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1.  High-Levels of Acquired Drug Resistance in Adult Patients Failing First-Line Antiretroviral Therapy in a Rural HIV Treatment Programme in KwaZulu-Natal, South Africa 
PLoS ONE  2013;8(8):e72152.
Objective
To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa.
Design
Cross-sectional study nested within HIV treatment programme.
Methods
Adult (≥18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms.
Results
A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32–53) and median duration of antiretroviral failure was 27 months (IQR 17–40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60–12.49).
Conclusions
There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved.
doi:10.1371/journal.pone.0072152
PMCID: PMC3749184  PMID: 23991055
2.  MaiMwana women’s groups: a community mobilisation intervention to improve mother and child health and reduce mortality in rural Malawi 
This article presents a detailed description of a community mobilization intervention involving women’s groups in Mchinji District, Malawi. The intervention was implemented between 2005 and 2010.
The intervention aims to build the capacities of communities to take control of the mother and child health issues that affect them. To achieve this it comprises trained local female facilitators establishing groups and using a manual, participatory rural appraisal tools and picture cards to guide them through a community action cycle to identify and implement solutions to mother and child health problems. Significant resource inputs include salaries for facilitators and supervisors, and training, equipment and materials to support their work with groups.
It is hypothesized that the groups will catalyse community collective action to address mother and child health issues and improve the health and reduce the mortality of mothers and children. Their impact, implementation and cost-effectiveness have been rigorously evaluated through a randomized controlled trial design. The results of these evaluations will be reported in 2011.
PMCID: PMC3345770  PMID: 21977831
3.  Breast-feeding and Transmission of HIV-1 
Breast-feeding substantially increases the risk of HIV-1 transmission from mother to child, and although peripartum antiretroviral therapy prophylaxis significantly decreases the risk of mother-to-child transmission around the time of delivery, this approach does not affect breast-feeding transmission. Increased maternal RNA viral load in plasma and breast milk is strongly associated with increased risk of transmission through breast-feeding, as is breast health, and it has been suggested that exclusive breast-feeding could be associated with lower rates of breast-feeding transmission than mixed feeding of both breast- and other milk or feeds. Transmission through breast-feeding can take place at any point during lactation, and the cumulative probability of acquisition of infection increases with duration of breast-feeding. HIV-1 has been detected in breast milk in cell-free and cellular compartments; infant gut mucosal surfaces are the most likely site at which transmission occurs. Innate and acquired immune factors may act most effectively in combination to prevent primary HIV-1 infection by breast milk.
PMCID: PMC3382106  PMID: 14722454
breastfeeding; mother-to-child transmission; postnatal transmission; risk factors; mechanisms
4.  Use of antiretroviral therapy in households and risk of HIV acquisition in rural KwaZulu-Natal, South Africa, 2004–12: a prospective cohort study 
The Lancet Global Health  2014;2(4):e209-e215.
Summary
Background
Studies of HIV-serodiscordant couples in stable sexual relationships have provided convincing evidence that antiretroviral therapy can prevent the transmission of HIV. We aimed to quantify the preventive effect of a public-sector HIV treatment and care programme based in a community with poor knowledge and disclosure of HIV status, frequent migration, late marriage, and multiple partnerships. Specifically, we assessed whether an individual's hazard of HIV acquisition was associated with antiretroviral therapy coverage among household members of the opposite sex.
Methods
In this prospective cohort study, we linked patients' records from a public-sector HIV treatment programme in rural KwaZulu-Natal, South Africa, with population-based HIV surveillance data collected between 2004 and 2012. We used information about coresidence to construct estimates of HIV prevalence and antiretroviral therapy coverage for each household. We then regressed the time to HIV seroconversion for 14 505 individuals, who were HIV-uninfected at baseline and individually followed up over time regarding their HIV status, on opposite-sex household antiretroviral therapy coverage, controlling for household HIV prevalence and a range of other potential confounders.
Findings
2037 individual HIV seroconversions were recorded during 54 845 person-years of follow-up. For each increase of ten percentage points in opposite-sex household antiretroviral therapy coverage, the HIV acquisition hazard was reduced by 6% (95% CI 2–9), after controlling for other factors. This effect size translates into large reductions in HIV acquisition hazards when household antiretroviral therapy coverage is substantially increased. For example, an increase of 50 percentage points in household antiretroviral therapy coverage (eg, from 20% to 70%) reduced the hazard of HIV acquisition by 26% (95% CI 9–39).
Interpretation
Our findings provide further evidence that antiretroviral therapy significantly reduces the risk of onward transmission of HIV in a real-world setting in sub-Saharan Africa. Awareness that antiretroviral therapy can prevent transmission to coresident sexual partners could be a powerful motivator for HIV testing and antiretroviral treatment uptake, retention, and adherence.
Funding
Wellcome Trust and National Institute of Child Health and Human Development (US National Institutes of Health).
doi:10.1016/S2214-109X(14)70018-X
PMCID: PMC3986029  PMID: 24782953
5.  Sexual behaviour in a rural high HIV prevalence South African community: time trends in the antiretroviral treatment era 
AIDS (London, England)  2013;27(15):2461-2470.
