Investigating the Associations between Drought, Poverty, High-Risk Sexual Behaviours, and HIV Incidence in Sub-Saharan Africa: A Cross-Sectional Study.

Climate change is increasing the likelihood of drought in sub-Saharan Africa, where HIV prevalence is high. Drought could increase HIV transmission through various mediating mechanisms; we investigated these associations. We used data on people aged 15-59 from Population-Based HIV Impact Assessment surveys from 2016 in Eswatini, Lesotho, Tanzania, Uganda, and Zambia. Survey data were geospatially linked to precipitation data for 2014-2016, with local droughts defined as cumulative rainfall between 2014 and 2016 being in < 15th percentile of all 2-year periods over 1981-2016. Using multivariable logistic regression, stratified by sex and rural/urban residence, we examined associations between (a) drought and poverty, (b) wealth quintiles and sexual behaviours (transactional, high-risk, and intergenerational sex), (c) sexual behaviours and recently acquiring HIV, and (d) drought and recent HIV. Among 102,081 people, 31.5% resided in areas affected by drought during 2014-2016. Experiencing drought was positively associated with poverty for women and men in rural, but not urban, areas. For each group, increasing wealth was negatively associated with transactional sex. For rural women, intergenerational sex was positively associated with wealth. Women reporting each sexual behaviour had higher odds of recent HIV, with strong associations seen for high-risk sex, and, for urban women, intergenerational sex, with weaker associations among men. Women in rural areas who had been exposed to drought had higher odds of having recently acquired HIV (2.10 [95%CI: 1.17-3.77]), but not women in urban areas, or men. Droughts could potentially increase HIV transmission through increasing poverty and then sexual risk behaviours, particularly among women in rural areas.

An agent-based model of binge drinking, inequitable gender norms and their contribution to HIV transmission, with application to South Africa.

BACKGROUND: Binge drinking, inequitable gender norms and sexual risk behaviour are closely interlinked. This study aims to model the potential effect of alcohol counselling interventions (in men and women) and gender-transformative interventions (in men) as strategies to reduce HIV transmission. METHODS: We developed an agent-based model of HIV and other sexually transmitted infections, allowing for effects of binge drinking on sexual risk behaviour, and effects of inequitable gender norms (in men) on sexual risk behaviour and binge drinking. The model was applied to South Africa and was calibrated using data from randomized controlled trials of alcohol counselling interventions (n = 9) and gender-transformative interventions (n = 4) in sub-Saharan Africa. The model was also calibrated to South African data on alcohol consumption and acceptance of inequitable gender norms. Binge drinking was defined as five or more drinks on a single day, in the last month. RESULTS: Binge drinking is estimated to be highly prevalent in South Africa (54% in men and 35% in women, in 2021), and over the 2000-2021 period 54% (95% CI: 34-74%) of new HIV infections occurred in binge drinkers. Binge drinking accounted for 6.8% of new HIV infections (0.0-32.1%) over the same period, which was mediated mainly by an effect of binge drinking in women on engaging in casual sex. Inequitable gender norms accounted for 17.5% of incident HIV infections (0.0-68.3%), which was mediated mainly by an effect of inequitable gender norms on male partner concurrency. A multi-session alcohol counselling intervention that reaches all binge drinkers would reduce HIV incidence by 1.2% (0.0-2.5%) over a 5-year period, while a community-based gender-transformative intervention would reduce incidence by 3.2% (0.8-7.2%) or by 7.3% (0.6-21.2%) if there was no waning of intervention impact. CONCLUSIONS: Although binge drinking and inequitable gender norms contribute substantially to HIV transmission in South Africa, recently-trialled alcohol counselling and gender-transformative interventions are likely to have only modest effects on HIV incidence. Further innovation in developing locally-relevant interventions to address binge drinking and inequitable gender norms is needed.

Associations of inter-annual rainfall decreases with subsequent HIV outcomes for persons with HIV on antiretroviral therapy in Southern Africa: a collaborative analysis of cohort studies.

