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Simplified drug regimens may improve retention in care for persons with chronic diseases. In April 2013, South Africa adopted a once-daily single-pill human immunodeficiency virus (HIV) treatment regimen as the standard of care, replacing a multiple-pill regimen. Because the regimens had similar biological efficacy, the shift to single-pill therapy offered a real-world test of the impact of simplified drug-delivery mechanisms on patient behavior. Using a quasi-experimental regression discontinuity design, we assessed retention in care among patients starting HIV treatment just before and just after the guideline change. The study included 4,484 patients starting treatment at a large public sector clinic in Johannesburg, South Africa. The share of patients prescribed a single-pill regimen increased by over 40 percentage points between March and April 2013. Initiating treatment after the policy change was associated with 11.7-percentage-points' higher retention at 12 months (95% confidence interval: -2.2, 29.4). Findings were robust to different measures of retention, different bandwidths, and different statistical models. Patients starting treatment early in HIV infection-a key population in the test-and-treat era-experienced the greatest improvements in retention from single-pill regimens., (© The Author(s) 2022. 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.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: While efficacy data exist, there are limited data on the outcomes of patients on third-line antiretroviral therapy (ART) in sub-Saharan Africa in actual practice. Being able to identify predictors of switch to third-line ART will be essential for planning for future need. We identify predictors of switch to third-line ART among patients with significant viraemia on a protease inhibitor (PI)-based second-line ART regimen. Additionally, we describe characteristics of all patients on third-line at a large public sector HIV clinic and present their early outcomes., Methods: Retrospective analysis of adults (≥ 18 years) on a PI-based second-line ART regimen at Themba Lethu Clinic, Johannesburg, South Africa as of 01 August 2012, when third-line treatment became available in South Africa, with significant viraemia on second-line ART (defined as at least one viral load ≥ 1000 copies/mL on second-line ART after 01 August 2012) to identify predictors of switch to third-line (determined by genotype resistance testing). Third-line ART was defined as a regimen containing etravirine, raltegravir or ritonavir boosted darunavir, between August 2012 and January 2016. To assess predictors of switch to third-line ART we used Cox proportional hazards regression among those with significant viraemia on second-line ART after 01 August 2012. Then among all patients on third-line ART we describe viral load suppression, defined as a viral load < 400 copies/mL, after starting third-line ART., Results: Among 719 patients in care and on second-line ART as of August 2012 (with at least one viral load ≥ 1000 copies/mL after 01 August 2012), 36 (5.0% over a median time of 54 months) switched to third-line. Time on second-line therapy (≥ 96 vs. < 96 weeks) (adjusted Hazard Ratio (aHR): 2.53 95% CI 1.03-6.22) and never reaching virologic suppression while on second-line ART (aHR: 3.37 95% CI 1.47-7.73) were identified as predictors of switch. In a separate cohort of patients on third-line ART, 78.3% (47/60) and 83.3% (35/42) of those in care and with a viral load suppressed their viral load at 6 and 12 months, respectively., Conclusions: Our results show that the need for third-line is low (5%), but that patients' who switch to third-line ART have good early treatment outcomes and are able to suppress their viral load. Adherence counselling and resistance testing should be prioritized for patients that are at risk of failure, in particular those who never suppress on second-line and those who have been on PI-based regimen for extended periods.

Background: While most HIV care is provided on an outpatient basis, hospitals continue to treat serious HIV-related admissions, which is relatively resource-intensive and expensive. This study reports the primary reasons for HIV-related admission at a regional, urban hospital in Johannesburg, South Africa and estimates the associated lengths of stay and costs., Methods and Findings: A retrospective cohort study of adult, medical admissions was conducted. Each admission was assigned a reason for admission and an outcome. The length of stay was calculated for all patients (N = 1,041) and for HIV-positive patients (n = 469), actual utilization and associated costs were also estimated. Just under half were known to be HIV-positive admissions. Deaths and transfers were proportionately higher amongst HIV-positive admissions compared to HIV-negative and unknown. The three most common reasons for admission were tuberculosis and other mycobacterial infections (18%, n = 187), cardiovascular disorders (12%, n = 127) and bacterial infections (12%, n = 121). The study sample utilized a total of 7,733 bed days of those, 55% (4,259/7,733) were for HIV-positive patients. The average cost per admission amongst confirmed HIV-positive patients, which was an average of 9.3 days in length, was $1,783 (United States Dollars)., Conclusions: Even in the era of large-scale antiretroviral treatment, inpatient facilities in South Africa shoulder a significant HIV burden. The majority of this burden is related to patients not on ART (298/469, 64%), and accounts for more than half of all inpatient resources. Reducing the costs of inpatient care is thus another important benefit of expanding access to ART, promoting earlier ART initiation, and achieving rates of ART retention and adherence.

