Modelling the Potential Population Impact and Cost-Effectiveness of Self-Testing for HIV: Evaluation of Data Requirements

HIV testing uptake has increased dramatically in recent years in resource limited settings. Nevertheless, over 50 % of the people living with HIV are still unaware of their status. HIV self-testing (HIVST) is a potential new approach to facilitate further uptake of testing which requires consideration, taking into account economic factors. Mathematical models and associated economic analysis can provide useful assistance in decision-making processes, offering insight, in this case, into the potential long-term impact at a population level and the price-point at which free or subsidized HIVST would be cost-effective in a given setting. However, models are based on assumptions, and if the required data are sparse or limited, this uncertainty will be reflected in the results from mathematical models. The aim of this paper is to describe the issues encountered in modeling the cost-effectiveness of introducing HIVST, to indicate the evidence needed to support various modeling assumptions, and thus which data on HIVST would be most beneficial to collect

Statistical design and analysis plan for an impact evaluation of an HIV treatment and prevention intervention for female sex workers in Zimbabwe: a study protocol for a cluster randomised controlled trial.

BACKGROUND: Pragmatic cluster-randomised trials should seek to make unbiased estimates of effect and be reported according to CONSORT principles, and the study population should be representative of the target population. This is challenging when conducting trials amongst 'hidden' populations without a sample frame. We describe a pair-matched cluster-randomised trial of a combination HIV-prevention intervention to reduce the proportion of female sex workers (FSW) with a detectable HIV viral load in Zimbabwe, recruiting via respondent driven sampling (RDS). METHODS: We will cross-sectionally survey approximately 200 FSW at baseline and at endline to characterise each of 14 sites. RDS is a variant of chain referral sampling and has been adapted to approximate random sampling. Primary analysis will use the 'RDS-2' method to estimate cluster summaries and will adapt Hayes and Moulton's '2-step' method to adjust effect estimates for individual-level confounders and further adjust for cluster baseline prevalence. We will adapt CONSORT to accommodate RDS. In the absence of observable refusal rates, we will compare the recruitment process between matched pairs. We will need to investigate whether cluster-specific recruitment or the intervention itself affects the accuracy of the RDS estimation process, potentially causing differential biases. To do this, we will calculate RDS-diagnostic statistics for each cluster at each time point and compare these statistics within matched pairs and time points. Sensitivity analyses will assess the impact of potential biases arising from assumptions made by the RDS-2 estimation. DISCUSSION: We are not aware of any other completed pragmatic cluster RCTs that are recruiting participants using RDS. Our statistical design and analysis approach seeks to transparently document participant recruitment and allow an assessment of the representativeness of the study to the target population, a key aspect of pragmatic trials. The challenges we have faced in the design of this trial are likely to be shared in other contexts aiming to serve the needs of legally and/or socially marginalised populations for which no sampling frame exists and especially when the social networks of participants are both the target of intervention and the means of recruitment. The trial was registered at Pan African Clinical Trials Registry (PACTR201312000722390) on 9 December 2013

Impact of HIV drug resistance on HIV/AIDS associated mortality, new infections and antiretroviral therapy program costs in sub-Saharan Africa

To inform the level of attention to be given by antiretroviral therapy (ART) programs to HIV drug resistance (HIVDR), we used an individual-level model to estimate its impact on future AIDS deaths, HIV-incidence and ART program costs in sub-Saharan Africa (SSA) for a range of program situations. We applied this to SSA through the Spectrum-Goals model. In a situation in which current levels of pre-treatment HIVDR are over 10% (mean 15%), 16% of AIDS deaths (890,000 deaths) , 9% of new infections (450,000) and 8% ($6.5 billion) of ART program costs in SSA in 2016-2030 will be attributable to HIVDR

Effectiveness of interventions aimed at reducing HIV acquisition and transmission among gay and bisexual men who have sex with men (GBMSM) in high income settings: A systematic review.

