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Antiretroviral Therapy and Mortality in Rural South Africa: A Comparison of Causal Modeling Approaches.

ABSTRACT: Estimation of causal effects from observational data is a primary goal of epidemiology. The use of multiple methods with different assumptions relating to exchangeability improves causal inference by demonstrating robustness across assumptions. We estimate the effect of antiretroviral therapy (ART) on mortality in rural KwaZulu-Natal, South Africa from 2007-2011 using two methods with substantially different assumptions: the regression discontinuity design (RDD), and inverse probability weighting of marginal structural models (IPW). The RDD analysis took advantage of a CD4 count-based threshold for ART initiation (200 cells/?l). The two methods yielded consistent but non-identical results for the effect of immediate initiation of ART (RDD intention-to-treat hazards ratio (HR) 0.66, 95% CI 0.35 to 1.26; RDD HR 0.56, 95% CI 0.41 to 0.77; IPW HR 0.49, 95% CI 0.42 to 0.58). Although RDD and IPW estimates had distinct identifying assumptions, strengths, and limitations in terms of internal and external validity, results in this application were similar. The differences in modeling approaches and external validity of each method may explain the minor differences in effect estimates, but the consistency of the results lends support for causal inference of the effect of ART and mortality from these data.

SUBMITTER: Oldenburg CE

PROVIDER: S-EPMC6070080 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Antiretroviral Therapy and Mortality in Rural South Africa: A Comparison of Causal Modeling Approaches.

Oldenburg Catherine E CE Seage George R GR Tanser Frank F De Gruttola Victor V Mayer Kenneth H KH Mimiaga Matthew J MJ Bor Jacob J Bärnighausen Till T

American journal of epidemiology 20180801 8

Estimation of causal effects from observational data is a primary goal of epidemiology. The use of multiple methods with different assumptions relating to exchangeability improves causal inference by demonstrating robustness across assumptions. We estimated the effect of antiretroviral therapy (ART) on mortality in rural KwaZulu-Natal, South Africa, from 2007 to 2011, using 2 methods with substantially different assumptions: the regression discontinuity design (RDD) and inverse-probability-weigh ...[more]

PMID: 29584868

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Project description:BackgroundUnderstanding the effects of socioeconomic disparities in health outcomes is important to implement specific preventive actions. We assessed socioeconomic disparities in mortality indicators in a rural South African population over the period 2001-13.MethodsWe used data from 21 villages of the Agincourt Health and socio-Demographic Surveillance System (HDSS). We calculated the probabilities of death from birth to age 5 years and from age 15 to 60 years, life expectancy at birth, and cause-specific and age-specific mortality by sex (not in children <5 years), time period, and socioeconomic status (household wealth) quintile for HIV/AIDS and tuberculosis, other communicable diseases (excluding HIV/AIDS and tuberculosis) and maternal, perinatal, and nutritional causes, non-communicable diseases, and injury. We also quantified differences with relative risk ratios and relative and slope indices of inequality.FindingsBetween 2001 and 2013, 10 414 deaths were registered over 1 058 538 person-years of follow-up, meaning the overall crude mortality was 9·8 deaths per 1000 person-years. We found significant socioecomonic status gradients for mortality and life expectancy at birth, with outcomes improving with increasing socioeconomic status. An inverse relation was seen for HIV/AIDS and tuberculosis mortality and socioeconomic status that persisted from 2001 to 2013. Deaths from non-communicable diseases increased over time in both sexes, and injury was an important cause of death in men and boys. Neither of these causes of death, however, showed consistent significant associations with household socioeconomic status.InterpretationThe poorest people in the population continue to bear a high burden of HIV/AIDS and tuberculosis mortality, despite free antiretroviral therapy being made available from public health facilities. Associations between socioeconomic status and increasing burden of mortality from non-communicable diseases is likely to become prominent. Integrated strategies are needed to improve access to and uptake of HIV testing, care, and treatment, and management of non-communicable diseases in the poorest populations.FundingWellcome Trust, South African Medical Research Council, and University of the Witwatersrand, South Africa.

