Higher-Than-Expected Rates of Lactic Acidosis Among Highly Active Antiretroviral Therapy-Treated Women in Botswana: Preliminary Results from a Large Randomized Clinical Trial

Wester, C William MD*†; Okezie, Okechukwu A MBBS*; Thomas, Ann Muir PhD*†; Bussmann, Hermann MD, MPH*†; Moyo, Sikhulile MSc, MPH*; Muzenda, Tanaka MBChB*; Makhema, Joseph MBChB*; Widenfelt, Erik van BSc*; Musonda, Rosemary PhD*; Novitsky, Vladimir MD, PhD*†; Gaolathe, Tendani MD‡; Ndwapi, Ndwapi MD§; Essex, Max DVM, PhD*†; Kuritzkes, Daniel R MD∥; deGruttola, Victor DSc¶; Marlink, Richard G MD*†

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 November 2007 - Volume 46 - Issue 3 - pp 318-322
doi: 10.1097/QAI.0b013e3181568e3f
Clinical Science

Background: The ability of nucleoside reverse transcriptase inhibitors (NRTIs) to inhibit human mitochondrial polymerase-γ results in impaired synthesis of mitochondrial enzymes that generate adenosine triphosphate (ATP) by oxidative phosphorylation. This has been associated with several long-term mitochondrial toxicities, which include lactic acidosis and pancreatitis, peripheral neuropathy, and lipoatrophy.

Methods: Enrolled highly active antiretroviral therapy (HAART)-treated adults have completed nearly 2 years of follow-up as part of the ongoing randomized clinical trial Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study. All patients were intensively screened for the presence of ARV-related toxicities.

Results: Six hundred fifty adults (69% female) were initiated on NRTI-based HAART. Overall, 2.0% of patients developed moderate to severe symptomatic hyperlactatemia, with 7 (1.0%), all female, diagnosed with lactic acidosis. Female gender (P = 0.008) and being overweight, namely having a body mass index (BMI) of greater than 25 (P = 0.001), were predictive for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis. Older age (age >40 years) showed a statistical trend (P = 0.053) as a predictor for the development of toxicity, whereas exposure to d4T and/or ddI for 6 or more months was not predictive (P = 0.102). Those diagnosed with lactic acidosis had a mean BMI of 32.38 (interquartile range [IQR] = 29.4 to 35) at the time of toxicity and had been receiving HAART for a mean of 12.1 months (IQR = 7 to 20.8). Four of the 7 (57%) died of lactic acidosis and/or hemorrhagic pancreatitis; these 4 patients also had a comorbid diagnosis of severe clinical pancreatitis with grade 3/4 lipase elevations and abdominal symptoms at the time of their demise.

Conclusions: Rates of lactic acidosis appear to be higher in southern Africa when compared with rates previously described elsewhere. Risk factors for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis appear to be multifactorial but include female gender and having a BMI of greater than 25. Additional studies are ongoing to evaluate for other possible risk factors, such as host genetic differences.

From *Botswana-Harvard School of Public Health AIDS Initiative Partnership for HIV Research and Education, Gaborone, Botswana; †Harvard School of Public Health, Boston, MA; ‡Princess Marina Hospital, Gaborone, Botswana; §National Operations Manager, National Antiretroviral Treatment (Masa) Programme, Ministry of Health, Botswana; ∥Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and the ¶Center for Biostatistics and AIDS Research, Harvard School of Public Health, Boston, MA.

Received for publication April 16, 2007; accepted July 25, 2007.

Supported by the Bristol-Myers Squibb Foundation and by grants from the National Institutes of Health (K24 RR16482 for Daniel Kuritzkes and K23-AI073141 for C. William Wester). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

Correspondence to: Richard G. Marlink, MD, Harvard School of Public Health, 651 Huntington Ave., Boston, MA 02115 (e-mail: marlink@hsph.harvard.edu).

© 2007 Lippincott Williams & Wilkins, Inc.