Comparison of QuantiFERON Gold In-Tube Versus Tuberculin Skin Tests on the Initiation of Tuberculosis Preventive Therapy Among Patients Newly Diagnosed With Human Immunodeficiency Virus in the North West Province of South Africa (the Teko Study): A Cluster Randomized Trial.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions. METHODS: This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes. FINDINGS: We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P < .001) and TPT prescriptions (45% vs 30%, P = .13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51-68; P < .001) more participants with TBI results and 12% (95% confidence interval, -6 to 31; P = .18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively). INTERPRETATION: In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm. CLINICAL TRIALS REGISTRATION: NCT02119130.

Reducing HIV-associated post-hospital mortality through home-based care in South Africa: a randomized controlled trial.

BACKGROUND: Twenty-three percent of people with HIV (PWH) die within 6-months of hospital discharge. We tested the hypothesis whether a series of structured home visits could reduce mortality. METHODS: We designed a disease neutral home visit package with up to 6 home visits starting 1-week post-hospitalization and every 2 weeks thereafter. The home visit team used a structured assessment algorithm to evaluate and triage social and medical needs of the participant and provide nutritional support. We compared all-cause mortality 6-months following discharge for the intervention compared to usual care in a pilot randomized trial conducted in South Africa. To inform potential scale-up we also included and separately analyzed a group of people without HIV (PWOH). RESULTS: We enrolled 125 people with HIV and randomized them 1:1 to the home visit intervention or usual care. Fourteen were late exclusions because of death prior to discharge or delayed discharge leaving 111 for analysis. The median age was 39 years, 31% were men; and 70% had advanced HIV disease. At six months among PWH 4 (7.3%) in the home visit arm and 10 (17.9%) in the usual care arm (p = 0.09) had died. Among the 70 PWOH enrolled overall 6-month mortality was 10.1%. Of those in the home visit arm, 91% received at least one home visit. CONCLUSIONS: We demonstrated feasibility of delivering post-hospital home visits and demonstrated preliminary efficacy among PWH with a substantial, but not statistically significant, effect size (59% reduction in mortality). COVID-19 related challenges resulted in under-enrollment.

Yield of Facility-based Targeted Universal Testing for Tuberculosis With Xpert and Mycobacterial Culture in High-Risk Groups Attending Primary Care Facilities in South Africa.

BACKGROUND: We report the yield of targeted universal tuberculosis (TB) testing of clinic attendees in high-risk groups. METHODS: Clinic attendees in primary healthcare facilities in South Africa with one of the following risk factors underwent sputum testing for TB: human immunodeficiency virus (HIV), contact with a TB patient in the past year, and having had TB in the past 2 years. A single sample was collected for Xpert-Ultra (Xpert) and culture. We report the proportion positive for Mycobacterium tuberculosis. Data were analyzed descriptively. The unadjusted clinical and demographic factors' relative risk of TB detected by culture or Xpert were calculated and concordance between Xpert and culture is described. RESULTS: A total of 30 513 participants had a TB test result. Median age was 39 years, and 11 553 (38%) were men. The majority (n = 21734, 71%) had HIV, 12 492 (41%) reported close contact with a TB patient, and 1573 (5%) reported prior TB. Overall, 8.3% were positive for M. tuberculosis by culture and/or Xpert compared with 6.0% with trace-positive results excluded. In asymptomatic participants, the yield was 6.7% and 10.1% in symptomatic participants (with trace-positives excluded). Only 10% of trace-positive results were culture-positive. We found that 55% of clinic attendees with a sputum result positive for M. tuberculosis did not have a positive TB symptom screen. CONCLUSIONS: A high proportion of clinic attendees with specific risk factors (HIV, close TB contact, history of TB) test positive for M. tuberculosis when universal testing is implemented.

Performance of Xpert MTB/RIF, Xpert Ultra, and Abbott RealTime MTB for Diagnosis of Pulmonary Tuberculosis in a High-HIV-Burden Setting.

