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Background: Successful scale-up of antiretroviral therapy (ART) during pregnancy has minimized infant HIV acquisition, and over 1 million infants are born HIV-exposed but uninfected (HEU), with an increasing proportion also exposed in utero to maternal ART. While benefits of ART in pregnancy outweigh risks, some studies have reported associations between in utero ART exposure and impaired fetal growth, highlighting the need to identify the safest ART regimens for use in pregnancy., Methods: We compared birth anthropometrics of infants who were HEU with those HIV-unexposed (HU) in Cape Town, South Africa. Pregnant women had gestational age assessed by ultrasound at enrolment. Women living with HIV were on ART (predominately tenofovir-emtricitabine-efavirenz) either prior to conception or initiated during pregnancy. Birth weights and lengths were converted to weight-for-age (WAZ) and length-for-age (LAZ) z-scores using Intergrowth-21st software. Linear regression was used to compare mean z-scores adjusting for maternal and pregnancy characteristics., Results: Among 888 infants, 49% (n = 431) were HEU and 51% (n = 457) HU. Of 431 HEU infants, 62% (n = 268) were exposed to HIV and antiretrovirals (ARVs) from conception and 38% (n = 163) were exposed to ARVs during gestation but after conception (median fetal ARV exposure of 21 weeks [IQR; 17-26]). In univariable analysis, infants who were HEU had lower mean WAZ compared with HU [β = - 0.15 (95% Confidence Interval (CI): - 0.28, - 0.020)]. After adjustment for maternal age, gravidity, alcohol use, marital and employment status the effect remained [adjusted β - 0.14 (95%CI: - 0.28, - 0.01]. Similar differences were noted for mean LAZ in univariable [β - 0.20 (95%CI: - 0.42, - 0.01] but not multivariable analyses [adjusted β - 0.18 (95%CI: - 0.41, + 0.04] after adjusting for the same variables. Mean WAZ and LAZ did not vary by in utero ARV exposure duration among infants who were HEU., Conclusion: In a cohort with high prevalence of ART exposure in pregnancy, infants who were HEU had lower birth WAZ compared with those HU. Studies designed to identify the mechanisms and clinical significance of these disparities, and to establish the safest ART for use in pregnancy are urgently needed.

Little is known about the functional relationship of delaying second-line treatment initiation for human immunodeficiency virus-positive patients and mortality, given a patient's immune status. We included 7,255 patients starting antiretroviral therapy during 2004-2017, from 9 South African cohorts, with virological failure and complete baseline data. We estimated the impact of switch time on the hazard of death using inverse probability of treatment weighting of marginal structural models. The nonlinear relationship between month of switch and the 5-year survival probability, stratified by CD4 count at failure, was estimated with targeted maximum likelihood estimation. We adjusted for measured time-varying confounding by CD4 count, viral load, and visit frequency. Five-year mortality was estimated to be 10.5% (95% CI: 2.2, 18.8) for immediate switch and to be 26.6% (95% CI: 20.9, 32.3) for no switch (51.1% if CD4 count was <100 cells/mm3). The hazard of death was estimated to be 0.37 (95% CI: 0.30, 0.46) times lower if everyone had been switched immediately compared with never. The shorter the delay in switching, the lower the hazard of death-delaying 30-59 days reduced the hazard by 0.53 (95% CI: 0.43, 0.65) times and 60-119 days by 0.58 (95% CI: 0.49, 0.69) times, compared with no switch. Early treatment switch is particularly important for patients with low CD4 counts at failure., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Efavirenz-based first-line regimens have been widely used for children ≥3 years of age starting antiretroviral therapy, despite possible resistance with prior exposure to non-nucleoside reverse transcriptase inhibitors for prevention of mother-to-child transmission (PMTCT). We used logistic regression to examine the association between PMTCT exposure and viral failure (VF) defined as two consecutive viral loads (VL)>1000 copies/ml between 6-18 months on ART. Children with previous nevirapine exposure for PMTCT were not at higher risk of VF compared to unexposed children (adjusted Odds Ratio (aOR): 0.79; 95% CI:0.56, 1.11)., Competing Interests: The authors have declared that no competing interests exist.

Background: Managing virologic failure (VF) in HIV-infected children is especially difficult in resource-limited settings, given limited availability of alternative drugs, concerns around adherence, and the development of HIV resistance mutations. We aimed to evaluate 4 management strategies for children following their first episode of VF by comparing their immunologic and virologic outcomes., Methods: We included children (< 16 years of age) with VF from 8 International Epidemiologic Database to Evaluate AIDS Southern Africa cohorts, initiating combination antiretroviral therapy (cART) between 2004 and 2010, who followed one of the 4 management strategies: continuing on their failing regimen; switching to a second-line regimen; switching to a holding regimen (either lamivudine monotherapy or other non-cART regimen); discontinuing all ART. We compared the effect of management strategy on the 52-week change in CD4% and log10VL from VF, using inverse probability weighting of marginal structural linear models., Results: Nine hundred eighty-two patients were followed over 54,168 weeks. Relative to remaining on a failing regimen, switching to second-line showed improved immunologic and virologic responses 52 weeks after VF with gains in CD4% of 1.5% (95% confidence interval [CI], 0.2-2.8) and declines in log10VL of -1.4 copies/mL (95% CI, -2.0, -0.8), while switching to holding regimens or discontinuing treatment had worse immunologic (-5.4% (95% CI, -12.1, 1.3) and -5.6% (95% CI, -15.4, 4.1) and virologic outcomes (0.2 (95% CI, -3.6, 4.1) and 0.8 (95% CI, -0.6, 2.1), respectively., Conclusions: The results provide useful guidance for managing children with VF. Consideration should be given to switching children failing first-line cART to second-line, given the improved virologic and immune responses when compared with other strategies.

