title: Lactic acidosis and symptomatic hyperlactataemia in a randomized trial of first-line therapy in HIV-infected adults in South Africa.
abstract: BACKGROUND
  Lactic acidosis (LA) is a potentially life-threatening complication of antiretroviral (ARV) therapy. Few randomized prospective studies have compared LA between different ARV regimens.
  
  
  METHODS
  Characterization of cases of LA (serum lactate >5 mmol/l and arterial pH<7.35 or bicarbonate <20 mmol/l) and symptomatic hyperlactataemia (SH; serum lactate >2.2 mmol/l and symptoms) was made in a randomized open-label 2×2 factorial study of stavudine/lamivudine (d4T/3TC)-based versus didanosine/zidovudine-based therapy and lopinavir/ritonavir-based versus efavirenz (EFV)-based therapy in 1,771 HIV-infected adults initiating therapy between 2004 and 2008.
  
  
  RESULTS
  The LA incident rate was 3.5/1,000 person-years (95% CI 1.8-5.9), and for combined LA/SH was 11.0/1,000 person-years (95% CI 7.9-14.9). There were two deaths (15% mortality) among 13 LA cases; all 11 survivors experienced symptom resolution and started new ARV regimens. LA cases were more likely to be female (OR 7.19, 95% CI 1.84-40.75; P=0.001) and had a higher body mass index (BMI; P<0.0001) compared with non-cases. There was no increase in LA according to ARV regimen, age or CD4(+) T-cell count at randomization. When combined, LA/SH cases (n=41) were more often female (OR 4.76, 95% CI 2.36-10.08; P<0.0001), had increased BMI (P<0.0001), were more likely to be assigned d4T/3TC (OR 3.17, 95% CI 1.50-7.28; P=0.001) and were more likely to be assigned EFV (OR 2.18, 95% CI 1.08-4.61; P=0.026).
  
  
  CONCLUSIONS
  Female sex and increased BMI were associated with severe LA in this large randomized trial of first-line ARV in South Africa. While female sex, increased BMI and d4T are previously described risk factors for the development of clinically significant lactate elevations, the independent risk associated with EFV is a novel observation warranting further investigation.
authors.affiliation: Project PHIDISA, South African Military Health Service, South African National Defence Force, Pretoria, South Africa.
authors.forename: Judith
authors.initials: J
authors.lastname: Dlamini
authors.forename: Lotty
authors.initials: L
authors.lastname: Ledwaba
authors.forename: Nthabiseng
authors.initials: N
authors.lastname: Mokwena
authors.forename: Thabo
authors.initials: T
authors.lastname: Mokhathi
authors.forename: Susan
authors.initials: S
authors.lastname: Orsega
authors.forename: Mary
authors.initials: M
authors.lastname: Tsoku
authors.forename: Hedwig
authors.initials: H
authors.lastname: Kowo
authors.forename: Michael
authors.initials: M
authors.lastname: Proschan
authors.forename: Paul
authors.initials: P
authors.lastname: Khabo
authors.forename: Patrick
authors.initials: P
authors.lastname: Maja
authors.forename: Colleen
authors.initials: C
authors.lastname: Hadigan
mesh_terms: D000140:Acidosis, Lactic / Q000453:epidemiology* / Q000401:mortality; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D007773:Lactates / Q000097:blood*; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D013019:South Africa / Q000453:epidemiology; D018119:Stavudine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D007773:Lactates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D018119:Stavudine; C098320:efavirenz