More sensitive tests are needed for the diagnosis of smear-negative and HIV-associated tuberculosis. This study compares the sensitivities and specificities of three molecular tests, namely, the Xpert MTB/RIF test, the Xpert Ultra (Ultra), and RealTime MTB (RT-MTB), in a high HIV prevalence setting. Symptomatic adults were recruited from three outpatient sites, and each provided 4 sputum specimens. The diagnostic performance of Xpert MTB/RIF, Ultra, and RT-MTB was evaluated, with culture as a reference standard. HIV infection occurred in 62% of patients, with a median CD4 count of 220 cells/µl. The Ultra test had the highest sensitivity of 89.3% (95% confidence interval [CI], 78.1 to 96) compared to those of the Xpert MTB/RIF at 82.1% (95% CI, 69.6 to 91.1; P = 0.12) and RT-MTB at 78.6% (95% CI, 65.6 to 88.4; P = 0.68). The specificity was highest with the Xpert MTB/RIF at 100% (95% CI, 98 to 100), followed by RealTime MTB at 96.7% (95% CI, 92.9 to 98.8; P = 0.03) and the Ultra at 95.6% (95% CI, 91.5 to 98.1; P = 0.08). In patients with smear-negative disease, the Ultra was more sensitive than the Xpert MTB/RIF (64.7% [95% CI, 38.3 to 85.8] versus 41.2% [95% CI, 18.4 to 67.1], respectively; P = 0.12), and RT-MTB performed equally to Xpert MTB/RIF. In a comparison of the Ultra and RT-MTB on the same sputum specimen pellets, the Ultra was more sensitive than RT-MTB in the overall cohort (88.9% [95% CI, 77.4 to 95.8] versus 77.8% [95% CI, 64.4 to 88], respectively; P = 0.03) and among people with HIV (87.5% [95% CI, 71 to 96.5] versus 68.6% [95% CI, 50 to 83.9], respectively; P = 0.03). Although these results did not reach statistical significance, they suggest that the Ultra is more sensitive than the Xpert MTB/RIF and RT-MTB, most prominently in smear-negative disease. This was accompanied by a loss of specificity.

Treatment outcomes of over 1000 patients on second-line, protease inhibitor-based antiretroviral therapy from four public-sector HIV treatment facilities across Johannesburg, South Africa.

OBJECTIVES: To report predictors of outcomes of second-line ART for HIV treatment in a resource-limited setting. METHODS: All adult ART-naïve patients who initiated standard first-line treatment between April 2004 and February 2012 at four public-sector health facilities in Johannesburg, South Africa, experienced virologic failure and initiated standard second-line therapy were included. We assessed predictors of attrition (death and loss to follow-up [≥3 months late for a scheduled visit]) using Cox proportional hazards regression and predictors of virologic suppression (viral load <400 copies/ml ≥3 months after switch) using modified Poisson regression with robust error estimation at 1 year and ever after second-line ART initiation. RESULTS: A total of 1236 patients switched to second-line treatment in a median (IQR) of 1.9 (0.9-4.6) months after first-line virologic failure. Approximately 13% and 45% of patients were no longer in care at 1 year and at the end of follow-up, respectively. Patients with low CD4 counts (<50 vs. ≥200, aHR: 1.85; 95% CI: 1.03-3.32) at second-line switch were at greater risk for attrition by the end of follow-up. About 75% of patients suppressed by 1 year, and 85% had ever suppressed by the end of follow-up. CONCLUSIONS: Patients with poor immune status at switch to second-line ART were at greater risk of attrition and were less likely to suppress. Additional adherence support after switch may improve outcomes.

Challenges in the Evaluation of Interventions to Improve Engagement Along the HIV Care Continuum in the United States: A Systematic Review.

