Impact and cost-effectiveness of the national scale-up of HIV pre-exposure prophylaxis among female sex workers in South Africa: a modelling analysis.

INTRODUCTION: In 2016, South Africa (SA) initiated a national programme to scale-up pre-exposure prophylaxis (PrEP) among female sex workers (FSWs), with ∼20,000 PrEP initiations among FSWs (∼14% of FSW) by 2020. We evaluated the impact and cost-effectiveness of this programme, including future scale-up scenarios and the potential detrimental impact of the COVID-19 pandemic. METHODS: A compartmental HIV transmission model for SA was adapted to include PrEP. Using estimates on self-reported PrEP adherence from a national study of FSW (67.7%) and the Treatment and Prevention for FSWs (TAPS) PrEP demonstration study in SA (80.8%), we down-adjusted TAPS estimates for the proportion of FSWs with detectable drug levels (adjusted range: 38.0-70.4%). The model stratified FSW by low (undetectable drug; 0% efficacy) and high adherence (detectable drug; 79.9%; 95% CI: 67.2-87.6% efficacy). FSWs can transition between adherence levels, with lower loss-to-follow-up among highly adherent FSWs (aHR: 0.58; 95% CI: 0.40-0.85; TAPS data). The model was calibrated to monthly data on the national scale-up of PrEP among FSWs over 2016-2020, including reductions in PrEP initiations during 2020. The model projected the impact of the current programme (2016-2020) and the future impact (2021-2040) at current coverage or if initiation and/or retention are doubled. Using published cost data, we assessed the cost-effectiveness (healthcare provider perspective; 3% discount rate; time horizon 2016-2040) of the current PrEP provision. RESULTS: Calibrated to national data, model projections suggest that 2.1% of HIV-negative FSWs were currently on PrEP in 2020, with PrEP preventing 0.45% (95% credibility interval, 0.35-0.57%) of HIV infections among FSWs over 2016-2020 or 605 (444-840) infections overall. Reductions in PrEP initiations in 2020 possibly reduced infections averted by 18.57% (13.99-23.29). PrEP is cost-saving, with $1.42 (1.03-1.99) of ART costs saved per dollar spent on PrEP. Going forward, existing coverage of PrEP will avert 5,635 (3,572-9,036) infections by 2040. However, if PrEP initiation and retention doubles, then PrEP coverage increases to 9.9% (8.7-11.6%) and impact increases 4.3 times with 24,114 (15,308-38,107) infections averted by 2040. CONCLUSIONS: Our findings advocate for the expansion of PrEP to FSWs throughout SA to maximize its impact. This should include strategies to optimize retention and should target women in contact with FSW services.

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.

Potential benefit of extended dose schedules of human papillomavirus vaccination in the context of scarce resources and COVID-19 disruptions in low-income and middle-income countries: a mathematical modelling analysis.

BACKGROUND: The WHO Strategic Advisory Group of Experts recommended that an extended interval of 3-5 years between the two doses of the human papillomavirus (HPV) vaccine could be considered to alleviate vaccine supply shortages. However, three concerns have limited the introduction of extended schedules: girls could be infected between the two doses, the vaccination coverage for the second dose could be lower at ages 13-14 years than at ages 9-10 years, and identifying girls vaccinated with a first dose to give them the second dose could be difficult. Using mathematical modelling, we examined the potential effect of these concerns on the population-level impact and efficiency of extended dose HPV vaccination schedules. METHODS: We used HPV-ADVISE, an individual-based, transmission-dynamic model of multitype HPV infection and disease, calibrated to country-specific data for four low-income and middle-income countries (India, Viet Nam, Uganda, and Nigeria). For the extended dose scenarios, we varied the vaccination coverage of the second dose among girls previously vaccinated, the one-dose vaccine efficacy, and the one-dose vaccine duration of protection. We also examined a strategy in which girls aged 14 years were vaccinated irrespective of their previous vaccination status. We used a scenario of girls-only two-dose vaccination at age 9 years (vaccine=9 valent, vaccine-type efficacy=100%, duration of protection=lifetime, and coverage=80%) as our comparator. We estimated two outcomes: the relative reduction in the age-standardised cervical cancer incidence (population-level impact) and the number of cervical cancers averted per 100 000 doses (efficiency). FINDINGS: Our model projected substantial reductions in cervical cancer incidence over 100 years with the two-dose schedule (79-86% depending on the country), compared with no vaccination. Projections for the 5-year extended schedule, in which the second dose is given only to girls previously vaccinated at age 9 years, were similar to the current two-dose schedule, unless vaccination coverage of the second dose is very low (reductions in cervical cancer incidence of 71-78% assuming 30% coverage at age 14 years among girls vaccinated at age 9 years). However, when the dose at age 14 years is given to girls irrespective of vaccination status and assuming high vaccination coverage, the model projected a substantially greater reduction in cervical cancer incidence compared with the current two-dose schedule (reductions in cervical cancer incidence of 86-93% assuming 70% coverage at age 14 years, irrespective of vaccination status). Efficiency of the extended schedule was greater than the two-dose schedule, even with a drop in vaccination coverage. INTERPRETATION: The three concerns are unlikely to have a substantial effect on the population-level impact of extended dose schedules. Hence, extended dose schedules will likely provide similar cervical cancer reductions as two-dose schedules, while reducing the number of doses required in the short-term, providing a more efficient use of scarce resources, and offering a 5-year time window to reassess the necessity of the second dose. FUNDING: WHO, Canadian Institute of Health Research Foundation, Fonds de recherche du Québec-Santé, Digital Research Alliance of Canada, and Bill & Melinda Gates Foundation.

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%, and a time horizon of 50 years. In sensitivity analyses, we considered a cost-effectiveness threshold of $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.

Economic Analysis of Low Volume Interventions Using Real-World Data: Costs of HIV Self-Testing Distribution and HIV Testing Services in West Africa From the ATLAS Project.

Achieving the first 95 of the UNAIDS targets requires the implementation of innovative approaches to knowing one's HIV status. Among these innovations is the provision of HIV self-testing (HIVST) kits in west Africa by the international partner organization Solthis (IPO). In order to provide guidance for the optimal use of financial resources, this study aims to estimate the program and site level costs of dispensing HIVST as well as HIV testing services (HTS)-excluding HIVST-in health facilities in Côte d'Ivoire, Mali and Senegal as part of the ATLAS project. We estimated from the provider's perspective, HIVST and HTS incremental costs using top-down and bottom-up costing approaches and conducted a time and motion study. We identified costs at the program level for HIVST (including IPO central costs) and at the site level for HIVST and HTS. The economic costs of distributing HIVST kits were assessed in 37 health facilities between July 2019 and March 2021 (21 months). Sensitivity analyses were also performed on unit costs to examine the robustness of our estimates related to key assumptions. In total, 16,001 HIVST kits were dispensed for 32,194 HTS sessions carried out. Program level HIVST average costs ranged $12-286, whereas site level costs ranged $4-26 across distribution channels and countries. Site level HTS costs ranged $7-8 per testing session, and ranged $72-705 per HIV diagnosis. Across countries and channels, HIVST costs were driven by personnel (27-68%) and HIVST kits (32-73%) costs. The drivers of HTS costs were personnel costs ranging between 65 and 71% of total costs across distribution channels and countries, followed by supplies costs between 21 and 30%. While program level HIVST average costs were high, site level HIVST average costs remained comparable to HTS costs in all countries. Health facility-based distribution channels operating at low volume exhibit high proportion of central costs which should be considered carefully for financial planning when run alongside high volumes mobile outreach distribution channels. HIVST can diversify the HIV testing offer at health facilities, thus improving access to screening for target populations not reached by HTS services.

Effect of police enforcement and extreme social inequalities on violence and mental health among women who sell sex: findings from a cohort study in London, UK.

