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1.  Retention in care under universal Antiretroviral Therapy for HIV Infected Pregnant and Breastfeeding Women (“Option B+”) in Malawi 
AIDS (London, England)  2014;28(4):589-598.
OBJECTIVE
To explore the levels and determinants of loss to follow-up (LTF) under universal lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (“Option B+”) in Malawi.
DESIGN, SETTING, and PARTICIPANTS
We examined retention in care, beginning at date of ART initiation and up to six months, for women in the Option B+ program. We analysed nation-wide facility-level data on women who started ART at 540 facilities (n=21 939). The study included individual-level data on patients who started ART at 19 large facilities (n=11 534).
RESULTS
Of the women who started ART under Option B+ (n=21 939), 17% appeared to be LTF six months after start. Most losses occurred in the first 3 months of therapy. Option B+ patients who started therapy during pregnancy were five times more likely than women who started ART in WHO stage 3/4 or with a CD4 cell count ≤350 cells/μl, to never return after their initial clinic visit (odds ratio 5.0, 95% CI 4.2-6.1). Option B+ patients who started therapy while breastfeeding were twice as likely to miss their first follow-up visit (odds ratio 2.2, 95% CI 1.8-2.8). LTF was highest in pregnant Option B+ patients who began ART at large clinics on the day they were diagnosed with HIV. LTF varied considerably between facilities, ranging from 0% to 58%.
CONCLUSION
Decreasing LTF will improve the effectiveness of the Option B+ approach. Tailored interventions, like community- or family-based PMTCT models could improve its effectiveness.
doi:10.1097/QAD.0000000000000143
PMCID: PMC4009400  PMID: 24468999
Option B+; Prevention of mother to child transmission / vertical transmission; Antiretroviral therapy; Retention in care; Loss to follow-up
2.  In-utero exposure to maternal HIV infection alters T-cell immune responses to vaccination in HIV-uninfected infants 
AIDS (London, England)  2014;28(10):1421-1430.
Objective
In sub-Saharan Africa, HIV-exposed uninfected (HEU) infants have higher morbidity and mortality than HIV-unexposed infants. To evaluate whether immune dysfunction contributes to this vulnerability of HEU infants, we conducted a longitudinal, observational cohort study to assess T-cell immune responses to infant vaccines (Mycobacterium bovis BCG and acellular pertussis) and staphylococcal enterotoxin B (SEB). In total, 46 HEU and 46 HIV-unexposed infants were recruited from Khayelitsha, Cape Town.
Methods
Vaccine-specific T-cell proliferation (Ki67 expression) and intracellular expression of four cytokines [interferon-γ, interleukin (IL)-2, IL-13 and IL-17] were measured after whole blood stimulation with antigens at 6 and 14 weeks of age.
Results
HEU infants demonstrated elevated BCG-specific CD4+ and CD8+ T-cell proliferative responses at 14 weeks (P = 0.041 and 0.002, respectively). These responses were significantly increased even after adjusting for birth weight, feeding mode and gestational age. Similar to BCG, increased CD4+ and CD8+ T-cell proliferation was evident in response to SEB stimulation (P = 0.004 and 0.002, respectively), although pertussis-specific T cells proliferated comparably between the two groups. Within HEU infants, maternal CD4+ cell count and length of antenatal antiretroviral exposure had no effect on T-cell proliferation to BCG or SEB. HIV exposure significantly diminished measurable cytokine polyfunctionality in response to BCG, Bordetella pertussis and SEB stimulation.
Conclusion
These data show for the first time, when adjusting for confounders, that exposure to HIV in utero is associated with significant alterations to CD4+ and CD8+T-cell immune responses in infants to vaccines and nonspecific antigens.
doi:10.1097/QAD.0000000000000292
PMCID: PMC4333196  PMID: 24785950
cytokines; infants; maternal HIV; proliferation; T-cell immunity; vaccination
3.  Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis 
PLoS Medicine  2015;12(1):e1001778.
In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.
Background
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
Methods and Findings
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15–49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24–1.83) for DMPA use, 1.24 (95% CI 0.84–1.82) for NET-EN use, and 1.03 (95% CI 0.88–1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23–1.67) and NET-EN use (aHR 1.32, 95% CI 1.08–1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99–1.50; for NET-EN use 0.67, 95% CI 0.47–0.96; and for COC use 0.91, 95% CI 0.73–1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC–HIV relationship.
Conclusions
This IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Editors’ Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981. About 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and every year, another 2.3 million people become newly infected with HIV. At the beginning of the epidemic, more men than women were infected with HIV. Now, about half of all adults infected with HIV are women. In 2013, almost 60% of all new HIV infections among young people aged 15–24 years occurred among women, and it is estimated that, worldwide, 50 young women are newly infected with HIV every hour. Most women become infected with HIV through unprotected intercourse with an infected male partner—biologically, women are twice as likely to become infected through unprotected intercourse as men. A woman’s risk of becoming infected with HIV can be reduced by abstaining from sex, by having one or a few partners, and by always using condoms.
Why Was This Study Done?
Women and societies both benefit from effective contraception. When contraception is available, women can avoid unintended pregnancies, fewer women and babies die during pregnancy and childbirth, and maternal and infant health improves. However, some (but not all) observational studies (investigations that measure associations between the characteristics of participants and their subsequent development of specific diseases) have reported an association between hormonal contraceptive use and an increased risk of HIV acquisition by women. So, does hormonal contraception increase the risk of HIV acquisition among women or not? Here, to investigate this question, the researchers undertake an individual participant data meta-analysis of studies conducted in sub-Saharan Africa (a region where both HIV infection and unintended pregnancies are common) to compare the incidence of HIV infection (the number of new cases in a population during a given time period) among women using and not using hormonal contraception. Meta-analysis is a statistical method that combines the results of several studies; an individual participant data meta-analysis combines the data recorded for each individual involved in the studies rather than the aggregated results from each study.