In the United States (US), there are high levels of disengagement along the HIV care continuum. We sought to characterize the heterogeneity in research studies and interventions to improve care engagement among people living with diagnosed HIV infection. We performed a systematic literature search for interventions to improve HIV linkage to care, retention in care, reengagement in care and adherence to antiretroviral therapy (ART) in the US published from 2007-mid 2015. Study designs and outcomes were allowed to vary in included studies. We grouped interventions into categories, target populations, and whether results were significantly improved. We identified 152 studies, 7 (5%) linkage studies, 33 (22%) retention studies, 4 (3%) reengagement studies, and 117 (77%) adherence studies. 'Linkage' studies utilized 11 different outcome definitions, while 'retention' studies utilized 39, with very little consistency in effect measurements. The majority (59%) of studies reported significantly improved outcomes, but this proportion and corresponding effect sizes varied substantially across study categories. This review highlights a paucity of assessments of linkage and reengagement interventions; limited generalizability of results; and substantial heterogeneity in intervention types, outcome definitions, and effect measures. In order to make strides against the HIV epidemic in the US, care continuum research must be improved and benchmarked against an integrated, comprehensive framework.

Characterizing breast conditions at an open-access breast clinic in South Africa: a model that is more than cancer care for a resource-limited setting.

BACKGROUND: While most breast-related research focuses on cancer, presentation of symptomatic persons in non-screened environments requires understanding the spectrum of breast diseases so as to plan services in resource-constrained settings. This study presents the variety of breast disease managed at a government, open-access breast clinic in South Africa. METHODS: We performed a retrospective file review using a systematic random sample of patients 18 years and above presenting for breast care over a 14-month period. We collected demographics, clinical characteristics, management and final diagnoses from the first visit and twelve subsequent months. RESULTS: The final sample contained 365 individuals (97 · 5% women). Most were black, unmarried and South African citizens with a median age of 43 years (IQR 31-55) . Of those reporting their status (24 · 1%) 38 · 6% were HIV-positive. A mass (57 · 0%) and/or pain (28 · 5%) were the most common symptoms. Imaging and breast biopsies were required in 78 and 25% of individuals, respectively. Nearly half of biopsies identified breast cancer (44 · 1% of women ≤40 and 57 · 3% for women >40). Benign conditions (47 · 7%) and no abnormality (18 · 2%) were common final classifications among women. There was no difference between the final classifications of patients who self-referred versus those who were formally referred from another health care provider. Nearly half of the participants (46 · 6%) travelled 20 km or more to attend the clinic. CONCLUSIONS: Benign breast conditions far outweighed cancer diagnoses. As breast cancer awareness increases in resource-limited countries, facilities offering breast care require administrative and clinical preparation to manage a range of non-cancer related conditions.

Impact of choice of NRTI in first-line antiretroviral therapy: a cohort analysis of stavudine vs. tenofovir.

OBJECTIVE: In April 2010, South Africa replaced stavudine with tenofovir in first-line antiretroviral therapy (ART) despite tenofovir's higher cost. We examined treatment outcomes over 24 months amongst patients initiated on tenofovir-based vs. stavudine-based first-line regimens. METHODS: Prospective cohort analysis of 3940 patients newly initiating either stavudine-based (April 2009 to March 2010) or tenofovir-based (April 2010 to March 2011) ART in Johannesburg, South Africa. Cox proportional hazards models and Fine and Gray's competing risk regression accounting for death were used to model mortality and loss to follow-up, respectively. Linear and log-binomial regression were used to evaluate associations with immunologic response and unsuppressed virus (≥ 400 copies/ml), respectively. RESULTS: About 1878 patients prescribed tenofovir and 2062 patients prescribed stavudine were included. One hundred and sixty-six (8.8%) tenofovir and 244 (11.8%) stavudine patients died. Three hundred and fifty (18.6%) tenofovir and 379 (18.4%) stavudine patients were lost to follow-up over 24 months on ART. Adjusted regression models showed tenofovir and stavudine were comparable regarding death, loss to follow-up, immunologic response and virologic status. CONCLUSIONS: We found no difference in mortality, loss to follow-up, immunological and virologic outcomes over the first 24-months on ART associated with tenofovir compared with stavudine.

Costs of inpatient treatment for multi-drug-resistant tuberculosis in South Africa.