Background: HIV and TB programs have rapidly scaled-up over the past decade in Sub-Saharan Africa and uninterrupted supplies of those medicines are critical to their success. However, estimates of stock-outs are largely unknown. This survey aimed to estimate the extent of stock-outs of antiretroviral and TB medicines in public health facilities across South Africa, which has the world's largest antiretroviral treatment (ART) program and a rising multidrug-resistant TB epidemic., Methods: We conducted a cross-sectional telephonic survey (October-December 2015) of public health facilities. Facilities were asked about the prevalence of stock-outs on the day of the survey and in the preceding three months, their duration and impact., Results: Nationwide, of 3547 eligible health facilities, 79% (2804) could be reached telephonically. 88% (2463) participated and 4% (93) were excluded as they did not provide ART or TB treatment. Of the 2370 included facilities, 20% (485) reported a stock-out of at least 1 ARV and/or TB-related medicine on the day of contact and 36% (864) during the three months prior to contact, ranging from 74% (163/220) of health facilities in Mpumalanga to 12% (32/261) in the Western Cape province. These 864 facilities reported 1475 individual stock-outs, with one to fourteen different medicines out of stock per facility. Information on impact was provided in 98% (1449/1475) of stock-outs: 25% (366) resulted in a high impact outcome, where patients left the facility without medicine or were provided with an incomplete regimen. Of the 757 stock-outs that were resolved 70% (527) lasted longer than one month., Interpretation: There was a high prevalence of stock-outs nationwide. Large interprovincial differences in stock-out occurrence, duration, and impact suggest differences in provincial ability to prevent, mitigate and cope within the same framework. End-user monitoring of the supply chain by patients and civil society has the potential to increase transparency and complement public sector monitoring systems., Competing Interests: The authors have declared that no competing interests exist.

Objective: Both isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) reduce tuberculosis risk in individuals living with HIV. We sought to estimate the broader, population-wide impact of providing a pragmatically implemented 12-month IPT regimen to ART recipients in a high-burden community., Design: Dynamic transmission model of a tuberculosis (TB)-HIV epidemic, calibrated to site-specific, historical epidemiologic and clinical trial data from Khayelitsha, South Africa., Methods: We projected the 5-year impact of delivering a 12-month IPT regimen community-wide to 85% of new ART initiators and 15%/year of those already on ART, accounting for IPT-attributable reductions in TB infection, progression, and transmission. We also evaluated scenarios of continuously-delivered IPT, ongoing ART scale-up, and lower tuberculosis incidence., Results: Under historical (early 2010) ART coverage, this ART-linked IPT intervention prevented one tuberculosis case per 18 [95% credible interval (CrI) 11-29] people treated. It lowered TB incidence by a projected 23% (95% CrI 14-30%) among people receiving ART, and by 5.2% (95% CrI 2.9-8.7%) in the total population. Continuous IPT reduced the number needed to treat to prevent one case of TB to 10 (95% CrI 7-16), though it required 74% more person-years of therapy (95% CrI 64-94%) to prevent one TB case, relative to 12-month therapy. Under expanding ART coverage, the tuberculosis incidence reduction achieved by 12-month IPT grew to 7.6% (95% CrI 4.3-12.6%). Effect sizes were similar in a simulated setting of lower TB incidence., Conclusions: IPT in conjunction with ART reduces tuberculosis incidence among those who receive therapy and has additional impact on tuberculosis transmission in the population.

