Higher-than-expected rates of lactic acidosis among highly active antiretroviral therapy-treated women in Botswana: preliminary results from a large randomized clinical trial.
BACKGROUND
The ability of nucleoside reverse transcriptase inhibitors (NRTIs) to inhibit human mitochondrial polymerase-gamma 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.
Wester
C William
CW
Botswana-Harvard School of Public Health AIDS Initiative Partnership for HIV Research and Education, Gaborone, Botswana.
Okezie
Okechukwu A
OA
Thomas
Ann Muir
AM
Bussmann
Hermann
H
Moyo
Sikhulile
S
Muzenda
Tanaka
T
Makhema
Joseph
J
van Widenfelt
Erik
E
Musonda
Rosemary
R
Novitsky
Vladimir
V
Gaolathe
Tendani
T
Ndwapi
Ndwapi
N
Essex
Max
M
Kuritzkes
Daniel R
DR
DeGruttola
Victor
V
Marlink
Richard G
RG
D000140:Acidosis, Lactic / Q000453:epidemiology*; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000188:drug therapy*; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D001902:Botswana; D018791:CD4 Lymphocyte Count; D005260:Female; D006801:Humans; D007773:Lactates / Q000097:blood; D008875:Middle Aged; D018579:Patient Selection
D007773:Lactates