BACKGROUND: Periods of droughts can lead to decreased food security, and altered behaviours, potentially affecting outcomes on antiretroviral therapy (ART) among persons with HIV (PWH). We investigated whether decreased rainfall is associated with adverse outcomes among PWH on ART in Southern Africa. METHODS: Data were combined from 11 clinical cohorts of PWH in Lesotho, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe, participating in the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration. Adult PWH who had started ART prior to 01/06/2016 and were in follow-up in the year prior to 01/06/2016 were included. Two-year rainfall from June 2014 to May 2016 at the location of each HIV centre was summed and ranked against historical 2-year rainfall amounts (1981-2016) to give an empirical relative percentile rainfall estimate. The IeDEA-SA and rainfall data were combined using each HIV centre's latitude/longitude. In individual-level analyses, multivariable Cox or generalized estimating equation regression models (GEEs) assessed associations between decreased rainfall versus historical levels and four separate outcomes (mortality, CD4 counts < 200 cells/mm3, viral loads > 400 copies/mL, and > 12-month gaps in follow-up) in the two years following the rainfall period. GEEs were used to investigate the association between relative rainfall and monthly numbers of unique visitors per HIV centre. RESULTS: Among 270,708 PWH across 386 HIV centres (67% female, median age 39 [IQR: 32-46]), lower rainfall than usual was associated with higher mortality (adjusted Hazard Ratio: 1.18 [95%CI: 1.07-1.32] per 10 percentile rainfall rank decrease) and unsuppressed viral loads (adjusted Odds Ratio: 1.05 [1.01-1.09]). Levels of rainfall were not strongly associated with CD4 counts < 200 cell/mm3 or > 12-month gaps in care. HIV centres in areas with less rainfall than usual had lower numbers of PWH visiting them (adjusted Rate Ratio: 0.80 [0.66-0.98] per 10 percentile rainfall rank decrease). CONCLUSIONS: Decreased rainfall could negatively impact on HIV treatment behaviours and outcomes. Further research is needed to explore the reasons for these effects. Interventions to mitigate the health impact of severe weather events are required.

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.

Impact of aetiological screening of sexually transmitted infections during pregnancy on pregnancy outcomes in South Africa.

BACKGROUND: Sexually transmitted infections (STIs) during pregnancy may increase the risk of adverse pregnancy outcomes. STI syndromic management is standard of care in South Africa but has its limitations. We evaluated the impact of diagnosing and treating curable STIs during pregnancy on adverse pregnancy and birth outcomes. METHODS: We combined data from two prospective studies of pregnant women attending public sector antenatal care (ANC) clinics in Tshwane District and Cape Town, South Africa. Pregnant women were enrolled, tested and treated for STIs. We evaluated the association between any STI at the first ANC visit and a composite adverse pregnancy outcome (miscarriage, stillbirth, preterm birth, early neonatal death, or low birthweight) using modified Poisson regression models, stratifying by HIV infection and adjusting for maternal characteristics. RESULTS: Among 619 women, 61% (n = 380) were from Tshwane District and 39% (n = 239) from Cape Town; 79% (n = 486) were women living with HIV. The prevalence of any STI was 37% (n = 228); C. trachomatis, 26% (n = 158), T. vaginalis, 18% (n = 120) and N. gonorrhoeae, 6% (n = 40). There were 93% (n = 574) singleton live births, 5% (n = 29) miscarriages and 2% (n = 16) stillbirths. Among the live births, there were 1% (n = 3) neonatal deaths, 7% (n = 35) low birthweight in full-term babies and 10% (n = 62) preterm delivery. There were 24% (n = 146) for the composite adverse pregnancy outcome. Overall, any STI diagnosis and treatment at first ANC visit was not associated with adverse outcomes in women living with HIV (adjusted relative risk (aRR); 1.43, 95% CI: 0.95-2.16) or women without HIV (aRR; 2.11, 95% CI: 0.89-5.01). However, C. trachomatis (aRR; 1.57, 95% CI: 1.04-2.39) and N. gonorrhoeae (aRR; 1.69, 95% CI: 1.09-3.08), were each independently associated with the composite adverse outcome in women living with HIV. CONCLUSION: Treated STIs at the first ANC visit were not associated with adverse pregnancy outcome overall. In women living with HIV, C. trachomatis or N. gonorrhoeae at first ANC were each independently associated with adverse pregnancy outcome. Our results highlights complex interactions between the timing of STI detection and treatment, HIV infection and pregnancy outcomes, which warrants further investigation.

Modelling the impact of prevention strategies on cervical cancer incidence in South Africa.

In 2020, the World Health Organisation (WHO) published a strategy to eliminate cervical cancer as a public health concern. In South Africa, despite having a national screening policy in place since 2000, diagnosed cervical cancer incidence has shown no signs of decline. We extend a previously developed individual-based model for human immunodeficiency virus (HIV) and human papillomavirus (HPV) infection to include progression to cervical cancer. The model accounts for future reductions in HIV incidence and prevalence and includes a detailed cervical cancer screening algorithm, based on individual-level data from the public health sector. We estimate the impact of the current prevention programme and alternative screening scenarios on cervical cancer incidence. The South African screening programme prevented 8600 (95%CI 4700-12 300) cervical cancer cases between 2000 and 2019. At current levels of prevention (status quo vaccination, screening, and treatment), age-standardised cervical cancer incidence will reduce from 49.4 per 100 000 women (95%CI 36.6-67.2) in 2020, to 12.0 per 100 000 women (95%CI 8.0-17.2) in 2120. Reaching WHO's prevention targets by 2030 could help South Africa reach elimination (at the 10/100 000 threshold) by 2077 (94% probability of elimination by 2120). Using new screening technologies could reduce incidence to 4.7 per 100 000 women (95%CI 2.8-6.7) in 2120 (44% probability of elimination at the 4/100 000 threshold). HPV vaccination and decreasing HIV prevalence will substantially reduce cervical cancer incidence in the long term, but improvements to South Africa's current screening strategy will be required to prevent cases in the short term. Switching to new screening technologies will have the greatest impact.

Effect of HIV Infection and Antiretroviral Treatment on Pregnancy Rates in the Western Cape Province of South Africa.

BACKGROUND: Previous studies suggest that untreated human immunodeficiency virus (HIV) infection is associated with a reduced incidence of pregnancy, but studies of the effect of antiretroviral treatment (ART) on pregnancy incidence have been inconsistent. METHODS: Routine data from health services in the Western Cape province of South Africa were linked to identify pregnancies during 2007-2017 and maternal HIV records. The time from the first (index) pregnancy outcome date to the next pregnancy was modeled using Cox proportional hazards models. RESULTS: During 2007-2017, 1 042 647 pregnancies were recorded. In all age groups, pregnancy incidence rates were highest in women who had started ART, lower in HIV-negative women, and lowest in ART-naive HIV-positive women. In multivariable analysis, after controlling for the most recent CD4+ T-cell count, pregnancy incidence rates in HIV-positive women receiving ART were higher than those in untreated HIV-positive women (adjusted hazard ratio, 1.63; 95% confidence interval, 1.59-1.67) and those in HIV-negative women. CONCLUSION: Among women who have recently been pregnant, receipt of ART is associated with high rates of second pregnancy. Better integration of family planning into HIV care services is needed.

Impact of scaling up dolutegravir on antiretroviral resistance in South Africa: A modeling study.

BACKGROUND: Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG's high genetic barrier to resistance. We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040. METHODS AND FINDINGS: We adapted the Modeling Antiretroviral drug Resistance In South Africa (MARISA) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modeled the introduction of DTG in 2020 under 2 scenarios: DTG as first-line regimen for ART initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Given the safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to (1) women beyond reproductive age; (2) women beyond reproductive age or using contraception; and (3) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI PDR in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI PDR would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI PDR from 52.4% (without DTG) to 10.4% (with universal DTG) in 2040. If only men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI PDR would reach 25.9% in 2040. Limitations include substantial uncertainty due to the long-term predictions and the current scarcity of knowledge about DTG efficacy in South Africa. CONCLUSIONS: Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels, whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would only slow down the increase in levels of NNRTI PDR.

