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1.  Decline in early life mortality in a high HIV prevalence rural area of South Africa: evidence of HIV prevention or treatment impact? 
AIDS (London, England)  2010;24(4):593-602.
We present early life mortality rates in a largely rural population with high antenatal HIV prevalence, and investigate temporal and spatial associations with a prevention of mother-to-child transmission (PMTCT) programme, an HIV treatment programme, and maternal HIV.
A retrospective cohort analysis.
All births from January 2000 to January 2007 to women in the Africa Centre demographic surveillance were included. Under-two child mortality rates (U2MR) computed as deaths per 1000 live-births per year; factors associated with mortality risk assessed with Weibull regression. Availability of PMTCT (single-dose nevirapine; sdNVP) and antiretroviral therapy (ART) in a programme included in multivariable analysis.
Eight hundred and forty-eight (6.2%) of 13 583 children under 2 years died. Deaths in under twos declined by 49% between 2001 and 2006, from 86.3 to 44.1 deaths per thousand live-births. Mortality was independently associated with birth season (adjusted hazard ratio 1.16, 95% confidence interval 1.02–1.33), maternal education (1.21, 1.02–1.43), maternal HIV (4.34, 3.11–6.04) and ART availability (0.46, 0.33–0.65). Children born at home (unlikely to have received sdNVP) had a 35% higher risk of dying than children born in a facility where sdNVP was available (1.35, 1.04–1.74). For 2005 births the availability of PMTCT and ART in public health programmes would have explained 8 and 31% of the decline in U2MR since 2000.
These findings confirm the importance of maternal survival, and highlight the importance of the PMTCT and especially maternal HIV treatment with direct benefits of improved survival of their young children.
PMCID: PMC4239477  PMID: 20071975
Africa; ART; HIV; mortality; PMTCT; rural
2.  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.
To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa.
Cross-sectional study nested within HIV treatment programme.
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.
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).
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.
PMCID: PMC3749184  PMID: 23991055
3.  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
4.  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
6.  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.
PMCID: PMC3049337  PMID: 21367736
7.  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
10.  Interventions to improve the performance of HIV health systems for treatment-as-prevention in sub-Saharan Africa: the experimental evidence 
Current opinion in HIV and AIDS  2012;7(2):140-150.
Purpose of review
To reduce HIV incidence, treatment-as-prevention (TasP) requires high rates of HIV testing, and antiretroviral treatment (ART) uptake, retention, and adherence, which are currently not achieved in general populations in sub-Saharan Africa. We review the experimental evidence on interventions to increase these rates.
Recent findings
In four rapid reviews, we found nine randomized controlled trials (RCTs) on HIV-testing uptake, two on ART uptake, one on ART retention, and 15 on ART adherence in sub-Saharan Africa. Only two RCTs on HIV testing investigated an intervention in general populations; the other examined interventions in selected groups (employees, or individuals attending public-sector facilities for services). One RCT demonstrated that nurse-managed ART led to the same retention rates as physician-managed ART, but failed to show how to increase retention to the rates required for successful TasP. Although the evidence on ART adherence is strongest – several RCTs demonstrate the effectiveness of cognitive and behavioural interventions – contradictory results in different settings suggest that the precise intervention content, or the context, are crucial for effectiveness.
Future studies need to test the effectiveness of interventions to increase testing and treatment uptake, retention, and adherence under TasP, that is, ART for all HIV-infected individuals, independent of disease stage.
PMCID: PMC4300338  PMID: 22248917
adherence; antiretroviral treatment; HIV testing; HIV treatment-as-prevention; randomized controlled trials; retention
11.  Factors associated with repeated refusal to participate in longitudinal population-based HIV surveillance in rural South Africa: an observational study, regression analyses 
For many estimation purposes, individuals who repeatedly refuse to participate in longitudinal HIV surveillance pose a bigger threat to valid inferences than individuals who participate at least occasionally. We investigate the determinants of repeated refusal to consent to HIV testing in a population-based longitudinal surveillance in rural South Africa.