While the diagnostic properties of the TB LAM urine assay (LAM) have been well-described, little is known about its predictive and prognostic properties at ART initiation in a routine clinic setting. We describe the predictive and prognostic properties of LAM in HIV-positive patients initiating ART at an urban hospital in Johannesburg, South Africa. Retrospective study of HIV-positive adults (>18 years) who initiated standard first-line ART between February 2012 and April 2013 and had a LAM test at initiation. In HIV-positive patients with no known TB at ART initiation, we assessed the sensitivity, specificity and positive/negative likelihood ratios of LAM to predict incident TB within 6 months of ART initiation. In addition, in patients with a TB diagnosis and on TB treatment <3 months at ART initiation, we measured the CD4 response at 6 months on ART. Of the 274 patients without TB at ART initiation, 65% were female with median CD4 count of 213 cells/mm(3). Among the 14 (5.1%) patients who developed active TB, none were urine LAM +ve at baseline. LAM had poor sensitivity (0.0% 95% CI 0.00-23.2) to predict incident TB within 6 months of initiation. We analyzed 22 patients with a confirmed TB diagnosis at initiation separately. Of these, LAM +ve patients (27%) showed lower CD4 gains compared to LAM negative patients (median increase 103 vs 199 cells/mm(3); p = 0.08). LAM has limited value for accurately predicting incident TB in patients with higher CD4 counts after ART initiation. LAM may help identify TB/HIV co-infected patients at ART initiation who respond more slowly to treatment and require targeted interventions to improve treatment outcomes. Larger studies with longer patient follow-up are needed.

Introduction: Several studies from resource-limited settings have demonstrated that clinical and immunologic criteria are poor predictors of virologic failure, confirming the need for viral load monitoring or at least an algorithm to target viral load testing. We used data from an electronic patient management system to develop an algorithm to identify patients at risk of viral failure using a combination of accessible and inexpensive markers., Methods: We analyzed data from HIV-positive adults initiated on antiretroviral therapy (ART) in Johannesburg, South Africa, between April 2004 and February 2010. Viral failure was defined as ≥ 2 consecutive HIV-RNA viral loads >400 copies/ml following suppression ≤ 400 copies/ml. We used Cox-proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI). Weights for each predictor associated with virologic failure were created as the sum of the natural logarithm of the adjusted HR and dichotomized with the optimal cut-off at the point with the highest sensitivity and specificity (i.e. ≤ 4 vs. >4). We assessed the diagnostic accuracy of predictor scores cut-offs, with and without CD4 criteria (CD4 <100 cells/mm(3); CD4 < baseline; >30% drop in CD4), by calculating the proportion with the outcome and the observed sensitivity, specificity, positive and negative predictive value of the predictor score compared to the gold standard of virologic failure., Results: We matched 919 patients with virologic failure (1:3) to 2756 patients without. Our predictor score included variables at ART initiation (i.e. gender, age, CD4 count <100 cells/mm(3), WHO stage III/IV and albumin) and laboratory and clinical follow-up data (drop in haemoglobin, mean cell volume (MCV) <100 fl, CD4 count <200 cells/mm(3), new or recurrent WHO stage III/IV condition, diagnosis of new condition or symptom and regimen change). Overall, 51.4% had a score 51.4% had a score ≥ 4 and 48.6% had a score <4. A predictor score including CD4 criteria performed better than a score without CD4 criteria and better than WHO clinico-immunological criteria or WHO clinical staging to predict virologic failure (sensitivity 57.1% vs. 40.9%, 25.2% and 20.9%, respectively)., Conclusions: Predictor scores or risk categories, with CD4 criteria, could be used to identify patients at risk of virologic failure in resource-limited settings so that these patients may be targeted for focused interventions to improve HIV treatment outcomes.