Objectives
Data from generalized epidemic settings have consistently found that patients on antiretroviral therapy (ART) reduce sexual risk behaviours, but how sexual behaviour changes in the general population in response to ART availability, including amongst HIV-uninfected and undiagnosed adults, has not been characterized in these settings.
Design
General population open cohort.
Methods
We report trends in sexual behaviour indicators for men aged 17–54 years and women aged 17–49 years in rural KwaZulu-Natal province, based on annual sexual behaviour surveys during ART scale-up from 2005 to 2011. Estimates are adjusted for survey non-participation and non-response to individual survey items using inverse probability weighting and multiple imputation. Trends are presented by HIV status, knowledge of status, age and marital status.
Results
Reports of condom use at last sex with a regular partner increased by 2.6% points per year [95% confidence interval (CI) 1.5%, 3.7%] for men and 4.1% per year (3.0%, 5.3%) for women. Condom use at last sex with a casual partner was high and did not change significantly over the period for both sexes. There were statistically significant declines in the percentage reporting multiple partnerships in the last year and the point prevalence of concurrency. Trends within subgroups are generally consistent with overall estimates.
Conclusion
We find no evidence of increased sexual risk-taking following ART availability and protective changes in some behaviours, suggesting that general trends in sexual behaviour are not counter-acting preventive effects of HIV treatment. Continued monitoring of population-level sexual behaviour indicators will be essential to interpret the success of combination-prevention programmes.
doi:10.1097/01.aids.0000432473.69250.19
PMCID: PMC3773237  PMID: 23842132
Africa; antiretroviral therapy; HIV; sexual behaviour; trends
7.  Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naïve women 
BMC Infectious Diseases  2014;14:127.
Background
Short-term zidovudine monotherapy (ZDVm) remains an option for some pregnant HIV-positive women not requiring treatment for their own health but may affect treatment responses once antiretroviral therapy (ART) is subsequently started.
Methods
Data were obtained by linking two UK studies: the UK Collaborative HIV Cohort (UK CHIC) study and the National Study of HIV in Pregnancy and Childhood (NSHPC). Treatment responses were assessed for 2028 women initiating ART at least one year after HIV-diagnosis. Outcomes were compared using logistic regression, proportional hazards regression or linear regression.
Results
In adjusted analyses, ART-naïve (n = 1937) and ZDVm-experienced (n = 91) women had similar increases in CD4 count and a similar proportion achieving virological suppression; both groups had a low risk of AIDS.
Conclusions
In this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman’s health.
doi:10.1186/1471-2334-14-127
PMCID: PMC3995971  PMID: 24593018
HIV; Pregnancy; Antiretroviral therapy; United Kingdom
8.  Cumulative Exposure to Cell-Free HIV in Breast Milk, Rather Than Feeding Pattern per se, Identifies Postnatally Infected Infants 
In a nested case-control study, postnatal HIV infection was strongly associated with cumulative HIV RNA breastmilk exposure, even after allowing for maternal CD4 and plasma viral load; cases ingested approximately 15 times more HIV-1 RNA particles than controls.
Background. We quantified the relationship between human immunodeficiency virus (HIV) RNA shedding in breast milk, cumulative RNA exposure, and postnatal transmission, relating timing of infection in the infant to estimated total volume of milk exposure.
Methods. Nested case-control study of 36 infants of HIV-infected mothers. Case patients were infants who acquired HIV infection through breastfeeding from age 6 through 28 weeks, and control subjects were uninfected infants matched on age at obtainment of a breast milk sample. Mothers and infants received peripartum single-dose nevirapine prophylaxis. Feeding data were collected daily; breast milk samples were collected and infant anthropometry was performed at 6 weeks and monthly thereafter. Volume of milk ingested was estimated using infant weight and feeding pattern.
Results. Before HIV acquisition in case patients, feeding pattern (exclusive breastfeeding; median duration, 65 vs 70 days; P = .6) and daily milk intake (mean volume, 638 vs 637 mL; P = .97) did not differ significantly between case patients and control subjects. Case mothers were more likely to shed virus (64% vs 9% always, 22% vs 20.5% intermittently, 14% vs 70.5% never shed; overall, P < .001). Case patients ingested ∼15 times more HIV-1 RNA particles than did control subjects (196.5 vs 13 × 106 copies; P < .001). Allowing for maternal antenatal CD4 cell count and plasma HIV-1 load, child sex and duration of mixed breastfeeding, the association between HIV RNA exposure and infection remained statistically significant (P < .001).
Conclusions. Postnatal acquisition of HIV-1 is more strongly associated with cumulative exposure to cell-free particles in breast milk than with feeding mode. Reducing breast milk viral load through antiretroviral therapy to mother or child can further decrease postnatal transmission in exclusively breastfed infants.
doi:10.1093/cid/ciq203
PMCID: PMC3049337  PMID: 21367736
9.  Increases in adult life expectancy in rural South Africa: valuing the scale-up of HIV treatment 
Science (New York, N.Y.)  2013;339(6122):10.1126/science.1230413.