BACKGROUND: In South Africa, patients with multi-drug-resistant tuberculosis (MDR-TB) are hospitalised from MDR-TB treatment initiation until culture conversion. Although MDR-TB accounts for <3% of incident TB in South Africa, 55% of the public sector TB budget is spent on MDR-TB. To inform new strategies for MDR-TB management, we estimated the per-patient cost (USD 2011) of inpatient MDR-TB treatment. METHODS: All resources used by patients admitted to the MDR-TB hospital with confirmed MDR-TB from March 2009 to February 2010 were abstracted from patient records for up to 12 months after initial admission or until the earliest of final discharge, abscondment or death. Costs of hospital stay/day were estimated from hospital expenditure records and costs for drugs, laboratory tests, radiography and surgery from public sector sources. 133 patients met study inclusion criteria of whom 121 had complete cost records. RESULTS: By 12 months, 86% were discharged with culture conversion, 8% died in hospital, 2% were still admitted, and 3% had absconded. The mean hospital stay was 105 days. The mean total cost per patient was $17 164, of which 95% were hospitalisation costs (buildings, staff, etc.) and ≤ 2% each for MDR-TB drugs ($380); TB laboratory tests, including drug susceptibility testing ($236); and other costs. CONCLUSIONS: The inpatient cost per patient treated for MDR-TB is more than 40 times the cost of treating drug-susceptible TB in South Africa. There is potential for substantial cost savings from improved management of drug-susceptible TB and shifting to a model of decentralised, outpatient MDR-treatment.

Loss to follow-up before and after delivery among women testing HIV positive during pregnancy in Johannesburg, South Africa.

OBJECTIVE: HIV-positive pregnant women are at heightened risk of becoming lost to follow-up (LTFU) from HIV care. We examined LTFU before and after delivery among pregnant women newly diagnosed with HIV. METHODS: Observational cohort study of all pregnant women ≥18 years (N = 300) testing HIV positive for the first time at their first ANC visit between January and June 2010, at a primary healthcare clinic in Johannesburg, South Africa. Women (n = 27) whose delivery date could not be determined were excluded. RESULTS: Median (IQR) gestation at HIV testing was 26 weeks (21-30). Ninety-eight per cent received AZT prophylaxis, usually started at the first ANC visit. Of 139 (51.3%) patients who were ART eligible, 66.9% (95% CI 58.8-74.3%) initiated ART prior to delivery; median (IQR) ART duration pre-delivery was 9.5 weeks (5.1-14.2). Among ART-eligible patients, 40.5% (32.3-49.0%) were cumulatively retained through 6 months on ART. Of those ART-ineligible patients at HIV testing, only 22.6% (95% CI 15.9-30.6%) completed CD4 staging and returned for a repeat CD4 test after delivery. LTFU (≥1 month late for last scheduled visit) before delivery was 20.5% (95% CI 16.0-25.6%) and, among those still in care, 47.9% (95% CI 41.2-54.6%) within 6 months after delivery. Overall, 57.5% (95% CI 51.6-63.3%) were lost between HIV testing and 6 months post-delivery. CONCLUSIONS: Our findings highlight the challenge of continuity of care among HIV-positive pregnant women attending antenatal services, particularly those ineligible for ART.

Strengthening HIV and HIV co-morbidity care in low- and middle-income countries: insights from behavioural economics to improve healthcare worker behaviour.

INTRODUCTION: Despite advances in HIV and HIV co-morbidity service delivery, substantial challenges remain in translating evidence-based interventions into routine practice to bring optimal care and prevention to all populations. While barriers to successful implementation are often multifactorial, healthcare worker behaviour is critical for on-the-ground and in-clinic service delivery. Implementation science offers a systematic approach to understanding service delivery, including approaches to overcoming delivery gaps. Behavioural economics is a field that seeks to understand when and how behaviour deviates from traditional models of decision-making, deviations which are described as biases. Clinical policies and implementation strategies that incorporate an understanding of behavioural economics can add to implementation science approaches and play an important role in bridging the gap between healthcare worker knowledge and service delivery. DISCUSSION: In HIV care in low- and middle-income countries (LMICs), potential behavioural economic strategies that may be utilized alone or in conjunction with more traditional approaches include using choice architecture to exploit status quo bias and reduce the effects of cognitive load, overcoming the impact of anchoring and availability bias through tailored clinical training and clinical mentoring, reducing the effects of present bias by changing the cost-benefit calculus of interventions with few short-term benefits and leveraging social norms through peer comparison. As with any implementation strategy, understanding the local context and catalysts of behaviour is crucial for success. CONCLUSIONS: As the focus of HIV care shifts beyond the goal of initiating patients on antiretroviral therapy to a more general retention in high-quality care to support longevity and quality of life, there is an increasing need for innovation to achieve improved care delivery and management. Clinical policies and implementation strategies that incorporate elements of behavioural economic theory, alongside local testing and adaptation, may increase the delivery of evidence-based interventions and improve health outcomes for people living with HIV in LMIC settings.

