Risk factors for and clinical characteristics of severe hyperlactataemia in patients receiving antiretroviral therapy: a case–control study

Abstract

BackgroundSymptomatic hyperlactataemia and lactic acidosis (SHLA) are potentially life-threatening complications associated with stavudine (d4T), an antiretroviral therapy (ART) drug widely used in developing countries. MethodsCases comprised all symptomatic patients with measured lactates ! 5 mmol/L referred to a South African hospital between August 2003 and November 2005. Matched controls were selected according to facility and duration on ART. ResultsSeventy-one cases and 142 controls were included in the study. The majority of cases presented between 6 and 18 months on ART. Female sex [adjusted odds ratio (AOR) 23.4; 95% confidence interval (CI) 4.0-136.6], a baseline weight between 60 and 75 kg (AOR 4.5; 95% CI 1.4-14.1) or, in particular, ! 75 kg (AOR 19.4; 95% CI 4.1-82.5) at ART initiation and gaining ! 6 kg in the first 3 months on therapy (AOR 3.5; 95% CI 1.3-9.5) were independent risk factors identifying patients who may subsequently develop SHLA. Weight loss of ! 2 kg (AOR 6.1; 95% CI 2.0-18.3), a rise in alanine aminotransferase (ALT) ! 10 U/L (AOR 3.1; 95% CI 1.1-8.9), the presence of at least one of three major symptoms (vomiting, nausea and abdominal pains) of SHLA (AOR 12.6; 95% CI 3.3-47.2) and peripheral neuropathy (AOR 3.4; 95% CI 1.1-9.8) were the clinical parameters that were most able to identify patients with early manifestations of SHLA. ConclusionsThis is the first case-control study for SHLA in Southern Africa. Given these findings, we advise that stavudine is avoided in overweight women. Weight loss, a rise in ALT, peripheral neuropathy and/or gastrointestinal symptoms should prompt healthcare workers to assess for SHLA, especially at between 6 and 18 months on ART.Keywords: antiretroviral therapy, case-control, hyperlactataemia, lactic acidosis, stavudine 121with ART, and the numbers are continuously increasing [7]. Although hyperlactataemia and lactic acidosis have become rare in developed world settings, they are still considered significant challenges to large-scale ART provision in developing countries. A better understanding of the risk factors for SHLA is important in combating the morbidity and mortality associated with such an adverse event.Although the World Health Organization (WHO) now recommends tenofovir (TDF) or zidovudine (ZDV) as the preferred NRTIs for combination with lamivudine (3TC) or emtricitabine (FTC) in standard first-line regimens [8], d4T-based regimens continue to be widely used in developing countries, for reasons of cost, availability, and ease of administration [9].The associations between SHLA and exposure to d4T and ddI were initially described in a number of small crosssectional and cohort studies [10][11][12][13][14][15]. Recently, 110 cases of SHLA were pooled across multiple countries to conduct a case-control study, which identified advanced age, low nadir CD4 cell count, exposure to d4I and ddI and female gender as additional associations [16].Globally there is a paucity of data on the risk factors for SHLA in the settings in which d4T use pre...

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa

“…Hence it is conceivable from this study that there is no association between CD4 count and SHL/ LA among the SA population, in good agreement with the reports of Osler and others. [11,27] However, our findings contradict the results obtained by some researchers, in which a strong association between patient age [25] and CD4 count [24,26] and SHL/LA was observed. Several POLG1 mutations have been studied, resulting in deletions or point mutations in mtDNA and decreased polymerase activity.…”

Effect of HIV-1 Infection and Sex on the Cellular Pharmacology of the Antiretroviral Drugs Zidovudine and Lamivudine

“…When the entirety of the literature is considered, no definitive statement on the effect of sex on intracellular levels of ZDV and 3TC in PBMC can be made at this time. Additional pharmacology studies with large sample sizes are warranted to help explain the 20-fold higher risk for lactic acidosis in women than in men (31,41). Sex differences in phosphorylation in tissues other than PBMC, such as liver, would be one avenue to explore.…”

“…Lactic acidosis, a rare but life-threatening mitochondrial toxicity associated with long-term NRTI use, occurs approximately 20-fold more frequently in women (31,41), suggesting possible sex-based differences in NRTI cellular pharmacology. Current data regarding associations between the cellular pharmacology of these drugs and sex are variable and inconclusive.…”

Review article: long‐term safety of oral anti‐viral treatment for chronic hepatitis B

“…51 There had been sporadic reports on lactic acidosis occurring during HBV treatment. Based on published cases related to TDF 52,53 and entecavir, 15,54 renal impairment seemed to be an important contributing factor, probably due to mitochondrial toxicity if renal dosage adjustments were not promptly enforced.…”