The scale-up of antiretroviral therapy (ART) is expected to raise adult life expectancy in populations with high HIV prevalence. Using data from a population cohort of over 101,000 individuals in rural KwaZulu-Natal, South Africa, we measured changes in adult life expectancy for 2000–2011. In 2003, the year before ART became available in the public sector health system, adult life expectancy was 49.2 years; by 2011, adult life expectancy had increased to 60.5 years – an 11.3-year gain. Based on standard monetary valuation of life, the survival benefits of ART far outweigh the costs of providing treatment in this community. These gains in adult life expectancy signify the social value of ART and have implications for investment decisions of individuals, governments, and donors.
doi:10.1126/science.1230413
PMCID: PMC3860268  PMID: 23430655
10.  The Association between Self-Reported Stigma and Loss-to-Follow Up in Treatment Eligible HIV Positive Adults in Rural Kwazulu-Natal, South Africa 
PLoS ONE  2014;9(2):e88235.
Background
The relationship between loss-to-follow-up (LTFU) in HIV treatment and care programmes and psychosocial factors, including self-reported stigma, is important to understand. This prospective cohort study explored stigma and LTFU in treatment eligible adults who had yet not started antiretroviral therapy (ART).
Methods
Psychosocial, clinical and demographic data were collected at a baseline interview. Self-reported stigma was measured with a multi-item scale. LTFU was defined as not attending clinic in the 90 days since last appointment or before death. Data was collected between January 2009 and January 2013 and analysed using Cox Regression.
Results
380 individuals were recruited (median time in study 3.35 years, total time at risk 1065.81 person-years). 203 were retained (53.4%), 109 were LTFU (28.7%), 48 had died and were not LTFU at death (12.6%) and 20 had transferred out (5.3%). The LTFU rate was 10.65 per 100 person-years (95% CI: 8.48–12.34). 362 individuals (95.3%) started ART. Stigma total score (categorised in quartiles) was not significantly associated with LTFU in either univariable or multivariable analysis (adjusting for other variables in the final model): second quartile aHR 0.77 (95%CI: 0.41–1.46), third quartile aHR 1.20(95%CI: 0.721–2.04), fourth quartile aHR 0.62 (95%CI: 0.35–1.11). In the final multivariable model, higher LTFU rates were associated with male gender, increased openness with friends/family and believing that community problems would be solved at higher levels. Lower LTFU rates were independently associated with increased year of age, greater reliance on family/friends, and having children.
Conclusions
Demographic and other psychosocial factors were more closely related to LTFU than self-reported stigma. This may be consistent with high levels of social exposure to HIV and ART and with stigma affecting LTFU less than other stages of care. Research and clinical implications are discussed.
doi:10.1371/journal.pone.0088235
PMCID: PMC3930529  PMID: 24586310
11.  Patient satisfaction with HIV and TB treatment in a public programme in rural KwaZulu-Natal: evidence from patient-exit interviews 
Background
Patient satisfaction is a determinant of treatment uptake, adherence and retention, and an important health systems outcome. Queues, health worker-patient contact time, staff attitudes, and facility cleanliness may affect patient satisfaction. We quantified dimensions of patient satisfaction among HIV and TB patients in a rural sub-district of KwaZulu-Natal, South Africa, and identified underlying satisfaction factors that explained the data.
Methods
We conducted patient-exit interviews with 300 HIV and 300 TB patients who were randomly selected using a two-stage cluster random sampling approach with primary sampling units (primary healthcare clinics) selected with probability-proportional-to-size sampling. We performed factor analysis to investigate underlying patient satisfaction factors. We compared the satisfaction with HIV and TB services and examined the relationships between patient satisfaction and patients’ socio-demographic characteristics in multivariable regression.
Results
Almost all patients (95% HIV, 97% TB) reported to be globally satisfied with the healthcare services received on the day of the interview. However, patient satisfaction with specific concrete aspects of the health services was substantially lower: 52% of HIV and 40% of TB patients agreed that some staff did not treat patients with sufficient respect (p = 0.02 for difference between the two patient groups); 65% of HIV and 40% of TB patients agreed that health worker queues were too long (p < 0.001). Based on factor analysis, we identified five factors underlying the HIV data and the TB data (availability, accommodation, acceptability and communication for HIV and TB patients; health worker preference for HIV patients only; and global satisfaction for TB patients only). The level of satisfaction did not vary significantly with patients’ socio-demographic characteristics.
Conclusions
In this rural area, HIV and TB patients’ evaluations of specific aspects of health services delivery revealed substantial dissatisfaction hidden in the global assessments of satisfaction. A wide range of patient satisfaction variables could be reduced to a few underlying factors that align broadly with concepts previously identified in the literature as affecting access to healthcare. Increases in health systems resources for HIV and TB, but also improvements in facility maintenance, staff attitudes and communication, are likely to substantially improve HIV and TB patients’ satisfaction with the care they receive in public-sector treatment programmes in rural communities in South Africa.
doi:10.1186/1472-6963-14-32
PMCID: PMC3904687  PMID: 24450409
Patient satisfaction; Factor analysis; HIV; TB; Health systems
12.  Reduction in early mortality on antiretroviral therapy for adults in rural South Africa since change in CD4+ cell count eligibility criteria 
Objective
To explore the impact of expanded eligibility criteria for antiretroviral therapy (ART) on median CD4+ cell count at ART initiation and early mortality on ART.