Bridging the gap between HIV epidemiology and antiretroviral resistance evolution: Modelling the spread of resistance in South Africa.

The scale-up of antiretroviral therapy (ART) in South Africa substantially reduced AIDS-related deaths and new HIV infections. However, its success is threatened by the emergence of resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI). The MARISA (Modelling Antiretroviral drug Resistance In South Africa) model presented here aims at investigating the time trends and factors driving NNRTI resistance in South Africa. MARISA is a compartmental model that includes the key aspects of the local HIV epidemic: continuum of care, disease progression, and gender. The dynamics of NNRTI resistance emergence and transmission are then added to this framework. Model parameters are informed using data from HIV cohorts participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) and literature estimates, or fitted to UNAIDS estimates. Using this novel approach of triangulating clinical and resistance data from various sources, MARISA reproduces the time trends of HIV in South Africa in 2005-2016, with a decrease in new infections, undiagnosed individuals, and AIDS-related deaths. MARISA captures the dynamics of the spread of NNRTI resistance: high levels of acquired drug resistance (ADR, in 83% of first-line treatment failures in 2016), and increasing transmitted drug resistance (TDR, in 8.1% of ART initiators in 2016). Simulation of counter-factual scenarios reflecting alternative public health policies shows that increasing treatment coverage would have resulted in fewer new infections and deaths, at the cost of higher TDR (11.6% in 2016 for doubling the treatment rate). Conversely, improving switching to second-line treatment would have led to lower TDR (6.5% in 2016 for doubling the switching rate) and fewer new infections and deaths. Implementing drug resistance testing would have had little impact. The rapid ART scale-up and inadequate switching to second-line treatment were the key drivers of the spread of NNRTI resistance in South Africa. However, even though some interventions could have substantially reduced the level of NNRTI resistance, no policy including NNRTI-based first line regimens could have prevented this spread. Thus, by combining epidemiological data on HIV in South Africa with biological data on resistance evolution, our modelling approach identified key factors driving NNRTI resistance, highlighting the need of alternative first-line regimens.

Population-level Mortality Associated with HIV Exposure in HIV-uninfected Infants in Botswana and South Africa: A Model-based Evaluation.

We aimed to quantify the contribution of excess mortality in HIV-exposed uninfected (HEU) infants to total mortality in HIV-uninfected infants in Botswana and South Africa in 2013. Population attributable fractions (PAFs) and excess infant deaths associated with HIV exposure in HIV-uninfected infants were estimated. Additionally, the Thembisa South African demographic model estimated the proportion of all infant mortality associated with excess mortality in HEU infants from 1990 to 2013. The PAF (lower bound; upper bound) of mortality associated with HIV exposure in HIV-uninfected infants was 16.8% (2.5; 31.2) in Botswana and 15.1% (2.2; 28.2) in South Africa. Excess infant deaths (lower bound; upper bound) associated with HIV exposure in 2013 were estimated to be 5.6 (0.5; 16.6)/1000 and 4.9 (0.6; 11.2)/1000 HIV-uninfected infants in Botswana and South Africa, respectively. In South Africa, the proportion of all infant (HIV-infected and HIV-uninfected) mortality associated with excess HEU infant mortality increased from 0.4% in 1990 to 13.8% in 2013.

Precarious transition: a mortality study of South African ex-miners.

BACKGROUND: Despite their burden of a triple epidemic of silicosis, tuberculosis and HIV infection, little is known about the mortality experience of miners from the South African mining industry once they leave employment. Such information is important because of the size and dispersion of this population across a number of countries and the progressive nature of these diseases. METHODS: This study included 306,297 South African miners who left the industry during 2001-2013. The study aimed to calculate crude and standardised mortality rates, identify secular trends in mortality and model demographic and occupational risk factors for mortality. RESULTS: Crude mortality rates peaked in the first year after exit (32.8/1000 person-years), decreasing with each year from exit. Overall mortality was 20% higher than in the general population. Adjusted annual mortality halved over the 12 year period. Mortality predictors were being a black miner [adjusted hazard ratio (aHR) 3.30; 95% confidence interval (CI) 3.15-3.46]; underground work (aHR 1.33; 95% CI 1.28-1.39); and gold aHR 1.15 (95% CI 1.12-1.19) or multiple commodity employment (aHR 1.15; 95% CI 1.11-1.19). CONCLUSIONS: This is the first long-term mortality assessment in the large ex-miner population from the South African mining industry. Mortality patterns follow that of the national HIV-tuberculosis epidemic and antiretroviral treatment availability. However, ex-miners have further elevated mortality and a very high mortality risk in the year after leaving the workforce. Coordinated action between the mining industry, governments and non-governmental organisations is needed to reduce the impact of this precarious transition.

Estimating the impact of antiretroviral treatment on adult mortality trends in South Africa: A mathematical modelling study.

BACKGROUND: Substantial reductions in adult mortality have been observed in South Africa since the mid-2000s, but there has been no formal evaluation of how much of this decline is attributable to the scale-up of antiretroviral treatment (ART), as previous models have not been calibrated to vital registration data. We developed a deterministic mathematical model to simulate the mortality trends that would have been expected in the absence of ART, and with earlier introduction of ART. METHODS AND FINDINGS: Model estimates of mortality rates in ART patients were obtained from the International Epidemiology Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaboration. The model was calibrated to HIV prevalence data (1997-2013) and mortality data from the South African vital registration system (1997-2014), using a Bayesian approach. In the 1985-2014 period, 2.70 million adult HIV-related deaths occurred in South Africa. Adult HIV deaths peaked at 231,000 per annum in 2006 and declined to 95,000 in 2014, a reduction of 74.7% (95% CI: 73.3%-76.1%) compared to the scenario without ART. However, HIV mortality in 2014 was estimated to be 69% (95% CI: 46%-97%) higher in 2014 (161,000) if the model was calibrated only to HIV prevalence data. In the 2000-2014 period, the South African ART programme is estimated to have reduced the cumulative number of HIV deaths in adults by 1.72 million (95% CI: 1.58 million-1.84 million) and to have saved 6.15 million life years in adults (95% CI: 5.52 million-6.69 million). This compares with a potential saving of 8.80 million (95% CI: 7.90 million-9.59 million) life years that might have been achieved if South Africa had moved swiftly to implement WHO guidelines (2004-2013) and had achieved high levels of ART uptake in HIV-diagnosed individuals from 2004 onwards. The model is limited by its reliance on all-cause mortality data, given the lack of reliable cause-of-death reporting, and also does not allow for changes over time in tuberculosis control programmes and ART effectiveness. CONCLUSIONS: ART has had a dramatic impact on adult mortality in South Africa, but delays in the rollout of ART, especially in the early stages of the ART programme, have contributed to substantial loss of life. This is the first study to our knowledge to calibrate a model of ART impact to population-level recorded death data in Africa; models that are not calibrated to population-level death data may overestimate HIV-related mortality.

Designing an optimal HIV programme for South Africa: Does the optimal package change when diminishing returns are considered?

