Predictive and prognostic properties of TB-LAM among HIV-positive patients initiating ART in Johannesburg, South Africa

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/mm3. 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/mm3; 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.Key words: Antiretroviral therapy, HIV, lipoarabinomannan, Mycobacterium, TB LAM, South Afric

Treatment initiation among persons diagnosed with drug resistant tuberculosis in Johannesburg, South Africa

In South Africa, roughly half of the drug-resistant TB cases diagnosed are reported to have been started on treatment. We determined the proportion of persons diagnosed with rifampicin resistant (RR-) TB who initiated treatment in Johannesburg after the introduction of decentralized RR-TB care in 2011

Missed appointments among rifampicin-resistant tuberculosis (RR-TB) patients at a decentralised RR-TB outpatient clinic in Johannesburg, South Africa

Background. With the implementation of outpatient (ambulatory) decentralised rifampicin-resistant tuberculosis (RR-TB) treatment in South Africa (SA) since late 2011, the high rates of loss from treatment are a significant concern. Missed appointments lead to treatment interruptions and may contribute to amplification of resistance, ongoing transmission of RR-TB and an increased risk of morbidity and mortality to the patient.Objective. To describe characteristics of patients who missed scheduled appointments during ambulatory RR-TB treatment.Methods. The study was a retrospective, deidentified electronic medical record review of RR-TB patients at an outpatient clinic in Johannesburg, SA, from March 2013 to December 2014. Associations between missed appointments and clinical and demographic characteristics were analysed using time-to-event Cox proportional hazards regression.Results. Of 172 patients who met the eligibility criteria, 53.5% missed at least one appointment and 39.5% missed three or more. More than half (59.8%) of first missed appointments occurred within the first 3 months after treatment initiation. The median number of days from initiation until the first missed appointment was 82 (interquartile range 52 - 260.5). HIV-infected patients with a CD4 count of ≤100 cells/µL (adjusted hazard ratio (aHR) 4.25, 95% confidence interval (CI) 1.49 - 12.18), patients referred from an inpatient facility (aHR 1.96, 95% CI 1.18 - 3.25) and patients aged 18 - 24 years as opposed to those aged 35 - 44 years (aHR 3.26, 95% CI 1.20 - 8.84) were all more likely to miss one or more appointments.Conclusion. HIV-infected patients with a low CD4 count, patients referred from inpatient care and young patients are at high risk of missing appointments and should receive interventions targeted at improving retention

A call to action: Addressing the reproductive health needs of women with drug-resistant tuberculosis

Although there is substantial risk to maternal and neonatal health in the situation of pregnancy during treatment for rifampicin-resistant tuberculosis (RR-TB), there is little evidence to guide clinicians as to how to manage this complexity. Of the 49 680 patients initiated on RR-TB treatment from 2009 to 2014 in South Africa, 47% were women and 80% of them were in their reproductive years (15 - 44). There is an urgent need for increased evidence of the safety of RR-TB treatment during pregnancy, increased access to contraception during RR-TB treatment, and inclusion of reproductive health in research on the prevention and treatment of TB.

Severe adverse events during second-line tuberculosis treatment in the context of high HIV Co-infection in South Africa: a retrospective cohort study

Background: According to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg, South Africa. Methods: We reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 - December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment. Results: Across the two sites, 578 eligible patient files were reviewed. 36.7 % were categorized as low weight (≤50 kg) at DR-TB initiation. 76.0 % had no history of TB treatment prior to the current episode of RR TB. 26.8 % were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5 % of patients were also HIV positive, of whom 43. 8 % were on ART prior to RR TB treatment and 32.1 % initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45-246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3 %) and 110 patients (19.0 %) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts ≤100 cells/mm3 and those newly initiating ART were more likely to experience a severe AE (sHR: 2.76, 95 % CI: 1.30–5.84 and sHR: 3.07, 95 % CI: 1.46–6.46, respectively). Conclusion: Severe AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment

Treatment outcomes among children, adolescents, and adults on treatment for tuberculosis in two metropolitan municipalities in Gauteng Province, South Africa