Methods
Analyses included all adults (≥16 years) initiated on first-line ART between August 2004 and July 2012. CD4+ cell count threshold 350 cells/μL for all adults was implemented in August 2011. Early mortality was defined as any death within 91 days of ART initiation. Trends in baseline CD4+ cell count and early mortality were examined by year (August-July) of ART initiation. Competing-risks analysis was used to examine early mortality.
Results
A total of 19 080 adults (67.6% female) initiated ART. Median CD4+ cell count at ART initiation was 110-120 cells/μL over the first six years, increasing marginally to 145 cells/μL in 2010/11 and more significantly to 199 cells/μL in 2011/12. Overall, there were 875 deaths within 91 days of ART initiation; early mortality rate 19.4 per 100 person-years (95% confidence interval (CI) 18.2-20.7). After adjustment for sex, age, baseline CD4+ cell count and concurrent TB, there was a 46% decrease in early mortality for those who initiated ART in 2011/12 compared to the reference period 2008/9 (sub-hazard ratio 0.54, 95% CI 0.41-0.71).
Conclusions
Since the expansion of eligibility criteria, there is evidence of earlier access to ART and a significant reduction in early mortality rates in this primary health care programme. These findings provide strong support for national ART policies and highlight the importance of earlier ART initiation for achieving reductions in HIV-related mortality.
doi:10.1097/QAI.0b013e31829ceb14
PMCID: PMC3867341  PMID: 23756374
HIV-1; anti-retroviral agents; CD4 lymphocyte count; mortality; access to health care
13.  Ageing with HIV in South Africa 
AIDS (London, England)  2011;25(13):10.1097/QAD.0b013e32834982ea.
We used an established microsimulation model, quantified to a rural South African setting with a well-developed antiretroviral treatment program, to predict the impact of antiretroviral therapy on the HIV epidemic in the population aged 50+. We show that the HIV prevalence in patients aged 50+ will nearly double in the next 30 years, while the fraction of HIV infected patients aged over 50 will triple in the same period. This ageing epidemic has important consequences for the South African health-care system, as older HIV patients require specialized care.
doi:10.1097/QAD.0b013e32834982ea
PMCID: PMC3886337  PMID: 21681056
HIV; Antiretroviral therapy; Ageing; Mathematical model; Epidemiological trends
14.  The impact of antiretroviral treatment on the age composition of the HIV epidemic in sub-Saharan Africa 
AIDS (London, England)  2012;26(0 1):10.1097/QAD.0b013e3283558526.
Introduction
Antiretroviral treatment (ART) coverage is rapidly expanding in sub-Saharan Africa (SSA). Based on the effect of ART on survival of HIV-infected people and HIV transmission the age composition of the HIV epidemic in the region is expected to change in the coming decades. We quantify the change of the age composition of HIV-infected people in all countries in SSA.
Methods
We used STDSIM, a stochastic microsimulation model, and developed an approach to represent HIV prevalence and treatment coverage in 43 countries in SSA, using publicly available data. We predict future trends in HIV prevalence and total number of infections among the populations aged 15-49 and 50 years and older (50+) for different ART coverage levels.
Results
We show that, if treatment coverage continues to increase at present rates, the total number of HIV-infected patients aged 50+ will nearly triple over the coming years: from 3.1 million in 2011 to 9.1 million in 2040, dramatically changing the age composition of the HIV epidemic in SSA. In 2011, about 1 in 7 HIV-infected people was aged 50 years or older; in 2040, this ratio will be larger than 1 in 4.
Conclusion
The HIV epidemic in SSA is rapidly ageing, implying changing needs and demands in many social sectors, including health, social care, and old-age pension systems. Health policymakers need to anticipate the impact of the changing HIV age composition in their planning for future capacity in these systems.
doi:10.1097/QAD.0b013e3283558526
PMCID: PMC3886374  PMID: 22781175
HIV; Antiretroviral therapy; Ageing; Mathematical model; Epidemiological trends
15.  Is the Risk of HIV Acquisition Increased during and Immediately after Pregnancy? A Secondary Analysis of Pooled HIV Community-Based Studies from the ALPHA Network 
PLoS ONE  2013;8(12):e82219.
Background
Previous studies of HIV acquisition in pregnancy have been in specific population groups, such as sero-discordant couples which have shown an increased risk of HIV acquisition during pregnancy and studies of sexually active women where the results have been ambiguous. However these studies are unable to tell us what the overall impact of pregnancy is on HIV acquisition in the general population.
Methods
Data from six community-based HIV cohorts were pooled to give 2,628 sero-conversions and a total of 178,000 person years of observation. Multiple imputation was used to allow for the uncertainty of exact sero-conversion date in surveillance intervals greater than the length of a pregnancy. Results were combined using Rubin’s rules to give appropriate error bounds. The analysis was stratified into two periods: pre- and post- widespread availability of prevention of mother-to-child HIV transmission services. This allows us to assess whether there is reporting bias relating to a person’s knowledge of their own HIV status which would become more widespread in the latter time period.