What Did the Researchers Do and Find?
The researchers included 18 studies that measured hormonal contraceptive use and incident HIV infection among women aged 15–49 years living in sub-Saharan Africa in their meta-analysis. More than 37,000 women took part in these studies, and 1,830 became newly infected with HIV. Half of the women were not using hormonal contraception, a quarter were using depot-medroxyprogesterone acetate (DMPA; an injectable hormonal contraceptive), and the remainder were using combined oral contraceptives (COCs) or norethisterone enanthate (NET-EN, another injectable contraceptive). After adjustment for other factors likely to influence HIV acquisition (for example, condom use), women using DMPA had a 1.5-fold increased risk of HIV acquisition compared to women not using hormonal contraception. There was a slightly increased risk of HIV acquisition among women using NET-EN compared to women not using hormonal contraception, but this increase was not statistically significant (it may have happened by chance alone). There was no increased risk of HIV acquisition associated with COC use. DMPA use was associated with a 1.43-fold and 1.32-fold increased risk of HIV acquisition compared with COC and NET-EN use, respectively. Finally, neither age nor herpes simplex virus 2 infection status modified the effect of hormonal contraceptive use on HIV acquisition.
What Do These Findings Mean?
The findings of this individual patient data meta-analysis provide no evidence that COC or NET-EN use increases a woman’s risk of acquiring HIV, but add to the evidence suggesting that DMPA use increases the risk of HIV acquisition. These findings are likely to be more accurate than those of previous meta-analyses that used aggregated data but are likely to be limited by the quality, design, and representativeness of the studies included in the analysis. These findings nevertheless highlight the need to develop additional safe and effective contraceptive options for women at risk of HIV, particularly those living in sub-Saharan Africa, where although contraceptive use is generally low, DMPA is the most widely used hormonal contraceptive. In addition, these findings highlight the need to initiate randomized controlled trials to provide more definitive evidence of the effects of hormonal contraception, particularly DMPA, on HIV risk.
Additional Information.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001778.
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, including personal stories about living with HIV/AIDS and a news report on this meta-analysis
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on women, HIV, and AIDS, and on HIV and AIDS in South Africa (in English and Spanish); personal stories of women living with HIV are available
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); information about a 2012 WHO technical consultation about hormonal contraception and HIV
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it; UNAIDS also provides information about HIV and hormonal contraception
doi:10.1371/journal.pmed.1001778
PMCID: PMC4303292  PMID: 25612136
4.  Intimate partner violence: associations with low infant birthweight in a South African birth cohort 
Metabolic brain disease  2014;29(2):281-299.
Violence against women is a global public health problem. Exposure to intimate partner violence (IPV) during pregnancy has been associated with a number of adverse maternal and fetal outcomes, including delivery of a low birthweight (LBW) infant. However, there is a paucity of data from low-middle income countries (LMIC). We examined the association between antenatal IPV and subsequent LBW in a South African birth cohort. This study reports data from the Drakenstein Child Lung Health Study (DCLHS), a multidisciplinary birth cohort investigation of the influence of a number of antecedent risk factors on maternal and infant health outcomes over time. Pregnant women seeking antenatal care were recruited at two different primary care clinics in a low income, semi-rural area outside Cape Town, South Africa. Antenatal trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ) and an IPV assessment tool specifically designed for the purposes of this study. Potential confounding variables including maternal sociodemographics, pregnancy intention, partner support, biomedical and mental illness, substance use and psychosocial risk were also assessed. Bivariate and multiple regression analyses were performed to determine the association between IPV during pregnancy and delivery of an infant with LBW and/or low weight-for-age z (WAZ) scores. The final study sample comprised 263 mother-infant dyads. In multiple regression analyses, the model run was significant [r2=0.14 (adjusted r2=0.11, F(8, 212) = 4.16, p=0.0001]. Exposure to physical IPV occurring during the past year was found to be significantly associated with LBW [t=−2.04, p=0.0429] when controlling for study site (clinic), maternal height, ethnicity, socioeconomic status, substance use and childhood trauma. A significant association with decreased WAZ scores was not demonstrated. Exposure of pregnant women to IPV may impact newborn health. Further research is needed in this field to assess the relevant underlying mechanisms, to inform public health policies and to develop appropriate trauma IPV interventions for LMIC settings.
doi:10.1007/s11011-014-9525-4
PMCID: PMC4300125  PMID: 24729207
Intimate partner violence; Trauma; Pregnancy; Low birth weight; South Africa
5.  Disengagement of HIV-positive pregnant and postpartum women from antiretroviral therapy services: a cohort study 
Introduction
Recent international guidelines call for expanded access to triple-drug antiretroviral therapy (ART) in HIV-positive women during pregnancy and postpartum. However, high levels of non-adherence and/or disengagement from care may attenuate the benefits of ART for HIV transmission and maternal health. We examined the frequency and predictors of disengagement from care among women initiating ART during pregnancy in Cape Town, South Africa.
Methods
We used routine medical records to follow-up pregnant women initiating ART within prevention of mother-to-child transmission of HIV services in Cape Town, South Africa. Outcomes assessed through six months postpartum were (1) disengagement (no attendance within 56 days of a scheduled visit) and (2) missed visits (returning to care 14–56 days late for a scheduled visit).
