title: Risk Factors for Acquired Rifamycin and Isoniazid Resistance: A Systematic Review and Meta-Analysis.
abstract: BACKGROUND
  Studies looking at acquired drug resistance (ADR) are diverse with respect to geographical distribution, HIV co-infection rates, retreatment status and programmatic factors such as regimens administered and directly observed therapy. Our objective was to examine and consolidate evidence from clinical studies of the multifactorial aetiology of acquired rifamycin and/or isoniazid resistance within the scope of a single systematic review. This is important to inform policy and identify key areas for further studies.
  
  
  METHODS
  Case-control and cohort studies and randomised controlled trials that reported ADR as an outcome during antitubercular treatment regimens including a rifamycin and examined the association of at least 1 risk factor were included. Post hoc, we carried out random effects Mantel-Haenszel weighted meta-analyses of the impact of 2 key risk factors 1) HIV and 2) baseline drug resistance on the binary outcome of ADR. Heterogeneity was assessed used I2 statistic. As a secondary outcome, we calculated median cumulative incidence of ADR, weighted by the sample size of the studies.
  
  
  RESULTS
  Meta-analysis of 15 studies showed increased risk of ADR with baseline mono- or polyresistance (RR 4.85 95% CI 3.26 to 7.23, heterogeneity I2 58%, 95% CI 26 to 76%). Meta-analysis of 8 studies showed that HIV co-infection was associated with increased risk of ADR (RR 3.02, 95% CI 1.28 to 7.11); there was considerable heterogeneity amongst these studies (I2 81%, 95% CI 64 to 90%). Non-adherence, extrapulmonary/disseminated disease and advanced immunosuppression in HIV co-infection were other risk factors noted. The weighted median cumulative incidence of acquired multi drug resistance calculated in 24 studies (assuming whole cohort as denominator, regardless of follow up DST) was 0.1% (5th to 95th percentile 0.07 to 3.2%).
  
  
  CONCLUSIONS
  Baseline drug resistance and HIV co-infection were significant risk factors for ADR. There was a trend of positive association with non-adherence which is likely to contribute to the outcome of ADR. The multifactorial aetiology of ADR in a programmatic setting should be further evaluated via appropriately designed studies.
authors.affiliation: Department of Medicine, Imperial College, London W2 1PG, United Kingdom; Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Neesha
authors.initials: N
authors.lastname: Rockwood
authors.affiliation: Vaccines for Africa Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Leila H
authors.initials: LH
authors.lastname: Abdullahi
authors.affiliation: Department of Medicine, Imperial College, London W2 1PG, United Kingdom; Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Francis Crick Institute Mill Hill Laboratory, London, United Kingdom; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: Department of Medicine, Imperial College, London W2 1PG, United Kingdom; Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000453:epidemiology*; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024881:Drug Resistance, Bacterial; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology* / Q000627:therapeutic use; D012294:Rifamycins / Q000494:pharmacology* / Q000627:therapeutic use; D012306:Risk; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology
chemical_list: D000995:Antitubercular Agents; D012294:Rifamycins; D007538:Isoniazid