title: A single CD4 test with 250 cells/mm3 threshold predicts viral suppression in HIV-infected adults failing first-line therapy by clinical criteria.
abstract: BACKGROUND
  In low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable.
  
  
  METHODS
  3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically-Driven (CDM, CD4s measured but blinded) or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s) in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4<100 cells/mm(3)) were reviewed in 361 LCM, 314 CDM participants who switched over median 5 years follow-up. Retrospective VLs were available in 368 (55%) participants.
  
  
  RESULTS
  Overall, 265/361 (73%) LCM participants failed with CD4<100 cells/mm(3); only 7 (2%) switched with CD4≥250 cells/mm(3), four switches triggered by WHO events. Without CD4 monitoring, 207/314 (66%) CDM participants failed with WHO 4 events, and 77(25%)/30(10%) with single/multiple WHO 3 events. Failure/switching with single WHO 3 events was more likely with CD4≥250 cells/mm(3) (28/77; 36%) (p = 0.0002). CD4 monitoring reduced switching with viral suppression: 23/187 (12%) LCM versus 49/181 (27%) CDM had VL<400 copies/ml at failure/switch (p<0.0001). Amongst CDM participants with CD4<250 cells/mm(3) only 11/133 (8%) had VL<400 copies/ml, compared with 38/48 (79%) with CD4≥250 cells/mm(3) (p<0.0001).
  
  
  CONCLUSIONS
  Multiple, but not single, WHO 3 events predicted first-line ART failure. A CD4 threshold 'tiebreaker' of ≥250 cells/mm(3) for clinically-monitored patients failing first-line could identify ∼80% with VL<400 copies/ml, who are unlikely to benefit from second-line. Targeting CD4s to single WHO stage 3 'clinical failures' would particularly avoid premature, costly switch to second-line ART.
authors: Department of Medicine, Imperial College, London, United Kingdom.
authors: Charles F
authors: CF
authors: Gilks
authors: A Sarah
authors: AS
authors: Walker
authors: Paula
authors: P
authors: Munderi
authors: Cissy
authors: C
authors: Kityo
authors: Andrew
authors: A
authors: Reid
authors: Elly
authors: E
authors: Katabira
authors: Ruth L
authors: RL
authors: Goodall
authors: Heiner
authors: H
authors: Grosskurth
authors: Peter
authors: P
authors: Mugyenyi
authors: James
authors: J
authors: Hakim
authors: Diana M
authors: DM
authors: Gibb
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000191:economics / Q000706:statistics & numerical data*; D015415:Biomarkers / Q000032:analysis; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D017211:Treatment Failure; D014454:Uganda; D019562:Viral Load / Q000187:drug effects; D015030:Zimbabwe
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers