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1.  Cohort Profile: The Themba Lethu Clinical Cohort, Johannesburg, South Africa 
The Themba Lethu Clinical Cohort was established in 2004 to allow large patient-level analyses from a single HIV treatment site to evaluate National Treatment Guidelines, answer questions of national and international policy relevance and to combine an economic and epidemiologic focus on HIV research. The current objectives of the Themba Lethu Clinical Cohort analyses are to: (i) provide cohort-level information on the outcomes of HIV treatment; (ii) evaluate aspects of HIV care and treatment that have policy relevance; (iii) evaluate the cost and cost-effectiveness of different approaches to HIV care and treatment; and (iv) provide a platform for studies on improving HIV care and treatment. Since 2004, Themba Lethu Clinic has enrolled approximately 30 000 HIV-positive patients into its HIV care and treatment programme, over 21 000 of whom have received anti-retroviral therapy since being enrolled. Patients on treatment are typically seen at least every 3 months with laboratory monitoring every 6 months to 1 year. The data collected include demographics, clinical visit data, laboratory data, medication history and clinical diagnoses. Requests for collaborations on analyses can be submitted to our data centre.
PMCID: PMC3619949  PMID: 22434860
2.  Postnatal Cytomegalovirus Exposure in Infants of Antiretroviral-Treated and Untreated HIV-Infected Mothers 
HIV-1 and CMV are important pathogens transmitted via breastfeeding. Furthermore, perinatal CMV transmission may impact growth and disease progression in HIV-exposed infants. Although maternal antiretroviral therapy reduces milk HIV-1 RNA load and postnatal transmission, its impact on milk CMV load is unclear. We examined the relationship between milk CMV and HIV-1 load (4–6 weeks postpartum) and the impact of antiretroviral treatment in 69 HIV-infected, lactating Malawian women and assessed the relationship between milk CMV load and postnatal growth in HIV-exposed, breastfed infants through six months of age. Despite an association between milk HIV-1 RNA and CMV DNA load (0.39 log10 rise CMV load per log10 rise HIV-1 RNA load, 95% CI 0.13–0.66), milk CMV load was similar in antiretroviral-treated and untreated women. Higher milk CMV load was associated with lower length-for-age (−0.53, 95% CI: −0.96, −0.10) and weight-for-age (−0.40, 95% CI: −0.67, −0.13) Z-score at six months in exposed, uninfected infants. As the impact of maternal antiretroviral therapy on the magnitude of postnatal CMV exposure may be limited, our findings of an inverse relationship between infant growth and milk CMV load highlight the importance of defining the role of perinatal CMV exposure on growth faltering of HIV-exposed infants.
PMCID: PMC3958696  PMID: 24723745
3.  The Table 2 Fallacy: Presenting and Interpreting Confounder and Modifier Coefficients 
American Journal of Epidemiology  2013;177(4):292-298.
It is common to present multiple adjusted effect estimates from a single model in a single table. For example, a table might show odds ratios for one or more exposures and also for several confounders from a single logistic regression. This can lead to mistaken interpretations of these estimates. We use causal diagrams to display the sources of the problems. Presentation of exposure and confounder effect estimates from a single model may lead to several interpretative difficulties, inviting confusion of direct-effect estimates with total-effect estimates for covariates in the model. These effect estimates may also be confounded even though the effect estimate for the main exposure is not confounded. Interpretation of these effect estimates is further complicated by heterogeneity (variation, modification) of the exposure effect measure across covariate levels. We offer suggestions to limit potential misunderstandings when multiple effect estimates are presented, including precise distinction between total and direct effect measures from a single model, and use of multiple models tailored to yield total-effect estimates for covariates.
PMCID: PMC3626058  PMID: 23371353
causal diagrams; causal inference; confounding; direct effects; epidemiologic methods; mediation analysis; regression modeling
4.  HIV Testing and Counseling Leads to Immediate Consistent Condom Use among South African Stable HIV-discordant Couples 
Effective behavioral HIV prevention is needed for stable HIV-discordant couples at risk for HIV, especially those without access to biomedical prevention. This analysis addressed whether HIV testing and counseling (HTC) with ongoing counseling and condom distribution lead to reduced unprotected sex in HIV-discordant couples.
Partners in Prevention HSV/HIV Transmission Study was a randomized trial conducted from 2004–2008 assessing whether acyclovir reduced HIV transmission from HSV-2/HIV-1 co-infected persons to HIV-uninfected sex partners. This analysis relied on self-reported behavioral data from 508 HIV-infected South African participants. The exposure was timing of first HTC: 0–7, 8–14, 15–30, or >30 days before baseline. In each exposure group, predicted probabilities of unprotected sex in the last month were calculated at baseline, month one, and month twelve using generalized estimating equations with a logit link and exchangeable correlation matrix.
At baseline, participants who knew their HIV status for less time experienced higher predicted probabilities of unprotected sex in the last month: 0–7 days, 0.71; 8–14 days, 0.52; 15–30 days, 0.49; >30 days, 0.26. At month one, once all participants had been aware of being in HIV-discordant relationships for ≥ 1 month, predicted probabilities declined: 0–7 days, 0.08; 8–14 days, 0.08; 15–30 days, 0.15; >30 days, 0.14. Lower predicted probabilities were sustained through month twelve: 0–7 days, 0.08; 8–14 days, 0.11; 15–30 days, 0.05; >30 days, 0.19.
Unprotected sex declined after HIV-positive diagnosis, and declined further after awareness of HIV-discordance. Identifying HIV-discordant couples for behavioral prevention is important for reducing HIV transmission risk.
PMCID: PMC3548982  PMID: 23117500
HIV; condom; unprotected sex; HIV counseling and testing; discordant couple; South Africa
5.  Gender Differences in Mortality and CD4 Count Response Among Virally Suppressed HIV-Positive Patients 
Journal of Women's Health  2013;22(2):113-120.
Treatment outcomes for antiretroviral therapy (ART) patients may vary by gender, but estimates from current evidence may be confounded by disease stage and adherence. We investigated the gender differences in treatment response among HIV-positive patients virally suppressed within 6 months of treatment initiation.
We analyzed data from 7,354 patients initiating ART between April 2004 and April 2010 at Themba Lethu Clinic, a large urban public sector treatment facility in South Africa. We estimated the relations among gender, mortality, and mean CD4 response in HIV-infected adults virally suppressed within 6 months of treatment initiation and used inverse probability of treatment weights to correct estimates for loss to follow-up.
Male patients had a 20% greater risk of death at both 24 months and 36 months of follow-up compared to females. Older patients and those with a low hemoglobin level or low body mass index (BMI) were at increased risk of mortality throughout follow-up. Men gained fewer CD4 cells after treatment initiation than did women. The mean differences in CD4 count gains made by women and men between baseline and 12, 24, and 36 months were 28.2 cells/mm3 (95% confidence interval [CI] 22.2–34.3), 60.8 cells/mm3 (95% CI 71.1-50.5 cells/mm3), and 83.0 cells/mm3 (95% CI 97.1-68.8 cells/mm3), respectively. Additionally, patients with a current detectable viral load (>400 copies/mL) and older patients had a lower mean CD4 increase at the same time points.
In this initially virally suppressed population, women showed consistently better immune response to treatment than did men. Promoting earlier uptake of HIV treatment among men may improve their immunologic outcomes.
PMCID: PMC3579326  PMID: 23350862
6.  Tenofovir use and pregnancy among women initiating HAART 
AIDS (London, England)  2012;26(18):2393-2397.
Recent studies have raised concerns about a change in rates of pregnancy among HIV-negative women exposed to tenofovir. Here, our objective was to determine among HIV-positive women whether use of tenofovir at HAART initiation or thereafter is associated with subsequent changes in incidence of pregnancy.
Analysis of prospectively collected clinical data.
We used Cox proportional hazards models and logistic regression to estimate hazard ratios and odds-ratios for the association of baseline tenofovir use and time to first incident pregnancy. We used marginal structural Cox models to estimate hazard ratios for the association of current tenofovir use and time to first incident pregnancy.
We studied 7,275 women, of whom 1,199 were initiated on tenofovir-based HAART regimens, and who experienced a total of 894 pregnancies in 17,200 person-years of follow-up. Analyses showed slight reductions in hazards of pregnancy among women who used tenofovir, but without sufficient precision to draw strong conclusions. Sensitivity analyses confirmed main results.
Tenofovir may be associated with a lower hazard or rate of pregnancy in women receiving HAART. However, conclusions are limited by low precision, the observational nature of the data, and possible uncontrolled confounding by temporal trends in contraception use and other factors.
PMCID: PMC3725726  PMID: 22951630
7.  Antiretroviral Therapy Initiation during Tuberculosis Treatment and HIV-RNA and CD4-T Lymphocyte Responses 
Setting and Objective
We examined the effect of initiating ART on CD4 and viral response at different time periods during TB therapy (< 14 days; 15–60 days; or ≥60 days) using prospectively collected clinical data from a large HIV clinic in South Africa.
Cohort data analysis for 1499 TB/HIV co-infected patients classified according to timing of ART after the initiation of TB therapy.
In adjusted modified Poisson regression models, CD4 and viral responses showed no significant differences according to timing of ART initiation (failure to increase CD4 by 6 months, <14 days vs. >60 days: RR 1.02 (95% CI 0.85–1.22), 15–60 days vs. >60 days: RR 1.00 (95% CI 0.86–1.15); failure to suppress virus by 6 months, <14 days vs. >60 days: RR 0.98 (95% CI 0.59–1.63), 15–60 days vs. >60 days: RR 0.96 (95% CI 0.66–1.41) and viral rebound at 12 months, 14 days vs. >60 days: RR 1.43 (95% CI 0.50–4.12), 15–60 days vs. >60 days: RR 1.14 (95% CI 0.39–3.34). Similar estimates were found in analysis restricted to patients with severe immunosuppression.
Concerns over the overlapping impact of TB treatment with ART on ART response should not be a reason to delay ART in patients with HIV-associated TB.
PMCID: PMC3727657  PMID: 22863288
Timing of ART; CD4 response; Viral response; TB–HIV co-infection
8.  A simulation study of finite-sample properties of marginal structural Cox proportional hazards models 
Statistics in medicine  2012;31(19):2098-2109.
Motivated by a previously published study of HIV treatment, we simulated data subject to time-varying confounding affected by prior treatment to examine some finite-sample properties of marginal structural Cox proportional hazards models. We compared (a) unadjusted, (b) regression-adjusted, (c) unstabilized and (d) stabilized marginal structural (inverse probability-of-treatment [IPT] weighted) model estimators of effect in terms of bias, standard error, root mean squared error (MSE) and 95% confidence limit coverage over a range of research scenarios, including relatively small sample sizes and ten study assessments. In the base-case scenario resembling the motivating example, where the true hazard ratio was 0.5, both IPT-weighted analyses were unbiased while crude and adjusted analyses showed substantial bias towards and across the null. Stabilized IPT-weighted analyses remained unbiased across a range of scenarios, including relatively small sample size; however, the standard error was generally smaller in crude and adjusted models. In many cases, unstabilized weighted analysis showed a substantial increase in standard error compared to other approaches. Root MSE was smallest in the IPT-weighted analyses for the base-case scenario. In situations where time-varying confounding affected by prior treatment was absent, IPT-weighted analyses were less precise and therefore had greater root MSE compared with adjusted analyses. The 95% confidence limit coverage was close to nominal for all stabilized IPT-weighted but poor in crude, adjusted, and unstabilized IPT-weighted analysis. Under realistic scenarios, marginal structural Cox proportional hazards models performed according to expectations based on large-sample theory and provided accurate estimates of the hazard ratio.
PMCID: PMC3641777  PMID: 22492660
Bias; Causal inference; Marginal structural models; Monte Carlo study
9.  Representation of Women and Pregnant Women in HIV Research: A Limited Systematic Review 
PLoS ONE  2013;8(8):e73398.
HIV-related outcomes may be affected by biological sex and by pregnancy. Including women in general and pregnant women in particular in HIV-related research is important for generalizability of findings.
To characterize representation of pregnant and non-pregnant women in HIV-related research conducted in general populations.
Data Sources
All HIV-related articles published in fifteen journals from January to March of 2011. We selected the top five journals by 2010 impact factor, in internal medicine, infectious diseases, and HIV/AIDS.
Study Eligibility Criteria
HIV-related studies reporting original research on questions applicable to both men and women of reproductive age were considered; studies were excluded if they did not include individual-level patient data.
Study appraisal and synthesis methods.
Articles were doubly reviewed and abstracted; discrepancies were resolved through consensus. We recorded proportion of female study participants, whether pregnant women were included or excluded, and other key factors.
In total, 2014 articles were published during this period. After screening, 259 articles were included as original HIV-related research reporting individual-level data; of these, 226 were determined to be articles relevant to both men and women of reproductive age. In these articles, women were adequately represented within geographic region. The vast majority of published articles, 183/226 (81%), did not mention pregnancy (or related issues); still fewer included pregnant women (n=33), reported numbers of pregnant women (n=19), or analyzed using pregnancy status (n=9).
Data were missing for some key variables, including pregnancy. The time period over which published works were evaluated was relatively short.
Conclusions and implications of key findings.
The under-reporting and inattention to pregnancy in the HIV literature may reduce policy-makers’ ability to set evidence-based policy around HIV/AIDS care for pregnant women and women of child-bearing age.
PMCID: PMC3751870  PMID: 24009750
10.  Prevalent pregnancy, biological sex, and virologic response to antiretroviral therapy 
Pregnancy is a common indication for initiation of highly active antiretroviral therapy (HAART) in sub-Saharan Africa. Our objective was to evaluate how pregnancy at treatment initiation predicts virologic response to HAART.
We evaluated an open cohort of 9,173 patients who initiated HAART between April 2004 and September 2009 in the Themba Lethu Clinic in Johannesburg, South Africa. Risk ratios were estimated using log-binomial regression; hazard ratios were estimated using Cox proportional hazards models; time ratios were estimated using accelerated failure time models. We controlled for calendar date, age, ethnicity, employment status, history of smoking, tuberculosis, WHO stage, weight, body mass index, hemoglobin, CD4 count and CD4 percent, and whether clinical care was free. Extensive sensitivity and secondary analyses were performed.
During follow-up, 822 non-pregnant women and 70 pregnant women experienced virologic failure. In adjusted analyses, pregnancy at baseline was associated with reduced risk of virologic failure by six months (risk ratio 0.66, 95% confidence limits [CL] 0.35, 1.22) and with reduced hazard of virologic failure over follow-up (hazard ratio 0.69, 95% CL 0.50, 0.95). The adjusted time ratio for failure was 1.44 (95% CL 1.13, 1.84), indicating 44% longer time to event among women pregnant at baseline. Sensitivity analyses generally confirmed main findings.
Pregnancy at HAART initiation is not associated with increased risk of virologic failure at six months or during longer follow-up.
PMCID: PMC3404188  PMID: 22487586
Pregnancy; HIV; highly active antiretroviral therapy (HAART); South Africa
11.  The Parametric G-Formula to Estimate the Effect of Highly Active Antiretroviral Therapy on Incident AIDS or Death 
Statistics in medicine  2012;31(18):2000-2009.
The parametric g-formula can be used to contrast the distribution of potential outcomes under arbitrary treatment regimes. Like g-estimation of structural nested models and inverse probability weighting of marginal structural models, the parametric g-formula can appropriately adjust for measured time-varying confounders that are affected by prior treatment. However, there have been few implementations of the parametric g-formula to date. Here, we apply the parametric g-formula to assess the impact of highly active antiretroviral therapy on time to AIDS or death in two US-based HIV cohorts including 1,498 participants. These participants contributed approximately 7,300 person-years of follow-up of which 49% was exposed to HAART and 382 events occurred; 259 participants were censored due to drop out. Using the parametric g-formula, we estimated that antiretroviral therapy substantially reduces the hazard of AIDS or death (HR=0.55; 95% confidence limits [CL]: 0.42, 0.71). This estimate was similar to one previously reported using a marginal structural model 0.54 (95% CL: 0.38, 0.78). The 6.5-year difference in risk of AIDS or death was 13% (95% CL: 8%, 18%). Results were robust to assumptions about temporal ordering, and extent of history modeled, for time-varying covariates. The parametric g-formula is a viable alternative to inverse probability weighting of marginal structural models and g-estimation of structural nested models for the analysis of complex longitudinal data.
PMCID: PMC3641816  PMID: 22495733
Cohort study; Confounding; g-formula; HIV/AIDS; Monte Carlo methods
13.  Prevalent tuberculosis and mortality among HAART initiators 
AIDS (London, England)  2012;26(6):770-773.
The effect of tuberculosis on mortality in people initiating highly active antiretroviral treatment (HAART) remains unclear; here, we strengthened a previous cohort analysis. Multivariate Cox proportional hazards models were used to assess the association of baseline tuberculosis and time to all-cause mortality among HAART initiators. In reanalysis, treatment for tuberculosis at time of HAART initiation remained unassociated with increased risks of all-cause mortality, with adjusted hazard ratios ranging from 1.00 to 1.09.
PMCID: PMC3348652  PMID: 22313956
14.  Incident Pregnancy and Time to Death or AIDS among HIV-Positive Women Receiving Antiretroviral Therapy 
PLoS ONE  2013;8(3):e58117.
Little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in sub-Saharan Africa. We examined the effect of incident pregnancy after HAART initiation on clinical response to HAART.
We evaluated a prospective clinical cohort of adult women initiating HAART in Johannesburg, South Africa between 1 April 2004 and 31 March 2011, and followed up until an event, transfer, drop-out, or administrative end of follow-up on 30 September 2011. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study. Main exposure was having experienced pregnancy after HAART initiation; main outcome was death and (separately) death or new AIDS event. We calculated adjusted hazard ratios (HRs) and 95% confidence limits (CL) using marginal structural Cox proportional hazards models.
The study included 7,534 women, and 20,813 person-years of follow-up; 918 women had at least one recognized pregnancy during follow-up. For death alone, the weighted (adjusted) HR was 0.84 (95% CL 0.44, 1.60). Sensitivity analyses confirmed main results, and results were similar for analysis of death or new AIDS event. Incident pregnancy was associated with a substantially reduced hazard of drop-out (HR = 0.62, 95% CL 0.51, 0.75).
Recognized incident pregnancy after HAART initiation was not associated with increases in hazard of clinical events, but was associated with a decreased hazard of drop-out. High rates of pregnancy after initiation of HAART may point to a need to better integrate family planning services into clinical care for HIV-infected women.
PMCID: PMC3592862  PMID: 23520489
15.  Early life soy exposure and age at menarche 
This study examines the timing of menarche in relation to infant feeding methods, specifically addressing the potential effects of soy isoflavone exposure through soy-based infant feeding. Subjects were participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers were enrolled during pregnancy and their children have been followed prospectively. Early life feeding regimes, categorized as primarily breast, early formula, early soy, and late soy were defined using infant feeding questionnaires administered during infancy. For this analysis, age at menarche was assessed through questionnaires administered approximately annually between ages 8 and 14.5. Eligible subjects were limited to term, singleton, white females. We used Kaplan-Meier survival curves and Cox proportional hazards models to assess age at menarche and risk of menarche over the study period.
The present analysis included 2,920 girls. Approximately 2% of mothers reported that soy products were introduced into the infant diet at or before 4 months of age (early soy). The median age at menarche [interquartile range (IQR)] in the study sample was 153 months [144–163], approximately 12.8 years. The median age at menarche among early soy fed girls was 149 months (12.4 years) [IQR, 140–159]. Compared to girls fed non-soy based infant formula or milk (early formula), early soy fed girls were at 25% higher risk of menarche throughout the course of follow up (Hazard Ratio 1.25 [95% confidence interval, 0.92, 1.71]). Our results also suggest that girls fed soy products in early infancy may have an increased risk of menarche specifically in early adolescence. These findings may be the observable manifestation of mild endocrine disrupting effects of soy isoflavone exposure. However, our study is limited by few soy-exposed subjects and is not designed to assess biological mechanisms. Because soy formula use is common in some populations, this subtle association with menarche warrants more indepth evaluation in future studies.
