title: Severe adverse events during second-line tuberculosis treatment in the context of high HIV Co-infection in South Africa: a retrospective cohort study.
abstract: 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/mm3and 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).
  
  
  CONCLUSIONS
  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.
authors: Right to Care, Johannesburg, South Africa. kschnipp@gmail.com.|Clinical HIV Research Unit, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. kschnipp@gmail.com.|Health Economics Unit, School of Family and Public Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. kschnipp@gmail.com.
authors: Kathryn
authors: http://orcid.org/0000-0003-0757-4325
authors: K
authors: Schnippel
authors: Right to Care, Johannesburg, South Africa.|Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.|School of Medicine, University of North Carolina, Chapel Hill, USA.
authors: Rebecca H
authors: RH
authors: Berhanu
authors: Wits Reproductive Health and HIV Research Institute, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors: Andrew
authors: A
authors: Black
authors: Right to Care, Johannesburg, South Africa.|Clinical HIV Research Unit, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors: Cynthia
authors: C
authors: Firnhaber
authors: Wits Reproductive Health and HIV Research Institute, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.|GlaxoSmithKline, Bryanston, South Africa.
authors: Norah
authors: N
authors: Maitisa
authors: Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.
authors: Denise
authors: D
authors: Evans
authors: Health Economics Unit, School of Family and Public Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors: Edina
authors: E
authors: Sinanovic
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002648:Child; D015331:Cohort Studies; D060085:Coinfection / Q000188:drug therapy; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012293:Rifampin / Q000627:therapeutic use; D013019:South Africa; D014376:Tuberculosis / Q000188:drug therapy*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D012293:Rifampin
keywords: Adverse drug reactions; Antiretroviral therapy; HIV; Multi-drug resistant TB; Tuberculosis