First-Line Therapy and Mitochondrial Damage: Different Nucleosides, Different Findings

BACKGROUND: Antiretroviral therapy has been associated with the development of morphologic body-shape changes and metabolic abnormalities, including dislipemia, insulin resistance, and hyperlactatemia. Mitochondrial damage secondary to the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) has been related to some of these complications, although the role of different NRTIs in their development is not well established. OBJECTIVES: To assess the incidence of hyperlactatemia and lipodystrophy body-shape changes in drug-naïve HIV-infected patients who began highly active antiretroviral therapy (HAART) based on a backbone of two different NRTI combinations. METHOD: Prospective, longitudinal, observational study of all consecutive drug-naïve HIV-infected individuals who started HAART with zidovudine (AZT) plus lamivudine (3TC) or didanosine (ddI) plus stavudine (d4T) between June 2000 and June 2001 at one single institution. Serum lactate levels and lipodystrophy body-shape changes were monitored periodically during 12 months. RESULTS: At 1 year, mean lactate values remained <2 mmol/L in all 26 patients who received AZT+3TC, but they significantly increased (mean, 2.6 mmol/L) in 50 patients treated with ddI+d4T. The percentage of patients with hyperlactatemia (lactate >or=2 mmol/L) steadily increased in those on ddI+d4T (from 30% at 3 months to 71% at 12 months), whereas it remained below 10% in patients treated with AZT+3TC. Two patients on ddI+d4T developed lactic acidosis. Mean serum lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), and amylase significantly increased in patients treated with ddI+d4T, whereas they remained unaltered in patients under AZT+3TC. Significant correlations were found between lactate and LDH, alkaline phosphatase (AP), and GGT. In the multivariate analysis, treatment with ddI+d4T, LDH, and AP was significantly associated with lactate levels. At 12 months, subcutaneous lipoatrophy was significantly more frequent in patients treated with ddI+d4T than in those on AZT+3TC (35% vs. 8%; p =.01). CONCLUSION: In drug-naïve HIV-infected patients who start antiretroviral therapy, ddI+d4T-based combinations produce a greater increase in serum lactate and lipoatrophy than therapies based on AZT+3TC within the first year of therapy. An increase in LDH, amylase, GGT, and AP levels may signal an increase in lactate, which may be harmful.