Objective: To assess the outcomes of linkage to TB and HIV care and identify risk factors for poor referral outcomes., Design: Cohort study of TB patients diagnosed at an urban hospital., Methods: Linkage to care was determined by review of clinic files, national death register, and telephone contact, and classified as linked to care, delayed linkage to care (>7 days for TB treatment, >30 days for HIV care), or failed linkage to care. We performed log-binomial regression to identify patient and referral characteristics associated with poor referral outcomes., Results: Among 593 TB patients, 23% failed linkage to TB treatment and 30.3% of the 77.0% who linked to care arrived late. Among 486 (86.9%) HIV-infected TB patients, 38.3% failed linkage to HIV care, and 32% of the 61.7% who linked to care presented late. One in six HIV-infected patients failed linkage to both TB and HIV care. Only 20.2% of HIV-infected patients were referred to a single clinic for integrated care. A referral letter was present in 90.3%, but only 23.7% included HIV status and 18.8% CD4 cell count. Lack of education (RR 1.85) and low CD4 count (CD4≤50 vs. >250cells/mm(3); RR 1.66) were associated with failed linkage to TB care. Risk factors for failed linkage to HIV care were antiretroviral-naïve status (RR 1.29), and absence of referral letter with HIV or CD4 cell count (RR1.23)., Conclusions: Linkage to TB/HIV care should be strengthened by communication of HIV and CD4 results, ART initiation during hospitalization and TB/HIV integration at primary care.

Objective: Pregnancy is a common indication for initiation of highly active antiretroviral therapy (HAART) in sub-Saharan Africa. Our objective was to evaluate how pregnancy at treatment initiation predicts virologic response to HAART., Methods: We evaluated an open cohort of 9173 patients who initiated HAART between April 2004 and September 2009 in the Themba Lethu Clinic in Johannesburg, South Africa. Risk ratios were estimated using log-binomial regression; hazard ratios were estimated using Cox proportional hazards models; time ratios were estimated using accelerated failure time models. We controlled for calendar date, age, ethnicity, employment status, history of smoking, tuberculosis, WHO stage, weight, body mass index, hemoglobin, CD4 count and CD4 percent, and whether clinical care was free. Extensive sensitivity and secondary analyses were performed., Results: During follow-up, 822 nonpregnant women and 70 pregnant women experienced virologic failure. In adjusted analyses, pregnancy at baseline was associated with reduced risk of virologic failure by 6 months [risk ratio 0.66, 95% confidence limits (CL): 0.35 to 1.22] and with reduced hazard of virologic failure over follow-up (hazard ratio: 0.69, 95% CL: 0.50 to 0.95). The adjusted time ratio for failure was 1.44 (95% CL: 1.13 to 1.84), indicating 44% longer time to event among women pregnant at baseline. Sensitivity analyses generally confirmed main findings., Conclusions: Pregnancy at HAART initiation is not associated with increased risk of virologic failure at 6 months or during longer follow-up.

Peripheral neuropathy (PN) is associated with advanced HIV disease and may be a complication of antiretroviral therapy (ART) or anti-tuberculosis (TB) drugs, specifically isoniazid (INH). The effect of non-ART-drug-related PN on treatment outcomes is yet to be determined. We analysed prospectively collected cohort data for HIV-infected ART-naive adults initiating ART at the Themba Lethu Clinic, Johannesburg, South Africa from June 2004 to June 2009. Patients who presented with signs and symptoms of numbness or dysesthesia prior to initiation of ART were defined as having PN. Cox proportional hazard models were used to estimate the effect of PN alone (HIV-related PN) or PN with a history of INH use (TB-related PN) on mortality, lost to follow-up (LTFU), persistent and recurrent PN by 12 months of follow-up. Of the 9,399 patients initiating ART, 3.9 % had HIV-related PN while a further 1.8 % had TB-related PN. Patients with PN did not have a significantly higher risk of mortality compared to those without PN (hazard ratio (HR) 1.17 95 % CI 0.92-1.49). Patients with TB-related PN were less likely to be LTFU by 12 months (HR 0.65 95 % CI 0.44-0.97) compared to those without PN. Patients with HIV-related PN were at increased risk of persistent PN at 3 months post-ART initiation. Patients with HIV-related PN had a similar risk of recurrent PN compared to those with TB-related PN (HR 1.28 95 % CI 0.72-2.27). We demonstrate that patients with PN at initiation of ART present with advanced HIV disease. Completion of TB treatment may reduce the risk of persistent PN in patients with TB-related PN. Use of HIV drugs, even neurotoxic ones, may overall limit neuropathy.