Modeling the impact of universal tuberculosis molecular testing and timing of tuberculosis preventive treatment during antiretroviral therapy initiation in South Africa.

OBJECTIVES: Targeted universal tuberculosis (TB) testing can improve TB detection among people with HIV. This approach is being scaled up in South Africa through Xpert MTB/RIF Ultra testing for individuals starting antiretroviral therapy and annually thereafter. Clarity is needed on how Universal Xpert testing may affect TB preventive treatment (TPT) provision, and on whether TPT should be delayed until TB is ruled out. DESIGN: State-transition microsimulation. METHODS: We simulated a cohort of South African patients being screened for TB while entering HIV care. We compared clinical and cost outcomes between four TB screening algorithms: symptom-based, C-reactive protein-based, and Universal Xpert testing with either simultaneous or delayed TPT initiation. RESULTS: Prompt TB treatment initiation among simulated patients with TB increased from 26% (24-28%) under symptom screening to 53% (50-56%) with Universal Xpert testing. Universal Xpert testing led to increased TPT uptake when TPT initiation was simultaneous, but to approximately 50% lower TPT uptake if TPT was delayed. Universal Xpert with simultaneous TPT prevented incident TB compared to either symptom screening (median 17 cases averted per 5000 patients) or Universal Xpert with delayed TPT (median 23 averted). Universal Xpert with Simultaneous TPT cost approximately $39 per incremental TPT course compared to Universal Xpert with delayed TPT. CONCLUSIONS: Universal Xpert testing can promote timely treatment for newly diagnosed people with HIV who have active TB. Pairing universal testing with immediate TPT will improve the promptness, uptake, and preventive effects of TPT. Simultaneous improvements to TB care cascades are needed to maximize impact.

Low prevalence of depressive symptoms among stable patients on antiretroviral therapy in Johannesburg, South Africa.

BACKGROUND: Depression is a leading cause of disability and may be associated with decreased adherence to ART. We sought to describe the prevalence of depressive symptoms and outcomes one year after screening among patients receiving ART at a large HIV Clinic in Johannesburg, South Africa. METHODS: Adult (≥18) patients who had been on first-line ART between 6-18 months who could communicate in English were eligible. Depressive symptoms were evaluated using the Patient Health Questionnaire (PHQ)-9 and a score ≥10 indicated depression. RESULTS: 97 patients enrolled. Patients had been on ART for a median (IQR) of 8 (7-10) months, 61% were female, the median (IQR) age at enrollment was 38 (33-42) years, and the median (IQR) CD4 count at ART initiation was 154.5 (65-263) cells/mm3. 7 (7%) patients were found to have symptoms of depression; 4 (4%) had symptoms of moderate depression (PHQ score of 10-14) and 3 (3%) had symptoms of moderate/severe depression (PHQ score of 15-19). Women (10%) were more likely to have symptoms of depression than men (3%; prevalence difference [PD]: 7.5%; 95% confidence interval [CI]:-1.7%-16.8%); as were patients under the age of 30 (14%) compared to those 30-39 (4%; PD: -10.2; 95% CI: -29.4-9.0%) or ≥40 (9%; PD: -5.5%; -26.1%-15.2%), those with lower CD4 counts at ART initiation (<200 cells/mm3 vs ≥200 cells/mm3: 8% vs 3%; PD: 4.8%; 95% CI: -4.5%-14.0%), and those with high viral loads (>1000 copies/mL vs. <400 copies/mL: 40% vs. 5%; PD: 34.6%; 95% CI: -8.6%-77.6%). No relationship between depressive symptoms and retention in HIV care one year after screening was observed. CONCLUSIONS: We found a lower prevalence of depressive symptoms compared to findings from other HIV-positive populations in South Africa but more than one-third of patients with an elevated viral load had evidence of depression. Further research on the relationship between depression, adherence, and viral failure is warranted as this may present an opportunity for early interventions to improve treatment outcomes and reduce the need for second-line treatment.

