title: A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on antiretroviral therapy.
abstract: BACKGROUND
  Stavudine continues to be used in antiretroviral treatment (ART) regimens in many resource-limited settings. The use of zidovudine instead of stavudine in higher-risk patients to reduce the likelihood of lactic acidosis and hyperlactatemia (LAHL) has not been examined.
  
  
  METHODS
  Antiretroviral-naïve, HIV-infected adults initiating ART between 2004 and 2007 were divided into cohorts of those initiated on stavudine- or zidovudine-containing therapy. We evaluated stavudine or zidovudine use, age, sex, body mass index (BMI), baseline CD4 cell count, creatinine, hemoglobin, alanine aminotransferase, and albumin as predictors of time to LAHL with Cox Proportional Hazards (PH) regression models.
  
  
  RESULTS
  Among 2062 patients contributing 2747 patient years (PY), the combined incidence of LAHL was 3.2/100 PY in those initiating stavudine- and 0.34/100 PY in those initiating zidovudine-containing ART (RR 9.26, 95% CI: 1.28-66.93). In multivariable Cox PH analysis, stavudine exposure (HR 14.31, 95% CI: 5.79-35.30), female sex (HR 3.41, 95% CI: 1.89-6.19), higher BMI (HR 3.21, 95% CI: 2.16-4.77), higher creatinine (1.63, 95% CI: 1.12-2.36), higher albumin (HR 1.04, 95% CI: 1.01-1.07), and lower CD4 cell count (HR 0.96, 95% CI: 0.92-1.0) at baseline were associated with higher LAHL rates. Among participants who started on stavudine, switching to zidovudine was associated with lower LAHL rates (HR 0.15, 95% CI: 0.06-0.35). Subgroup analysis limited to women with higher BMI≥25 kg/m2 initiated on stavudine also showed that switch to zidovudine was protective when controlling for other risk factors (HR 0.21, 95% CI .07-0.64).
  
  
  CONCLUSIONS
  Stavudine exposure, female sex, and higher BMI are strong, independent predictors for developing LAHL. Patients with risk factors for lactic acidosis have less LAHL while on zidovudine- rather than stavudine-containing ART. Switching patients from stavudine to zidovudine is protective. Countries continuing to use stavudine should avoid this drug in women and patients with higher BMI.
authors.affiliation: Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America. ltmatthe@bidmc.harvard.edu
authors.forename: Lynn T
authors.initials: LT
authors.lastname: Matthews
authors.forename: Janet
authors.initials: J
authors.lastname: Giddy
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.forename: Jane
authors.initials: J
authors.lastname: Hampton
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Guarino
authors.forename: Aba
authors.initials: A
authors.lastname: Ewusi
authors.forename: Emma
authors.initials: E
authors.lastname: Carver
authors.forename: Karen
authors.initials: K
authors.lastname: Axten
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Geary
authors.forename: Rajesh T
authors.initials: RT
authors.lastname: Gandhi
authors.forename: David R
authors.initials: DR
authors.lastname: Bangsberg
mesh_terms: D000140:Acidosis, Lactic / Q000097:blood* / Q000517:prevention & control*; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D015992:Body Mass Index; D016923:Cell Death; D015331:Cohort Studies; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000097:blood*; D008297:Male; D008928:Mitochondria / Q000473:pathology; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D019344:Lactic Acid