Introduction: Estimating the incidence of antiretroviral discontinuations due to adverse drug reactions (ADRs) is important to inform antiretroviral treatment (ART) regimen recommendations, and to guide prescribing and monitoring policies. Routinely collected clinical data is a useful source of pharmacovigilance data. We estimated the incidences of first-line antiretroviral discontinuations due to ADRs using routine clinical data, and compared them with incidences estimated using data enhanced by folder review, in two South African cohorts., Methods: We included patients 16 years and older on first-line ART. We selected a stratified random sample of 25% for checking of ART prescription data and reasons for antiretroviral discontinuations retrospectively, including folders reviews where required (enhanced-data sample). We estimated the incidence of antiretroviral discontinuations using Kaplan-Meier and competing risk analyses., Results: In 15396 patients, 40% had a first-line antiretroviral discontinuation by three years on ART. We could determine the reason for 65% of discontinuations using routine data only, and 84% of discontinuations, in the enhanced-data sample of 3837 patients. ADR was the most common reason for discontinuations. In the enhanced-data sample, the cumulative incidence of discontinuations due to ADRs by three years was 30.4% (95% CI: 24.4-36.6) for stavudine; 2.0% (95% CI: 1.5-2.6) for tenofovir, and 1.3% (95% CI: 0.8-2.1) for efavirenz. Using routine data only, the cumulative incidences of discontinuations due to ADRs by three years for stavudine, tenofovir, and efavirenz respectively were 23.9% (95% CI: 20.3-27.7), 1.2% (95% CI: 0.9-1.4) and 0.5% (95% CI: 0.3-0.7)., Conclusions: Although the relative rankings were similar using routine or enhanced data, lack of checking for missing reasons for discontinuation resulted in underestimates of the incidence of antiretroviral discontinuations due to ADRs. Systems to improve data collection of reasons for regimen changes prospectively would increase the capacity of routine data to answer pharmacovigilance questions., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Seasonal variations in tuberculosis diagnoses have been attributed to seasonal climatic changes and indoor crowding during colder winter months. We investigated trends in pulmonary tuberculosis (PTB) diagnosis at antiretroviral therapy (ART) programmes in Southern Africa., Setting: Five ART programmes participating in the International Epidemiology Database to Evaluate AIDS in South Africa, Zambia and Zimbabwe., Participants: We analysed data of 331 634 HIV-positive adults (>15 years), who initiated ART between January 2004 and December 2014., Primary Outcome Measure: We calculated aggregated averages in monthly counts of PTB diagnoses and ART initiations. To account for time trends, we compared deviations of monthly event counts to yearly averages, and calculated correlation coefficients. We used multivariable regressions to assess associations between deviations of monthly ART initiation and PTB diagnosis counts from yearly averages, adjusted for monthly air temperatures and geographical latitude. As controls, we used Kaposi sarcoma and extrapulmonary tuberculosis (EPTB) diagnoses., Results: All programmes showed monthly variations in PTB diagnoses that paralleled fluctuations in ART initiations, with recurrent patterns across 2004-2014. The strongest drops in PTB diagnoses occurred in December, followed by April-May in Zimbabwe and South Africa. This corresponded to holiday seasons, when clinical activities are reduced. We observed little monthly variation in ART initiations and PTB diagnoses in Zambia. Correlation coefficients supported parallel trends in ART initiations and PTB diagnoses (correlation coefficient: 0.28, 95% CI 0.21 to 0.35, P<0.001). Monthly temperatures and latitude did not substantially change regression coefficients between ART initiations and PTB diagnoses. Trends in Kaposi sarcoma and EPTB diagnoses similarly followed changes in ART initiations throughout the year., Conclusions: Monthly variations in PTB diagnosis at ART programmes in Southern Africa likely occurred regardless of seasonal variations in temperatures or latitude and reflected fluctuations in clinical activities and changes in health-seeking behaviour throughout the year, rather than climatic factors., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Retention in care is an essential component of meeting the UNAIDS "90-90-90" HIV treatment targets. In Khayelitsha township (population ~500,000) in Cape Town, South Africa, more than 50,000 patients have received antiretroviral therapy (ART) since the inception of this public-sector program in 2001. Disengagement from care remains an important challenge. We sought to determine the incidence of and risk factors associated with disengagement from care during 2013-2014 and outcomes for those who disengaged., Methods and Findings: We conducted a retrospective cohort study of all patients ≥10 years of age who visited 1 of the 13 Khayelitsha ART clinics from 2013-2014 regardless of the date they initiated ART. We described the cumulative incidence of first disengagement (>180 days not attending clinic) between 1 January 2013 and 31 December 2014 using competing risks methods, enabling us to estimate disengagement incidence up to 10 years after ART initiation. We also described risk factors for disengagement based on a Cox proportional hazards model, using multiple imputation for missing data. We ascertained outcomes (death, return to care, hospital admission, other hospital contact, alive but not in care, no information) after disengagement until 30 June 2015 using province-wide health databases and the National Death Registry. Of 39,884 patients meeting our eligibility criteria, the median time on ART to 31 December 2014 was 33.6 months (IQR 12.4-63.2). Of the total study cohort, 592 (1.5%) died in the study period, 1,231 (3.1%) formally transferred out, 987 (2.5%) were silent transfers and visited another Western Cape province clinic within 180 days, 9,005 (22.6%) disengaged, and 28,069 (70.4%) remained in care. Cumulative incidence of disengagement from care was estimated to be 25.1% by 2 years and 50.3% by 5 years on ART. Key factors associated with disengagement (age, male sex, pregnancy at ART start [HR 1.58, 95% CI 1.47-1.69], most recent CD4 count) and retention (ART club membership, baseline CD4) after adjustment were similar to those found in previous studies; however, notably, the higher hazard of disengagement soon after starting ART was no longer present after adjusting for these risk factors. Of the 9,005 who disengaged, the 2 most common initial outcomes were return to ART care after 180 days (33%; n = 2,976) and being alive but not in care in the Western Cape (25%; n = 2,255). After disengagement, a total of 1,459 (16%) patients were hospitalized and 237 (3%) died. The median follow-up from date of disengagement to 30 June 2015 was 16.7 months (IQR 11-22.4). As we included only patient follow-up from 2013-2014 by design in order to maximize the generalizability of our findings to current programs, this limited our ability to more fully describe temporal trends in first disengagement., Conclusions: Twenty-three percent of ART patients in the large cohort of Khayelitsha, one of the oldest public-sector ART programs in South Africa, disengaged from care at least once in a contemporary 2-year period. Fifty-eight percent of these patients either subsequently returned to care (some "silently") or remained alive without hospitalization, suggesting that many who are considered "lost" actually return to care, and that misclassification of "lost" patients is likely common in similar urban populations. A challenge to meeting ART retention targets is developing, testing, and implementing program designs to target mobile populations and retain them in lifelong care. This should be guided by risk factors for disengagement and improving interlinkage of routine information systems to better support patient care across complex care platforms.

Objective: We assessed the relationship between phasing out stavudine in first-line antiretroviral therapy (ART) in accordance with WHO 2010 policy and single-drug substitutions (SDS) (substituting the nucleoside reverse transcriptase inhibitor in first-line ART) in sub-Saharan Africa., Design: Prospective cohort analysis (International epidemiological Databases to Evaluate AIDS-Multiregional) including ART-naive, HIV-infected patients aged at least 16 years, initiating ART between January 2005 and December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine-based regimen, whereas thereafter tenofovir or zidovudine replaced stavudine in first-line ART., Methods: We evaluated the frequency of stavudine use and SDS by calendar year 2004-2014. Competing risk regression was used to assess the association between nucleoside reverse transcriptase inhibitor use and SDS in the first 24 months on ART., Results: In all, 33 441 (8.9%; 95% confience interval 8.7-8.9%) SDS occurred among 377 656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20-95% less likely to require a SDS than patients on stavudine, whereas patients on zidovudine had a 75-85% decrease in the hazards of SDS when compared to stavudine., Conclusion: The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine.

Background: Previous studies have reported improvements in life expectancies of patients on antiretroviral treatment (ART) over time, but it is not clear whether these improvements are explained by changes in baseline clinical characteristics, longer duration on ART or changes in clinical practices., Method: Two parametric survival models were fitted to mortality data from South African ART cohorts that had linked patient records to the national vital registration system. The first model estimated mortality by age, sex, cohort, baseline CD4 cell count, time since ART initiation and period of ART initiation; the second model included only age, sex, cohort and period of follow-up. Life expectancies were calculated from the estimated mortality rates., Results: The first model estimated little change in mortality over time: women starting ART at age 35 years, at CD4 cell counts of 200 cells/μl or higher, had life expectancies of 32.7 years [95% confidence interval (CI): 31.6-33.6], 32.4 years (95% CI: 31.3-33.4) and 33.0 years (95% CI: 32.0-34.1) in the 2001-2006, 2007-2009 and 2010-2014 periods, respectively. However, the second model estimated a significant improvement in life expectancy; for all women on ART at age 35 years, corresponding life expectancies were 13.0 years (95% CI: 12.1-14.2), 20.4 years (95% CI: 19.5-21.4) and 26.1 years (95% CI: 25.2-26.9), respectively., Conclusion: Although life expectancies in South African ART patients have improved over time, these improvements are not observed after controlling for changes in baseline CD4 cell count and ART duration. This suggests that changes in clinical practice and programme scale have had little impact on ART mortality in South Africa., Competing Interests: and sources of funding: The authors declare no conflicts of interest. This research was funded by the National Institutes of Health (grant U01AI069924).