The right combination - treatment outcomes among HIV-positive patients initiating first-line fixed-dose antiretroviral therapy in a public sector HIV clinic in Johannesburg, South Africa.

BACKGROUND: Long-term antiretroviral therapy (ART) adherence is critical for achieving optimal HIV treatment outcomes. Fixed-dose combination (FDC) single-pill regimens, introduced in South Africa in April 2013, has simplified pill taking. We evaluated treatment outcomes among patients initiated on a FDC compared to a similar multi-pill ART regimen in Johannesburg, South Africa. METHODS: We conducted a retrospective cohort study of ART-naïve HIV-positive non-pregnant adult (≥18 years) patients without tuberculosis who initiated first-line ART on tenofovir and emtricitabine or lamivudine with efavirenz at Themba Lethu Clinic in Johannesburg, South Africa. We compared those initiated on a multi-pill ART regimen (3-5 pills/day; September 1, 2011-August 31, 2012) to those initiated on a FDC ART regimen (one pill/day; September 1, 2013-August 31, 2014). Treatment outcomes included attrition (combination of lost to follow-up and mortality), missed medical visits, and virologic suppression (viral load <400 copies/mL) by 12 months post-ART initiation. Cox proportional hazards models and Poisson regression were used to estimate the association between FDCs vs multiple pills and treatment outcomes. RESULTS: We included 3151 patients in our analysis; 2230 (70.8%) patients initiated multi-pill ART and 921 (29.2%) patients initiated on a FDC. By 12 months post-initiation, attrition (adjusted hazard ratio: 0.98; 95% CI: 0.77-1.24) was similar across regimen types (FDC vs multi-pill). Although not significant, patients on a FDC were marginally more likely to achieve viral suppression by 6 (adjusted relative rate [aRR]: 1.10; 95% CI: 0.99-1.23) and 12 months (aRR: 1.12; 95% CI: 0.92-1.36) on ART. Patients initiated on a FDC were significantly less likely to miss medical visits during the first 12 months of treatment (aRR: 0.66; 95% CI: 0.52-0.83). CONCLUSION: Our results suggest FDCs may have a role to play in supporting patient adherence and medical monitoring through improved medical visit attendance. This may potentially improve treatment outcomes later on in treatment.

Citizenship status and engagement in HIV care: an observational cohort study to assess the association between reporting a national ID number and retention in public-sector HIV care in Johannesburg, South Africa.

OBJECTIVE: In many resource-limited settings, people from rural areas migrate to urban hubs in search of work. Thus, urban public-sector HIV clinics in South Africa (SA) often cater to both local residents and patients from other provinces and/or countries. The objective of this analysis was to compare programmatic treatment outcomes by citizenship status in an urban clinic in SA. SETTING: An urban public-sector HIV treatment facility in Johannesburg, SA. PARTICIPANTS: We included all antiretroviral therapy (ART)-naïve, non-pregnant patients who initiated standard first-line treatment from January 2008 to December 2013. 12 219 patients were included and 59.5% were women. PRIMARY OUTCOME MEASURE: Patients were followed from ART initiation until death, transfer, loss to follow-up (LTF), or data set closure. We describe attrition (mortality and LTF) stratified by SA citizenship status (confirmed SA citizens (with national ID number), unconfirmed SA citizens (no ID), and foreign nationals) and model the risk of attrition using Cox proportional hazards regression. RESULTS: 70% of included patients were confirmed SA citizens, 19% were unconfirmed SA citizens, and 11% were foreign nationals. Unconfirmed SA citizens were far more likely to die or become LTF than other patients. A similar proportion of foreign nationals (18.2%) and confirmed SA citizens (17.7%) had left care at 1 year compared with 47.0% of unconfirmed SA citizens (adjusted hazard ratio (aHR) unconfirmed SA vs confirmed SA: 2.68; 95% CI 2.42 to 2.97). By the end of follow-up, 75.5% of unconfirmed SA citizens had left care, approximately twice that of any other group. CONCLUSIONS: Unconfirmed SA citizens were more likely to drop out of care after ART initiation than other patients. Further research is needed to determine whether this observed attrition is representative of migration and/or self-transfer to another HIV clinic as such high rates of attrition pose challenges for the success of the national ART programme.

