Background South Africa implemented universal test and treat (UTT) in September 2016 in an effort... more Background South Africa implemented universal test and treat (UTT) in September 2016 in an effort to encourage earlier initiation of antiretroviral therapy (ART). Methods We therefore conducted an interrupted time series (ITS) analysis to assess the impact of UTT on mean CD4 count at ART initiation among adults aged ≥16 years attending 17 public sector primary care clinics in rural South Africa, between July 2014 and March 2019. Results Among 20 599 individuals (69% women), CD4 counts were available for 74%. Mean CD4 at ART initiation increased from 317.1 cells/μL (95% confidence interval [CI], 308.6 to 325.6) 1 to 8 months prior to UTT to 421.0 cells/μL (95% CI, 413.0 to 429.0) 1 to 12 months after UTT, including an immediate increase of 124.2 cells/μL (95% CI, 102.2 to 146.1). However, mean CD4 count subsequently fell to 389.5 cells/μL (95% CI, 381.8 to 397.1) 13 to 30 months after UTT but remained above pre-UTT levels. Men initiated ART at lower CD4 counts than women (–118.2 cell...
Purpose of Review The ANRS 12249 treatment as prevention (TasP) trial investigated the impact of ... more Purpose of Review The ANRS 12249 treatment as prevention (TasP) trial investigated the impact of a universal test and treat (UTT) approach on reducing HIV incidence in one of the regions of the world most severely affected by the HIV epidemic—KwaZulu-Natal, South Africa. We summarize key findings from this trial as well as recent findings from controlled studies conducted in the linked population cohort quantifying the long-term effects of expanding ART on directly measured HIV incidence (2004–2017). Recent Findings The ANRS TasP trial did not—and could not—demonstrate a reduction in HIV incidence, because the offer of UTT in the intervention communities did not increase ART coverage and population viral suppression compared to the standard of care in the control communities. Ten controlled studies from the linked population cohort—including several quasi-experimental study designs—exploit heterogeneity in ART exposure to show a consistent and substantial impact of expanding provisi...
The effect of HIV treatment on hospitalization rates for HIV-infected people has never been estab... more The effect of HIV treatment on hospitalization rates for HIV-infected people has never been established. We quantified this effect in a rural South African community for the period 2009-13. We linked clinical data on HIV treatment start dates for more than 2,000 patients receiving care in the public-sector treatment program with five years of longitudinal data on self-reported hospitalizations from a community-based population cohort of more than 100,000 adults. Hospitalization rates peaked during the first year of treatment and were about five times higher, compared to hospitalization rates after four years on treatment. Earlier treatment initiation could save more than US$300,000 per 1,000 patients over the first four years of HIV treatment, freeing up scarce resources. Future studies on the cost-effectiveness of HIV treatment should include these effects.
International journal of health geographics, Jul 11, 2018
Large geographical variations in the intensity of the HIV epidemic in sub-Saharan Africa call for... more Large geographical variations in the intensity of the HIV epidemic in sub-Saharan Africa call for geographically targeted resource allocation where burdens are greatest. However, data available for mapping the geographic variability of HIV prevalence and detecting HIV 'hotspots' is scarce, and population-based surveillance data are not always available. Here, we evaluated the viability of using clinic-based HIV prevalence data to measure the spatial variability of HIV in South Africa and Tanzania. Population-based and clinic-based HIV data from a small HIV hyper-endemic rural community in South Africa as well as for the country of Tanzania were used to map smoothed HIV prevalence using kernel interpolation techniques. Spatial variables were included in clinic-based models using co-kriging methods to assess whether cofactors improve clinic-based spatial HIV prevalence predictions. Clinic- and population-based smoothed prevalence maps were compared using partial rank correlati...
The universal test and treat strategy (UTT) was developed to maximize the proportion of all HIV-p... more The universal test and treat strategy (UTT) was developed to maximize the proportion of all HIV-positive individuals on antiretroviral treatment (ART) and virally suppressed, assuming that it will lead to a reduction in HIV incidence at the population level. The evolution over time of the cross-sectional HIV care cascade is determined by individual longitudinal trajectories through the HIV care continuum and underlying population dynamics. The purpose of this paper is to quantify the contribution of each component of population change (in- and out-migration, HIV seroconversion, ageing into the cohort and definitive exit such as death) on the HIV care cascade in the context of the ANRS 12249 Treatment as Prevention (TasP) cluster-randomized trial, investigating UTT in rural KwaZulu-Natal, South Africa, between 2012 and 2016. HIV test results and information on clinic visits, ART prescriptions, viral load and CD4 count, migration and deaths were used to calculate residency status, HIV...
In the context of a severe generalized African HIV epidemic, the value of geographically targeted... more In the context of a severe generalized African HIV epidemic, the value of geographically targeted prevention interventions has only recently been given serious consideration. However, to date no study has performed a population-based analysis of the micro-geographical clustering of HIV incident infections, limiting the evidential support for such a strategy. We followed 17 984 HIV-uninfected individuals aged 15-54 in a population-based cohort in rural KwaZulu-Natal, South Africa, and observed individual HIV sero-conversions between 2004 and 2014. We geo-located all individuals to an exact homestead of residence (accuracy <2 m). We then employed a two-dimensional Gaussian kernel of radius 3 km to produce robust estimates of HIV incidence which vary across continuous geographical space. We also applied Tango's flexibly shaped spatial scan statistic to identify irregularly shaped clusters of high HIV incidence. Between 2004 and 2014, we observed a total of 2 311 HIV sero-convers...
We investigate the effect of immediate antiretroviral therapy (ART) eligibility on HIV incidence ... more We investigate the effect of immediate antiretroviral therapy (ART) eligibility on HIV incidence among HIV-uninfected household members. Regression discontinuity study arising from a population-based cohort. Household members of patients seeking care at the Hlabisa HIV Treatment and Care Programme in rural KwaZulu-Natal South Africa between January 2007 and August 2011 with CD4 cell counts up to 350 cells/μl were eligible for inclusion if they had at least two HIV tests and were HIV-uninfected at the time the index patient linked to care (N = 4115). Regression discontinuity was used to assess the intention-to-treat effect of immediate versus delayed ART eligibility on HIV incidence among household members. Exploiting the CD4 cell count-based threshold rule for ART initiation (CD4 < 200 cells/μl until August 2011), we used Cox proportional hazards models to compare outcomes for household members of patients who presented for care with CD4 cell counts just above versus just below t...
Loss to follow-up is high among HIV patients not yet receiving antiretroviral therapy (ART). Clin... more Loss to follow-up is high among HIV patients not yet receiving antiretroviral therapy (ART). Clinical trials have demonstrated the clinical efficacy of early ART; however, these trials may miss an important real-world consequence of providing ART at diagnosis: its impact on retention in care. We examined the effect of immediate (versus deferred) ART on retention in care using a regression discontinuity design. The analysis included all patients (N = 11,306) entering clinical HIV care with a first CD4 count between 12 August 2011 and 31 December 2012 in a public-sector HIV care and treatment program in rural South Africa. Patients were assigned to immediate versus deferred ART eligibility, as determined by a CD4 count < 350 cells/μl, per South African national guidelines. Patients referred to pre-ART care were instructed to return every 6 months for CD4 monitoring. Patients initiated on ART were instructed to return at 6 and 12 months post-initiation and annually thereafter for CD...