Background: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized., Methods: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART., Results: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively., Conclusions: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: In HIV-uninfected individuals, isoniazid preventive therapy (IPT) has been associated with long-term protection against tuberculosis (TB). For HIV-infected/antiretroviral therapy (ART)-naive individuals, high TB rates have been observed following completion of IPT, consistent with a lack of 'cure' of infection. Recent trial data of IPT among HIV-infected individuals on ART in Khayelitsha, South Africa, have suggested that the effect of IPT persisted following completion of IPT., Methods: Using mathematical modelling, we explored if this increased duration of protection may be due to an increased curative ability of IPT when given in combination with ART. The model was used to estimate the annual risk of infection and proportion of individuals whose latent infection was 'cured' by IPT, defined such that they must be reinfected to be at risk of disease., Results: The estimated annual risk of infection was 4.0% (2.6-5.8) and the estimated proportion of individuals whose latent Mycobacterium tuberculosis infection was cured following IPT was 35.4% (2.4-76.4), higher than that previously estimated for HIV-infected/ART-naive individuals. Our results suggest that IPT can cure latent M. tuberculosis infection in approximately one-third of HIV-infected individuals on ART and therefore provide protection beyond the period of treatment., Conclusion: Among HIV-infected individuals on ART in low incidence settings, 12 months of IPT may provide additional long-term benefit. Among HIV-infected individuals on ART in high incidence settings, the durability of this protection will be limited because of continued risk of reinfection, and continuous preventive therapy together with improved infection control efforts will be required to provide long-term protection against TB.

Background: HIV is still a global public health problem. More than 75 % of HIV-infected people are in Africa, and most of them are unaware of their HIV status, which is a barrier to accessing antiretroviral treatment. Our review aims, firstly, to determine whether HIV self-testing is an effective method to increase the uptake of testing, the yield of new HIV-positive diagnoses, and the linkage to antiretroviral treatment. Secondly, we aim to review the factors that facilitate or impede the uptake of HIV self-testing., Methods/design: Participants will be adults living in Africa. For the first aim, the intervention will be HIV self-testing either alone or in addition to HIV testing standard of care. The comparison will be HIV testing standard of care. The primary outcomes will be (i) uptake of HIV testing and (ii) yield of new HIV-positive diagnoses. The secondary outcomes will be (a) linkage to antiretroviral (ARV) treatment and (b) incidence of social harms. For the second aim, we will review barriers and facilitators to the uptake of self-testing. We will search PubMed, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, WHOLIS, Africa Wide, and CINAHL for eligible studies from 1998, with no language limits. We will check reference lists of included studies for other eligible reports. Eligible studies will include experimental and observational studies. Two authors will independently screen the search output, select studies, and extract data, resolving discrepancies by consensus and discussion. Two authors will use Cochrane risk of bias tools for experimental studies, the Newcastle-Ottawa Quality Assessment Scale for observational studies, and the Critical Appraisal Skills Programme (CASP) quality assessment tool for qualitative studies., Discussion: Innovative and cost-effective community-based HIV testing strategies, such as self-testing, will contribute to universal coverage of HIV testing in Africa. The findings from this systematic review will guide development of self-testing policy in African countries., Systematic Review Registration: PROSPERO CRD42015023935.

The public sector scale-up of antiretroviral therapy (ART) in South Africa commenced in 2004. We aimed to describe the hospital-level disease burden and factors contributing to morbidity and mortality among hospitalized HIV-positive patients in the era of widespread ART availability. Between June 2012 and October 2013, unselected patients admitted to medical wards at a public sector district hospital in Cape Town were enrolled in this cross-sectional study with prospective follow-up. HIV testing was systematically offered and HIV-infected patients were systematically screened for TB. The spectrum of admission diagnoses among HIV-positive patients was documented, vital status at 90 and 180 days ascertained and factors independently associated with death determined. Among 1018 medical admissions, HIV status was ascertained in 99.5%: 60.1% (n = 609) were HIV-positive and 96.1% (n = 585) were enrolled. Of these, 84.4% were aware of their HIV-positive status before admission. ART status was naive in 35.7%, current in 45.0%, and interrupted in 19.3%. The most frequent primary clinical diagnoses were newly diagnosed TB (n = 196, 33.5%), other bacterial infection (n = 100, 17.1%), and acquired immunodeficiency syndrome (AIDS)-defining illnesses other than TB (n = 64, 10.9%). By 90 days follow-up, 175 (29.9%) required readmission and 78 (13.3%) died. Commonest causes of death were TB (37.2%) and other AIDS-defining illnesses (24.4%). Independent predictors of mortality were AIDS-defining illnesses other than TB, low hemoglobin, and impaired renal function. HIV still accounts for nearly two-thirds of medical admissions in this South African hospital and is associated with high mortality. Strategies to improve linkage to care, ART adherence/retention and TB prevention are key to reducing HIV-related hospitalizations in this setting., Competing Interests: The authors have no conflicts of interest to disclose.