We used data from two years (2005 & 2006) of the annual HIV surveillance conducted by the Africa Centre for Health and Population Studies, linking the HIV surveillance data to demographic and socioeconomic data. The outcome for the analysis was “repeated refusal”. Demographic variables included sex, age, highest educational attainment, and place of residence. We also included a measure of wealth and the variable “ever had sex”. To compare the association of each variable with the outcome, unadjusted odds ratios and standard errors were estimated. Multivariable logistic regression was used to estimate adjusted odds ratios and their standard errors. Data were analyzed using STATA 10.0.
Of 15,557 eligible individuals, 46% refused to test for HIV in both rounds. Males were significantly more likely than females to repeatedly refuse testing. Holding all other variables constant, individuals in the middle age groups were more likely to repeatedly refuse testing compared with younger and older age groups. The odds of repeated refusal increased with increasing level of education and relative wealth. People living in urban areas were significantly more likely to repeatedly refuse an HIV test than people living in peri-urban or rural areas. Compared to those who had ever had sex, both males and females who had not yet had sex were significantly more likely to refuse to participate.
The likelihood of repeated refusal to test for HIV in this longitudinal surveillance increases with education, wealth, urbanization, and primary sexual abstinence. Since the factors determining repeated HIV testing refusal are likely associated with HIV status, it is critical that selection effects are controlled for in the analysis of HIV surveillance data. Interventions to increase consent to HIV testing should consider targeting the relatively well educated and wealthy, people in urban areas, and individuals who have not yet sexually debuted.
PMCID: PMC4300340  PMID: 25621095
12.  Dramatic increases in HIV prevalence after scale-up of antiretroviral treatment: a longitudinal population-based HIV surveillance study in rural kwazulu-natal 
AIDS (London, England)  2013;27(14):2301-2305.
To investigate HIV prevalence trends in a rural South African community after the scale-up of antiretroviral treatment (ART) in 2004.
We estimated adult HIV prevalence (ages 15–49 years) using data from a large, longitudinal, population-based HIV surveillance in rural KwaZulu-Natal, South Africa, over the period from 2004 (the year when the public-sector ART scale-up started) through 2011. We control for selection effects due to surveillance non-participation using multiple imputation. We further linked the surveillance data to patient records from the local HIV treatment programme to estimate ART coverage.
ART coverage of all HIV-infected people in this community increased from 0% in 2004 to 31% in 2011. Over the same observation period adult HIV prevalence increased steadily from 21% to 29%. The overall increase in HIV prevalence was largely driven by the prevalence trends in women and men older than 24 years of age, i.e., the age group in which the largest proportions of HIV-infected people received ART.
The observed dramatic rise in adult HIV prevalence can be largely explained by increased survival of HIV-infected people due to ART. This interpretation is supported by the fact that the overall HIV prevalence trend is mostly due to increases in prevalence in older adults, i.e., in the age groups that currently benefit most from the local ART scale-up. Future studies should decompose HIV prevalence trends into HIV incidence and HIV-specific mortality changes to further improve the causal attribution of prevalence increases to treatment success rather than prevention failure.
PMCID: PMC4264533  PMID: 23669155
antiretroviral treatment; HIV prevalence; HIV surveillance; KwaZulu-Natal; population-based longitudinal cohort study
13.  High Coverage of ART Associated with Decline in Risk of HIV Acquisition in Rural KwaZulu-Natal, South Africa 
Science (New York, N.Y.)  2013;339(6122):966-971.