Project description:BackgroundThe provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland.Methods and findingsWe analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/mul in South Africa and 204 cells/mul in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%-97%) in South Africa and 96% (94%-97%) in Switzerland, and 26% (22%-29%) and 27% (24%-31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81-19.2) during months 1-3 and 1.77 (0.90-3.50) during months 4-24.ConclusionsCompared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.

Project description:BackgroundMortality in HIV-infected patients who have access to highly active antiretroviral therapy (ART) has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV-infected population. We compared mortality rates observed in HIV-1-infected patients starting ART with non-HIV-related background mortality in four countries in sub-Saharan Africa.Methods and findingsPatients enrolled in antiretroviral treatment programmes in Côte d'Ivoire, Malawi, South Africa, and Zimbabwe were included. We calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 y, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting ART. The excess mortality rate was 17.5 (95% CI 14.5-21.1) per 100 person-years SMR in patients who started ART with a CD4 cell count of less than 25 cells/microl and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55-1.81) per 100 person-years in patients who started with 200 cells/microl or above with WHO stage I/II. The corresponding SMRs were 47.1 (39.1-56.6) and 3.44 (1.91-6.17). Among patients who started ART with 200 cells/microl or above in WHO stage I/II and survived the first year of ART, the excess mortality rate was 0.27 (0.08-0.94) per 100 person-years and the SMR was 1.14 (0.47-2.77).ConclusionsMortality of HIV-infected patients treated with combination ART in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of ART. Much of the excess mortality might be prevented by timely initiation of ART.

Project description:Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study's finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ?350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study's major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled.Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors' Summary.

Project description:BackgroundAntiretroviral therapy (ART) was highly efficacious in preventing human immunodeficiency virus (HIV) transmission in stable serodiscordant couples in the HPTN-052 study, a resource-intensive randomized controlled trial with near-perfect ART adherence and mutual HIV status disclosure among all participating couples. However, minimal evidence exists of the effectiveness of ART in preventing HIV acquisition in stable serodiscordant couples in "real-life" population-based settings in hyperendemic communities of sub-Saharan Africa, where health systems are typically resource-poor and overburdened, adherence to ART is often low, and partners commonly do not disclose their HIV status to each other.MethodsData arose from a population-based open cohort in KwaZulu-Natal, South Africa. A total of 17 016 HIV-uninfected individuals present between January 2005 and December 2013 were included. Interval-censored time-updated proportional hazards regression was used to assess how the ART status affected HIV transmission risk in stable serodiscordant relationships.ResultsWe observed 1619 HIV seroconversions in 17 016 individuals, over 60 349 person-years follow-up time. During the follow-up period, 1846 individuals had an HIV-uninfected and 196 had an HIV-infected stable partner HIV incidence was 3.8/100 person-years (PY) among individuals with an HIV-infected partner (95% confidence interval [CI], 2.3-5.6), 1.4/100 PY (.4-3.5) among those with HIV-infected partners receiving ART, and 5.6/100 PY (3.5-8.4) among those with HIV-infected partners not receiving ART. Use of ART was associated with a 77% decrease in HIV acquisition risk among serodiscordant couples (adjusted hazard ratio, 0.23; 95% CI, .07-.80).ConclusionsART initiation was associated with a very large reduction in HIV acquisition in serodiscordant couples in rural KwaZulu-Natal. However, this "real-life" effect was substantially lower than the effect observed in the HPTN-052 trial. To eliminate HIV transmission in serodiscordant couples, additional prevention interventions are probably needed.

Dataset Information

Antiretroviral Therapy and Mortality in Rural South Africa: A Comparison of Causal Modeling Approaches.

Publications

Antiretroviral Therapy and Mortality in Rural South Africa: A Comparison of Causal Modeling Approaches.

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