OBJECTIVES: To examine legal and social determinants of violence, anxiety/depression among sex workers. METHODS: A participatory prospective cohort study among women (inclusive of transgender) ≥18 years, selling sex in the last 3 months in London between 2018 and 2019. We used logistic generalised estimating equation models to measure associations between structural factors on recent (6 months) violence from clients or others (local residents, strangers), depression/anxiety (Patient Health Questionnaire-4). RESULTS: 197 sex workers were recruited (96% cisgender-women; 46% street-based; 54% off-street) and 60% completed a follow-up questionnaire. Street-based sex workers experienced greater inequalities compared with off-street in relation to recent violence from clients (73% vs 36%); police (42% vs 7%); intimate partner violence (IPV) (56% vs 18%) and others (67% vs 17%), as well as homelessness (65% vs 7%) and recent law enforcement (87% vs 9%). Prevalence of any STI was 17.5% (17/97). For street-based sex workers, recent arrest was associated with violence from others (adjusted OR (aOR) 2.77; 95% CI 1.11 to 6.94) and displacement by police was associated with client violence (aOR 4.35; 95% CI 1.36 to 13.90). Financial difficulties were also associated with client violence (aOR 4.66; 95% CI 1.64 to 13.24). Disability (aOR 3.85; 95% CI 1.49 to 9.95) and client violence (aOR 2.55; 95% CI 1.10 to 5.91) were associated with anxiety/depression. For off-street sex workers, financial difficulties (aOR 3.66; 95% CI 1.64 to 8.18), unstable residency (aOR 3.19; 95% CI 1.36 to 7.49), IPV (aOR 3.77; 95% CI 1.30 to 11.00) and alcohol/drug use were associated with client violence (aOR 3.16; 95% CI 1.26 to 7.92), while always screening and refusing clients was protective (aOR 0.36; 95% CI 0.15 to 0.87). Disability (aOR 5.83; 95% CI 2.34 to 14.51), unmet mental health needs (aOR 3.08; 95% CI 1.15 to 8.23) and past eviction (aOR 3.99; 95% CI 1.23 to 12.92) were associated with anxiety/depression. CONCLUSIONS: Violence, anxiety/depression are linked to poverty, unstable housing and police enforcement. We need to modify laws to allow sex workers to work safely and increase availability of housing and mental health services.

Optimal human papillomavirus vaccination strategies to prevent cervical cancer in low-income and middle-income countries in the context of limited resources: a mathematical modelling analysis.

BACKGROUND: Introduction of human papillomavirus (HPV) vaccination has been slow in low-income and middle-income countries (LMICs) because of resource constraints and worldwide shortage of vaccine supplies. To help inform WHO recommendations, we modelled various HPV vaccination strategies to examine the optimal use of limited vaccine supplies and best allocation of scarce resources in LMICs in the context of the WHO global call to eliminate cervical cancer as a public health problem. METHODS: In this mathematical modelling analysis, we developed HPV-ADVISE LMIC, a transmission-dynamic model of HPV infection and diseases calibrated to four LMICs: India, Vietnam, Uganda, and Nigeria. For different vaccination strategies that encompassed use of a nine-valent vaccine (or a two-valent or four-valent vaccine assuming high cross-protection), we estimated three outcomes: reduction in the age-standardised rate of cervical cancer, number of doses needed to prevent one case of cervical cancer (NNV; as a measure of efficiency), and the incremental cost-effectiveness ratio (ICER; in 2017 international $ per disability-adjusted life-year [DALY] averted). We examined different vaccination strategies by varying the ages of routine HPV vaccination and number of age cohorts vaccinated, the population targeted, and the number of doses used. In our base case, we assumed 100% lifetime protection against HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58; vaccination coverage of 80%; and a time horizon of 100 years. For the cost-effectiveness analysis, we used a 3% discount rate. Elimination of cervical cancer was defined as an age-standardised incidence of less than four cases per 100 000 woman-years. FINDINGS: We predicted that HPV vaccination could lead to cervical cancer elimination in Vietnam, India, and Nigeria, but not in Uganda. Compared with no vaccination, strategies that involved vaccinating girls aged 9-14 years with two doses were predicted to be the most efficient and cost-effective in all four LMICs. NNV ranged from 78 to 381 and ICER ranged from $28 per DALY averted to $1406 per DALY averted depending on the country. The most efficient and cost-effective strategies were routine vaccination of girls aged 14 years, with or without a later switch to routine vaccination of girls aged 9 years, and routine vaccination of girls aged 9 years with a 5-year extended interval between doses and a catch-up programme at age 14 years. Vaccinating boys (aged 9-14 years) or women aged 18 years or older resulted in substantially higher NNVs and ICERs. INTERPRETATION: We identified two strategies that could maximise efforts to prevent cervical cancer in LMICs given constraints on vaccine supplies and costs and that would allow a maximum of LMICs to introduce HPV vaccination. FUNDING: World Health Organization, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, PATH, and The Bill & Melinda Gates Foundation. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Costs and Scale-Up Costs of Integrating HIV Self-Testing Into Civil Society Organisation-Led Programmes for Key Populations in Côte d'Ivoire, Senegal, and Mali.