INTRODUCTION: HIV transmission continues among gay and bisexual men who have sex with men (GBMSM), with those who are younger, or recent migrants, or of minority ethnicity or who are gender diverse remaining at increased risk. We aimed to identify and describe recent studies evaluating the effectiveness of HIV prevention interventions for GBMSM in high income countries. METHODS: We searched ten electronic databases for randomized controlled trials (RCTs), conducted in high income settings, and published since 2013 to update a previous systematic review (Stromdahl et al, 2015). We predefined four outcome measures of interest: 1) HIV incidence 2) STI incidence 3) condomless anal intercourse (CLAI) (or measure of CLAI) and 4) number of sexual partners. We used the National Institute for Health and Care Excellence (UK) Quality Appraisal of Intervention Studies tool to assess the quality of papers included in the review. As the trials contained a range of effect measures (e.g. odds ratio, risk difference) comparing the arms in the RCTs, we converted them into standardized effect sizes (SES) with 95% confidence intervals (CI). RESULTS: We identified 39 original papers reporting 37 studies. Five intervention types were identified: one-to-one counselling (15 papers), group interventions (7 papers), online interventions (9 papers), Contingency Management for substance use (2 papers) and Pre-exposure Prophylaxis (PrEP) (6 papers). The quality of the studies was mixed with over a third of studies rated as high quality and 11% rated as poor quality. There was some evidence that one-to-one counselling, group interventions (4-10 participants per group) and online (individual) interventions could be effective for reducing HIV transmission risk behaviours such as condomless anal intercourse. PrEP was the only intervention that was consistently effective at reducing HIV incidence. CONCLUSIONS: Our systematic review of the recent evidence that we were able to analyse indicates that PrEP is the most effective intervention for reducing HIV acquisition among GBMSM. Targeted and culturally tailored behavioural interventions for sub-populations of GBMSM vulnerable to HIV infection and other STIs should also be considered, particularly for GBMSM who cannot access or decline to use PrEP

Estimating the hospital costs of care for people living with HIV in England using routinely collected data

Background: Understanding the health care activity and associated hospital costs of caring for people living with HIV is an important component of assessing the cost effectiveness of new technologies and for budget planning. Methods: Data collected between 2010 and 2017 from an English HIV treatment centre were combined with national reference costs to estimate the rate of hospital attendances and costs per quarter year, according to demographic and clinical factors. The final dataset included records for 1763 people living with HIV, which was analysed using negative binomial regression models and general estimating equations. Results: People living with HIV experienced an unadjusted average of 0.028 (standard deviation [SD] 0.20) inpatient episodes per quarter, equivalent to one every 9 years, and 1.85 (SD 2.30) outpatient visits per quarter. The unadjusted mean quarterly cost per person with HIV (excluding antiretroviral drug costs) was £439 (SD 604). Outpatient appointments and inpatient episodes accounted for 88% and 6% of total costs, respectively. In adjusted models, low CD4 count was the strongest predictor of inpatient stays and outpatient visits. Low CD4 count and new patient status (having a first visit at the Trust in the last 6 months) were the factors that most increased estimated costs. Associations were weaker or less consistent for demographic factors (age, sex/sexual orientation/ethnicity). Sensitivity analyses suggest that the findings were generally robust to alternative parameter and modelling assumptions. Conclusion: A number of factors predicted hospital activity and costs, but CD4 cell count and new patient status were the strongest. The study results can be incorporated into future economic evaluations and budget impact assessments of HIV‐related technologies

Behaviour changes following HIV diagnosis among men who have sex with men in the era of treatment as prevention: data from a prospective study

We described the longitudinal changes in sexual behaviour and associated factors among newly diagnosed with HIV men who have sex with men participating in a prospective observational study from a London HIV clinic (2015-2018). Participants self-completed questionnaires at baseline, months 3 and 12. Information collected included socio-demographic, sexual behaviour, health, lifestyle and social support. Trends in sexual behaviours over one year following diagnosis and associated factors were assessed using generalized estimating equations with logit link. Condomless sex (CLS) dropped from 62.2% at baseline to 47.6% at month-three but increased again to 61.8% at month-12 (p-trend = 0.790). Serodiscordant-CLS increased between month-three and month-12 (from 13.1% to 35.6%, p-trend < 0.001). The prevalence of serodiscordant-CLS with high risk of transmitting to their partners at month-three was 10.7%. CLS was higher among men who reported recreational drug use (adjusted Odds Ratio (aOR) 3.03, 95%CI 1.47-6.24, p = 0.003), those with undetectable viral load (aOR 2.17, 95%CI 1.22-3.84, p = 0.008) and those who agreed with a statement "condoms are not necessary when HIV viral load is undetectable" (aOR 3.41, 95%CI 1.58-7.38, p = 0.002). MSM continued to engage in CLS after HIV diagnosis, which coincided with U = U publications and increased throughout the study

Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis.