Results
A total of 358 women (median age, 28 years; median gestational age, 26 weeks) initiated ART during pregnancy. By six months postpartum, 24% of women (n=86) had missed at least one visit and an additional 32% (n=115) had disengaged from care; together, 49% of women had either missed a visit or had disengaged by six months postpartum. Disengagement was more than twice as frequent postpartum compared to in the antenatal period (6.2 vs. 2.4 per 100 woman-months, respectively; p<0.0001). In a proportional hazards model, later gestational age at initiation (HR: 1.04; 95% CI: 1.00–1.07; p=0.030) and being newly diagnosed with HIV (HR: 1.57; 95% CI: 1.07–2.33; p=0.022) were significant predictors of disengagement after adjusting for patient age, starting CD4 cell count and site of ART initiation.
Conclusions
These results demonstrate that missed visits and disengagement from care occur frequently, particularly post-delivery, among HIV-positive women initiating ART during pregnancy. Women who are newly diagnosed with HIV may be particularly vulnerable and there is an urgent need for interventions both to promote retention overall, as well as targeting women newly diagnosed with HIV during pregnancy.
doi:10.7448/IAS.17.1.19242
PMCID: PMC4192834  PMID: 25301494
antiretroviral therapy; pregnancy; postpartum; retention; prevention of mother-to-child transmission (PMTCT); HIV/AIDS; South Africa
6.  Impact of definitions of loss to follow-up (LTFU) in antiretroviral therapy program evaluation: variation in the definition can have an appreciable impact on estimated proportions of LTFU 
Journal of clinical epidemiology  2013;66(9):1006-1013.
Objective
To examine the impact of different definitions of loss to follow-up (LTFU) on estimates of program outcomes in cohort studies of patients on antiretroviral therapy (ART).
Study Design and Setting
We examined the impact of different definitions of LTFU using data from the International Epidemiological Databases to Evaluate AIDS—Southern Africa. The reference approach, Definition A, was compared with five alternative scenarios that differed in eligibility for analysis and the date assigned to the LTFU outcome. Kaplan–Meier estimates of LTFU were calculated up to 2 years after starting ART.
Results
Estimated cumulative LTFU were 14% and 22% at 12 and 24 months, respectively, using the reference approach. Differences in the proportion LTFU were reported in the alternative scenarios with 12-month estimates of LTFU varying by up to 39% compared with Definition A. Differences were largest when the date assigned to the LTFU outcome was 6 months after the date of last contact and when the site-specific definition of LTFU was used.
Conclusion
Variation in the definitions of LTFU within cohort analyses can have an appreciable impact on estimated proportions of LTFU over 2 years of follow-up. Use of a standardized definition of LTFU is needed to accurately measure program effectiveness and comparability between programs.
doi:10.1016/j.jclinepi.2013.03.013
PMCID: PMC3759810  PMID: 23774112
Antiretroviral therapy; Program outcomes; Loss to follow-up; Cohort; Retention; Survival analysis
7.  Smoking estimates from around the world: data from the first 17 participating countries in the World Mental Health Survey Consortium 
Tobacco control  2009;19(1):65-74.
Objective
To contribute new multinational findings on basic descriptive features of smoking and cessation, based upon standardised community surveys of adults residing in seven low-income and middle-income countries and 10 higher-income countries from all regions of the world.
Methods
Data were collected using standardised interviews and community probability sample survey methods conducted as part of the WHO World Mental Health Surveys Initiative. Demographic and socioeconomic correlates of smoking are studied using cross-tabulation and logistic regression approaches. Within-country sample weights were applied with variance estimation appropriate for complex sample survey designs.
Results
Estimated prevalence of smoking experience (history of ever smoking) and current smoking varied across the countries under study. In all but four countries, one out of every four adults currently smoked. In higher-income countries, estimated proportions of former smokers (those who had quit) were roughly double the corresponding estimates for most low-income and middle-income countries. Characteristics of smokers varied within individual countries, and in relation to the World Bank's low-medium-high gradient of economic development. In stark contrast to a sturdy male-female difference in the uptake of smoking seen in each country, there is no consistent sex-associated pattern in the odds of remaining a smoker (versus quitting).
Conclusion
The World Mental Health Surveys estimates complement existing global tobacco monitoring efforts. The observed global diversity of associations with smoking and smoking cessation underscore reasons for implementation of the Framework Convention on Tobacco Control provisions and prompt local adaptation of prevention and control interventions.
doi:10.1136/tc.2009.032474
PMCID: PMC4124902  PMID: 19965796
8.  The association between timing of initiation of antenatal care and stillbirths: a retrospective cohort study of pregnant women in Cape Town, South Africa 
Background
There is renewed interest in stillbirth prevention for lower-middle income countries. Early initiation of and properly timed antenatal care (ANC) is thought to reduce the risk of many adverse birth outcomes. To this end we examined if timing of the first ANC visit influences the risk of stillbirth.
Methods
We conducted an analysis of a retrospective cohort of women (n = 34,671) with singleton births in a public perinatal service in Cape Town, South Africa. The main exposure was the gestational age at the first ANC visit. Bivariable analyses examining maternal characteristics by stillbirth status and gestational age at the first ANC visit, were conducted. Logistic regression, adjusting for maternal characteristics, was conducted to determine the risk of stillbirth.