Despite significant progress on the proportion of individuals who know their HIV status in 2020, Côte d'Ivoire (76%), Senegal (78%), and Mali (48%) remain far below, and key populations (KP) including female sex workers (FSW), men who have sex with men (MSM), and people who use drugs (PWUD) are the most vulnerable groups with a HIV prevalence at 5-30%. HIV self-testing (HIVST), a process where a person collects his/her own specimen, performs a test, and interprets the result, was introduced in 2019 as a new testing modality through the ATLAS project coordinated by the international partner organisation Solthis (IPO). We estimate the costs of implementing HIVST through 23 civil society organisations (CSO)-led models for KP in Côte d'Ivoire (N = 7), Senegal (N = 11), and Mali (N = 5). We modelled costs for programme transition (2021) and early scale-up (2022-2023). Between July 2019 and September 2020, a total of 51,028, 14,472, and 34,353 HIVST kits were distributed in Côte d'Ivoire, Senegal, and Mali, respectively. Across countries, 64-80% of HIVST kits were distributed to FSW, 20-31% to MSM, and 5-8% to PWUD. Average costs per HIVST kit distributed were $15 for FSW (Côte d'Ivoire: $13, Senegal: $17, Mali: $16), $23 for MSM (Côte d'Ivoire: $15, Senegal: $27, Mali: $28), and $80 for PWUD (Côte d'Ivoire: $16, Senegal: $144), driven by personnel costs (47-78% of total costs), and HIVST kits costs (2-20%). Average costs at scale-up were $11 for FSW (Côte d'Ivoire: $9, Senegal: $13, Mali: $10), $16 for MSM (Côte d'Ivoire: $9, Senegal: $23, Mali: $17), and $32 for PWUD (Côte d'Ivoire: $14, Senegal: $50). Cost reductions were mainly explained by the spreading of IPO costs over higher HIVST distribution volumes and progressive IPO withdrawal at scale-up. In all countries, CSO-led HIVST kit provision to KP showed relatively high costs during the study period related to the progressive integration of the programme to CSO activities and contextual challenges (COVID-19 pandemic, country safety concerns). In transition to scale-up and integration of the HIVST programme into CSO activities, this model shows large potential for substantial economies of scale. Further research will assess the overall cost-effectiveness of this model.

Cost-Effectiveness of Accelerated HIV Response Scenarios in Côte d'Ivoire.

BACKGROUND: Despite Côte d'Ivoire epidemic being labeled as "generalized," key populations (KPs) are important to overall transmission. Using a dynamic model of HIV transmission, we previously estimated the impact of several treatment-as-prevention strategies that reached-or missed-the UNAIDS 90-90-90 targets in different populations groups, including KP and clients of female sex workers (CFSWs). To inform program planning and resources allocation, we assessed the cost-effectiveness of these scenarios. METHODS: Costing was performed from the provider's perspective. Unit costs were obtained from the Ivorian Programme national de lutte contre le Sida (USD 2015) and discounted at 3%. Net incremental cost-effectiveness ratios (ICER) per adult HIV infection prevented and per disability-adjusted life-years (DALY) averted were estimated over 2015-2030. RESULTS: The 3 most cost-effective and affordable scenarios were the ones that projected current programmatic trends [ICER = $210; 90% uncertainty interval (90% UI): $150-$300], attaining the 90-90-90 objectives among KP and CFSW (ICER = $220; 90% UI: $80-$510), and among KP only (ICER = $290; 90% UI: $90-$660). The least cost-effective scenario was the one that reached the UNAIDS 90-90-90 target accompanied by a 25% point drop in condom use in KP (ICER = $710; 90% UI: $450-$1270). In comparison, the UNAIDS scenario had a net ICER of $570 (90% UI: $390-$900) per DALY averted. CONCLUSIONS: According to commonly used thresholds, accelerating the HIV response can be considered very cost-effective for all scenarios. However, when balancing epidemiological impact, cost-effectiveness, and affordability, scenarios that sustain both high condom use and rates of viral suppression among KP and CFSW seem most promising in Côte d'Ivoire.