BACKGROUND: South Africa has a large domestically funded HIV programme with highly saturated coverage levels for most prevention and treatment interventions. To further optimise its allocative efficiency, we designed a novel optimisation method and examined whether the optimal package of interventions changes when interaction and non-linear scale-up effects are incorporated into cost-effectiveness analysis. METHODS: The conventional league table method in cost-effectiveness analysis relies on the assumption of independence between interventions. We added methodology that allowed the simultaneous consideration of a large number of HIV interventions and their potentially diminishing marginal returns to scale. We analysed the incremental cost effectiveness ratio (ICER) of 16 HIV interventions based on a well-calibrated epidemiological model that accounted for interaction and non-linear scale-up effects, a custom cost model, and an optimisation routine that iteratively added the most cost-effective intervention onto a rolling baseline before evaluating all remaining options. We compared our results with those based on a league table. RESULTS: The rank order of interventions did not differ substantially between the two methods- in each, increasing condom availability and male medical circumcision were found to be most cost-effective, followed by anti-retroviral therapy at current guidelines. However, interventions were less cost-effective throughout when evaluated under the optimisation method, indicating substantial diminishing marginal returns, with ICERs being on average 437% higher under our optimisation routine. CONCLUSIONS: Conventional league tables may exaggerate the cost-effectiveness of interventions when programmes are implemented at scale. Accounting for interaction and non-linear scale-up effects provides more realistic estimates in highly saturated real-world settings.

A Comparison of Two Mathematical Modeling Frameworks for Evaluating Sexually Transmitted Infection Epidemiology.

BACKGROUND: Different models of sexually transmitted infections (STIs) can yield substantially different conclusions about STI epidemiology, and it is important to understand how and why models differ. Frequency-dependent models make the simplifying assumption that STI incidence is proportional to STI prevalence in the population, whereas network models calculate STI incidence more realistically by classifying individuals according to their partners' STI status. METHODS: We assessed a deterministic frequency-dependent model approximation to a microsimulation network model of STIs in South Africa. Sexual behavior and demographic parameters were identical in the 2 models. Six STIs were simulated using each model: HIV, herpes, syphilis, gonorrhea, chlamydia, and trichomoniasis. RESULTS: For all 6 STIs, the frequency-dependent model estimated a higher STI prevalence than the network model, with the difference between the 2 models being relatively large for the curable STIs. When the 2 models were fitted to the same STI prevalence data, the best-fitting parameters differed substantially between models, with the frequency-dependent model suggesting more immunity and lower transmission probabilities. The fitted frequency-dependent model estimated that the effects of a hypothetical elimination of concurrent partnerships and a reduction in commercial sex were both smaller than estimated by the fitted network model, whereas the latter model estimated a smaller impact of a reduction in unprotected sex in spousal relationships. CONCLUSIONS: The frequency-dependent assumption is problematic when modeling short-term STIs. Frequency-dependent models tend to underestimate the importance of high-risk groups in sustaining STI epidemics, while overestimating the importance of long-term partnerships and low-risk groups.

Simultaneous Treatment of Missing Data and Measurement Error in HIV Research Using Multiple Overimputation.

BACKGROUND: Both CD4 count and viral load in HIV-infected persons are measured with error. There is no clear guidance on how to deal with this measurement error in the presence of missing data. METHODS: We used multiple overimputation, a method recently developed in the political sciences, to account for both measurement error and missing data in CD4 count and viral load measurements from four South African cohorts of a Southern African HIV cohort collaboration. Our knowledge about the measurement error of ln CD4 and log10 viral load is part of an imputation model that imputes both missing and mismeasured data. In an illustrative example, we estimate the association of CD4 count and viral load with the hazard of death among patients on highly active antiretroviral therapy by means of a Cox model. Simulation studies evaluate the extent to which multiple overimputation is able to reduce bias in survival analyses. RESULTS: Multiple overimputation emphasizes more strongly the influence of having high baseline CD4 counts compared to both a complete case analysis and multiple imputation (hazard ratio for >200 cells/mm vs. <25 cells/mm: 0.21 [95% confidence interval: 0.18, 0.24] vs. 0.38 [0.29, 0.48], and 0.29 [0.25, 0.34], respectively). Similar results are obtained when varying assumptions about measurement error, when using p-splines, and when evaluating time-updated CD4 count in a longitudinal analysis. The estimates of the association with viral load are slightly more attenuated when using multiple imputation instead of multiple overimputation. Our simulation studies suggest that multiple overimputation is able to reduce bias and mean squared error in survival analyses. CONCLUSIONS: Multiple overimputation, which can be used with existing software, offers a convenient approach to account for both missing and mismeasured data in HIV research.