Results
Of the 34,671 women who initiated ANC, 27,713 women (80%) were retained until delivery. The population stillbirth rate was 4.3 per 1000 births. The adjusted models indicated there was no effect of gestational age at first ANC visit on stillbirth outcomes when analyzed as a continuous variable (aOR 1.01; 95% CI: 0.99-1.04) or in trimesters (2nd Trimester aOR 0.78, 95% CI: 0.39-1.59; 3rd Trimester OR 1.03, 95% CI: 0.50-2.13, both with 1st Trimester as reference category). The findings were unchanged in sensitivity analyses of unobserved outcomes in non-retained women.
Conclusion
The timing of a woman’s first ANC visit may not be an important determinant of stillbirths in isolation. Further research is required to examine how quality of care, incorporating established, effective biomedical interventions, influences outcomes in this setting.
doi:10.1186/1471-2393-14-204
PMCID: PMC4062506  PMID: 24923284
Stillbirths; Antenatal care; Gestational age; Prenatal care; South Africa
9.  Mother-to-child transmission of HIV in a community-based antiretroviral clinic in South Africa 
Objective
To examine the uptake of ART among pregnant women referred to an ART service and the associated rates and risk factors for vertical HIV transmission.
Method
Retrospective analysis of an observational cohort at a community ART clinic in Cape Town.
Results
Between 2002 and 2008, 367 treatment-naïve pregnant women accessed the clinic. The median age was 27.5 years, and median gestation at presentation was 28 weeks. The median baseline CD4 count and viral load were 134 cells/µl and 28 282 copies/ml. Two hundred and sixty-five women (72%) commenced ART before giving birth, 73 women (20%) were referred for prevention of mother-to-child transmission therapy (PMTCT), and 29 (8%) received no intervention. Among ART-eligible women, 13% were lost to follow-up. Of those starting ART, median duration of therapy prior to birth was 7.6 weeks (interquartile range (IQR) 4 – 11.9). The HIV transmission rate was 5.1% (95% confidence interval (CI) 2.8 – 9.0%). Factors associated with transmission were advanced maternal WHO disease stage (odds ratio (OR) 9.57, p=0.02), and follow-up viral load above 50 copies/ml (OR 3.64, p=0.03). Each additional week on ART reduced transmission by 20% (p=0.05). There was no HIV transmission among women who received more than 8 weeks’ therapy.
Conclusions
The rate of HIV transmission in this study was higher than reported in high-income countries. Prevention of vertical transmission with ART was hindered by women presenting late in pregnancy and with advanced stage of HIV disease. Interventions that facilitate earlier ART commencement and improve programmatic retention of pregnant women are required.
PMCID: PMC3954611  PMID: 21414276
10.  Rates of tuberculosis transmission to children and adolescents in a community with high adult HIV prevalence 
doi:10.1086/589750
PMCID: PMC3816246  PMID: 18558885
tuberculin skin test; HIV; TB transmission; children; annual risk of TB infection
11.  Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa 
AIDS (London, England)  2008;22(15):10.1097/QAD.0b013e32830007cd.
Two-thirds of the world's HIV-infected people live in sub-Saharan Africa and more than 1.5 million of them die annually. As access to antiretroviral treatment (ART) has expanded within the region, early pessimism concerning the delivery of ART using a large-scale public health approach has, at least in the short term, proved to be broadly unfounded. Immunological and virological responses to ART are similar to responses in patients treated in high-income countries. Despite this, however, early mortality rates in sub-Saharan Africa are very high; between 8% and 26% of patients die in the first year of ART, with most deaths occurring in the first few months. Patients typically access ART with advanced symptomatic disease, and mortality is strongly associated with baseline CD4 cell count <50 cells/μL and WHO stage 4 disease (AIDS). Although data are limited, leading causes of death appear to be tuberculosis, acute sepsis, cryptococcal meningitis, malignancy and wasting syndrome. Mortality rates are likely to depend not only on the care delivered by ART programmes, but more fundamentally on how advanced disease is at programme enrolment and the quality of preceding health-care. In addition to improving delivery of ART and providing this free of charge to the patient, strategies to reduce mortality must include earlier diagnosis of HIV infection, strengthening of longitudinal HIV care and timely initiation of ART. Health systems delays in ART initiation must be minimised, especially in patients who present with advanced immunodeficiency.
doi:10.1097/QAD.0b013e32830007cd
PMCID: PMC3816249  PMID: 18784453
HIV; AIDS; antiretroviral treatment; HAART; ART; mortality; death; Africa
12.  Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa 
AIDS (London, England)  2009;23(13):1717-1725.
Objective
To determine the short-term and long-term risks of tuberculosis (TB) associated with CD4 cell recovery during antiretroviral therapy (ART).
Design
Observational community-based ART cohort in South Africa.
Methods
TB incidence was determined among patients (n = 1480) receiving ART for up to 4.5 years in a South African community-based service. Updated CD4 cell counts were measured 4-monthly. Person-time accrued within a range of CD4 cell count strata (CD4 cell strata) was calculated and used to derive CD4 cell-stratified TB rates. Factors associated with incident TB were identified using Poisson regression models.
Results
Two hundred and three cases of TB were diagnosed during 2785 person-years of observation (overall incidence, 7.3 cases/100 person-years). During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500 and more than 500 cells/µl unadjusted TB incidence rates were 16.8, 9.3, 5.5, 4.6, 4.2 and 1.5 cases/100 person-years, respectively (P < 0.001). During early ART (first 4 months), adjusted TB rates among those with CD4 cell counts 0–200 cells/µl were 1.7-fold higher than during long-term ART (P = 0.026). Updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk.
