Sociodemographic differences in symptom severity and duration among women referred to secondary care for menorrhagia in England and Wales: a cohort study from the National Heavy Menstrual Bleeding Audit.

OBJECTIVE: To examine symptom severity and duration at time of referral to secondary care for heavy menstrual bleeding (HMB) by socioeconomic deprivation, age and ethnicity DESIGN: Cohort analysis of data from the National HMB Audit linked to Hospital Episode Statistics data. SETTING: English and Welsh National Health Services (secondary care): February 2011 to January 2012. PARTICIPANTS: 15 325 women aged 18-60 years in England and Wales who had a new referral for HMB to a gynaecology outpatient department METHODS: Multivariable linear regression to calculate adjusted differences in mean symptom severity and quality of life scores at first outpatient visit. Multivariable logistic regression to calculate adjusted ORs. Adjustment for body mass index, parity and comorbidities. PRIMARY OUTCOME MEASURES: Mean symptom severity score (0=best, 100=worst), mean condition-specific quality of life score (0=worst, 100=best) and symptom duration (≥1 year). RESULTS: Women were on average 42 years old and 12% reported minority ethnic backgrounds. Mean symptom severity and condition-specific quality of life scores were 61.8 and 34.7. Almost three-quarters of women (74%) reported having had symptoms for ≥1 year. Women from more deprived areas had more severe symptoms at their first outpatient visit (difference -6.1; 95% CI-7.2 to -4.9, between least and most deprived quintiles) and worse condition-specific quality of life (difference 6.3; 95% CI 5.1 to 7.5). Symptom severity declined with age while quality of life improved. CONCLUSIONS: Women living in more deprived areas reported more severe HMB symptoms and poorer quality of life at the start of treatment in secondary care. Providers should examine referral practices to explore if these differences reflect women's health-seeking behaviour or how providers decide whether or not to refer

Factors associated with receiving surgical treatment for menorrhagia in England and Wales: findings from a cohort study of the National Heavy Menstrual Bleeding Audit.

OBJECTIVE: To examine the factors associated with receiving surgery for heavy menstrual bleeding (HMB) in England and Wales. DESIGN: National cohort study. SETTING: National Health Service hospitals. PARTICIPANTS: Women with HMB aged 18-60 who had a new referral to secondary care. METHODS: Patient-reported data linked to administrative hospital data. Risk ratios (RR) estimated using multivariable Poisson regression. PRIMARY OUTCOME MEASURE: Surgery within 1 year of first outpatient clinic visit. RESULTS: 14 545 women were included. At their first clinic visit, mean age was 42 years, mean symptom severity score was 62 (scale ranging from 0 (least) to 100 (most severe)), 73.9% of women reported having symptoms for >1 year and 30.4% reported no prior treatment in primary care. One year later, 42.6% had received surgery. Of these, 57.8% had endometrial ablation and 37.2% hysterectomy. Women with more severe symptoms were more likely to have received surgery (most vs least severe quintile, 33.1% vs 56.0%; RR 1.6, 95% CI 1.5 to 1.7). Surgery was more likely among those who reported prior primary care treatment compared with those who did not (48.0% vs 31.1%; RR 1.5, 95% CI 1.4 to 1.6). Surgery was less likely among Asian and more likely among black women, compared with white women. Surgery was not associated with socioeconomic deprivation. CONCLUSIONS: Receipt of surgery for HMB depends on symptom severity and prior treatment in primary care. Referral pathways should be locally audited to ensure women with HMB receive care that addresses their individual needs and preferences, especially for those who do not receive treatment in primary care

A quantitative assessment of the consistency of projections from five mathematical models of the HIV epidemic in South Africa: a model comparison study