Do increasing rates of loss to follow-up in antiretroviral treatment programs imply deteriorating patient retention?

In several studies of antiretroviral treatment (ART) programs for persons with human immunodeficiency virus infection, investigators have reported that there has been a higher rate of loss to follow-up (LTFU) among patients initiating ART in recent years than among patients who initiated ART during earlier time periods. This finding is frequently interpreted as reflecting deterioration of patient retention in the face of increasing patient loads. However, in this paper we demonstrate by simulation that transient gaps in follow-up could lead to bias when standard survival analysis techniques are applied. We created a simulated cohort of patients with different dates of ART initiation. Rates of ART interruption, ART resumption, and mortality were assumed to remain constant over time, but when we applied a standard definition of LTFU, the simulated probability of being classified LTFU at a particular ART duration was substantially higher in recently enrolled cohorts. This suggests that much of the apparent trend towards increased LTFU may be attributed to bias caused by transient interruptions in care. Alternative statistical techniques need to be used when analyzing predictors of LTFU--for example, using "prospective" definitions of LTFU in place of "retrospective" definitions. Similar considerations may apply when analyzing predictors of LTFU from treatment programs for other chronic diseases.

Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women.

BACKGROUND: Persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities. METHODS: Participants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction. RESULTS: HIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV-negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts >350/µl had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 ≤350/µl (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women. CONCLUSION: HIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology.

Increasing age and duration of sex work among female sex workers in South Africa and implications for HIV incidence estimation: Bayesian evidence synthesis and simulation exercise.

Introduction: In sub-Saharan Africa, accurate estimates of the HIV epidemic in female sex workers are crucial for effective prevention and care strategies. These estimates are typically derived from mathematical models that assume certain demographic and behavioural characteristics like age and duration of sex work to remain constant over time. We reviewed this assumption for female sex workers in South Africa. Methods: We reviewed studies that reported estimates on either the age or the duration of sex work among female sex workers in South Africa. We used Bayesian hierarchical models to synthesize reported estimates and to study time trends. In a simulation exercise, we also investigated the potential impact of the "constant age and sex work duration"-assumption on estimates of HIV incidence. Results: We included 24 different studies, conducted between 1996 and 2019, contributing 42 estimates on female sex worker age and 27 estimates on sex work duration. There was evidence suggesting an increase in both the duration of sex work and the age of female sex workers over time. According to the fitted models, over each decade the expected duration of sex work increased by 55.6% (95%-credible interval [CrI]: 23.5%-93.9%) and the expected age of female sex workers increased by 14.3% (95%-CrI: 9.1%-19.1%). Over the 23-year period, the predicted mean duration of sex work increased from 2.7 years in 1996 to 7.4 years in 2019, while the predicted mean age increased from 26.4 years to 32.3 years. Allowing for these time trends in the simulation exercise resulted in a notable decline in estimated HIV incidence rate among sex workers over time. This decline was significantly more pronounced than when assuming a constant age and duration of sex work. Conclusions: In South Africa, age and duration of sex work in female sex workers increased over time. While this trend might be influenced by factors like expanding community mobilization and improved rights advocacy, the ongoing criminalisation, stigmatisation of sex work and lack of alternative employment opportunities could also be contributing. It is important to account for these changes when estimating HIV indicators in female sex workers.

Updated Data and Methods for the 2023 UNAIDS HIV Estimates.

ABSTRACT: Each year, supported by the Joint United Nations Programme on HIV/AIDS (UNAIDS), country teams across the globe produce estimates that chart the state of their HIV epidemics. In 2023, HIV estimates were available for 174 countries, accounting for 99% of the global population, of which teams from 150 countries actively engaged in this process. The methods used to derive these estimates are developed under the guidance of the UNAIDS Reference Group on Estimates, Modeling, and Projections (www.epidem.org). Updates to these methods and epidemiological analyses that inform parameters and assumptions are documented in this supplement.