Background and Objectives: Little is known about outcomes after transfer out (TFO) and loss to follow-up (LTF) and how differential outcomes might bias mortality estimates, as analyses generally censor or exclude TFOs/LTF. Using data linked to the National Population Register, we explored mortality among TFO and LTF patients compared with patients who were retained and investigated how linkage impacted on mortality estimates., Methods: A cohort analysis of routine data on adults with civil identification numbers starting antiretroviral therapy (ART) 2004-2009 in 4 large South African ART cohorts. The number, proportion, timing, and mortality of TFOs and LTF were reported. Mortality was compared using Kaplan-Meier curves, Cox's proportional hazards, and competing risks regression., Results: Before linkage, 1207 patients (6%) had died, 2624 (13%) were LTF, 1067 (5%) were TFO and 14,583 (75%) were retained. Compared with retained, mortality risk was 3 times higher among TFO patients [adjusted hazard ratio (aHR), 3.11; 95% confidence interval (CI): 2.42 to 3.99] and 20 times higher among LTF patients (aHR, 22.03; 95% CI: 20.05 to 24.21). Excluding early deaths after TFO or LTF, the risk was comparable among TFOs and retained (aHR, 0.75; 95% CI: 0.54 to 1.03) and higher among LTF (aHR, 2.85; 95% CI: 2.43 to 3.33). After linkage, corrected mortality was higher than site-reported mortality. Censoring did not, however, lead to substantial underestimation of mortality among TFOs., Conclusions: Although TFO and LTF predicted mortality, the lower incidence of TFO and subsequent death compared with LTF meant that censoring TFOs did not bias mortality estimates. Future cohort analyses should explicitly consider proportions of TFO/LTF and mortality event rates.

Background: Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy., Methods: For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086., Findings: 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6-3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8-4·7; hazard ratio [HR] 0·63, 95% CI 0·41-0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90-4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21-0·86] and 0·43 [0·20-0·96]; for positive tests 0·86 [0·37-2·00] and 0·55 [0·26-1·24], respectively)., Interpretation: Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status., Funding: Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Prognostic models for children starting antiretroviral therapy (ART) in Africa are lacking. We developed models to estimate the probability of death during the first year receiving ART in Southern Africa., Methods: We analyzed data from children ≤10 years of age who started ART in Malawi, South Africa, Zambia or Zimbabwe from 2004 to 2010. Children lost to follow up or transferred were excluded. The primary outcome was all-cause mortality in the first year of ART. We used Weibull survival models to construct 2 prognostic models: 1 with CD4%, age, World Health Organization clinical stage, weight-for-age z-score (WAZ) and anemia and the other without CD4%, because it is not routinely measured in many programs. We used multiple imputation to account for missing data., Results: Among 12,655 children, 877 (6.9%) died in the first year of ART. We excluded 1780 children who were lost to follow up/transferred from main analyses; 10,875 children were therefore included. With the CD4% model probability of death at 1 year ranged from 1.8% [95% confidence interval (CI): 1.5-2.3] in children 5-10 years with CD4% ≥10%, World Health Organization stage I/II, WAZ ≥ -2 and without severe anemia to 46.3% (95% CI: 38.2-55.2) in children <1 year with CD4% < 5%, stage III/IV, WAZ< -3 and severe anemia. The corresponding range for the model without CD4% was 2.2% (95% CI: 1.8-2.7) to 33.4% (95% CI: 28.2-39.3). Agreement between predicted and observed mortality was good (C-statistics = 0.753 and 0.745 for models with and without CD4%, respectively)., Conclusions: These models may be useful to counsel children/caregivers, for program planning and to assess program outcomes after allowing for differences in patient disease severity characteristics.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To investigate the incidence of selected opportunistic infections (OIs) and cancers and the role of a history of tuberculosis (TB) as a risk factor for developing these conditions in HIV-infected patients starting antiretroviral treatment (ART) in Southern Africa., Methods: Five ART programmes from Zimbabwe, Zambia and South Africa participated. Outcomes were extrapulmonary cryptococcal disease (CM), pneumonia due to Pneumocystis jirovecii (PCP), Kaposi's sarcoma and Non-Hodgkin lymphoma. A history of TB was defined as a TB diagnosis before or at the start of ART. We used Cox models adjusted for age, sex, CD4 cell count at ART start and treatment site, presenting results as adjusted hazard ratios (aHR) with 95% confidence intervals (CI)., Results: We analysed data from 175,212 patients enrolled between 2000 and 2010 and identified 702 patients with incident CM (including 205 with a TB history) and 487 with incident PCP (including 179 with a TB history). The incidence per 100 person-years over the first year of ART was 0.48 (95% CI 0.44-0.52) for CM, 0.35 (95% CI 0.32-0.38) for PCP, 0.31 (95% CI 0.29-0.35) for Kaposi's sarcoma and 0.02 (95% CI 0.01-0.03) for Non-Hodgkin lymphoma. A history of TB was associated with cryptococcal disease (aHR 1.28, 95% CI 1.05-1.55) and Pneumocystis jirovecii pneumonia (aHR 1.61, 95% CI 1.27-2.04), but not with Non-Hodgkin lymphoma (aHR 1.09, 95% CI 0.45-2.65) or Kaposi's sarcoma (aHR 1.02, 95% CI 0.81-1.27)., Conclusions: Our study suggests that there may be interactions between different OIs in HIV-infected patients., (© 2012 Blackwell Publishing Ltd.)

Background: Current symptom screening algorithms for intensified tuberculosis case finding or prior to isoniazid preventive therapy (IPT) in patients infected with human immunodeficiency virus (HIV) were derived from antiretroviral-naive cohorts. There is a need to validate screening algorithms in patients on antiretroviral therapy (ART)., Methods: We performed cross-sectional evaluation of the diagnostic accuracy of symptom screening, including the World Health Organization (WHO) algorithm, to rule out tuberculosis in HIV-infected individuals pre-ART and on ART undergoing screening prior to IPT., Results: A total of 1429 participants, 54% on ART, had symptom screening and a sputum culture result available. Culture-positive tuberculosis was diagnosed in 126 patients (8.8%, 95% confidence interval [CI], 7.4%-10.4%). The WHO symptom screen in the on-ART compared with the pre-ART group had a lower sensitivity (23.8% vs 47.6%), but higher specificity (94.4% vs 79.8%). The effect of ART was independent of CD4(+) count in multivariable analyses. The posttest probability of tuberculosis following a negative WHO screen was 8.9% (95% CI, 7.4%-10.8%) and 4.4% (95% CI, 3.7%-5.2%) for the pre-ART and on-ART groups, respectively. Addition of body mass index to the WHO screen significantly improved discriminatory ability in both ART groups, which was further improved by adding CD4 count and ART duration., Conclusions: The WHO symptom screen has poor sensitivity, especially among patients on ART, in a clinic where regular tuberculosis screening is practiced. Consequently, a significant proportion of individuals with tuberculosis would inadvertently be placed on isoniazid monotherapy despite high negative predictive values. Until more sensitive methods of ruling out tuberculosis are established, it would be prudent to do a sputum culture prior to IPT where this is feasible.