The landmark HIV Prevention Trials Network (HPTN) 052 trial in HIV-discordant couples demonstrated unequivocally that treatment with antiretroviral therapy (ART) substantially lowers the probability of HIV transmission to the HIV-uninfected partner. However, it has been vigorously debated whether substantial population-level reductions in the rate of new HIV infections could be achieved in “real-world” sub-Saharan African settings where stable, cohabiting couples are often not the norm and where considerable operational challenges exist to the successful and sustainable delivery of treatment and care to large numbers of patients. We used data from one of Africa’s largest population-based prospective cohort studies (in rural KwaZulu-Natal, South Africa) to follow up a total of 16,667 individuals who were HIV-uninfected at baseline, observing individual HIV seroconversions over the period 2004 to 2011. Holding other key HIV risk factors constant, individual HIV acquisition risk declined significantly with increasing ART coverage in the surrounding local community. For example, an HIV-uninfected individual living in a community with high ART coverage (30 to 40% of all HIV-infected individuals on ART) was 38% less likely to acquire HIV than someone living in a community where ART coverage was low (<10% of all HIV-infected individuals on ART).
PMCID: PMC4255272  PMID: 23430656
14.  Interventions to increase antiretroviral adherence in sub-Saharan Africa: a systematic review of evaluation studies 
The Lancet. Infectious diseases  2011;11(12):942-951.
The success of potent antiretroviral treatment (ART) for HIV infection is primarily determined by the level of medication adherence. We systematically review the evidence on effectiveness of interventions to enhance ART adherence in sub-Saharan Africa (SSA), where four fifths of the more than five million people receiving ART live. We identified 26 relevant publications reporting on 25 studies, conducted between 2003 and 2010, of behavioural, cognitive, biological, structural, and combination interventions. The majority (16) of the studies took place in hospital outpatient facilities in urban settings. Studies differed widely in design, sample size, length of follow-up, and outcome measurement. Despite study diversity and limitations, the evidence to date suggest that treatment supporters, directly observed therapy, cell phone short message services, diary cards and food rations and can be effective in increasing adherence in some settings in SSA. However, our synthesis of studies also shows that some interventions are unlikely to produce large or lasting effects, while other interventions are effective in some but not in other settings, emphasizing the need for more research, in particular, RCTs, to allow examination of the influence of context and particular features of intervention content on effectiveness. Important avenues for future work include intervention targeting and selection of interventions based on behavioural theories relevant to SSA.
PMCID: PMC4250825  PMID: 22030332
15.  HIV status, breastfeeding modality at 5 months and postpartum maternal weight changes over 24 months in rural South Africa 
To determine the effect of infant feeding practices on postpartum weight change among HIV-infected and -uninfected women in South Africa.
In a non-randomised intervention cohort study of antiretroviral therapy-naïve women in South Africa, infants were classified as exclusive (EBF), mixed (MF) or non-breastfed (NBF) at each visit. We analysed infant feeding cumulatively from birth to 5 months using 24-hour feeding history (collected weekly for each of the preceding 7 days). Using generalised estimating equation mixed models, allowing for repeated measures, we compared postpartum weight change (kg) from the first maternal postpartum weight within the first 6 weeks (baseline weight) to each subsequent visit through 24 months among 2340 HIV-infected and -uninfected women with live births and at least two postpartum weight measurements.
HIV-infected (−0.2 kg CI: −1.7 to 1.3 kg; P = 0.81) and -uninfected women (−0.5 kg; 95% CI: −2.1 to 1.2 kg; P = 0.58) had marginal non-significant weight loss from baseline to 24 months postpartum. Adjusting for HIV status, socio-demographic, pregnancy-related and infant factors, 5-month feeding modality was not significantly associated with postpartum weight change: weight change by 24 months postpartum, compared to the change in the reference EBF group, was 0.03 kg in NBF (95% CI: −2.5 to +2.5 kg; P = 0.90) and 0.1 kg in MF (95% CI: −3.0 to +3.2 kg; P = 0.78).
HIV-infected and -uninfected women experienced similar weight loss over 24 months. Weight change postpartum was not associated with 5-month breastfeeding modality among HIV-infected and -uninfected women.
PMCID: PMC4251550  PMID: 24720779
HIV infection; body weight change; breastfeeding; postpartum
16.  Human Papillomavirus Seropositivity and Subsequent Risk of HIV Acquisition in Rural South African Women 
Sexually transmitted diseases  2013;40(7):601-606.