Conclusion
Updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. Among those with baseline CD4 cell counts less than 200 cells/µl, the excess adjusted risk of TB during early ART was consistent with ‘unmasking’ of disease missed at baseline screening. TB incidence rates at CD4 cell counts of 200–500 cells/µl remained high and adjunctive interventions are required. TB prevention would be improved by ART policies that minimized the time patients spend with CD4 cell counts below a threshold of 500 cells/µl.
doi:10.1097/QAD.0b013e32832d3b6d
PMCID: PMC3801095  PMID: 19461502
Africa; antiretroviral; CD4 cell; HIV; immune reconstitution; resource-limited country; tuberculosis
13.  Antiretroviral therapy and TB notification rates in a high HIV prevalence South African community 
Background
Antiretroviral therapy (ART) has been proposed as an intervention for reducing tuberculosis (TB) burdens in areas with high HIV prevalence. However, little data is available on the impact of ART on population-level TB.
Methods
Trends in adult TB case fatality and notifications were assessed prior to and during increasing ART coverage in a well-defined peri-urban community, from 1997 to 2008. Mean changes in TB rates were measured using linear autoregression models. ART coverage increased from 1% in 2003, to 5%, 13% and 21% of HIV-infected population in 2004, 2005 and 2008 respectively.
Results
From 1997 to end of 2004 TB notification rates increased by an average of 187 cases/100,000/yr (p<0.001), reaching a peak of 2,536/100,000 in 2005. From 2005 to 2008, TB notification rates declined by approximately 183 cases/100,000/yr (p<0.001). TB rates were initially stable in HIV-uninfected individuals, but declined moderately from 2005. TB rates declined in HIV-infected adults from 6,513/100,000 in 2005 to 4,741/100,000 in 2008. The predominant decline in TB notifications occurred among HIV-infected patients receiving ART (1,156 cases/100,000/yr) and was less marked in those not receiving ART (416cases/100,000/yr). Similarly, TB case fatality was constant for HIV-uninfected individuals but declined in HIV-infected individuals from 23% in 2002 to 8% in 2008 (p=0.01).
Conclusions
In this community heavily affected by both HIV and TB epidemics, rapid and high ART coverage was associated with significant reductions in TB notifications and TB-associated case fatality.
doi:10.1097/QAI.0b013e31820413b3
PMCID: PMC3801097  PMID: 21317585
tuberculosis; notification rates; HIV; antiretroviral; community
14.  Comparison of point-of-care versus laboratory-based CD4 cell enumeration in HIV-positive pregnant women 
Introduction
Early initiation of antiretroviral therapy (ART) in eligible pregnant women is a key intervention for prevention of mother-to-child transmission (PMTCT) of HIV. However, in many settings in sub-Saharan Africa where ART-eligibility is determined by CD4 cell counts, limited access to laboratories presents a significant barrier to rapid ART initiation. Point-of-care (POC) CD4 cell count testing has been suggested as one approach to overcome this challenge, but there are few data on the agreement between POC CD4 cell enumeration and standard laboratory-based testing.
Methods
Working in a large antenatal clinic in Cape Town, South Africa, we compared POC CD4 cell enumeration (using the Alere PimaTM Analyzer) to laboratory-based flow cytometry in consecutive HIV-positive pregnant women. Bland–Altman methods were used to compare the two methods, including analyses by subgroups of participant gestational age.
Results
Among the 521 women participating, the median gestational age was 23 weeks, and the median CD4 cell count according to POC and laboratory-based methods was 388 and 402 cells/µL, respectively. On average, the Pima POC test underestimated CD4 cell count relative to flow cytometry: the mean difference (laboratory test minus Pima POC) was 22.7 cells/µL (95% CI, 16.1 to 29.2), and the limits of agreement were −129.2 to 174.6 cells/µL. When analysed by gestational age categories, there was a trend towards increasing differences between laboratory and POC testing with increasing gestational age; in women more than 36 weeks’ gestation, the mean difference was 45.0 cells/µL (p=0.04).
Discussion
These data suggest reasonable overall agreement between Pima POC CD4 testing and laboratory-based flow cytometry among HIV-positive pregnant women. The finding for decreasing agreement with increasing gestational age requires further investigation, as does the operational role of POC CD4 testing to increase access to ART within PMTCT programmes.
doi:10.7448/IAS.16.1.18649
PMCID: PMC3776301  PMID: 24044627
point-of-care test; CD4 cell count; reliability; pregnancy; HIV; antiretroviral therapy; South Africa
15.  Viewpoint Men and antiretroviral therapy in Africa: our blindspot 
doi:10.1111/j.1365-3156.2011.02767.x
PMCID: PMC3749374  PMID: 21418449
16.  Screening for Serious Mental Illness in the General Population with the K6 screening scale: Results from the WHO World Mental Health (WMH) Survey Initiative 
Data are reported on the background and performance of the K6 screening scale for serious mental illness (SMI) in the World Health Organization (WHO) World Mental Health (WMH) surveys. The K6 is a 6-item scale developed to provide a brief valid screen for DSM-IV SMI based on the criteria in the US ADAMHA Reorganization Act. Although methodological studies have documented good K6 validity in a number of countries, optimal scoring rules have never been proposed. Such rules are presented here based on analysis of K6 data in nationally or regionally representative WMH surveys in 14 countries (combined n = 41,770 respondents). Twelve-month prevalence of DSM-IV SMI was assessed with the fully-structured WHO Composite International Diagnostic Interview. Nested logistic regression analysis was used to generate estimates of the predicted probability of SMI for each respondent from K6 scores taking into consideration the possibility of variable concordance as a function of respondent age, gender, education, and country. Concordance, assessed by calculating the area under the receiver operating characteristic curve (AUC), was generally substantial (Median .83; Range .76-.89; Inter-quartile range .81-.85). Based on this result, optimal scaling rules are presented for use by investigators working with the K6 scale in the countries studied.