Objectives: To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure., Methods: Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Immunological failure was defined according to both WHO 2010 and United States Department of Health and Human Services (DHHS) 2008 criteria. Confirmed virological failure was defined as HIV-RNA >5000 copies/ml on two consecutive occasions <365 days apart in a child on ART for ≥18 months., Results: Among 2798 children on ART for ≥18 months [median (IQR) age 50 (21-84) months at ART initiation], the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS immunological failure criteria alone increased positive predictive value from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%., Conclusion: The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second-line treatment in virologically suppressed children., (© 2012 Blackwell Publishing Ltd.)

Objectives: Tenofovir (TDF) is increasingly used in second-line antiretroviral treatment (ART) in sub-Saharan Africa. We compared outcomes of second-line ART containing and not containing TDF in cohort studies from Zambia and the Republic of South Africa (RSA)., Methods: Patients aged 16 years and older starting protease-inhibitor-based second-line ART in Zambia (1 cohort) and RSA (5 cohorts) were included. We compared mortality, immunological failure (all cohorts), and virological failure (RSA only) between patients receiving and not receiving TDF. Competing risk models and Cox models adjusted for age, sex, CD4 count, time on first-line ART, and calendar year were used to analyze mortality and treatment failure, respectively. Hazard ratios (HRs) were combined in fixed-effects meta-analysis., Findings: 1687 patients from Zambia and 1556 patients from RSA, including 1350 (80.0%) and 206 (13.2%) patients starting TDF, were followed over 4471 person-years. Patients on TDF were more likely to have started second-line ART in recent years and had slightly higher baseline CD4 counts than patients not on TDF. Overall, 127 patients died, 532 were lost to follow-up, and 240 patients developed immunological failure. In RSA, 94 patients had virologic failure. Combined HRs comparing TDF with other regimens were 0.60 (95% confidence interval [CI]: 0.41 to 0.87) for immunologic failure and 0.63 (0.38-1.05) for mortality. The HR for virologic failure in RSA was 0.28 (0.09-0.90)., Conclusions: In this observational study, patients on TDF-containing second-line ART were less likely to develop treatment failure than patients on other regimens. TDF seems to be an effective component of second-line ART in southern Africa.

Objectives: To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure (VF) in children on antiretroviral therapy (ART)., Methods: Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/ml between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/ml in a child on ART for ≥18 months who had achieved suppression during the first year on treatment., Results: Among 3115 children [median (interquartile range) age 48 (20-84) months at ART initiation] on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006, WHO 2010 and DHHS 2008 criteria, respectively. The corresponding positive predictive values (PPV) were 31%, 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008)., Conclusion: Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify VF in children., (© 2011 Blackwell Publishing Ltd.)

Background: Loss to follow-up (LTF) challenges the reporting of antiretroviral treatment (ART) programmes, since it encompasses patients alive but lost to programme and deaths misclassified as LTF. We describe LTF before and after correction for mortality in a primary care ART programme with linkages to the national vital registration system., Methods and Findings: We included 6411 patients enrolled on ART between March 2001 and June 2007. Patients LTF with available civil identification numbers were matched with the national vital registration system to ascertain vital status. Corrected mortality and true LTF were determined by weighting these patients to represent all patients LTF. We used Kaplan-Meier estimates and Cox regression to describe LTF, mortality among those LTF, and true LTF. Of 627 patients LTF, 85 (28.8%) had died within 3 months after their last clinic visits. Respective estimates of LTF before and after correction for mortality were 6.9% (95% confidence interval [CI] 6.2-7.6) and 4.3% (95% CI 3.5-5.3) at one year on ART, and 23.9% (95% CI 21.0-27.2) and 19.7% (95% CI 16.1-23.7) at 5 years. After correction for mortality, the hazard of LTF was reversed from decreasing to increasing with time on ART. Younger age, higher baseline CD4 count, pregnancy and increasing calendar year were associated with higher true LTF. Mortality of patients LTF at 1, 12 and 24 months after their last visits was respectively 23.1%, 30.9% and 43.8%; 78.0% of deaths occurred during the first 3 months after last visit and 45.0% in patients on ART for 0 to 3 months., Conclusions: Mortality of patients LTF was high and occurred early after last clinic visit, especially in patients recently started on ART. Correction for these misclassified deaths revealed that the risk of true LTF increased over time. Research targeting groups at higher risk of LTF (youth, pregnant women and patients with higher CD4 counts) is needed.

Objective: Little is known about the temporal impact of the rapid scale-up of large antiretroviral therapy (ART) services on programme outcomes. We describe patient outcomes [mortality, loss-to-follow-up (LTFU) and retention] over time in a network of South African ART cohorts., Design: Cohort analysis utilizing routinely collected patient data., Methods: Analysis included adults initiating ART in eight public sector programmes across South Africa, 2002-2007. Follow-up was censored at the end of 2008. Kaplan-Meier methods were used to estimate time to outcomes, and proportional hazards models to examine independent predictors of outcomes., Results: Enrolment (n = 44 177, mean age 35 years; 68% women) increased 12-fold over 5 years, with 63% of patients enrolled in the past 2 years. Twelve-month mortality decreased from 9% to 6% over 5 years. Twelve-month LTFU increased annually from 1% (2002/2003) to 13% (2006). Cumulative LTFU increased with follow-up from 14% at 12 months to 29% at 36 months. With each additional year on ART, failure to retain participants was increasingly attributable to LTFU compared with recorded mortality. At 12 and 36 months, respectively, 80 and 64% of patients were retained., Conclusion: Numbers on ART have increased rapidly in South Africa, but the programme has experienced deteriorating patient retention over time, particularly due to apparent LTFU. This may represent true loss to care, but may also reflect administrative error and lack of capacity to monitor movements in and out of care. New strategies are needed for South Africa and other low-income and middle-income countries to improve monitoring of outcomes and maximize retention in care with increasing programme size.