Background: Mathematical models are increasingly used to inform HIV policy and planning. Comparing estimates obtained using different mathematical models can test the robustness of estimates and highlight research gaps. As part of a larger project aiming to determine the optimal allocation of funding for HIV services, in this study we compare projections from five mathematical models of the HIV epidemic in South Africa: EMOD-HIV, Goals, HIV-Synthesis, Optima, and Thembisa. // Methods: The five modelling groups produced estimates of the total population, HIV incidence, HIV prevalence, proportion of people living with HIV who are diagnosed, ART coverage, proportion of those on ART who are virally suppressed, AIDS-related deaths, total deaths, and the proportion of adult males who are circumcised. Estimates were made under a “status quo” scenario for the period 1990 to 2040. For each output variable we assessed the consistency of model estimates by calculating the coefficient of variation and examining the trend over time. // Results: For most outputs there was significant inter-model variability between 1990 and 2005, when limited data was available for calibration, good consistency from 2005 to 2025, and increasing variability towards the end of the projection period. Estimates of HIV incidence, deaths in people living with HIV, and total deaths displayed the largest long-term variability, with standard deviations between 35 and 65% of the cross-model means. Despite this variability, all models predicted a gradual decline in HIV incidence in the long-term. Projections related to the UNAIDS 95–95-95 targets were more consistent, with the coefficients of variation below 0.1 for all groups except children. // Conclusions: While models produced consistent estimates for several outputs, there are areas of variability that should be investigated. This is important if projections are to be used in subsequent cost-effectiveness studies

The potential role of long-acting injectable cabotegravir-rilpivirine in the treatment of HIV in sub-Saharan Africa : a modelling analysis

BACKGROUND: The 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. METHODS: We 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. FINDINGS: In 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. INTERPRETATION: Our 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. FUNDING: Bill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655)

Potential cost-effectiveness of community availability of tenofovir, lamivudine, and dolutegravir for HIV prevention and treatment in east, central, southern, and west Africa: a modelling analysis

BACKGROUND: Post-exposure prophylaxis (PEP) offers protection from HIV after condomless sex, but is not widely available in a timely manner in east, central, southern, and west Africa. To inform the potential pilot implementation of such an approach, we modelled the effect and cost-effectiveness of making PEP consisting of tenofovir, lamivudine, and dolutegravir (TLD) freely and locally available in communities without prescription, with the aim of enabling PEP use within 24 h of condomless sex. Free community availability of TLD (referred to as community TLD) might also result in some use of TLD as pre-exposure prophylaxis (PrEP) and as antiretroviral therapy for people living with HIV. METHODS: Using an existing individual-based model (HIV Synthesis), we explicitly modelled the potential positive and negative effects of community TLD. Through the sampling of parameter values we created 1000 setting-scenarios, reflecting the uncertainty in assumptions and a range of settings similar to those seen in east, central, southern, and west Africa (with a median HIV prevalence of 14·8% in women and 8·1% in men). For each setting scenario, we considered the effects of community TLD. TLD PEP was assumed to have at least 90% efficacy in preventing HIV infection after condomless sex with a person living with HIV. FINDINGS: The modelled effects of community TLD availability based on an assumed high uptake of TLD resulted in a mean reduction in incidence of 31% (90% range over setting scenarios, 6% increase to 57% decrease) over 20 years, with an HIV incidence reduction over 50 years in 91% of the 1000 setting scenarios, deaths averted in 55% of scenarios, reduction in costs in 92% of scenarios, and disability-adjusted life-years averted in 64% of scenarios with community TLD. Community TLD was cost-effective in 90% of setting scenarios and cost-saving (with disability-adjusted life-years averted) in 58% of scenarios. When only examining setting scenarios in which there was lower uptake of community TLD, community TLD is cost-effective in 92% of setting scenarios. INTERPRETATION: The introduction of community TLD, enabling greater PEP access, is a promising approach to consider further in pilot implementation projects. FUNDING: Bill & Melinda Gates Foundation to the HIV Modelling Consortium

Identifying key drivers of the impact of an HIV cure intervention in sub-Saharan Africa

BACKGROUND:  The properties required of an intervention that results in eradication or control of HIV in absence of antiretroviral therapy (ART-free viral suppression) to make it cost-effective in low income settings are unknown. METHODS:  We used a model of HIV and ART to investigate the effect of introducing an ART-free viral suppression intervention in 2022 in an example country of Zimbabwe. We assumed that the intervention (cost: $500) would be accessible for 90$300 million (8.7% saving). An intervention of this efficacy costing anything up to $1400 is likely to be cost-effective in this setting. CONCLUSION:  Interventions aimed at curing HIV have the potential to improve overall disease burden and to reduce costs. Given the effectiveness and cost of ART, such interventions would have to be inexpensive and highly effective

Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical models

BACKGROUND: In this so-called treat-all era, antiretroviral therapy (ART) interruptions contribute to an increasing proportion of HIV infections and deaths. Many strategies to improve retention on ART cost more than standard of care. In this study, we aimed to estimate the upper-bound costs at which such interventions should be adopted. METHODS: In this combined analysis, we compared the infections averted, disability-adjusted life-years (DALYs) averted, and upper-bound costs of interventions that improve ART retention in three HIV models with diverse structures, assumptions, and baseline settings: EMOD in South Africa, Optima in Malawi, and Synthesis in sub-Saharan African low-income and middle-income countries (LMICs). We modelled estimates over a 40-year time horizon, from a baseline of Jan 1, 2022, when interventions would be implemented, to Jan 1, 2062. We varied increment of ART retention (25%, 50%, 75%, and 100% retention), the extent to which interventions could be targeted towards individuals at risk of interrupting ART, and cost-effectiveness thresholds in each setting. FINDINGS: Despite simulating different settings and epidemic trends, all three models produced consistent estimates of health benefit (ie, DALYs averted) and transmission reduction per increment in retention. The range of estimates was 1·35-3·55 DALYs and 0·12-0·20 infections averted over the 40-year time horizon per additional person-year retained on ART. Upper-bound costs varied by setting and intervention effectiveness. Improving retention by 25% among all people receiving ART, regardless of risk of ART interruption, gave an upper-bound cost per person-year of US$2-6 in Optima (Malawi),$43-68 in Synthesis (LMICs in sub-Saharan Africa), and $28-180 in EMOD (South Africa). A maximally targeted and effective retention intervention had an upper-bound cost per person-year of US$93-223 in Optima (Malawi), $871-1389 in Synthesis (LMICs in sub-Saharan Africa), and$1013-6518 in EMOD (South Africa). INTERPRETATION: Upper-bound costs that could improve ART retention vary across sub-Saharan African settings and are likely to be similar to or higher than was estimated before the start of the treat-all era. Upper-bound costs could be increased by targeting interventions to those most at risk of interrupting ART. FUNDING: Bill & Melinda Gates Foundation

Potential impact and cost-effectiveness of condomless-sex-concentrated PrEP in KwaZulu-Natal accounting for drug resistance

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) in the form of tenofovir-disoproxil-fumarate/emtricitabine is being implemented in selected sites in South Africa. Addressing outstanding questions on PrEP cost-effectiveness can inform further implementation. METHODS: We calibrated an individual-based model to KwaZulu-Natal to predict the impact and cost-effectiveness of PrEP, with use concentrated in periods of condomless sex, accounting for effects on drug resistance. We consider (i) PrEP availability for adolescent-girls-and-young-women (aged 15-24; AGYW) and female sex workers (FSW), and (ii) availability for everyone aged 15-64. Our primary analysis represents a level of PrEP use hypothesized to be attainable by future PrEP programmes. RESULTS: In the context of PrEP use in adults aged 15-64 there was a predicted 33% reduction in incidence, and 36% reduction in women aged 15-24. PrEP was cost effective, including in a range of sensitivity analyses, although with substantially reduced (cost) effectiveness under a policy of ART initiation with efavirenz- rather than dolutegravir-based regimens due to PrEP undermining ART effectiveness by increasing HIV drug resistance. CONCLUSIONS: PrEP use concentrated during time periods of condomless sex has the potential to substantively impact HIV incidence and be cost-effective

90-90-90 by 2020? Estimation and projection of the adult HIV epidemic and ART programme in Zimbabwe - 2017 to 2020.