Tropical medicine & international health : TM & IH, Feb 21, 2017
To assess the relationship between CD4 count at presentation and ART uptake and assess predictors... more To assess the relationship between CD4 count at presentation and ART uptake and assess predictors of timely treatment initiation in rural KwaZulu-Natal, South Africa. We used Cox Proportional Hazards models to assess the association between first CD4 count and time from first CD4 to ART initiation amongst all treatment-naïve adults presenting to the Hlabisa HIV Treatment and Care Program between August 2011 and December 2012, with CD4<350 cells. For a sub-set of healthier patients (200≤CD4<350 cells) residing within the population surveillance of the Africa Health Research Institute, we assessed sociodemographic, economic, and geographic predictors hypothesized to influence ART uptake. 4,739 patients presented for care with eligible CD4 counts. The proportion initiating ART within six months of diagnosis was 67% (95% CI 63, 71) in patients with CD4≤50, 59% (0.55, 0.63) in patients with CD4 151-200, and 48% (95% CI 44, 51) in patients with CD4 301- 350. The hazard of starting A...
The World Health Organization recommends initiating antiretroviral therapy (ART) regardless of CD... more The World Health Organization recommends initiating antiretroviral therapy (ART) regardless of CD4 count. We assessed the effect of ART eligibility on treatment uptake and simulated the impact of WHO's recommendations in South Africa. We conducted an empirical analysis of cohort data using a regression discontinuity design, and then used this model for policy simulation. We enrolled all patients (n = 19,279) diagnosed with HIV between August 2011 and December 2013 in the Hlabisa HIV Treatment and Care Programme in rural South Africa. Patients were ART-eligible with CD4<350 cells/mm3 or Stage III/IV illness. We estimated: (1) distribution of first CD4 counts in 2013; (2) probability of initiating ART ≤6 months of HIV diagnosis under existing criteria at each CD4 count; (3) probability of initiating ART by CD4 count if thresholds were eliminated; and (4) number of expected new initiators if South Africa eliminates thresholds. In 2013, 38.9% of patients diagnosed had a CD4 count...
Clinic-based studies have shown that patients with human immunodeficiency virus (HIV) gain weight... more Clinic-based studies have shown that patients with human immunodeficiency virus (HIV) gain weight after initiation of antiretroviral therapy (ART). This study aimed to determine whether the scale-up of ART was associated with a population-level increase in body mass index (BMI) and blood pressure (BP) in a community with high HIV and obesity prevalence. A household survey was conducted in rural KwaZulu-Natal before ART scale-up (in 2004) and when ART coverage had reached 25% (in 2010). Anthropometric data was linked with HIV surveillance data. Mean BMI decreased in women from 29.9 to 29.1 kg/m(2) (P = 0.002) and in men from 24.2 to 23.0 kg/m(2) (P < 0.001). Similarly, overweight and obesity prevalence declined significantly in both sexes. Mean systolic BP decreased from 123.0 to 118.2 mm Hg (P < 0.001) among women and 128.4 to 123.2 mm Hg (P < 0·001) among men. Large-scale ART provision is likely to have caused a decline in BMI at the population level, because ART has impro...
International journal of epidemiology, Jan 10, 2016
Despite the importance of HIV testing for controlling the HIV epidemic, testing rates remain low.... more Despite the importance of HIV testing for controlling the HIV epidemic, testing rates remain low. Efforts to scale up testing coverage and frequency in hard-to-reach and at-risk populations commonly focus on home-based HIV testing. This study evaluates the effect of a gift (a US$5 food voucher for families) on consent rates for home-based HIV testing. We use data on 18 478 individuals (6 418 men and 12 060 women) who were successfully contacted to participate in the 2009 and 2010 population-based HIV surveillance carried out by the Wellcome Trust's Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Of 18 478 potential participants contacted in both years, 35% (6 518) consented to test in 2009, and 41% (7 533) consented to test in 2010. Our quasi-experimental difference-in-differences approach controls for unobserved confounding in estimating the causal effect of the intervention on HIV-testing consent rates. Allocation of the gift to a family in 2010 increase...
Genome-wide association studies (GWAS) have considerably advanced our understanding of human trai... more Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics. We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1st line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naïve to the respective treatment. GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we high...
Background South Africa implemented universal test and treat (UTT) in September 2016 in an effort... more Background South Africa implemented universal test and treat (UTT) in September 2016 in an effort to encourage earlier initiation of antiretroviral therapy (ART). Methods We therefore conducted an interrupted time series (ITS) analysis to assess the impact of UTT on mean CD4 count at ART initiation among adults aged ≥16 years attending 17 public sector primary care clinics in rural South Africa, between July 2014 and March 2019. Results Among 20 599 individuals (69% women), CD4 counts were available for 74%. Mean CD4 at ART initiation increased from 317.1 cells/μL (95% confidence interval [CI], 308.6 to 325.6) 1 to 8 months prior to UTT to 421.0 cells/μL (95% CI, 413.0 to 429.0) 1 to 12 months after UTT, including an immediate increase of 124.2 cells/μL (95% CI, 102.2 to 146.1). However, mean CD4 count subsequently fell to 389.5 cells/μL (95% CI, 381.8 to 397.1) 13 to 30 months after UTT but remained above pre-UTT levels. Men initiated ART at lower CD4 counts than women (–118.2 cell...
Purpose of Review The ANRS 12249 treatment as prevention (TasP) trial investigated the impact of ... more Purpose of Review The ANRS 12249 treatment as prevention (TasP) trial investigated the impact of a universal test and treat (UTT) approach on reducing HIV incidence in one of the regions of the world most severely affected by the HIV epidemic—KwaZulu-Natal, South Africa. We summarize key findings from this trial as well as recent findings from controlled studies conducted in the linked population cohort quantifying the long-term effects of expanding ART on directly measured HIV incidence (2004–2017). Recent Findings The ANRS TasP trial did not—and could not—demonstrate a reduction in HIV incidence, because the offer of UTT in the intervention communities did not increase ART coverage and population viral suppression compared to the standard of care in the control communities. Ten controlled studies from the linked population cohort—including several quasi-experimental study designs—exploit heterogeneity in ART exposure to show a consistent and substantial impact of expanding provisi...
The effect of HIV treatment on hospitalization rates for HIV-infected people has never been estab... more The effect of HIV treatment on hospitalization rates for HIV-infected people has never been established. We quantified this effect in a rural South African community for the period 2009-13. We linked clinical data on HIV treatment start dates for more than 2,000 patients receiving care in the public-sector treatment program with five years of longitudinal data on self-reported hospitalizations from a community-based population cohort of more than 100,000 adults. Hospitalization rates peaked during the first year of treatment and were about five times higher, compared to hospitalization rates after four years on treatment. Earlier treatment initiation could save more than US$300,000 per 1,000 patients over the first four years of HIV treatment, freeing up scarce resources. Future studies on the cost-effectiveness of HIV treatment should include these effects.
International journal of health geographics, Jul 11, 2018
Large geographical variations in the intensity of the HIV epidemic in sub-Saharan Africa call for... more Large geographical variations in the intensity of the HIV epidemic in sub-Saharan Africa call for geographically targeted resource allocation where burdens are greatest. However, data available for mapping the geographic variability of HIV prevalence and detecting HIV 'hotspots' is scarce, and population-based surveillance data are not always available. Here, we evaluated the viability of using clinic-based HIV prevalence data to measure the spatial variability of HIV in South Africa and Tanzania. Population-based and clinic-based HIV data from a small HIV hyper-endemic rural community in South Africa as well as for the country of Tanzania were used to map smoothed HIV prevalence using kernel interpolation techniques. Spatial variables were included in clinic-based models using co-kriging methods to assess whether cofactors improve clinic-based spatial HIV prevalence predictions. Clinic- and population-based smoothed prevalence maps were compared using partial rank correlati...