Background: Prognostic models have been developed for patients infected with HIV-1 who start combination antiretroviral therapy (ART) in high-income countries, but not for patients in sub-Saharan Africa. We developed two prognostic models to estimate the probability of death in patients starting ART in sub-Saharan Africa., Methods: We analysed data for adult patients who started ART in four scale-up programmes in Côte d'Ivoire, South Africa, and Malawi from 2004 to 2007. Patients lost to follow-up in the first year were excluded. We used Weibull survival models to construct two prognostic models: one with CD4 cell count, clinical stage, bodyweight, age, and sex (CD4 count model); and one that replaced CD4 cell count with total lymphocyte count and severity of anaemia (total lymphocyte and haemoglobin model), because CD4 cell count is not routinely measured in many African ART programmes. Death from all causes in the first year of ART was the primary outcome., Findings: 912 (8.2%) of 11 153 patients died in the first year of ART. 822 patients were lost to follow-up and not included in the main analysis; 10 331 patients were analysed. Mortality was strongly associated with high baseline CD4 cell count (>/=200 cells per muL vs <25; adjusted hazard ratio 0.21, 95% CI 0.17-0.27), WHO clinical stage (stages III-IV vs I-II; 3.45, 2.43-4.90), bodyweight (>/=60 kg vs <45 kg; 0.23, 0.18-0.30), and anaemia status (none vs severe: 0.27, 0.20-0.36). Other independent risk factors for mortality were low total lymphocyte count, advanced age, and male sex. Probability of death at 1 year ranged from 0.9% (95% CI 0.6-1.4) to 52.5% (43.8-61.7) with the CD4 model, and from 0.9% (0.5-1.4) to 59.6% (48.2-71.4) with the total lymphocyte and haemoglobin model. Both models accurately predict early mortality in patients starting ART in sub-Saharan Africa compared with observed data., Interpretation: Prognostic models should be used to counsel patients, plan health services, and predict outcomes for patients with HIV-1 infection in sub-Saharan Africa., Funding: US National Institute of Allergy And Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Cancer Institute., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: Previous studies have demonstrated a cross-sectional relationship between antiretroviral adherence and HIV virological suppression. We assessed the predictive value of baseline adherence in determining long-term virological failure., Design: We assessed baseline adherence via an adherence questionnaire between administered to all consenting patients attending antiretroviral clinics in Khayelitsha township, South Africa, between May 2002 and March 2004. Virological status was ascertained after five years of follow up and multivariate analysis used to model associations of baseline variables and medication adherence with time to viral suppression or failure., Results: Our adherence cohort comprised 207 patients, among whom 72% were female. Median age was 30 years and median CD4 count at initiation was 55 cells/mm(3). We found no statistically significant differences between baseline characteristics and early adherence groups. Multivariate analysis adjusting for baseline CD4 and age found that patients with suboptimal baseline adherence had a hazard ratio of 2.82 (95% CI 1.19-6.66, p = 0.018) for progression to virological failure compared to those whose baseline adherence was considered optimal., Conclusions: Our longitudinal study provides further confirmation of adherence as a primary determinant of subsequent confirmed virological failure, and serves as a reminder of the importance of initial early investments in adherence counseling and support as an effective way to maximize long-term treatment success.

Objectives: To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment., Methods: Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/microl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements > or =10 0000 copies/ml (higher threshold) or > or =500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated., Results: A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6-33.6%) for the higher and 12.6% (6.7-21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3-97.8%) and 97.3% (96.5-98.0%), for positive predictive value 9.5% (3.6-19.6%) and 19.0% (10.2-30.9%) and for negative predictive value 98.5% (97.9-99.0%) and 95.7% (94.7-96.6%)., Conclusions: The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.

Objectives: To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20% of the South African national treatment programme., Design and Setting: Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and KwaZulu-Natal provinces., Subjects: ART-naive children (< or = 16 years) who commenced treatment with > or = 3 antiretroviral drugs before March 2008., Outcome Measures: Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox proportional hazards models stratified by site. Immune status, virological suppression and growth were described in relation to duration of ART., Results: The median (interquartile range) age of 6 078 children with 9 368 child-years of follow-up was 43 (15 - 83) months, with 29% being < 18 months. Most were severely ill at ART initiation. More than 75% of children were appropriately monitored at 6-monthly intervals with viral load suppression (< 400 copies/ml) being 80% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7% (95% confidence interval 7.0 - 8.6%) and 81.4% (80.1 - 82.6%), respectively. Together with young age, all markers of disease severity (low weight-for-age z-score, high viral load, severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality., Conclusions: Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.

Objectives: To introduce the combined South African cohorts of the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterise patients accessing these services; and to describe changes in services and patients from 2003 to 2007., Design and Setting: Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal., Subjects: Adults and children (<16 years old) who initiated ART with > or =3 antiretroviral drugs before 2008., Results: Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17,835 patients per site. Among 45,383 adults and 6,198 children combined, median age (interquartile range) was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5), respectively. Of adults, 68% were female. The median CD4 cell count was 102 cells/microl (44-164) and was lower among males than females (86, 34-150 v. 110, 50-169, p<0.001). Median CD4% among children was 12% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/microl, p<0.001) and for those in stage IV (39-89 cells/microl, p<0.001). Among children <5 years, baseline CD4% increased over time (11.5-16.0%, p<0.001)., Conclusions: IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increased enrolment over time. Late diagnosis and ART initiation, especially of men and children, need attention. Investment in sentinel sites will ensure good individual-level data while freeing most sites to continue with simplified reporting.