This study aimed to provide a population-based estimate of human papillomavirus (HPV) seropositivity for women in a rural African context and to evaluate the impact of HPV serostatus on subsequent acquisition of HIVoutside a clinical setting.
A random sample of women participating in a longitudinal, population-based HIV survey combined with a case-control study.
Blood samples of women participating in a single round of population-based HIV surveillance (N = 1049) in a rural South African population were used to measure vaccine-preventable HPV seropositivity (types 6, 11, 16, and 18) in the general population in 2010. Using results from the repeat HIV surveys, a case-control analysis was then performed comparing HPV sero-status in samples taken from HIV sero-converting women (prior to infection with HIV) against samples from HIV-uninfected, sexually-active controls matched 1:1 according to 5-year age band (377:377). Unconditional multivariable logistic regression with multiple imputations was used to control for sociodemographic and behavioral variables associated with HIV acquisition.
Human papillomavirus seropositivity in the population-based sample of women was 20.8% (95% confidence interval [CI], 18.3–23.4), and HIV prevalence was 27.6% (95% CI, 24.9–30.4). In the case-control analysis, allowing for variables known to be associated with HIV incidence, HPV seropositivity was associated with nearly 2.5 times the odds of subsequent acquisition of HIV (adjusted odds ratio, 2.33 [95% CI, 1.61–3.39]; P < 0.001).
These results suggest that HPV vaccination before or soon after sexual debut could lower HIV infection risk. Randomized trials that quantify the impact of HPV vaccination in girls on the risk of acquiring HIV are urgently required.
PMCID: PMC4239474  PMID: 23965780
17.  Starting a Home and Mobile HIV Testing Service in a Rural Area of South Africa 
To compare users of a home and mobile HIV counseling and testing service implemented in rural KwaZulu-Natal, South Africa.
Communities of similar population size and density were allocated HIV counseling and testing provision be either home or mobile services. Uptake of services was compared, including results from a brief questionnaire.
Majority of individuals proceeded to test. Mobile services reported a higher proportion of clients who were male (41% vs. 31%; P < 0.001), younger than 25 years (53% vs. 28%; P < 0.001), single (66% vs. 40%; P < 0.001), and never previously tested (62% vs. 56%; P = 0.003). Home services reported a higher proportion of clients older than of 35 years (56% vs. 35%; P < 0.001) and married/partner (43% vs. 30%; P < 0.001). HIV prevalence amongst clients of the 2 services was comparable, with both services testing more clients daily than the local primary health care clinics, but similar to the local hospital.
The numbers tested, different populations reached, and high detection rates suggest both modalities have an important role to play, especially in rural communities where cost of transport may be a deterrent.
PMCID: PMC4239475  PMID: 22107821
HIV testing; home based; mobile based; resource constrained
19.  Does pregnancy increase the risk of ART-induced hepatotoxicity among HIV-positive women? 
Journal of the International AIDS Society  2014;17(4Suppl 3):19486.
High rates of hepatotoxicity have been observed among HIV-positive pregnant women using antiretroviral therapy (ART). However, the extent to which pregnancy affects the risk of ART-induced hepatotoxicity is unclear since studies in this area have generated conflicting results.
Material and Methods
Combined data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC) were used. Alanine aminotransferase (ALT) data were assessed according to the Division of AIDS toxicity guidelines to identify factors associated with liver enzyme elevation (LEE) (grade 1–4). Women starting ART in 2000–11 aged 16–49 years were included irrespective of pregnancy status at ART start. Cox proportional hazards were used to assess the associations between fixed (ethnicity, exposure group, HBV/HCV co-infection, prior ART use, and age, year, pregnancy status, viral load and CD4 count at ART start) and time-dependent covariates (pregnancy status, age, year, CD4 count, viral load, duration on ART) and the risk of LEE.