The universal test and treat strategy (UTT) was developed to maximize the proportion of all HIV-p... more The universal test and treat strategy (UTT) was developed to maximize the proportion of all HIV-positive individuals on antiretroviral treatment (ART) and virally suppressed, assuming that it will lead to a reduction in HIV incidence at the population level. The evolution over time of the cross-sectional HIV care cascade is determined by individual longitudinal trajectories through the HIV care continuum and underlying population dynamics. The purpose of this paper is to quantify the contribution of each component of population change (in- and out-migration, HIV seroconversion, ageing into the cohort and definitive exit such as death) on the HIV care cascade in the context of the ANRS 12249 Treatment as Prevention (TasP) cluster-randomized trial, investigating UTT in rural KwaZulu-Natal, South Africa, between 2012 and 2016. HIV test results and information on clinic visits, ART prescriptions, viral load and CD4 count, migration and deaths were used to calculate residency status, HIV...
In the context of a severe generalized African HIV epidemic, the value of geographically targeted... more In the context of a severe generalized African HIV epidemic, the value of geographically targeted prevention interventions has only recently been given serious consideration. However, to date no study has performed a population-based analysis of the micro-geographical clustering of HIV incident infections, limiting the evidential support for such a strategy. We followed 17 984 HIV-uninfected individuals aged 15-54 in a population-based cohort in rural KwaZulu-Natal, South Africa, and observed individual HIV sero-conversions between 2004 and 2014. We geo-located all individuals to an exact homestead of residence (accuracy <2 m). We then employed a two-dimensional Gaussian kernel of radius 3 km to produce robust estimates of HIV incidence which vary across continuous geographical space. We also applied Tango's flexibly shaped spatial scan statistic to identify irregularly shaped clusters of high HIV incidence. Between 2004 and 2014, we observed a total of 2 311 HIV sero-convers...
We investigate the effect of immediate antiretroviral therapy (ART) eligibility on HIV incidence ... more We investigate the effect of immediate antiretroviral therapy (ART) eligibility on HIV incidence among HIV-uninfected household members. Regression discontinuity study arising from a population-based cohort. Household members of patients seeking care at the Hlabisa HIV Treatment and Care Programme in rural KwaZulu-Natal South Africa between January 2007 and August 2011 with CD4 cell counts up to 350 cells/μl were eligible for inclusion if they had at least two HIV tests and were HIV-uninfected at the time the index patient linked to care (N = 4115). Regression discontinuity was used to assess the intention-to-treat effect of immediate versus delayed ART eligibility on HIV incidence among household members. Exploiting the CD4 cell count-based threshold rule for ART initiation (CD4 < 200 cells/μl until August 2011), we used Cox proportional hazards models to compare outcomes for household members of patients who presented for care with CD4 cell counts just above versus just below t...
Loss to follow-up is high among HIV patients not yet receiving antiretroviral therapy (ART). Clin... more Loss to follow-up is high among HIV patients not yet receiving antiretroviral therapy (ART). Clinical trials have demonstrated the clinical efficacy of early ART; however, these trials may miss an important real-world consequence of providing ART at diagnosis: its impact on retention in care. We examined the effect of immediate (versus deferred) ART on retention in care using a regression discontinuity design. The analysis included all patients (N = 11,306) entering clinical HIV care with a first CD4 count between 12 August 2011 and 31 December 2012 in a public-sector HIV care and treatment program in rural South Africa. Patients were assigned to immediate versus deferred ART eligibility, as determined by a CD4 count < 350 cells/μl, per South African national guidelines. Patients referred to pre-ART care were instructed to return every 6 months for CD4 monitoring. Patients initiated on ART were instructed to return at 6 and 12 months post-initiation and annually thereafter for CD...