Objective: To describe the electronic medical databases used in antiretroviral therapy (ART) programmes in lower-income countries and assess the measures such programmes employ to maintain and improve data quality and reduce the loss of patients to follow-up., Methods: In 15 countries of Africa, South America and Asia, a survey was conducted from December 2006 to February 2007 on the use of electronic medical record systems in ART programmes. Patients enrolled in the sites at the time of the survey but not seen during the previous 12 months were considered lost to follow-up. The quality of the data was assessed by computing the percentage of missing key variables (age, sex, clinical stage of HIV infection, CD4+ lymphocyte count and year of ART initiation). Associations between site characteristics (such as number of staff members dedicated to data management), measures to reduce loss to follow-up (such as the presence of staff dedicated to tracing patients) and data quality and loss to follow-up were analysed using multivariate logit models., Findings: Twenty-one sites that together provided ART to 50 060 patients were included (median number of patients per site: 1000; interquartile range, IQR: 72-19 320). Eighteen sites (86%) used an electronic database for medical record-keeping; 15 (83%) such sites relied on software intended for personal or small business use. The median percentage of missing data for key variables per site was 10.9% (IQR: 2.0-18.9%) and declined with training in data management (odds ratio, OR: 0.58; 95% confidence interval, CI: 0.37-0.90) and weekly hours spent by a clerk on the database per 100 patients on ART (OR: 0.95; 95% CI: 0.90-0.99). About 10 weekly hours per 100 patients on ART were required to reduce missing data for key variables to below 10%. The median percentage of patients lost to follow-up 1 year after starting ART was 8.5% (IQR: 4.2-19.7%). Strategies to reduce loss to follow-up included outreach teams, community-based organizations and checking death registry data. Implementation of all three strategies substantially reduced losses to follow-up (OR: 0.17; 95% CI: 0.15-0.20)., Conclusion: The quality of the data collected and the retention of patients in ART treatment programmes are unsatisfactory for many sites involved in the scale-up of ART in resource-limited settings, mainly because of insufficient staff trained to manage data and trace patients lost to follow-up.

The South African Department of Health has embraced the primary health care approach in the provision of antiretroviral therapy (ART) to children. This paper compares clinical outcomes of children treated at primary healthcare clinics, district hospitals, and secondary and tertiary hospitals. A retrospective review of routine data captured by the provincial antiretroviral monitoring system was completed. Simplified cohort analysis was used to determine the cumulative incidence of baseline characteristics and outcomes. Data on 1741 children started at level 2 & 3, level 1 and primary healthcare clinic facilities between April 2004 and April 2006 were analysed. Kaplan-Meier survival estimates for these groups were 0.88 (95% CI 0.86-0.90), 0.94 (95% CI 0.89-0.97) and 0.94 (95% CI 0.89-0.96) at 12 months of ART, respectively, on intention-to-treat analysis. The overall cumulative proportion of children with a suppressed viral load was 73% (95% CI 69-77%) at 12 months of ART. There was no significant difference in viral load suppression rates between the three groups. This study confirms the feasibility of providing antiretrovirals at all levels of the healthcare service in the Western Cape. The higher death rates at level 2 & 3 facilities are most likely due to recruitment of sicker patients at this level.

Introduction: Whereas cost-effectiveness/utility analyses theoretically assess efficiency in HIV treatment, in practice they are of limited use to policy makers who are also concerned with the total costs of scaling up. This paper proposes an approach to simultaneously assessing both factors when setting priorities for HIV treatment., Methods: Three interventions were assessed: a no antiretroviral therapy (ART) status quo, ART including first-line only, and ART including first and second-line regimens. Data were from a cohort receiving healthcare in a poor South African setting. Markov modelling was used to calculate patient-level lifetime costs and quality-adjusted life-years (QALY) as well as population-level total costs and QALY in each intervention. Linear programming was used to assess efficiency at the population level., Results: First-line ART costs US$795 per QALY gained compared to no ART, while first and second-line costs US$1625 compared to first-line alone. The efficiency of either ART strategy depends on the HIV treatment budget. If this is less than US$10 billion during the planning period, first-line ART is most efficient. A combination of first-line with first and second-line treatment is most efficient if the budget is US$10-12 billion. Using both first and second-line treatment for everyone becomes efficient as the main strategy only at budgets greater than US$13 billion., Conclusion: An approach has been developed to HIV treatment priority setting that simultaneously considers efficiency and the costs of scaling up. This can help to establish explicit and evidence-based priorities and budgets to meet scaling up challenges.

Background: The effectiveness of the South African government's expanding antiretroviral treatment program is unknown. Observational studies of treatment effectiveness are prone to selection bias, rarely compare patients receiving antiretroviral treatment with similar patients not receiving antiretroviral treatment, and underestimate mortality rates unless patients are actively followed up., Methods: We followed up 14 267 patients in the Public Sector Anti-Retroviral Treatment project in Free State, South Africa, for up to 20 months after enrollment. A total of 3619 patients received highly active triple antiretroviral treatment (HAART) for up to 19 months (median, 6 months; interquartile range, 3-9 months) after enrollment. Patients' clinical data were linked with the national mortality register. Marginal structural regression models adjusted for baseline and time-varying covariates., Results: Of 4570 patients followed up for at least 1 year, 53.2% died. Eighty-seven percent of patients who died had not received HAART. HAART was associated with lower mortality (hazard ratio, 0.14; 95% confidence interval [CI], 0.11-0.18) and with the presence of tuberculosis (hazard ratio, 0.61; 95% CI, 0.46-0.81) after adjusting for age, sex, weight, clinic, district, CD4 cell count, cotrimoxazole therapy, tuberculosis at baseline, and previous antiretroviral therapy. Cotrimoxazole therapy was associated with lower mortality (hazard ratio, 0.37; 95% CI, 0.32-0.42). Each month of HAART was associated with an increase in CD4 cell count of 15.1 cells/microL (95% CI, 14.7-15.5 cells/microL) and with an increase in body weight of 602 g (95% CI, 548-658 g)., Conclusions: HAART provided through these South African government health services seems as effective as that provided in high-income countries. Delays starting HAART contributed to high mortality rates. Faster expansion and timely commencement of HAART are needed.

We examined the incidence of and risk factors for tuberculosis during the first year of highly active antiretroviral therapy in low-income (4540 patients) and high-income (22,217 patients) countries. Although incidence was much higher in low-income countries, the reduction in the incidence of tuberculosis associated with highly active antiretroviral therapy was similar: the rate ratio for months 7-12 versus months 1-3 was 0.48 (95% confidence interval, 0.36-0.64) in low-income countries and 0.36 (95% confidence interval, 0.26-0.50) in high-income countries. A low CD4 cell count at the start of therapy was the most important risk factor in both settings.