Fatal Toxicity from Symptomatic Hyperlactataemia

Abstract

Background In many Sub-Saharan African countries, first-line therapy for HIV may include a nucleoside reverse transcriptase inhibitor (NRTI). Long-term NRTI use is associated with symptomatic hyperlactataemia due to inhibition of mitochondrial DNA polymerase γ, a potentially fatal complication. Objective The purpose of the study was to evaluate the factors associated with inhospital fatality for HIV inpatients prescribed NRTIs long term who presented with symptomatic hyperlactataemia. Methods We performed a retrospective cohort study at a 900-bed university hospital in South Africa over 4 years (2005–2008). We included HIV inpatients prescribed NRTIs long term who presented with symptomatic hyperlactataemia (long-term NRTI use; lactate >4.0 mmol/L; absence of infectious source; symptoms requiring admission). Data included demographics, medical history, NRTI duration, blood pressure, symptom duration and relevant laboratory data. Results Of 79 patients who met inclusion criteria (mean age 38.2 ± 10.5 years, 97% female) there were 46 fatalities (58%). Factors significantly associated with fatality were presence of diabetes mellitus (p = 0.04), lactate ≥10 mmol/L (p = 0.003), pH <7.2 (p = 0.002), creatinine ≥200 μmol/L (p = 0.03) and altered mental status (p = 0.03). Conclusions In this study, NRTI-related symptomatic hyperlactataemia occurred predominantly in females. Mortality was associated with severely elevated lactate (≥10 mmol/L), the degree of acidosis, elevated creatinine, history of diabetes and altered mental status on presentation.

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

“…[9,19] Female gender, age, high initiating body weight and treatment with stavudine were significantly associated with increased risk of SHL/LA. These risk factors are consistent with those reported by other studies in related settings, [10,12,14] as well as in other studies globally. [8,15,[24][25][26] In this study, the baseline age of the cases and controls was significantly different (p=0.015), with a median age of 38 (IQR 33 -45) and 33 (IQR 28 -40) years for cases and controls, respectively.…”

“…Similar factors have been reported by other investigators in both local and international settings. [10,12,14,24] The R964C and E1143G polymorphisms within POLG1 were not observed in this study population. The study confirms that …”

“…Eleven months of exposure to stavudine in the cases compared with 68 months in the controls (p<0.001) clearly demonstrates that the use of stavudine poses a risk in the development of SHL/LA, as documented by other investigators. [8,9,11,12,14,21] While a significant number of the cases (42/59) were on zidovudine treatment at the time of enrolment in the study, only one patient among the control group (n=57) was on similar treatment. The 42 cases on zidovudine did not show any symptoms or relapse of SHL/LA, …”

“…Literature reports from developed countries suggest an incidence rate for SHL of 5 -10/1 000 patients per year on NRTIs and 1/1 000 patients per year for the very severe form (LA), which is associated with a high expected mortality. [8] In South Africa (SA), SHL/LA incidence appears notably high, [9][10][11][12][13][14][15] especially in KwaZulu-Natal (KZN) Province, which is predominantly inhabited by the SA Zulu-speaking population. [10,12,14] The objective of this study was to detect if known mutations in mtDNA polymerase-γ (POLG1) [16,17] reported to be associated with mitochondrial toxicity are also linked with NRTI-induced SHL/LA in the SA Zulu-speaking population.…”