INTRODUCTION: The 90-90-90 targets set by the United Nations aspire to 73% of people living with HIV (PLHIV) being virally suppressed by 2020. Using the HIV Synthesis Model, we aim to mimic the epidemic in Zimbabwe and make projections to assess whether Zimbabwe is on track to meet the 90-90-90 targets and assess whether recently proposed UNAIDS HIV transition metrics are likely to be met. METHODS: We used an approximate Bayesian computation approach to identify model parameter values which result in model outputs consistent with observed data, evaluated using a calibration score. These parameter values were then used to make projections to 2020 to compare with the 90-90-90 targets and other key indicators. We also calculated HIV transition metrics proposed by UNAIDS (percentage reduction in new HIV infections and AIDS-related mortality from 2010 to 2020, absolute rate of new infections and AIDS-related mortality, incidence-mortality ratio and incidence-prevalence ratios). RESULTS: After calibration, there was general agreement between modelled and observed data. The median predicted outcomes in 2020 were: proportion of PLHIV (aged 15 to 65) diagnosed 0.91 (90% uncertainty range 0.87, 0.94) (0.84 men, 0.95 women); of those diagnosed, proportion on treatment 0.92 (0.90, 0.93); of those receiving treatment, proportion with viral suppression 0.86 (0.81, 0.91). This results in 72% of PLHIV having viral suppression in 2020. We estimated a percentage reduction of 36.5% (13.7% increase to 67.4% reduction) in new infections from 2010 to 2020, and of 30.4% (9.7% increase to 56.6% reduction) in AIDS-related mortality (UNAIDS target 75%). The modelled absolute rates of HIV incidence and AIDS-related mortality in 2020 were 5.48 (2.26, 9.24) and 1.93 (1.31, 2.71) per 1000 person-years respectively. The modelled incidence-mortality ratio and incidence-prevalence ratios in 2020 were 1.05 (0.46, 1.66) and 0.009 (0.004, 0.013) respectively. CONCLUSIONS: Our model was able to produce outputs that are simultaneously consistent with an array of observed data and predicted that while the 90-90-90 targets are within reach in Zimbabwe, increased efforts are required in diagnosing men in particular. Calculation of the HIV transition metrics suggest increased efforts are needed to bring the HIV epidemic under control

Strengthening the scale-up and uptake of effective interventions for sex workers for population impact in Zimbabwe.

INTRODUCTION: UNAIDS' goal of ending AIDS by 2030 is unreachable without better targeting of testing, prevention and care. Female sex workers (FSW) in Zimbabwe are at high risk of HIV acquisition and transmission. Here, we report on collated programme and research data from Zimbabwe's national sex work programme. We also assess the potential for wider population impact of FSW programmes by modelling the impact on HIV incidence of eliminating transmission through FSW (i.e. calculate the population attributable fraction of incidence attributable to sex work). METHODS: Descriptive analyses of individual-level programme data collected from FSW between 2009 and June 2018 are triangulated with data collected through 37 respondent driven sampling surveys from 19 sites in Zimbabwe 2011 to 2017. We describe programme coverage, uptake, retention and patterns of sex work behaviour and gaps in service provision. An individual-level stochastic simulation model is used to reconstruct the epidemic and then the incidence compared with the counter-factual trend in incidence from 2010 had transmission through sex work been eliminated from that date. RESULTS: Sisters has reached >67,000 FSW since 2009, increasing attendance as number of sites, programme staff and peer educators were increased. Over 57% of all FSW estimated to be working in Zimbabwe in 2017 (n = 40,000) attended the programme at least once. The proportion of young FSW reached has increased with introduction of the "Young Sisters programme." There are no clear differences in pattern of sex work across settings. Almost all women report condom use with clients at last sex (95%); however, consistent condom use with clients in the last month varies from 52% to 95% by site. Knowledge of HIV-positive status has increased from 48 to 78% between 2011 and 2016, as has prevalence of ART use among diagnosed women (29 to 67%). Although subject to uncertainty, modelling suggests that 70% (90% range: 32%, 93%) of all new infections in Zimbabwe from 2010 are directly or indirectly attributable to transmission via sex work. CONCLUSIONS: It is feasible to increase coverage and impact of sex work programming through community-led scale-up of evidence-based interventions. Eliminating transmission through commercial sex would likely have a substantial impact on new infections occurring more widely across Zimbabwe