (irrid)PRR1-10.2196/44961.
| S-EPMC10157454 | biostudies-literature
Project description:BackgroundAlthough long-acting, injectable cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) has proven efficacious for HIV prevention in clinical trials, research is needed to guide effective implementation in real-world settings. Formative work with community members and health care providers (HCPs) is important to provide insight into the needs and contexts of specific populations and reveal potential barriers and facilitators for implementation projects.ObjectiveWe aimed to describe the results from formative work to develop an implementation package for CAB-LA PrEP within the ImPrEP CAB Brasil study.MethodsImPrEP CAB Brasil is an implementation study of same-day delivery of CAB-LA PrEP for young sexual and gender minority (SGM) groups (aged 18-30 years) in 6 existing oral PrEP public health clinics. We conducted formative research to prepare for the implementation of ImPrEP CAB Brasil through community mobilization, process mapping with HCPs with experience in CAB-LA, and focus group discussions (FGDs) with young SGM groups (n=92) and HCPs (n=20) to identify initial perceptions of facilitators and barriers for CAB-LA PrEP implementation, refine the mobile health (mHealth) educational tool, and evaluate the acceptability of using a text message appointment reminder intervention through WhatsApp. FGDs were recorded, transcribed, systematically coded, and analyzed with thematic categorization by trained researchers using a qualitative data analysis program ATLAS.ti (version 7).ResultsA community mobilization team comprising 34 SGM community leaders collaborated in creating a prototype for an mHealth educational tool and contributed to the planning of peer education activities. We created 3 process maps for each site to describe the initial visit, follow-up visits, and laboratory flow. The main challenge identified for same-day CAB-LA PrEP delivery was the extended duration of clinic visits due to the numerous laboratory tests and HIV counseling steps required. Proposed solutions included having point-of-care HIV rapid tests instead of laboratory tests and additional counseling staff. Barriers for CAB-LA PrEP implementation identified through FGDs were the training of HCPs, support for adherence to injection appointments, and stigma or discrimination against SGM groups and persons using PrEP. The mHealth educational tool and WhatsApp reminders were highly acceptable by SGM groups and HCPs, indicating their potential to support PrEP choice and adherence. Content analysis on the cultural appropriateness of the language and overall clarity of the material contributed to the refinement of the mHealth tool.ConclusionsStructured formative work with SGM persons and HCPs generated important refinements to context-specific materials and plans to launch ImPrEP CAB Brasil in public health clinics. Ongoing implementation monitoring will use the process maps to identify additional barriers and potential solutions to same-day delivery of CAB-LA PrEP. Summative evaluations are needed to measure the effectiveness of the mHealth educational tool to support PrEP choice and the use of WhatsApp appointment reminders.
| S-EPMC11544328 | biostudies-literature
Project description:BackgroundThe HIV Prevention Trials Network (HPTN) 083 trial showed that long-acting injectable cabotegravir was more effective than tenofovir disoproxil fumarate plus emtricitabine in preventing HIV in cisgender men and transgender women who have sex with men. We aimed to characterise the cohort of transgender women included in HPTN 083.MethodsHPTN 083 is an ongoing, phase 2b/3, randomised, multicentre, double-blind, double-dummy clinical trial done at 43 sites in seven countries (Argentina, Brazil, Peru, the USA, South Africa, Thailand, and Viet Nam). HIV-negative participants were randomly assigned (1:1) to receive injectable cabotegravir or tenofovir disoproxil fumarate plus emtricitabine. The study design and primary outcomes of the blinded phase of HPTN 083 have already been reported. An enrolment minimum of 10% transgender women was set for the trial. Here we characterise the cohort of transgender women enrolled from Dec 6, 2016, to May 14, 2020, when the study was unblinded. We report sociodemographic characteristics, use of gender affirming hormone therapy, and behavioural assessments of the transgender women participants. Laboratory testing and safety evaluations are also reported. The trial is registered at ClinicalTrials.gov, NCT02720094.FindingsHPTN 083 enrolled 570 transgender women (304 tenofovir disoproxil fumarate plus emtricitabine; 266 injectable cabotegravir). Transgender women were primarily from Asia (225 [39%]) and Latin America (205 [36%]); 330 (58%) reported using gender affirming hormone therapy. Intimate partner violence was common (270 [47%] reported emotional abuse and 172 [30%] reported physical abuse) and 323 (57%) reported a history of childhood sexual abuse. 159 (28%) transgender women disagreed that they were at risk for HIV, and 142 (25%) screened positive for depressive symptoms. During study follow-up, incidence of syphilis was 16·25% (95% CI 13·28-19·69), rectal gonorrhoea was 11·66% (9·14-14·66), and chlamydia was 20·61% (17·20-24·49). Frequency of adverse events was similar between the treatment groups. Nine seroconversions occurred among transgender women during the blinded phase of the study (seven in the tenofovir disoproxil fumarate plus emtricitabine group and two in the injectable cabotegravir group); overall incidence was 1·19 per 100 person-years (95% CI 0·54-2·25): 1·80 per 100 person-years (0·73-3·72) in the tenofovir disoproxil fumarate plus emtricitabine group and 0·54 per 100 person-years (0·07-1·95) in the injectable cabotegravir group (hazard ratio 0·34 [95% CI 0·08-1·56]). Cabotegravir concentrations did not differ by gender affirming hormone therapy use.InterpretationHIV prevention strategies for transgender women cannot be addressed separately from social and structural vulnerabilities. Transgender women were well represented in HPTN 083 and should continue to be prioritised in HIV prevention studies. Our results suggest that injectable cabotegravir is a safe and effective pre-exposure prophylaxis option for transgender women.FundingNational Institute of Allergy and Infectious Diseases and ViiV Healthcare.
| S-EPMC10842527 | biostudies-literature