Results
Results suggest that women while pregnant have a lower risk of acquiring HIV infection over all periods (HRR 0.79, 95%CI 0.70-0.89) than women who were not pregnant. There is no evidence for a difference in the rate of HIV acquisition between postpartum and non-pregnant women (HRR 0.92 95%CI 0.84-1.03).
Discussion
Although there may be immunological reasons for increased risk of HIV acquisition during pregnancy, at a population level this study indicates a lower risk of HIV acquisition for pregnant women. Pregnant women may be more likely to be concordant with their current sexual partner than non-pregnant women, i.e. either already HIV positive prior to the pregnancy or if negative at the time of becoming pregnant more likely to have a negative partner.
doi:10.1371/journal.pone.0082219
PMCID: PMC3873249  PMID: 24386091
16.  Preventing postnatal transmission of HIV-1 through breast-feeding: modifying infant feeding practices 
Approaches to reduce or prevent the risk of postnatal transmission through breastfeeding include the avoidance of all BF and the use of exclusive replacement feeds (RF) or exclusive breastfeeding for a limited duration with early and rapid cessation of BF around 4–6 months of age. The efficacy and safety of the latter approach has not been established and studies are in progress to provide further information. In addition, inactivation of HIV in breastmilk would allow breastfeeding to continue while reducing the risk of postnatal transmission of HIV, and may be usefully applied in certain circumstances, such as for premature infants or while a mother recovers from mastitits. In this review, experience from clinical trials or studies additional to their main objective of assessing rates and risk factors for MTCT, is discussed. This may inform policy, programming and training options, and be especially valuable in the absence of conclusive data of the efficacy of the interventions to be applied during the breastfeeding period.
PMCID: PMC2475579  PMID: 14722453
Acquired Immunodeficiency Syndrome; prevention & control; transmission; Breast Feeding; adverse effects; Disease Transmission; Vertical; prevention & control; Female; Humans; Infant; Milk; Human; virology; Pregnancy; Safety
17.  Mortality in women of reproductive age in rural South Africa 
Global Health Action  2013;6:10.3402/gha.v6i0.22834.
Objective
To determine causes of death and associated risk factors in women of reproductive age in rural South Africa.
Methods
Deaths and person-years of observation (pyo) were determined for females (aged 15–49 years) resident in 15,526 households in a rural South African Demographic and Health Surveillance site from 2000 to 2009. Cause of death was ascertained by verbal autopsy and ICD-10 coded; causes were categorized as HIV/TB, non-communicable, communicable/maternal/perinatal/nutrition, injuries, and undetermined (unknown). Characteristics of women were obtained from regularly updated household visits, while HIV and self-reported health status was obtained from the annual HIV surveillance. Overall and cause-specific mortality rates (MRs) with 95% confidence intervals (CI) were calculated. The Weibull regression model (HR, 95% CI) was used to determine risk factors associated with mortality.
Results
A total of 42,703 eligible women were included; 3,098 deaths were reported for 212,607 pyo. Overall MRwas 14.6 deaths/1,000 pyo (95% CI: 14.1–15.1), peaking in 2003 (MR 18.2/1,000 pyo, 95% CI: 16.4–20.1) and declining thereafter (2009: MR 9.6/1,000 pyo, 95% CI: 8.4–10.9). Mortality was highest for HIV/TB (MR 10.6/1,000 pyo, 95% CI: 10.2–11.1), accounting for 73.1% of all deaths, ranging from 61.2% in 2009 to 82.7% in 2002. Adjusting for education level, marital status, age, employment status, area of residence, and migration, all-cause mortality was associated with external migration (adjusted hazard ratio, or aHR), 1.70, 95% CI: 1.41–2.05), self-reported poor health status (aHR 8.26, 95% CI: 2.94–23.15), and HIV-infection (aHR 7.84, 95% CI: 6.26–9.82); external migration and HIV infection were also associated with causes of mortality other than HIV/TB (aHR 1.62, 95% CI: 1.12–2.34 and aHR 2.59, 95% CI: 1.79–3.75).
Conclusion
HIV/TB was the leading cause of death among women of reproductive age, although rates declined with the rollout of HIV treatment in the area from 2004. Women's age, external migration status and HIV-positive status were significantly associated with all-cause and cause-specific mortality.
doi:10.3402/gha.v6i0.22834
PMCID: PMC3869952  PMID: 24360403
reproductive age; women; mortality; rural South Africa; risk factors
18.  Exclusive Breastfeeding, Diarrhoeal Morbidity and All-Cause Mortality in Infants of HIV-Infected and HIV Uninfected Mothers: An Intervention Cohort Study in KwaZulu Natal, South Africa 
PLoS ONE  2013;8(12):e81307.
Introduction
Antiretroviral drug interventions significantly reduce the risk of HIV transmission to infants through breastfeeding. We report diarrhoea prevalence and all-cause mortality at 12 months of age according to infant feeding practices, among infants born to HIV-infected and uninfected mothers in South Africa.