BACKGROUND : Gauteng Province has the second lowest tuberculosis (TB) incidence rate in South Africa but the greatest proportion of TB/HIV co-infection, with 68% of TB patients estimated to have HIV. TB treatment outcomes are well documented at the national and provincial level; however, knowledge gaps remain on how outcomes differ across detailed age groups. METHODS : Using data from South Africa’s National Electronic TB Register (ETR), we assessed all-cause mortality and loss to follow-up (LTFU) among patients initiating treatment for TB between 01/2010 and 12/2015 in the metropolitan municipalities of Ekurhuleni Metropolitan Municipality and the City of Johannesburg in Gauteng Province. We excluded patients who were missing age, had known drug-resistance, or transferred into TB care from sites outside the two metropolitan municipalities. Among patients assigned a treatment outcome, we investigated the association between age group at treatment initiation and mortality or LTFU (treatment interruption of ≥2 months) within 10 months after treatment initiation using Cox proportional hazard models and present hazard ratios and Kaplan-Meier survival curves. RESULTS : We identified 182,890 children (<10 years), young adolescent (10–14), older adolescent (15–19), young adult (20–24), adult (25–49), and older adult (≥50) TB cases without known drug-resistance. ART coverage among HIV co-infected patients was highest for young adolescents (64.3%) and lowest for young adults (54.0%) compared to other age groups (all over 60%). Treatment success exceeded 80% in all age groups (n = 170,017). All-cause mortality increased with age. Compared to adults, young adults had an increased hazard of LTFU (20–24 vs 25–49 years; aHR 1.43 95% CI: 1.33, 1.54) while children, young adolescents, and older adults had lower hazard of LTFU. Patients with HIV on ART had a lower risk of LTFU, but greater risk of death when compared to patients without HIV. CONCLUSIONS : Young adults in urban areas of Gauteng Province experience a disproportionate burden of LTFU and low coverage of ART among co-infected patients. This group should be targeted for interventions aimed at improving clinical outcomes and retention in both TB and HIV care.The American People and the President’s Emergency Plan for AIDS Relief (PEPFAR) through USAID under the terms of Cooperative Agreements AID- 674-A-12-00029 and 72067419CA00004 to HE2RO.https://bmcpublichealth.biomedcentral.comam2020Medical Microbiolog

Predictors of switch to and early outcomes on third-line antiretroviral therapy at a large public-sector clinic in Johannesburg, South Africa

Abstract 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

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.S1 Fig. Illustration of allocation of person time in marginal structural models. Hypothetical person time contributed to each of the 6 exposure groups in marginal structural models.S1 Table. Alternative stratifications for adjusted marginal structural models for hazard ratios of death after first-line failure.S2 Table. Adjusted marginal structural model hazard ratios for death after first-line failure, limiting to patients with 2 weeks to <8 months between failing viral loads on first-line (n = 4908).S3 Table. Adjusted Cox proportional hazards ratios for alternative virologic outcomes on second-line ART, stratified by peak CD4 count prior to first-line failure.S4 Table. Adjusted marginal structural models for hazard ratios of death after first-line failure (a) and adjusted Cox proportional hazards ratios for confirmed failure on second-line ART (b), with weighting by inverse probability of censoring after second-line switch to account for loss to follow-up.JKR, KS, MM, LL and MPF were funded for this work by United States Agency for International Development (USAID) through the following agreement: 674-A-12-00029. Additional support to KS was provided by the National Institutes of Health (NIH) (T32AI102623).http://www.plosone.orgam2016Medical Microbiolog

Assessing the association between changing NRTIs when initiating second-line ART and treatment outcomes.

BACKGROUND After first-line antiretroviral therapy (ART) failure, the importance of change in nucleoside reverse transcriptase inhibitor (NRTI) in second-line is uncertain due to the high potency of protease inhibitors used in second-line. SETTING We used clinical data from 6,290 adult patients in South Africa and Zambia from the International Epidemiologic Databases to Evaluate AIDS-Southern Africa cohort. METHODS We included patients who initiated on standard first-line ART and had evidence of first-line failure. We used propensity score-adjusted Cox proportional hazards models to evaluate the impact of change in NRTI on second-line failure compared to remaining on the same NRTI in second-line. In South Africa, where viral load monitoring was available, treatment failure was defined as two consecutive viral loads >1,000 copies/mL. In Zambia, it was defined as two consecutive CD4 counts <100 cells/mm. RESULTS Among patients in South Africa initiated on zidovudine, the adjusted hazard ratio for second-line virologic failure was 0.25 (95% CI: 0.11, 0.57) for those switching to tenofovir vs. remaining on zidovudine. Among patients in South Africa initiated on tenofovir, switching to zidovudine in second-line was associated with reduced second-line failure (adjusted hazard ratio = 0.35 [95% CI: 0.13, 0.96]). In Zambia where viral load monitoring was not available, results were less conclusive. CONCLUSION Changing NRTI in second-line was associated with better clinical outcomes in South Africa. Additional clinical trial research regarding second-line NRTI choices for patients initiated on tenofovir or with contraindications to specific NRTIs is needed