Developing a predictive risk model for first-line antiretroviral therapy failure in South Africa.

INTRODUCTION: A substantial number of patients with HIV in South Africa have failed first-line antiretroviral therapy (ART). Although individual predictors of first-line ART failure have been identified, few studies in resource-limited settings have been large enough for predictive modelling. Understanding the absolute risk of first-line failure is useful for patient monitoring and for effectively targeting limited resources for second-line ART. We developed a predictive model to identify patients at the greatest risk of virologic failure on first-line ART, and to estimate the proportion of patients needing second-line ART over five years on treatment. METHODS: A cohort of patients aged ≥18 years from nine South African HIV clinics on first-line ART for at least six months were included. Viral load measurements and baseline predictors were obtained from medical records. We used stepwise selection of predictors in accelerated failure-time models to predict virologic failure on first-line ART (two consecutive viral load levels >1000 copies/mL). Multiple imputations were used to assign missing baseline variables. The final model was selected using internal-external cross-validation maximizing model calibration at five years on ART, and model discrimination, measured using Harrell's C-statistic. Model covariates were used to create a predictive score for risk group of ART failure. RESULTS: A total of 72,181 patients were included in the analysis, with an average of 21.5 months (IQR: 8.8-41.5) of follow-up time on first-line ART. The final predictive model had a Weibull distribution and the final predictors of virologic failure were men of all ages, young women, nevirapine use in first-line regimen, low baseline CD4 count, high mean corpuscular volume, low haemoglobin, history of TB and missed visits during the first six months on ART. About 24.4% of patients in the highest quintile and 9.4% of patients in the lowest quintile of risk were predicted to experience treatment failure over five years on ART. CONCLUSIONS: Age, sex, CD4 count and having any missed visits during the first six months on ART were the strongest predictors of ART failure. The predictive model identified patients at high risk of failure, and the predicted failure rates over five years closely reflected actual rates of failure.

Marginal Structural Models to Assess Delays in Second-Line HIV Treatment Initiation in South Africa.

BACKGROUND: South African HIV treatment guidelines call for patients who fail first-line antiretroviral therapy (ART) to be switched to second-line ART, yet logistical issues, clinician decisions and patient preferences make delay in switching to second-line likely. We explore the impact of delaying second-line ART after first-line treatment failure on rates of death and virologic failure. METHODS: We include patients with documented virologic failure on first-line ART from an observational cohort of 9 South African clinics. We explored predictors of delayed second-line switch and used marginal structural models to analyze rates of death following first-line failure by categorical time to switch to second-line. Cox proportional hazards models were used to examine virologic failure on second-line ART among patients who switched to second-line. RESULTS: 5895 patients failed first-line ART, and 63% switched to second-line. Among patients who switched, median time to switch was 3.4 months (IQR: 1.1-8.7 months). Longer time to switch was associated with higher CD4 counts, lower viral loads and more missed visits prior to first-line failure. Worse outcomes were associated with delay in second-line switch among patients with a peak CD4 count on first-line treatment ≤100 cells/mm3. Among these patients, marginal structural models showed increased risk of death (adjusted HR for switch in 6-12 months vs. 0-1.5 months = 1.47 (95% CI: 0.94-2.29), and Cox models showed increased rates of second-line virologic failure despite the presence of survivor bias (adjusted HR for switch in 3-6 months vs. 0-1.5 months = 2.13 (95% CI: 1.01-4.47)). CONCLUSIONS: Even small delays in switch to second-line ART were associated with increased death and second-line failure among patients with low CD4 counts on first-line. There is opportunity for healthcare providers to switch patients to second-line more quickly.