PMCID: PMC3443957  PMID: 22324503
16.  Berkson’s bias, selection bias, and missing data 
Epidemiology (Cambridge, Mass.)  2012;23(1):159-164.
While Berkson’s bias is widely recognized in the epidemiologic literature, it remains underappreciated as a model of both selection bias and bias due to missing data. Simple causal diagrams and 2×2 tables illustrate how Berkson’s bias connects to collider bias and selection bias more generally, and show the strong analogies between Berksonian selection bias and bias due to missing data. In some situations, considerations of whether data are missing at random or missing not at random is less important than the causal structure of the missing-data process. While dealing with missing data always relies on strong assumptions about unobserved variables, the intuitions built with simple examples can provide a better understanding of approaches to missing data in real-world situations.
PMCID: PMC3237868  PMID: 22081062
18.  A comparison of methods to estimate the hazard ratio under conditions of time-varying confounding and nonpositivity 
Epidemiology (Cambridge, Mass.)  2011;22(5):718-723.
In occupational epidemiologic studies, the healthy-worker survivor effect refers to a process that leads to bias in the estimates of an association between cumulative exposure and a health outcome. In these settings, work status acts both as an intermediate and confounding variable, and may violate the positivity assumption (the presence of exposed and unexposed observations in all strata of the confounder). Using Monte Carlo simulation, we assess the degree to which crude, work-status adjusted, and weighted (marginal structural) Cox proportional hazards models are biased in the presence of time-varying confounding and nonpositivity. We simulate data representing time-varying occupational exposure, work status, and mortality. Bias, coverage, and root mean squared error (MSE) were calculated relative to the true marginal exposure effect in a range of scenarios. For a base-case scenario, using crude, adjusted, and weighted Cox models, respectively, the hazard ratio was biased downward 19%, 9%, and 6%; 95% confidence interval coverage was 48%, 85%, and 91%; and root MSE was 0.20, 0.13, and 0.11. Although marginal structural models were less biased in most scenarios studied, neither standard nor marginal structural Cox proportional hazards models fully resolve the bias encountered under conditions of time-varying confounding and nonpositivity.
PMCID: PMC3155387  PMID: 21747286
19.  Incidence of Pregnancy after Initiation of Antiretroviral Therapy in South Africa: A Retrospective Clinical Cohort Analysis 
Background. Little is known about rates of incident pregnancy among HIV-positive women initiating highly active antiretroviral therapy (HAART). Methods. We conducted a retrospective clinical cohort study among therapy-naïve women ages 18–45 initiating HAART between 1 April 2004 and 30 September 2009 at an adult HAART clinic in Johannesburg, South Africa. We used Poisson regression to characterize rates and rate ratios of pregnancy. Results. We evaluated 5,996 women who experienced 727 pregnancies during 14,095 person-years at risk. The overall rate of pregnancy was 5.2 per 100 person-years (95% confidence limits [CL] 4.8, 5.5). By six years, cumulative incidence of first pregnancy was 22.9% (95% CL 20.6%, 25.4%); among women ages 18–25 at HAART initiation, cumulative incidence was 52.2% (95% CL 35.0%, 71.8%). The strongest predictor of incidence of pregnancy was age, with women 18–25 having 13.2 times the rate of pregnancy of women ages 40–45 in adjusted analysis. CD4 counts below 100 and worse adherence to HAART were associated with lower rates of incident pregnancy. Conclusions. Women experience high rates of incident pregnancy after HAART initiation. Understanding which women are most likely to experience pregnancy will help planning and future efforts to understand the implications of pregnancy for response to HAART.
PMCID: PMC3388336  PMID: 22778536
20.  Highly active antiretroviral therapy and cervical dysplasia in HIV-positive women in South Africa 
The risk of squamous intra-epithelial lesions (SIL) is higher in HIV-positive women. As these women begin to live longer due to highly active antiretroviral therapy (HAART), their risk of cervical cancer may increase. Few data exist regarding the effect of HAART on the incidence and progression of SIL in HIV-positive African women. The aim of this study was to evaluate the effect of HAART on the incidence and progression of SIL in HIV-positive women in South Africa.