BACKGROUND: Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. METHODS: We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK), a borough with high HIV prevalence (≥0·2% adult prevalence). We constructed a dynamic, compartmental model representing incidence of infection and the effect of screening for HIV in general practices in Hackney. We assessed cost-effectiveness of the RHIVA2 trial by fitting model diagnosis rates to the trial data, parameterising with epidemiological and behavioural data from the literature when required, using trial testing costs and projecting future costs of treatment. FINDINGS: Over a 40 year time horizon, incremental cost-effectiveness ratios were £22 201 (95% credible interval 12 662-132 452) per quality-adjusted life-year (QALY) gained, £372 207 (268 162-1 903 385) per death averted, and £628 874 (434 902-4 740 724) per HIV transmission averted. Under this model scenario, with UK cost data, RHIVA2 would reach the upper National Institute for Health and Care Excellence cost-effectiveness threshold (about £30 000 per QALY gained) after 33 years. Scenarios using cost data from Canada (which indicate prolonged and even higher health-care costs for patients diagnosed late) suggest this threshold could be reached in as little as 13 years. INTERPRETATION: Screening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high-prevalence regions are much higher (≥60%) than those of patients diagnosed earlier. Screening for HIV in primary care is cost-effective and should be promoted. FUNDING: NHS City and Hackney, UK Department of Health, National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care

Cost-effectiveness of pre-exposure prophylaxis for HIV prevention in men who have sex with men in the UK: a modelling study and health economic evaluation.

BACKGROUND: In the UK, HIV incidence among men who have sex with men (MSM) has remained high for several years, despite widespread use of antiretroviral therapy and high rates of virological suppression. Pre-exposure prophylaxis (PrEP) has been shown to be highly effective in preventing further infections in MSM, but its cost-effectiveness is uncertain. METHODS: In this modelling study and economic evaluation, we calibrated a dynamic, individual-based stochastic model, the HIV Synthesis Model, to multiple data sources (surveillance data provided by Public Health England and data from a large, nationally representative survey, Natsal-3) on HIV among MSM in the UK. We did a probabilistic sensitivity analysis (sampling 22 key parameters) along with a range of univariate sensitivity analyses to evaluate the introduction of a PrEP programme with sexual event-based use of emtricitabine and tenofovir for MSM who had condomless anal sexual intercourse in the previous 3 months, a negative HIV test at baseline, and a negative HIV test in the preceding year. The main model outcomes were the number of HIV infections, quality-adjusted life-years (QALYs), and costs. FINDINGS: Introduction of such a PrEP programme, with around 4000 MSM initiated on PrEP by the end of the first year and almost 40 000 by the end of the 15th year, would result in a total cost saving (£1·0 billion discounted), avert 25% of HIV infections (42% of which would be directly because of PrEP), and lead to a gain of 40 000 discounted QALYs over an 80-year time horizon. This result was particularly sensitive to the time horizon chosen, the cost of antiretroviral drugs (for treatment and PrEP), and the underlying trend in condomless sex. INTERPRETATION: This analysis suggests that the introduction of a PrEP programme for MSM in the UK is cost-effective and possibly cost-saving in the long term. A reduction in the cost of antiretroviral drugs (including the drugs used for PrEP) would substantially shorten the time for cost savings to be realised. FUNDING: National Institute for Health Research

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

Predictors of starting and stopping chemsex in men who have sex with men in England: findings from the AURAH2 prospective study

BACKGROUND: Chemsex (the use of psychoactive drugs in sexual contexts) has been associated with HIV acquisition and other STIs, so there is benefit in identifying those most likely to start chemsex to offer risk reduction interventions such as pre-exposure prophylaxis (PrEP). To date, there have been no data from a longitudinal study analysing factors most associated with starting and stopping chemsex. METHODS: The prospective cohort study, Attitudes to and Understanding Risk of Acquisition of HIV over Time (AURAH2), collected 4 monthly and annual online questionnaire data from men who have sex with men (MSM) from 2015 to 2018. We investigate the association of sociodemographic factors, sexual behaviours and drug use with starting and stopping chemsex among 622 men who completed at least one follow-up questionnaire. Poisson models with generalised estimating equations were used to produce risk ratios (RRs) accounting for multiple starting or stopping episodes from the same individual. Multivariable analysis was adjusted for age group, ethnicity, sexual identity and university education. FINDINGS: In the multivariable analysis, the under 40 age group was significantly more likely to start chemsex by the next assessment (RR 1.79, 95% CI 1.12 to 2.86). Other factors which showed significant association with starting chemsex were unemployment (RR 2.10, 95% CI 1.02 to 4.35), smoking (RR 2.49, 95% CI 1.63 to 3.79), recent condomless sex (CLS), recent STI and postexposure prophylaxis (PEP) use in the past year (RR 2.10, 95% CI 1.33 to 3.30). Age over 40 (RR 0.71, 95% CI 0.51 to 0.99), CLS, and use of PEP (RR 0.64, 95% CI 0.47 to 0.86) and PrEP (RR 0.47, 95% CI 0.29 to 0.78) were associated with lower likelihood of stopping chemsex by the next assessment. INTERPRETATION: Knowledge of these results allows us to identify men most likely to start chemsex, thus providing an opportunity for sexual health services to intervene with a package of risk mitigation measures, especially PrEP use