Methods
A non-randomised intervention cohort study that followed both HIV-infected and HIV-uninfected mothers and their infants until 18 months of age. Mothers were supported in their infant feeding choice. Detailed morbidity and vital status data were collected over the first year. At the time, only single dose nevirapine was available to prevent mother-to-child transmission of HIV.
Results
Among 2,589 infants, detailed feeding data and vital status were available for 1,082 HIV-exposed infants and 1,155 HIV non-exposed infants. Among exclusively breastfed (EBF) infants there were 9.4 diarrhoeal days per 1,000 child days (95%CI. 9.12-9.82) while among infants who were never breastfed there were 15.6 diarrhoeal days per 1,000 child days (95%CI. 14.62-16.59). Exclusive breastfeeding was associated with fewer acute, persistent and total diarrhoeal events than mixed or no breastfeeding in both HIV-exposed infants and also infants of HIV uninfected mothers. In an adjusted cox regression analysis, the risk of death among all infants by 12 months of age was significantly greater in those who were never breastfed (aHR 3.5, p<0.001) or mixed fed (aHR 2.65, p<0.001) compared with those who were EBF. In separate multivariable analyses, infants who were EBF for shorter durations had an increased risk of death compared to those EBF for 5-6 months [aHR 2.18 (95% CI, 1.56-3.01); p<0.001].
Discussion
In the context of antiretroviral drugs being scaled-up to eliminate new HIV infections among children, there is strong justification for financial and human resource investment to promote and support exclusive breastfeeding to improve HIV-free survival of HIV-exposed and non-exposed infants.
doi:10.1371/journal.pone.0081307
PMCID: PMC3846835  PMID: 24312545
19.  Nearly Full Employment Recovery Among South African HIV Patients On Antiretroviral Therapy: Evidence From A Large Population Cohort 
Health affairs (Project Hope)  2012;31(7):10.1377/hlthaff.2012.0407.
Antiretroviral therapy for HIV may have important economic benefits for patients and their households. We quantified the impact of HIV treatment on employment status among HIV patients in rural South Africa who were enrolled in a public-sector HIV treatment program supported by the U.S. President’s Emergency Plan for AIDS Relief. We linked clinical data from more than 2000 patients in the treatment program with ten years of longitudinal socioeconomic data from a complete community-based population cohort of over 30,000 adults residing in the clinical catchment area. We estimated the employment effects of HIV treatment in fixed effects regressions. Four years after the initiation of antiretroviral therapy, employment among HIV patients had recovered to about 90 percent of baseline rates observed in the same patients three to five years before they started treatment. Many patients initiated treatment early enough that they were able to avoid any loss of employment due to HIV. These results represent the first estimates of employment recovery among HIV patients in a general population, relative to the employment levels that these patients had prior to job-threatening illness and the decision to seek care. We find large economic benefits to HIV treatment. For some patients, further gains could be obtained from initiating antiretroviral therapy earlier, prior to HIV-related job loss.
doi:10.1377/hlthaff.2012.0407
PMCID: PMC3819460  PMID: 22778335
20.  Maternal anaemia and duration of zidovudine in antiretroviral regimens for preventing mother-to-child transmission: a randomized trial in three African countries 
BMC Infectious Diseases  2013;13:522.
Background
Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common.
Methods
Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12–24 months after delivery (n = 1070). Women with a CD4 count of 200-500cells/mm3 and gestational age 28–36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: <200 cells/mm3 initiated antiretroviral therapy, and >500 cells/mm3 received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin < 8.0 g/dl) occurrence were assessed across study arms, using Kaplan-Meier and multivariable Cox proportional hazards models.
Results
At enrolment (corresponded to a median 32 weeks gestation), median haemoglobin was 10.3 g/dl (IQR = 9.2-11.1). Severe anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P-value = 0.32). After 1–2 months of ARV’s, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort.
Conclusions
Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring.
Trial registration number
ISRCTN71468401
doi:10.1186/1471-2334-13-522
PMCID: PMC3829097  PMID: 24192332
Zidovudine; Pregnancy; HIV; Sub-Saharan Africa; Anaemia; Drug toxicity
21.  Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study 
PLoS Medicine  2013;10(10):e1001534.
Using nine structurally different models, Jan Hontelez and colleagues investigate timeframes for HIV elimination in South Africa using a universal test and treat strategy.
Please see later in the article for the Editors' Summary
Background
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.
Methods and Findings
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.
Conclusions
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
Editors' Summary
Background
About 34 million people (mostly in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS, and every year another 2.5 million people become infected. HIV, which is usually transmitted through unprotected sex with an infected partner, gradually destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, people infected with HIV often died within ten years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and, for people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive, so HIV/AIDS remained a fatal condition for people living in resource-limited countries. In 2006, the international community set a target of achieving universal ART coverage by 2010, and ART programs were initiated in many resource-limited countries. Although universal ART coverage has still not been achieved in South Africa, where nearly 6 million people are HIV-positive, 80% of people in need of ART were receiving a World Health Organization–recommended ART regimen by October 2012.
Why Was This Study Done?
