title: Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.
abstract: BACKGROUND
  HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.
  
  
  METHODS
  In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779.
  
  
  RESULTS
  Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases).
  
  
  CONCLUSIONS
  ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment.
  
  
  BACKGROUND
  UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.
authors.affiliation: MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK.
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authors.lastname: Katabira
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000349:Africa / Q000453:epidemiology; D000368:Aged; D000740:Anemia / Q000453:epidemiology; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D003404:Creatinine / Q000032:analysis; D015224:Dideoxynucleosides / Q000627:therapeutic use; D018450:Disease Progression; D016903:Drug Monitoring; D005260:Female; D005919:Glomerular Filtration Rate; D015658:HIV Infections / Q000145:classification / Q000188:drug therapy* / Q000401:mortality; D015497:HIV-1 / Q000235:genetics; D039682:HIV-Associated Lipodystrophy Syndrome / Q000453:epidemiology; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000453:epidemiology; D009504:Neutrophils / Q000378:metabolism; D019829:Nevirapine / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use; D012367:RNA, Viral / Q000378:metabolism; D000068698:Tenofovir; D014508:Urea / Q000032:analysis; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use; D000099227:Abacavir
chemical_list: D000225:Adenine; D044966:Anti-Retroviral Agents; D003404:Creatinine; D015224:Dideoxynucleosides; D006454:Hemoglobins; D019259:Lamivudine; D019829:Nevirapine; D063065:Organophosphonates; D012367:RNA, Viral; D000068698:Tenofovir; D014508:Urea; D015215:Zidovudine; D000099227:Abacavir