A prospective observational study of HIV-seropositive women was conducted over 5 years in an HIV treatment clinic in Johannesburg, South Africa. The participants consisted of 601 women on and off HAART who had repeat Pap smears greater than 6 months apart. The effect of HAART use on incidence and progression rates of SIL was determined using multivariate Poisson regression to obtain incidence rate ratios (IRRs), adjusted for age, CD4 count and other potential confounders.
Median follow-up time was 445 days (inter-quartile range 383, 671). The crude rate of incidence of any SIL was 15.9 episodes (95% confidence limit (CL) 12.7, 19.9) per 100 person-years; the crude rate of all progression of cervical dysplasia among women was 13.5 episodes (95% CL 11.3, 16.1) per 100 person-years. HAART use was associated with a robust reduction in the rate of incidence and progression of cervical lesions, adjusted IRR=0.55 (95% CL 0.37, 0.80). Sensitivity analyses confirmed this main association held for incidence and progression when they were considered separately, and that the result was not dependent on the length of HAART exposure.
HAART use was associated with a reduction in the rate of both incidence and progression of cervical lesions among HIV-positive women.
PMCID: PMC3499783  PMID: 22713259
HAART effect; cervical dysplasia; HIV-positive women; South Africa
21.  Tuberculosis in patients receiving antiretroviral treatment: incidence, risk factors and prevention strategies 
To determine tuberculosis (TB) incidence rates and risk factors among individuals receiving antiretroviral treatment (ART).
Observational cohort in Johannesburg, South Africa.
Incident TB was classified as early (<6 months of ART) or late (>6 months of ART) incident TB. CD4 cell counts, viral load (VL), body mass index (BMI) and hemoglobin were measured 6-monthly. Hazard ratios for factors associated with early and late incident TB were assessed using Cox proportional hazards regression.
During 13,416 person-years (py) follow-up, 501 TB cases occurred among 7,536 individuals, corresponding to a 10% risk in the first four years of ART, and an overall incidence rate of 4.2 cases/100 py. The highest incidence rate (21.7 /100 py) was observed in the first 3 months of ART among people with CD4 count below 50 cells/mm3. Low baseline CD4 count, anemia, and low BMI were the strongest risk factor for early incident TB. Low updated CD4 count, low updated BMI, anemia, and high VL on ART were strong risk factors for late incident TB.
Severity of HIV disease and unfavorable response to ART are associated with early and late incident TB, respectively. Early ART initiation and intensified TB screening at ART initiation are crucial to reduce incident TB.
PMCID: PMC3319435  PMID: 20926954
tuberculosis; TB; antiretroviral treatment; incidence; risk factors; South Africa
22.  Doubly Robust Estimation of Causal Effects 
American Journal of Epidemiology  2011;173(7):761-767.
Doubly robust estimation combines a form of outcome regression with a model for the exposure (i.e., the propensity score) to estimate the causal effect of an exposure on an outcome. When used individually to estimate a causal effect, both outcome regression and propensity score methods are unbiased only if the statistical model is correctly specified. The doubly robust estimator combines these 2 approaches such that only 1 of the 2 models need be correctly specified to obtain an unbiased effect estimator. In this introduction to doubly robust estimators, the authors present a conceptual overview of doubly robust estimation, a simple worked example, results from a simulation study examining performance of estimated and bootstrapped standard errors, and a discussion of the potential advantages and limitations of this method. The supplementary material for this paper, which is posted on the Journal's Web site (, includes a demonstration of the doubly robust property (Web Appendix 1) and a description of a SAS macro (SAS Institute, Inc., Cary, North Carolina) for doubly robust estimation, available for download at∼mfunk/dr/.
PMCID: PMC3070495  PMID: 21385832
causal inference; epidemiologic methods; propensity score
23.  The role of the c-statistic in variable selection for propensity score models 
The applied literature on propensity scores has often cited the c-statistic as a measure of the ability of the propensity score to control confounding. However, a high c-statistic in the propensity model is neither necessary nor sufficient for control of confounding. Moreover, use of the c-statistic as a guide in constructing propensity scores may result in less overlap in propensity scores between treated and untreated subjects; this may require the analyst to restrict populations for inference. Such restrictions may reduce precision of estimates and change the population to which the estimate applies. Variable selection based on prior subject matter knowledge, empirical observation, and sensitivity analysis is preferable and avoids many of these problems.