ART is usually started when a person's CD4 count falls below 350 cells/µl blood, but it is thought that treatment of all HIV-positive individuals, regardless of their CD4 count, could reduce HIV transmission by reducing the infectiousness of HIV-positive individuals (“treatment as prevention”). Might it be possible, therefore, to eliminate HIV by screening everyone annually for infection and treating all HIV-positive individuals immediately? In 2009, a mathematical modeling study suggested that seven years of universal test and treat (UTT) could eliminate HIV in South Africa. The deterministic (nonrandom) model used in that study has been widely criticized, however, and some subsequent modeling studies have reached different conclusions, probably because of differences in the models' structures and in the assumptions built into them. A better understanding of the reasons for the discrepancies between models would help policy-makers decide whether to introduce UTT, so, here, the researchers developed several increasingly complex and realistic models of the South African HIV epidemic and used these models to predict the long-term impact of UTT in South Africa.
What Did the Researchers Do and Find?
The researchers developed nine structurally different mathematical models of the South African HIV epidemic based on the STDSIM framework, a stochastic microsimulation model that simulates the life course of individuals in a dynamic network of sexual contacts and in which events such as HIV infection are random processes. The simplest model, which resembled the original deterministic model, was extended by sequentially adding in factors such as different HIV transmission rates at different stages of HIV infection and up-to-date assumptions regarding the ability of ART to reduce HIV infectiousness. All the models replicated the prevalence of HIV in South Africa (the proportion of the population that was HIV-positive) between 1990 and 2010, and all predicted that UTT (defined as annual screening of individuals age 15+ years and immediate ART for all HIV-infected adults starting in 2012 and scaled up to 90% coverage by 2019) would result in HIV elimination (less than one new infection per 1,000 person-years). However, whereas the simplest model predicted that UTT would eliminate HIV after seven years, the more complex, realistic models predicted elimination at much later time points. Importantly, the most comprehensive model predicted that, although elimination would be reached after about 17 years of UTT, the current strategy of ART initiation for HIV-positive individuals at a CD4 cell count at or below 350 cells/µl would also lead to HIV elimination, albeit ten years later than UTT.
What Do These Findings Mean?
These findings confirm previous predictions that UTT could eliminate HIV in South Africa, but the development of more realistic models than those used in the past suggests that HIV elimination would occur substantially later than originally predicted. Importantly, the most comprehensive model suggests that HIV could be eliminated in South Africa using the current strategy for ART treatment alone. As with all modeling studies, the accuracy of these findings depends on the assumptions built into the models and on the structure of the models. Thus, although these findings support the use of UTT as an intervention to eliminate HIV, more research with comprehensive models that incorporate factors such as data from ongoing trials of treatment as prevention is needed to determine the population-level impact and overall cost-effectiveness of UTT.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001534.
This study is further discussed in a PLOS Medicine Perspective by Ford and Hirnschall
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in South Africa, on HIV treatment as prevention and the possibility of HIV elimination (in English and Spanish)
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
The PLOS Medicine Collection Investigating the Impact of Treatment on New HIV Infections provides more information about HIV treatment as prevention
Personal stories about living with HIV/AIDS are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001534
PMCID: PMC3805487  PMID: 24167449
22.  Decreased Chronic Morbidity but Elevated HIV Associated Cytokine Levels in HIV-Infected Older Adults Receiving HIV Treatment: Benefit of Enhanced Access to Care? 
PLoS ONE  2013;8(10):e77379.
Background
The association of HIV with chronic morbidity and inflammatory markers (cytokines) in older adults (50+years) is potentially relevant for clinical care, but data from African populations is scarce.
Objective
To examine levels of chronic morbidity by HIV and ART status in older adults (50+years) and subsequent associations with selected pro-inflammatory cytokines and body mass index.
Methods
Ordinary, ordered and generalized ordered logistic regression techniques were employed to compare chronic morbidity (heart disease (angina), arthritis, stroke, hypertension, asthma and diabetes) and cytokines (Interleukins-1 and -6, C-Reactive Protein and Tumor Necrosis Factor-alpha) by HIV and ART status on a cross-sectional random sample of 422 older adults nested within a defined rural South African population based demographic surveillance.
Results
Using a composite measure of all morbidities, controlling for age, gender, BMI, smoking and wealth quintile, HIV-infected individuals on ART had 51% decreased odds (95% CI:0.26-0.92) of current morbidity compared to HIV-uninfected. In adjusted regression, compared to HIV-uninfected, the proportional odds (aPOR) of having elevated inflammation markers of IL6 (>1.56pg/mL) was nearly doubled in HIV-infected individuals on (aPOR 1.84; 95%CI: 1.05-3.21) and not on (aPOR 1.94; 95%CI: 1.11-3.41) ART. Compared to HIV-uninfected, HIV-infected individuals on ART had >twice partial proportional odds (apPOR=2.30;p=0.004) of having non-clinically significant raised hsCRP levels(>1ug/mL); ART-naïve HIV-infected individuals had >double apPOR of having hsCRP levels indicative of increased heart disease risk(>3.9ug/mL;p=0.008).