Predictors of mortality and treatment success during treatment for rifampicin-resistant tuberculosis within the South African National TB Programme, 2009 to 2011: a cohort analysis of the national case register.

BACKGROUND: The South African Electronic Drug-Resistant Tuberculosis Register (EDRweb) is the national database of registered drug-resistant tuberculosis (DR-TB) cases. METHODS: This study was a retrospective, de-identified secondary analysis of EDRweb patients initiating treatment for rifampicin-resistant TB (January 2009 to September 2011). The relative risks of death and treatment success were estimated using modified Poisson regression with robust error estimation. RESULTS: Seventeen thousand six hundred and ninety-seven cases of DR-TB were registered and met the inclusion criteria; 52.0% (n=9207) were male and the median age was 35 years (interquartile range 27-43 years). Of the 9419 cases with HIV infection (53.2%), 7157 (76.0%) were on antiretroviral therapy. Most had undergone previous TB treatment (76.5%, n=13531). Multidrug-resistant TB was the most common diagnosis, at 80.6% (n=14272). No treatment outcome was available for 6934 patients (39.2%). For patients with outcomes, 4227 (39.4%) were successfully treated, 2987 (27.8%) died, 2533 (23.7%) were lost to follow-up, and 996 (9.3%) failed. Second-line drug resistance was the strongest predictor of death during DR-TB treatment; extensively drug-resistant TB patients were more likely to have died during treatment (adjusted relative risk 2.63, 95% confidence interval 2.45-2.84). CONCLUSIONS: Testing for second-line drug resistance at initiation of DR-TB treatment can identify patients most at risk of treatment failure and death and most in need of individualized treatment.

The relation between efavirenz versus nevirapine and virologic failure in Johannesburg, South Africa.

INTRODUCTION: Previous research has raised concerns that patients given nevirapine (NVP)-based regimens experience more virologic failure than patients given efavirenz (EFV)-based regimens. We investigated this hypothesis in a cohort of HIV-positive patients at a large HIV treatment clinic in South Africa. METHODS: All antiretroviral therapy (ART)-naïve non-pregnant patients, ≥ 18 years old, without tuberculosis, who initiated treatment with either NVP or EFV from April 2004 to August 2011 at the Themba Lethu Clinic in Johannesburg, South Africa, were included. Log-binomial regression and modified Poisson regression were used to estimate risk ratios (RR) with 95% confidence intervals (CI) for predictors of virologic failure, virologic suppression, and loss to follow-up (LTF), whereas a Cox proportional hazards model was used to estimate the risk of death, all within one year. RESULTS: Of 12,840 included patients, 62.0% were female and the median baseline CD4 count was 98 cells/mm(3) (36-169). Of these patients, 93.2% initiated an EFV-based regimen. After adjusting for baseline characteristics, no difference in death (adjusted Hazards Ratio (aHR): 0.92; 95% CI: 0.68-1.25), LTF (adjusted Risk Ratio (aRR): 1.00; 95% CI: 0.79-1.25), nor suppression (aRR: 0.98; 95% CI: 0.95-1.00) at one year was found between regimens. Among patients with ≥ 1 viral load ≥ 4 months after ART initiation, 4% (n=350) experienced virologic failure within 12 months of initiation. Patients initiating NVP-based regimens were 60% more likely to fail than patients initiating EFV-based regimens (aRR: 1.58; 95% CI: 1.13-2.22). CONCLUSIONS: In this cohort, patients initiating NVP-based regimens experienced more virologic failure than patients initiating EFV-based regimens. Future guidelines should consider the implications of different efficacy profiles when making recommendations for which drugs to prioritize.