Tropical medicine & international health : TM & IH, Feb 21, 2017
To assess the relationship between CD4 count at presentation and ART uptake and assess predictors... more To assess the relationship between CD4 count at presentation and ART uptake and assess predictors of timely treatment initiation in rural KwaZulu-Natal, South Africa. We used Cox Proportional Hazards models to assess the association between first CD4 count and time from first CD4 to ART initiation amongst all treatment-naïve adults presenting to the Hlabisa HIV Treatment and Care Program between August 2011 and December 2012, with CD4<350 cells. For a sub-set of healthier patients (200≤CD4<350 cells) residing within the population surveillance of the Africa Health Research Institute, we assessed sociodemographic, economic, and geographic predictors hypothesized to influence ART uptake. 4,739 patients presented for care with eligible CD4 counts. The proportion initiating ART within six months of diagnosis was 67% (95% CI 63, 71) in patients with CD4≤50, 59% (0.55, 0.63) in patients with CD4 151-200, and 48% (95% CI 44, 51) in patients with CD4 301- 350. The hazard of starting A...
The World Health Organization recommends initiating antiretroviral therapy (ART) regardless of CD... more The World Health Organization recommends initiating antiretroviral therapy (ART) regardless of CD4 count. We assessed the effect of ART eligibility on treatment uptake and simulated the impact of WHO's recommendations in South Africa. We conducted an empirical analysis of cohort data using a regression discontinuity design, and then used this model for policy simulation. We enrolled all patients (n = 19,279) diagnosed with HIV between August 2011 and December 2013 in the Hlabisa HIV Treatment and Care Programme in rural South Africa. Patients were ART-eligible with CD4<350 cells/mm3 or Stage III/IV illness. We estimated: (1) distribution of first CD4 counts in 2013; (2) probability of initiating ART ≤6 months of HIV diagnosis under existing criteria at each CD4 count; (3) probability of initiating ART by CD4 count if thresholds were eliminated; and (4) number of expected new initiators if South Africa eliminates thresholds. In 2013, 38.9% of patients diagnosed had a CD4 count...
Clinic-based studies have shown that patients with human immunodeficiency virus (HIV) gain weight... more Clinic-based studies have shown that patients with human immunodeficiency virus (HIV) gain weight after initiation of antiretroviral therapy (ART). This study aimed to determine whether the scale-up of ART was associated with a population-level increase in body mass index (BMI) and blood pressure (BP) in a community with high HIV and obesity prevalence. A household survey was conducted in rural KwaZulu-Natal before ART scale-up (in 2004) and when ART coverage had reached 25% (in 2010). Anthropometric data was linked with HIV surveillance data. Mean BMI decreased in women from 29.9 to 29.1 kg/m(2) (P = 0.002) and in men from 24.2 to 23.0 kg/m(2) (P < 0.001). Similarly, overweight and obesity prevalence declined significantly in both sexes. Mean systolic BP decreased from 123.0 to 118.2 mm Hg (P < 0.001) among women and 128.4 to 123.2 mm Hg (P < 0·001) among men. Large-scale ART provision is likely to have caused a decline in BMI at the population level, because ART has impro...
International journal of epidemiology, Jan 10, 2016
Despite the importance of HIV testing for controlling the HIV epidemic, testing rates remain low.... more Despite the importance of HIV testing for controlling the HIV epidemic, testing rates remain low. Efforts to scale up testing coverage and frequency in hard-to-reach and at-risk populations commonly focus on home-based HIV testing. This study evaluates the effect of a gift (a US$5 food voucher for families) on consent rates for home-based HIV testing. We use data on 18 478 individuals (6 418 men and 12 060 women) who were successfully contacted to participate in the 2009 and 2010 population-based HIV surveillance carried out by the Wellcome Trust's Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Of 18 478 potential participants contacted in both years, 35% (6 518) consented to test in 2009, and 41% (7 533) consented to test in 2010. Our quasi-experimental difference-in-differences approach controls for unobserved confounding in estimating the causal effect of the intervention on HIV-testing consent rates. Allocation of the gift to a family in 2010 increase...
Genome-wide association studies (GWAS) have considerably advanced our understanding of human trai... more Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics. We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1st line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naïve to the respective treatment. GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we high...
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