PMCID: PMC3081361  PMID: 21351315
Propensity scores; c-statistic; variable selection; confounding
24.  Effectiveness and safety of 30 mg versus 40 mg stavudine regimens: a cohort study among HIV-infected adults initiating HAART in South Africa 
As stavudine remains an important and widely prescribed drug in resource-limited settings, the effect of a reduced dose of stavudine (from 40 mg to 30 mg) on outcomes of highly active antiretroviral therapy (HAART) remains an important public health question.
We analyzed prospectively collected data from the Themba Lethu Clinic in Johannesburg, South Africa. We assessed the relationship between stavudine dose and six- and/or 12-month outcomes of stavudine substitution, failure to suppress viral load to below 400 copies/ml, development of peripheral neuropathy, lipoatrophy and hyperlactatemia/lactic acidosis. Since individuals with a baseline weight of less than 60 kg were expected to have received the same dose of stavudine throughout the study period, analysis was restricted to individuals who weighed 60 kg or more at baseline. Data were analyzed using logistic regression.
Between 1 April 2004 and 30 September 2009, 3910 patients were initiated on antiretroviral therapy (ART) with a recorded stavudine dose and were included in the analysis. Of these, 2445 (62.5%) received a 40 mg stavudine dose while 1565 (37.5%) received 30 mg. In multivariate analysis, patients receiving a 40 mg dose were more likely to discontinue stavudine use (adjusted odds ratio, OR 1.71; 95% confidence limits, CI 1.13-2.57) than those receiving 30 mg by 12 months on ART. Additionally, patients receiving 40 mg doses of stavudine were more likely to report peripheral neuropathy (OR 3.12; 95% CI 1.86-5.25), lipoatrophy (OR 11.8; 95% CI 3.2-43.8) and hyperlactatemia/lactic acidosis (OR 8.37; 95% CI 3.83-18.29) in the same time period. Failure to suppress HIV viral load within 12 months of HAART initiation was somewhat more common among those given 40 mg doses (OR 1.62; 95% CI 0.88, 2.97) although this result lacked precision. Sensitivity analyses accounting for death and loss to follow up generally supported these estimates.
Lower stavudine dosage is associated with fewer reports of several stavudine-associated adverse events and also a lower risk of stavudine discontinuation within the first year on ART.
PMCID: PMC3313885  PMID: 22410312
Antiretroviral toxicity; Stavudine; Resource-limited setting; Cohort study; Virologic failure
25.  Pregnancy and Virologic Response to Antiretroviral Therapy in South Africa 
PLoS ONE  2011;6(8):e22778.
Although women of reproductive age are the largest group of HIV-infected individuals in sub-Saharan Africa, little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in that setting. We examined the effect of incident pregnancy after HAART initiation on virologic response to HAART.
Methods and Findings
We evaluated a prospective clinical cohort of adult women who initiated HAART in Johannesburg, South Africa between 1 April 2004 and 30 September 2009, and followed up until an event, death, transfer, drop-out, or administrative end of follow-up on 31 March 2010. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study; final sample size for analysis was 5,494 women. Main exposure was incident pregnancy, experienced by 541 women; main outcome was virologic failure, defined as a failure to suppress virus to ≤400 copies/ml by six months or virologic rebound >400 copies/ml thereafter. We calculated adjusted hazard ratios using marginal structural Cox proportional hazards models and weighted lifetable analysis to calculate adjusted five-year risk differences. The weighted hazard ratio for the effect of pregnancy on time to virologic failure was 1.34 (95% confidence limit [CL] 1.02, 1.78). Sensitivity analyses generally confirmed these main results.
Incident pregnancy after HAART initiation was associated with modest increases in both relative and absolute risks of virologic failure, although uncontrolled confounding cannot be ruled out. Nonetheless, these results reinforce that family planning is an essential part of care for HIV-positive women in sub-Saharan Africa. More work is needed to confirm these findings and to explore specific etiologic pathways by which such effects may operate.
PMCID: PMC3149058  PMID: 21829650

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