Objectives: Hepatitis B virus (HBV) infection with undetectable hepatitis B surface antigen (HBsAg) has been reported in HIV patients, but the clinical significance is unknown. This study presents the prevalence of HBV DNA in HIV-positive patients negative for all HBV serological markers and a retrospective evaluation of the clinical course of mono- and co-infection., Methods: Of 502 HIV-positive patients, 222 tested negative for HBsAg, antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). An in-house real-time PCR targeting the HBV S-region was used to quantify HBV DNA. HBV isolates were genotyped. Baseline demographic and clinical characteristics of HBV DNA-positive and HBV DNA-negative patients were described. Treatment outcomes of patients at 6, 12, and 24 months after initiation of antiretroviral therapy (ART) were summarized., Results: HBV DNA was detected in 5.4% (12/222) of serologically negative patients. Mean HBV viral load was 5359.2 IU/ml (standard deviation (SD) ±12 768.27). Eleven HBV isolates belonged to genotype A and one to genotype C. There were no significant differences in baseline characteristics or clinical course between the HBV DNA-positive and HBV DNA-negative groups., Conclusions: We found 5.4% of the HBV serologically-negative HIV-positive patients had low levels of HBV DNA. There were no significant differences in clinical outcome between the mono- and co-infected groups., (Copyright © 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: In April 2010, the South African government added tenofovir disoproxil fumarate to its first-line antiretroviral therapy (ART) for HIV patients. We analyzed the relationship between renal dysfunction at tenofovir initiation, nephrotoxicity and mortality., Design: Cohort analysis of HIV-infected adults who received tenofovir and had a creatinine clearance done at initiation at the Themba Lethu Clinic, Johannesburg, South Africa, between April 2004 and September 2009., Methods: We estimated the relationship between renal dysfunction, nephrotoxicity [any decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs)] and mortality for patients initiated onto tenofovir-containing regimens using marginal structural models and inverse probability of treatment weights to correct estimates for lost to follow-up and confounding., Results: Of 890 patients initiated onto tenofovir, 573 (64.4%) had normal renal function (≥90 ml/min), 271 (30.4%) had mild renal dysfunction (60-89 ml/min) and 46 (5.2%) had moderate renal dysfunction (30-59 ml/min). A total of 2.4% experienced nephrotoxicity, 7.8% died and 9.7% were lost during 48 months of follow-up. Patients with mild [hazard ratio 4.8; 95% confidence interval (CI) 1.5-15.2] or moderate (hazard ratio 15.0; 95% CI 3.4-66.5) renal dysfunction were at greatest risk of nephrotoxicity, whereas those with mild (hazard ratio 1.2; 95% CI 0.7-2.3) or moderate (hazard ratio 3.2; 95% CI 1.3-7.8) renal dysfunction vs. normal renal function were at highest risk of death by 48 months., Conclusion: Much of the incident renal dysfunction in tenofovir patients is likely related to preexisting renal disorder, which may be exacerbated by tenofovir. With expanded use of tenofovir, screening for renal dysfunction prior to initiation and dose adjustment is necessary to help improve ART outcomes.

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. [ABSTRACT FROM AUTHOR]

Background: In 2010 South Africa revised its HIV treatment guidelines to allow the initiation and management of patients on antiretroviral therapy (ART) by nurses, rather than solely doctors, under a program called NIMART (Nurse Initiated and Managed Antiretroviral Therapy). We compared the outcomes and costs of NIMART between the two major public sector HIV treatment delivery models in use in South Africa today, primary health clinics and hospital-based HIV clinics. Methods and findings: The study was conducted at one hospital-based outpatient HIV clinic and one primary health clinic (PHC) in Gauteng Province. A retrospective cohort of adult patients initiated on ART at the PHC was propensity-score matched to patients initiated at the hospital outpatient clinic. Each patient was assigned a 12-month outcome of alive and in care or died/lost to follow up. Costs were estimated from the provider perspective for the 12 months after ART initiation. The proportion of patients alive and in care at 12 months did not differ between the PHC (76.5%) and the hospital-based site (74.2%). The average annual cost per patient alive and in care at 12 months after ART initiation was significantly lower at the PHC (US$238) than at the hospital outpatient clinic (US$428). Conclusions: Initiating and managing ART patients at PHCs under NIMART is producing equally good outcomes as hospital-based HIV clinic care at much lower cost. Evolution of hospital-based clinics into referral facilities that serve complicated patients, while investing most program expansion resources into PHCs, may be a preferred strategy for achieving treatment coverage targets. [ABSTRACT FROM AUTHOR]

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