Of the 3426 women included, one-quarter (25.0%, n=857) were pregnant during follow-up and 14.4% (n=492) started ART during pregnancy. The rate of LEE was 15/100 person-years (PY) during pregnancy and 6.1/100 PY outside pregnancy. The risk of LEE was increased during pregnancy (adjusted hazard ratio (aHR) 1.61 [1.26–2.06], p<0.001), including in secondary analysis excluding 493 women pregnant when starting ART. Other factors independently associated with LEE were lower CD4 count (<250 cells/mm3 vs. 251–350 cells/mm3 aHR 1.25 [1.02–1.54], p=0.03), HBV/HCV co-infection (aHR 1.94 [1.58–2.39], p<0.001), HIV acquired via injecting drug use (aHR 1.61 [1.15–2.24], p=0.01 vs. heterosexually) and calendar year (aHR 1.05 [1.02–1.08], p<0.001 per one year increase). Three ART drugs were associated with increased risk of LEE (efavirenz aHR 1.27 [1.06–1.50], p-value 0.008; maraviroc 4.19 [1.34–13.1], p=0.01; and nevirapine 1.59 [1.30–1.95], p-value <0.001). Use of zidovudine was associated with decreased risk of LEE (aHR 0.74 [0.63–0.87], p<0.001) as was increasing time on an NNRTI-based regimen (aHR 0.91 [0.86–0.96], p<0.001 per additional year).
Pregnant women were at increased risk of LEE, highlighting the importance of close monitoring of toxicity biomarkers during pregnancy.
PMCID: PMC4224861  PMID: 25393995
20.  The impact of the 2013 WHO antiretroviral therapy guidelines on the feasibility of HIV population prevention trials 
HIV clinical trials  2014;15(5):185-198.
Several cluster-randomized HIV prevention trials aim to demonstrate the population-level preventive impact of antiretroviral therapy (ART). 2013 World Health Organization guidelines raising the ART initiation threshold to CD4<500/µL could attenuate these trials’ effect size by increasing ART usage in control clusters.
We used a computational model to simulate strategies from a hypothetical cluster-randomized HIV prevention trial. The primary model outcome was the relative reduction in 24-month HIV incidence between control (ART offered with CD4 below threshold) and intervention (ART offered to all) strategies. We assessed this incidence reduction using the revised (CD4<500/µL) and prior (CD4<350/µL) control ART initiation thresholds. Additionally, we evaluated changes to trial characteristics that could bolster the incidence reduction.
With a control ART initiation threshold of CD4<350/µL, 24-month HIV incidence under control and intervention strategies was 2.46/100PY and 1.96/100PY, a 21% reduction. Raising the threshold to CD4<500/µL decreased the incidence reduction by more than one-third, to 12%. Using this higher threshold, moving to a 36-month horizon (vs. 24-month), yearly control-strategy HIV screening (vs. biannual), and 2-monthly intervention-strategy screening (vs. biannual), resulted in a 31% incidence reduction, similar to effect size projections for ongoing trials. Alternate assumptions regarding cross-cluster contamination had the greatest influence on the incidence reduction.
Implementing the 2013 WHO HIV treatment threshold could substantially diminish the incidence reduction in HIV population prevention trials. Alternative HIV testing frequencies and trial horizons can bolster this incidence reduction, but could be logistically and ethically challenging. The feasibility of HIV population prevention trials should be reassessed as implementation of treatment guidelines evolves.
PMCID: PMC4212337  PMID: 25350957
HIV; highly-active antiretroviral therapy; prevention; randomized controlled trials as topic
21.  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.
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.
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.
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).
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.
Wellcome Trust and National Institute of Child Health and Human Development (US National Institutes of Health).
PMCID: PMC3986029  PMID: 24782953
22.  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.
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.
General population open cohort.
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.
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.
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.
PMCID: PMC3773237  PMID: 23842132
Africa; antiretroviral therapy; HIV; sexual behaviour; trends
23.  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.
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.
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.
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.
In this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman’s health.
PMCID: PMC3995971  PMID: 24593018
HIV; Pregnancy; Antiretroviral therapy; United Kingdom
24.  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.
PMCID: PMC3860268  PMID: 23430655
25.  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.
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).
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.
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.
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.
PMCID: PMC3930529  PMID: 24586310

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