The global response and unmet actions for HIV and sex workers.

Female, male, and transgender sex workers continue to have disproportionately high burdens of HIV infection in low-income, middle-income, and high-income countries in 2018. 4 years since our Lancet Series on HIV and sex work, our updated analysis of the global HIV burden among female sex workers shows that HIV prevalence is unacceptably high at 10·4% (95% CI 9·5-11·5) and is largely unchanged. Comprehensive epidemiological data on HIV and antiretroviral therapy (ART) coverage are scarce, particularly among transgender women. Sustained coverage of treatment is markedly uneven and challenged by lack of progress on stigma and criminalisation, and sustained human rights violations. Although important progress has been made in biomedical interventions with pre-exposure prophylaxis and early ART feasibility and demonstration projects, limited coverage and retention suggest that sustained investment in community and structural interventions is required for sex workers to benefit from the preventive interventions and treatments that other key populations have. Evidence-based progress on full decriminalisation grounded in health and human rights-a key recommendation in our Lancet Series-has stalled, with South Africa a notable exception. Additionally, several countries have rolled back rights to sex workers further. Removal of legal barriers through the decriminalisation of sex work, alongside political and funding investments to support community and structural interventions, is urgently needed to reverse the HIV trajectory and ensure health and human rights for all sex workers.

In what circumstances could nondaily preexposure prophylaxis for HIV substantially reduce program costs?

OBJECTIVES: To review the main factors influencing the costs of nondaily oral preexposure prophylaxis (PrEP) with tenofovir (±emtricitabine). To estimate the cost reductions possible with nondaily PrEP compared with daily PrEP for different populations (MSM and heterosexual populations). DESIGN: Systematic review and data triangulation. METHODS: We estimated the required number of tablets/person/week for dosing regimens used in the HPTN 067/ADAPT (daily/time-driven/event-driven) and IPERGAY (on-demand) trials for different patterns of sexual intercourse. Using trial data, and behavioural and cost data obtained through systematic literature reviews, we estimated cost savings resulting from tablet reductions for nondaily versus daily oral PrEP, assuming 100% adherence. RESULTS: Among different populations being prioritized for PrEP, the median reported number of days of sexual activity varied between 0 and 2 days/week (0-1.5 days/week for MSM, 1-2 days/week for heterosexual populations). With 100% adherence and two or fewer sex-days/week, HPTN 067/ADAPT nondaily regimens reduced the number of tablets/week by more than 40% compared with daily PrEP. PrEP program costs were reduced the most in settings with high drug costs, for example, by 66-69% with event-driven PrEP for French/US populations reporting on average one sex-day/week. CONCLUSION: Nondaily oral PrEP could lower costs substantially (>50%) compared with daily PrEP, particularly in high-income countries. Adherence and efficacy data are needed to determine cost-effectiveness.

Health and Economic Impact of Switching from a 4-Valent to a 9-Valent HPV Vaccination Program in the United States.