doi:10.1002/mpr.310
PMCID: PMC3659799  PMID: 20527002
K6 screening scale; psychiatric epidemiology; serious mental illness (SMI)
17.  Integration of Antiretroviral Therapy Services into Antenatal Care Increases Treatment Initiation during Pregnancy: A Cohort Study 
PLoS ONE  2013;8(5):e63328.
Objectives
Initiation of antiretroviral therapy (ART) during pregnancy is critical to promote maternal health and prevent mother-to-child HIV transmission (PMTCT). The separation of services for antenatal care (ANC) and ART may hinder antenatal ART initiation. We evaluated ART initiation during pregnancy under different service delivery models in Cape Town, South Africa.
Methods
A retrospective cohort study was conducted using routinely collected clinic data. Three models for ART initiation in pregnancy were evaluated ART ‘integrated’ into ANC, ART located ‘proximal’ to ANC, and ART located some distance away from ANC (‘distal’). Kaplan-Meier methods and Poisson regression were used to examine the association between service delivery model and antenatal ART initiation.
Results
Among 14 617 women seeking antenatal care in the three services, 30% were HIV-infected and 17% were eligible for ART based on CD4 cell count <200 cells/µL. A higher proportion of women started ART antenatally in the integrated model compared to the proximal or distal models (55% vs 38% vs 45%, respectively, global p = 0.003). After adjusting for age and gestation at first ANC visit, women who at the integrated service were significantly more likely to initiate ART antenatally (rate ratio 1.33; 95% confidence interval: 1.09–1.64) compared to women attending the distal model; there was no difference between the proximal and distal models in antenatal ART initiation however (p = 0.704).
Conclusions
Integration of ART initiation into ANC is associated with higher levels of ART initiation in pregnancy. This and other forms of service integration may represent a valuable intervention to enhance PMTCT and maternal health.
doi:10.1371/journal.pone.0063328
PMCID: PMC3656005  PMID: 23696814
18.  Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 hours 
BMC Pediatrics  2013;13:52.
Background
An early clinical score predicting an abnormal amplitude-integrated electroencephalogram (aEEG) or moderate-severe hypoxic ischemic encephalopathy (HIE) may allow rapid triage of infants for therapeutic hypothermia. We aimed to determine if early clinical examination could predict either an abnormal aEEG at age 6 hours or moderate-severe HIE presenting within 72 hours of birth.
Methods
Sixty infants ≥ 36 weeks gestational age were prospectively enrolled following suspected intrapartum hypoxia and signs of encephalopathy. Infants who were moribund, had congenital conditions that could contribute to the encephalopathy or had severe cardio-respiratory instability were excluded. Predictive values of the Thompson HIE score, modified Sarnat encephalopathy grade (MSEG) and specific individual signs at age 3–5 hours were calculated.
Results
All of the 60 infants recruited had at least one abnormal primitive reflex. Visible seizures and hypotonia at 3–5 hours were strongly associated with an abnormal 6-hour aEEG (specificity 88% and 92%, respectively), but both had a low sensitivity (47% and 33%, respectively). Overall, 52% of the infants without hypotonia at 3–5 hours had an abnormal 6-hour aEEG. Twelve of the 29 infants (41%) without decreased level of consciousness at 3–5 hours had an abnormal 6-hour aEEG (sensitivity 67%; specificity 71%). A Thompson score ≥ 7 and moderate-severe MSEG at 3–5 hours, both predicted an abnormal 6-hour aEEG (sensitivity 100 vs. 97% and specificity 67 vs. 71% respectively). Both assessments predicted moderate-severe encephalopathy within 72 hours after birth (sensitivity 90%, vs. 88%, specificity 92% vs. 100%). The 6-hour aEEG predicted moderate-severe encephalopathy within 72 hours (sensitivity 75%, specificity 100%) but with lower sensitivity (p = 0.0156) than the Thompson score (sensitivity 90%, specificity 92%). However, all infants with a normal 3- and 6-hour aEEG with moderate-severe encephalopathy within 72 hours who were not cooled had a normal 24-hour aEEG.
Conclusions
The encephalopathy assessment described by the Thompson score at age 3–5 hours is a sensitive predictor of either an abnormal 6-hour aEEG or moderate-severe encephalopathy presenting within 72 hours after birth. An early Thompson score may be useful to assist with triage and selection of infants for therapeutic hypothermia.
doi:10.1186/1471-2431-13-52
PMCID: PMC3635928  PMID: 23574923
Asphyxia; Neonate; Hypoxic ischemic encephalopathy; Electroencephalogram; aEEG; Prognostic
19.  Increasing Transfers-Out from an Antiretroviral Treatment Service in South Africa: Patient Characteristics and Rates of Virological Non-Suppression 
PLoS ONE  2013;8(3):e57907.
Objectives
To determine the proportion, characteristics and outcomes of patients who transfer-out from an antiretroviral therapy (ART) service in a South African township.
