Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy

Arenas‐Pinto, Alejandro; Ad, Grant; Dunn, David; Carr, Andrew; Reiss, Peter; Edwards, SG; Lundgren, JD; Overton, Turner; Martínez, Estebán; Copas, Andrew; Chan, Philip; Weber, Rainer; Bhaskaran, Krishnan; Weller, I. V. D.

doi:10.1097/qad.0b013e3282f08cdc

Cited by 69 publications

(29 citation statements)

References 27 publications

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“…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.…”

Section: Researchcontrasting

confidence: 96%

“…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 …”

Section: Discussionmentioning

confidence: 56%

“…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. This is in good agreement with studies that have shown associations between SHL/ LA and advanced age.…”

Section: Researchmentioning

confidence: 54%

“…This is in good agreement with studies that have shown associations between SHL/ LA and advanced age. [24,25] Other studies have reported low baseline CD4 count [12,24,26] as a factor associated with SHL/LA. In this study, the controls had a lower baseline CD4 count median, of 89 cells/µL (IQR 26 -170) compared with 121 cells/µL (IQR 56 -156) in cases, at the time of hyperlactataemia diagnosis.…”

Section: Researchmentioning

confidence: 97%

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

et al. 2016

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Background. Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA. Objective. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/ LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy. Methods. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results. Results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p<0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 -114.25) compared with males. Conclusion. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA.

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Section: Researchcontrasting

confidence: 96%

Section: Discussionmentioning

confidence: 56%

Section: Researchmentioning

confidence: 54%

Section: Researchmentioning

confidence: 97%

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

et al. 2016

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“…[11] Risk factors that are associated with developing this complication include female sex, pregnancy, use of stavudine and/or didanosine, prolonged HAART duration, obesity, reduced creatinine clearance and low-baseline CD4 count. [10,12-14] Treatment of lactic acidosis is predominantly supportive. There has been anecdotal success with thiamine, [15] riboflavin, [16] ubiquone, [17] biotin, [17] zinc picolinate, [17] N-acetylcysteine, [17] uridine, [17] and L-carnitine.…”

Section: Introductionmentioning

confidence: 99%

Fatal Toxicity from Symptomatic Hyperlactataemia

Leung¹,

Wilson

Manini

2011

Drug Safety

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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.

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Clinical syndromes and consequences of antiretroviral-related hepatotoxicity

Núñez

2010

Hepatology

156

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Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy

Cited by 69 publications

References 27 publications

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

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

Fatal Toxicity from Symptomatic Hyperlactataemia

Clinical syndromes and consequences of antiretroviral-related hepatotoxicity

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