Conclusions
Although HIV status was associated with increased inflammatory markers, our results highlight reduced morbidity in those receiving ART and underscore the need of pro-actively extending these services to HIV-uninfected older adults, beyond mere provision at fixed clinics. Providing health services through regular community chronic disease screening would ensure health care reaches all older adults in need.
doi:10.1371/journal.pone.0077379
PMCID: PMC3797035  PMID: 24143226
23.  Effect of women’s groups and volunteer peer counselling on rates of mortality, morbidity, and health behaviours in mothers and children in rural Malawi (MaiMwana): a factorial, cluster-randomised controlled trial 
Lancet  2013;381(9879):1721-1735.
Summary
Background
Women’s groups and health education by peer counsellors can improve the health of mothers and children. We assessed their effects on mortality and breastfeeding rates in rural Malawi.
Methods
We did a 2×2 factorial, cluster-randomised trial in 185 888 people in Mchinji district. 48 equal-sized clusters were randomly allocated to four groups with a computer-generated number sequence. 24 facilitators guided groups through a community action cycle to tackle maternal and child health problems. 72 trained volunteer peer counsellors made home visits at five timepoints during pregnancy and after birth to support breastfeeding and infant care. Primary outcomes for the women’s group intervention were maternal, perinatal, neonatal, and infant mortality rates (MMR, PMR, NMR, and IMR, respectively); and for the peer counselling were IMR and exclusive breastfeeding (EBF) rates. Analysis was by intention to treat. The trial is registered as ISRCTN06477126.
Findings
We monitored outcomes of 26 262 births between 2005 and 2009. In a factorial model adjusted only for clustering and the volunteer peer counselling intervention, in women’s group areas, for years 2 and 3, we noted non-significant decreases in NMR (odds ratio 0·93, 0·64–1·35) and MMR (0·54, 0·28–1·04). After adjustment for parity, socioeconomic quintile, and baseline measures, effects were larger for NMR (0·85, 0·59–1·22) and MMR (0·48, 0·26–0·91). Because of the interaction between the two interventions, a stratified analysis was done. For women’s groups, in adjusted analyses, MMR fell by 74% (0·26, 0·10–0·70), and NMR by 41% (0·59, 0·40–0·86) in areas with no peer counsellors, but there was no effect in areas with counsellors (1·09, 0·40–2·98, and 1·38, 0·75–2·54). Factorial analysis for the peer counselling intervention for years 1–3 showed a fall in IMR of 18% (0·82, 0·67–1·00) and an improvement in EBF rates (2·42, 1·48–3·96). The results of the stratified, adjusted analysis showed a 36% reduction in IMR (0·64, 0·48–0·85) but no effect on EBF (1·18, 0·63–2·25) in areas without women’s groups, and in areas with women’s groups there was no effect on IMR (1·05, 0·82–1·36) and an increase in EBF (5·02, 2·67–9·44) . The cost of women’s groups was US$114 per year of life lost (YLL) averted and that of peer counsellors was $33 per YLL averted, using stratified data from single intervention comparisons.
Interpretation
Community mobilisation through women’s groups and volunteer peer counsellor health education are methods to improve maternal and child health outcomes in poor rural populations in Africa.
Funding
Saving Newborn Lives, UK Department for International Development, and Wellcome Trust.
doi:10.1016/S0140-6736(12)61959-X
PMCID: PMC3796349  PMID: 23683639
24.  Disengagement from care in a decentralised primary health care antiretroviral treatment programme: cohort study in rural South Africa 
OBJECTIVE
To determine rates of, and factors associated with, disengagement from care in a decentralised antiretroviral programme.
METHODS
Adults (≥16 years) who initiated antiretroviral therapy (ART) in the Hlabisa HIV Treatment and Care Programme August 2004–March 2011 were included. Disengagement from care was defined as no clinic visit for 180 days, after adjustment for mortality. Cumulative incidence functions for disengagement from care, stratified by year of ART initiation, were obtained; competing-risks regression was used to explore factors associated with disengagement from care.
RESULTS
A total of 4,674 individuals (median age 34 years, 29% male) contributed 13 610 person-years of follow-up. After adjustment for mortality, incidence of disengagement from care was 3.4 per 100 person-years (95% confidence interval (CI) 3.1–3.8). Estimated retention at 5 years was 61%. The risk of disengagement from care increased with each calendar year of ART initiation (P for trend <0.001). There was a strong association between disengagement from care and higher baseline CD4+ cell count (subhazard ratio (SHR) 1.94 (P < 0.001) and 2.35 (P < 0.001) for CD4+ cell count 150–200 cells/μl and >200 cells/μl respectively, compared with CD4 count <50 cells/μl). Of those disengaged from care with known outcomes, the majority (206/303, 68.0%) remained resident within the local community.
CONCLUSIONS
Increasing disengagement from care threatens to limit the population impact of expanded antiretroviral coverage. The influence of both individual and programmatic factors suggests that alternative service delivery strategies will be required to achieve high rates of long-term retention.
doi:10.1111/tmi.12135
PMCID: PMC3775257  PMID: 23731253
HIV-1; antiretroviral agents; primary health care; delivery of health care; lost to follow-up; disengagement from care

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