BACKGROUND: Randomized clinical trials have shown the 9-valent human papillomavirus (HPV) vaccine to be highly effective against types 31/33/45/52/58 compared with the 4-valent. Evidence on the added health and economic benefit of the 9-valent is required for policy decisions. We compare population-level effectiveness and cost-effectiveness of 9- and 4-valent HPV vaccination in the United States. METHODS: We used a multitype individual-based transmission-dynamic model of HPV infection and disease (anogenital warts and cervical, anogenital, and oropharyngeal cancers), 3% discount rate, and societal perspective. The model was calibrated to sexual behavior and epidemiologic data from the United States. In our base-case, we assumed 95% vaccine-type efficacy, lifelong protection, and a cost/dose of $145 and $158 for the 4- and 9-valent vaccine, respectively. Predictions are presented using the mean (80% uncertainty interval [UI] = 10(th)-90(th) percentiles) of simulations. RESULTS: Under base-case assumptions, the 4-valent gender-neutral vaccination program is estimated to cost $5500 (80% UI = 2400-9400) and $7300 (80% UI = 4300-11 000)/quality-adjusted life-year (QALY) gained with and without cross-protection, respectively. Switching to a 9-valent gender-neutral program is estimated to be cost-saving irrespective of cross-protection assumptions. Finally, the incremental cost/QALY gained of switching to a 9-valent gender-neutral program (vs 9-valent girls/4-valent boys) is estimated to be $140 200 (80% UI = 4200->1 million) and $31 100 (80% UI = 2100->1 million) with and without cross-protection, respectively. Results are robust to assumptions about HPV natural history, screening methods, duration of protection, and healthcare costs. CONCLUSIONS: Switching to a 9-valent gender-neutral HPV vaccination program is likely to be cost-saving if the additional cost/dose of the 9-valent is less than $13. Giving females the 9-valent vaccine provides the majority of benefits of a gender-neutral strategy.

Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.

BACKGROUND: Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations. METHODS: We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I(2) and χ(2) statistics and we did trends analysis to examine the dose-response association between HPV vaccination coverage and each study effect measure. FINDINGS: We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19-0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22-0·71) in girls 13-19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54-0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47-0·91]) and in women 20-39 years of age (0·68 [95% CI 0·51-0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34-0·74]) and in anogenital warts (0·86 [95% CI 0·79-0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects. INTERPRETATION: Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement. FUNDING: The Canadian Institutes of Health Research.

Changing inequalities in cervical cancer: modeling the impact of vaccine uptake, vaccine herd effects, and cervical cancer screening in the post-vaccination era.

BACKGROUND: Inequalities in cervical cancer may be increased following mass vaccination against the human papillomavirus (HPV) if girls with low vaccine uptake also have low future participation in cervical cancer screening. We evaluated how vaccine uptake distribution affects inequalities in squamous cell carcinoma (SCC) incidence between groups with different screening participation. METHODS: We used an individual-based transmission dynamic model of HPV infection and disease (HPV-ADVISE). Females were stratified by routine screening frequency. We modeled the impact of vaccination on SCC incidence rate differences (absolute inequality) and incidence rate ratios (relative inequality) between women who have routine screening intervals of <5 years (frequently screened), ≥5 years (underscreened), and who are never screened. We compared simulations with uniform vaccine uptake with scenarios with unequal vaccine uptake, in which never and underscreened women have lower vaccine uptake than frequently screened women. RESULTS: Absolute SCC inequalities between groups with different screening rates were predicted to decrease after vaccination, even when women with the lowest screening participation had the lowest vaccine uptake. Herd effects helped reduce absolute inequalities when vaccine uptake was unequal. Conversely, relative SCC inequalities remained unchanged or increased after vaccination. Results were robust to different overall vaccination coverages and sexual mixing scenarios. CONCLUSION: Though mass HPV vaccination is predicted to substantially decrease SCC incidence rates, never screened women will still have the highest disease burden after vaccination. IMPACT: To reduce both absolute and relative SCC inequalities, public health initiatives will need to address inequalities in both vaccine uptake and in cervical cancer screening participation.

An action agenda for HIV and sex workers.

