A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on antiretroviral therapy.

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.

Outcomes after virologic failure of first-line ART in South Africa.

OBJECTIVE: To determine initial 24-week outcomes among prospectively enrolled patients with failure of initial antiretroviral therapy (ART). METHODS: Baseline virologic failure was defined as HIV-1 viral load greater than 1000 copies/ml. Second-line ART was informed by results of genotype testing and selected from agents in the South-African public sector. Twenty-four week endpoints included virologic suppression and mortality. RESULTS: The cohort consisted of 141 patients (median CD4 cell count and viral load at failure of 173 cells/microl and 17 500 copies/ml). The median prior duration of initial ART was 12.0 months. At least one major resistance mutation was found in 87% of patients. After 24 weeks of follow-up, intent-to-treat virologic suppression (<50 copies/ml) was 65%, as-treated virologic suppression was 78%, the median CD4 cell count improvement was 88 cells/microl and the mortality was 6%. The median CD4 cell count at initial virologic failure among those who died was 70 cells/microl, compared to 182 cells/microl among patients who survived (P = 0.01). Patients with wild-type virus at initial failure (N = 19) had inferior outcomes after switch. The presence of nucleoside analogue resistance mutations at failure did not affect early efficacy of boosted-protease inhibitor regimens. CONCLUSIONS: Virologic monitoring linked to resistance testing helped demonstrate the efficacy of lopinavir/ritonavir-containing second-line regimens in South Africa. A switch to second-line regimens in patients with virologic failure and drug resistance has substantial and rapid immunological and clinical benefits. Resistance testing identified a high-risk group without resistance who might benefit from increased medication access and/or adherence support.