Methods
This retrospective cohort study included all patients aged ≥15 years who enrolled between September 2002 and December 2009. Follow-up data were censored in December 2010. Kaplan-Meier survival analysis was used to describe time to transfer-out and cox proportional hazard analysis was used to determine associated risk factors.
Results
4511 patients (4003 ART-naïve and 508 non-naïve at baseline) received ART during the study period. Overall, 597 (13.2%) transferred out. The probability of transferring out by one year of ART steadily increased from 1.4% in 2002/2004 cohort to 8.9% for the 2009 cohort. Independent risk factors for transfer-out were more recent calendar year of enrolment, younger age (≤25 years) and being ART non-naïve at baseline (i.e., having previously transferred into this clinic from another facility). The proportions of patients transferred out who had a CD4 cell count <200 cells/µL and/or a viral load ≥1000 copies/mL were 19% and 20%, respectively.
Conclusions
With scale-up of ART over time, an increasing proportion of patients are transferring between ART services and information systems are needed to track patients. Approximately one-fifth of these have viral loads >1000 copies/mL around the time of transfer, suggesting the need for careful adherence counseling and assessment of medication supplies among those planning transfer.
doi:10.1371/journal.pone.0057907
PMCID: PMC3589459  PMID: 23472118
20.  Complications of Antiretroviral Therapy Initiation in Hospitalised Patients with HIV-Associated Tuberculosis 
PLoS ONE  2013;8(2):e54145.
Background
HIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries.
Methods
Prospective, observational cohort study of adult inpatients with HIV-associated tuberculosis starting antiretroviral therapy in a dedicated tuberculosis hospital in Cape Town, South Africa. Causes of clinical deterioration and outcome were recorded in the first 12 weeks of antiretroviral therapy. Patients with rifampicin-resistant tuberculosis were excluded.
Results
Between May 2009 and November 2010, 112 patients (60% female), with a median age of 32 years were enrolled. At baseline the median CD4 count was 55 cells/mm3 (IQR 31–106) and HIV viral load 5.6 log copies/mL. All patients had significant comorbidity: 82% were bed-bound, 65% had disseminated tuberculosis and 27% had central nervous system tuberculosis. Seventy six patients (68%) developed 144 clinical events after starting antiretroviral therapy. TB-IRIS, hospital-acquired infections and significant drug toxicities occurred in 42%, 20.5% and 15% of patients respectively. A new opportunistic disease occurred in 15% of patients and a thromboembolic event in 8%. Mortality during the 12 week period was 10.6%.
Conclusions
High rates of TB-IRIS, hospital-acquired infections and drug toxicities complicate the course of patients with HIV-associated tuberculosis starting antiretroviral therapy in hospital. Despite the high morbidity, mortality was relatively low. Careful clinical management and adequate resources are needed in hospitalised HIV-TB patients in the 1st three months following ART initiation.
doi:10.1371/journal.pone.0054145
PMCID: PMC3568128  PMID: 23408935
21.  Linkage of HIV-Infected Infants from Diagnosis to Antiretroviral Therapy Services across the Western Cape, South Africa 
PLoS ONE  2013;8(2):e55308.
Introduction
Early infant diagnosis (EID) of HIV infection is an important service to reduce paediatric morbidity and mortality related to HIV/AIDS. Although South Africa has a national EID programme based on PCR testing, there are no population-wide data on the linkage of infants testing HIV PCR-positive to HIV care and treatment services.
Methods
We conducted a retrospective analysis of all public sector laboratory data from across the Western Cape province between 2005 and 2011. We linked positive HIV PCR results to subsequent HIV viral load testing to determine the proportion of infants who were successfully linked to HIV care.
Results
A total of 83 698 unique infant HIV PCR tests were documented, of which 6322 (8%) were PCR positive. The proportion of PCR-positive children declined from 12% in 2005 to 3% in 2011. Of the children testing PCR-positive, 4105 (65%) had subsequent viral load testing indicating successful linkage to care. The proportion of successfully linked infants increased from 54% in 2005 to 71% in 2010, while the median delay in days to successful linkage decreased from 146 days in 2005 to 33 days in 2010.
Discussion
From 2005 to 2011 there has been a reduction in the proportion of children testing HIV PCR-positive, and an increase in the proportion of infected infants successfully linked to HIV care and treatment, in this setting. However a large proportion of infected infants remain unlinked to antiretroviral therapy services and there is a clear need for interventions to further strengthen EID programmes.
doi:10.1371/journal.pone.0055308
PMCID: PMC3566187  PMID: 23405133
22.  Immune Activation in the Female Genital Tract During HIV Infection Predicts Mucosal CD4 Depletion and HIV Shedding 
The Journal of Infectious Diseases  2011;204(10):1550-1556.
Plasma viral load predicts genital tract human immunodeficiency virus (HIV) shedding in HIV-infected women. We investigated whether local mucosal T-cell activation (HLA-DR, CD38, CCR5, and Ki67) contributed to HIV shedding in the genital tracts of HIV-infected women. We showed that cervical cytobrush-derived T cells expressed higher frequencies of T-cell activation markers (CD38+ and HLA-DR+) than blood-derived T cells. Expression was significantly higher in HIV-infected women than in uninfected women. We found that the frequency of activated proliferating cervical T cells (Ki67+; Ki67+CCR5+) broadly predicted HIV shedding in the genital tract in HIV-infected women, independently of plasma viral loads. Furthermore, activated cervical T cells (HLA-DR+CD38+ and HLA-DR+CCR5+) and local HIV shedding were independently associated with CD4 depletion in the genital tract. These data suggest that the presence of high frequencies of activated T cells in the female genital mucosa during HIV infection facilitates both local HIV shedding and CD4 T-cell depletion.
doi:10.1093/infdis/jir591
PMCID: PMC3192190  PMID: 21940422
23.  Effect of Caregivers' Depression and Alcohol Use on Child Antiretroviral Adherence in South Africa 
AIDS Patient Care and STDs  2011;25(10):595-600.
Abstract
Pediatric antiretroviral adherence is difficult to assess, and subjective measures are affected by reporting bias, which in turn may depend on psychosocial factors such as alcohol use and depression. We enrolled 56 child–caregiver dyads from Cape Town, South Africa and followed their adherence over 1 month via various methods. The Alcohol Use Disorder Inventory Tool and Beck Depression Inventory 1 were used to assess these factors and their affect on pediatric adherence. The median age of the children was 4 years, and median time on antiretrovirals was 20 months. Increased time on ART was associated with poorer adherence via 3-day recall (3DR; p=0.03). Ethanol use was inversely associated with adherence by both subjective measures, 3DR and visual analogue scale (VAS) (both p<0.01), and with Medication Event Monitoring System (MEMS) adherence as a continuous variable. In a multivariate analysis predicting MEMS adherence greater than 95%, including variables that were associated with adherence in univariate analyses, having a mother as a caregiver and shorter time on highly active antiretroviral therapy (HAART) were significantly associated with adherence (odds ratio [OR] 19.2; 95% confidence interval [CI] 1.1–327 and 0.9; 95% CI 0.9–0.99). Pediatric adherence is affected by caregiver alcohol use, but caregiver relationship to the child is most important. This small study suggests that interventions should aim to keep mothers healthy and alive, as well as alcohol-free.
doi:10.1089/apc.2010.0323
PMCID: PMC3183652  PMID: 21470047
24.  Mental illness and lost income among adult South Africans 
Purpose
Little is known regarding the links between mental disorder and lost income in low- and middle-income countries. The purpose of this study was to investigate the association between mental disorder and lost income in the first nationally representative psychiatric epidemiology survey in South Africa.
Methods
A probability sample of South African adults was administered the World Health Organization Composite International Diagnostic Interview schedule to assess the presence of mental disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders, version IV.
Results
The presence of severe depression or anxiety disorders was associated with a significant reduction in earnings in the previous 12 months among both employed and unemployed South African adults (p = 0.0043). In simulations of costs to individuals, the mean estimated lost income associated with severe depression and anxiety disorders was $4,798 per adult per year, after adjustment for age, gender, substance abuse, education, marital status, and household size. Projections of total annual cost to South Africans living with these disorders in lost earnings, extrapolated from the sample, were $3.6 billion. These data indicate either that mental illness has a major economic impact, through the effect of disability and stigma on earnings, or that people in lower income groups are at increased risk of mental illness. The indirect costs of severe depression and anxiety disorders stand in stark contrast with the direct costs of treatment in South Africa, as illustrated by annual government spending on mental health services, amounting to an estimated $59 million for adults.
Conclusions
The findings of this study support the economic argument for investing in mental health care as a means of mitigating indirect costs of mental illness.
doi:10.1007/s00127-012-0587-5
PMCID: PMC3627034  PMID: 23007296
Income; Mental disorder; South Africa; Economics; Health policy
25.  Systemic delays in the initiation of antiretroviral therapy during pregnancy do not improve outcomes of HIV-positive mothers: a cohort study 
Background
Antiretroviral therapy (ART) initiation in eligible HIV-infected pregnant women is an important intervention to promote maternal and child health. Increasing the duration of ART received before delivery plays a major role in preventing vertical HIV transmission, but pregnant women across Africa experience significant delays in starting ART, partly due the perceived need to deliver ART counseling and patient education before ART initiation. We examined whether delaying ART to provide pre-ART counseling was associated with improved outcomes among HIV-infected women in Cape Town, South Africa.
Methods
We undertook a retrospective cohort study of 490 HIV-infected pregnant women referred to initiate treatment at an urban ART clinic. At this clinic all patients including pregnant women are screened by a clinician and then undergo three sessions of counseling and patient education prior to starting treatment, commonly introducing delays of 2–4 weeks before ART initiation. Data on viral suppression and retention in care after ART initiation were taken from routine clinic records.
Results
A total of 382 women initiated ART before delivery (78%); ART initiation before delivery was associated with earlier gestational age at presentation to the ART service (p < 0.001). The median delay between screening and ART initiation was 21 days (IQR, 14–29 days). Overall, 84.7%, 79.6% and 75.0% of women who were pregnant at the time of ART initiation were retained in care at 4, 8 and 12 months after ART initiation, respectively. Among those retained, 91% were virally suppressed at each follow-up visit. However the delay from screening to ART initiation was not associated with retention in care and/or viral suppression throughout the first year on ART in unadjusted or adjusted analyses.
Conclusions
A substantial proportion of eligible pregnant women referred for ART do not begin treatment before delivery in this setting. Among women who do initiate ART, delaying initiation for patient preparation is not associated with improved maternal outcomes. Given the need to maximize the duration of ART before delivery for prevention of mother-to-child HIV transmission, there is an urgent need for new strategies to help expedite ART initiation in eligible pregnant women.
doi:10.1186/1471-2393-12-94
PMCID: PMC3490939  PMID: 22963318
Antiretroviral therapy; Pregnancy; Patient preparation; Prevention of mother-to-child transmission (PMTCT); HIV/AIDS; South Africa

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