The women, men, and transgender people who sell sex globally have disproportionate risks and burdens of HIV in countries of low, middle, and high income, and in concentrated and generalised epidemic contexts. The greatest HIV burdens continue to be in African female sex workers. Worldwide, sex workers still face reduced access to needed HIV prevention, treatment, and care services. Legal environments, policies, police practices, absence of funding for research and HIV programmes, human rights violations, and stigma and discrimination continue to challenge sex workers' abilities to protect themselves, their families, and their sexual partners from HIV. These realities must change to realise the benefits of advances in HIV prevention and treatment and to achieve global control of the HIV pandemic. Effective combination prevention and treatment approaches are feasible, can be tailored for cultural competence, can be cost-saving, and can help to address the unmet needs of sex workers and their communities in ways that uphold their human rights. To address HIV in sex workers will need sustained community engagement and empowerment, continued research, political will, structural and policy reform, and innovative programmes. But such actions can and must be achieved for sex worker communities everywhere.

Community mobilisation and empowerment interventions as part of HIV prevention for female sex workers in Southern India: a cost-effectiveness analysis.

BACKGROUND: Most HIV prevention for female sex workers (FSWs) focuses on individual behaviour change involving peer educators, condom promotion and the provision of sexual health services. However, there is a growing recognition of the need to address broader societal, contextual and structural factors contributing to FSW risk behaviour. We assess the cost-effectiveness of adding community mobilisation (CM) and empowerment interventions (eg. community mobilisation, community involvement in programme management and services, violence reduction, and addressing legal policies and police practices), to core HIV prevention services delivered as part of Avahan in two districts (Bellary and Belgaum) of Karnataka state, Southern India. METHODS: An ingredients approach was used to estimate economic costs in US$ 2011 from an HIV programme perspective of CM and empowerment interventions over a seven year period (2004-2011). Incremental impact, in terms of HIV infections averted, was estimated using a two-stage process. An 'exposure analysis' explored whether exposure to CM was associated with FSW's empowerment, risk behaviours and HIV/STI prevalence. Pathway analyses were then used to estimate the extent to which behaviour change may be attributable to CM and to inform a dynamic HIV transmission model. FINDINGS: The incremental costs of CM and empowerment were US$ 307,711 in Belgaum and US$ 592,903 in Bellary over seven years (2004-2011). Over a 7-year period (2004-2011) the mean (standard deviation, sd.) number of HIV infections averted through CM and empowerment is estimated to be 1257 (308) in Belgaum and 2775 (1260) in Bellary. This translates in a mean (sd.) incremental cost per disability adjusted life year (DALY) averted of US$ 14.12 (3.68) in Belgaum and US$ 13.48 (6.80) for Bellary--well below the World Health Organisation recommended willingness to pay threshold for India. When savings from ART are taken into account, investments in CM and empowerment are cost saving. CONCLUSIONS: Our findings suggest that CM and empowerment is, at worst, highly cost-effective and, at best, a cost-saving investment from an HIV programme perspective. CM and empowerment interventions should therefore be considered as core components of HIV prevention programmes for FSWs.

Cost-effectiveness of HIV prevention for high-risk groups at scale: an economic evaluation of the Avahan programme in south India.

BACKGROUND: Avahan is a large-scale, HIV preventive intervention, targeting high-risk populations in south India. We assessed the cost-effectiveness of Avahan to inform global and national funding institutions who are considering investing in worldwide HIV prevention in concentrated epidemics. METHODS: We estimated cost effectiveness from a programme perspective in 22 districts in four high-prevalence states. We used the UNAIDS Costing Guidelines for HIV Prevention Strategies as the basis for our costing method, and calculated effect estimates using a dynamic transmission model of HIV and sexually transmitted disease transmission that was parameterised and fitted to locally observed behavioural and prevalence trends. We calculated incremental cost-effective ratios (ICERs), comparing the incremental cost of Avahan per disability-adjusted life-year (DALY) averted versus a no-Avahan counterfactual scenario. We also estimated incremental cost per HIV infection averted and incremental cost per person reached. FINDINGS: Avahan reached roughly 150 000 high-risk individuals between 2004 and 2008 in the 22 districts studied, at a mean cost per person reached of US$327 during the 4 years. This reach resulted in an estimated 61 000 HIV infections averted, with roughly 11 000 HIV infections averted in the general population, at a mean incremental cost per HIV infection averted of $785 (SD 166). We estimate that roughly 1 million DALYs were averted across the 22 districts, at a mean incremental cost per DALY averted of $46 (SD 10). Future antiretroviral treatment (ART) cost savings during the lifetime of the cohort exposed to HIV prevention were estimated to be more than $77 million (compared with the slightly more than $50 million spent on Avahan in the 22 districts during the 4 years of the study). INTERPRETATION: This study provides evidence that the investment in targeted HIV prevention programmes in south India has been cost effective, and is likely to be cost saving if a commitment is made to provide ART to all that can benefit from it. Policy makers should consider funding and sustaining large-scale targeted HIV prevention programmes in India and beyond. FUNDING: Bill & Melinda Gates Foundation.

Optimal allocation of resources in female sex worker targeted HIV prevention interventions: model insights from Avahan in South India.

BACKGROUND: The Avahan programme has provided HIV prevention activities, including condom promotion, to female sex workers (FSWs) in southern India since 2004. Evidence suggests Avahan averted 202,000 HIV infections over 4 years. For replicating this intervention elsewhere, it is essential to understand how the intervention's impact could have been optimised for different budget levels. METHODS: Behavioural data were used to determine how condom use varied for FSWs with different levels of intervention intensity. Cost data from 64 Avahan districts quantified how district-level costs related to intervention scale and intensity. A deterministic model for HIV transmission amongst FSWs and clients projected the impact and cost of intervention strategies for different scale and intensity, and identified the optimal strategies that maximise impact for different budget levels. RESULTS: As budget levels increase, the optimal intervention strategy is to first increase intervention intensity which achieves little impact, then scale-up coverage to high levels for large increases in impact, and lastly increase intensity further for small additional gains. The cost-effectiveness of these optimal strategies generally improves with increasing resources, while straying from these strategies can triple costs for the same impact. Projections suggest Avahan was close to being optimal, and moderate budget reductions (≥ 20%) would have reduced impact considerably (>40%). DISCUSSION: Our analysis suggests that tailoring the design of HIV prevention programmes for FSWs can improve impact, and that a certain level of resources are required to achieve demonstrable impact. These insights are critical for optimising the use of limited resources for preventing HIV.

Comparing the cost-effectiveness of two- and three-dose schedules of human papillomavirus vaccination: a transmission-dynamic modelling study.

BACKGROUND: Recent evidence suggests that two doses of HPV vaccines may be as protective as three doses in the short-term. We estimated the incremental cost-effectiveness of two- and three-dose schedules of girls-only and girls & boys HPV vaccination programmes in Canada. METHODS: We used HPV-ADVISE, an individual-based transmission-dynamic model of multi-type HPV infection and diseases (anogenital warts, and cancers of the cervix, vulva, vagina, anus, penis and oropharynx). We conducted the analysis from the health payer perspective, with a 70-year time horizon and 3% discount rate, and performed extensive sensitivity analyses, including duration of vaccine protection and vaccine cost. FINDINGS: Assuming 80% coverage and a vaccine cost per dose of $85, two-dose girls-only vaccination (vs. no vaccination) produced cost/quality-adjusted life-year (QALY)-gained varying between $7900-24,300. The incremental cost-effectiveness ratio of giving the third dose to girls (vs. two doses) was below $40,000/QALY-gained when: (i) three doses provide longer protection than two doses and (ii) two-dose protection was shorter than 30 years. Vaccinating boys (with two or three doses) was not cost-effective (vs. girls-only vaccination) under most scenarios investigated. INTERPRETATION: Two-dose HPV vaccination is likely to be cost-effective if its duration of protection is at least 10 years. A third dose of HPV vaccine is unlikely to be cost-effective if two-dose duration of protection is longer than 30 years. Finally, two-dose girls & boys HPV vaccination is unlikely to be cost-effective unless the cost per dose for boys is substantially lower than the cost for girls.

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per µL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per µL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per µL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. FINDINGS: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per µL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per µL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per µL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective. INTERPRETATION: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets. FUNDING: Bill & Melinda Gates Foundation, WHO.