Severe Nucleoside-Associated Lactic Acidosis in Human Immunodeficiency Virus–Infected Patients: Report of 12 Cases and Review of the Literature

Abstract

Lactic acidosis is a rare but often fatal complication reported in some human immunodeficiency virus (HIV)-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. We report a series of 12 patients with HIV infection treated with nucleoside analogues who developed unexplained metabolic acidosis. We have also reviewed 60 additional published cases. The aim of the present study is to describe the clinical picture, prognostic factors, and final outcome for nucleoside-associated lactic acidosis. The mortality rate is high: 33% for our patients, and 57% for the patients described in the literature. In the multivariate analysis, a lactate serum level of >10 mM (odds ratio [OR], 13.23; 95% confidence interval [CI], 2.96-59.25) was the only factor associated with higher mortality. The administration of specific therapy with cofactors against acidosis was associated with a lower mortality (OR, 0.17; 95% CI, 0.04-0.73). We conclude that specific therapy with cofactors may improve the outcome for patients with this syndrome.

A Review of the Toxicity of HIV Medications

“…The incidence of severe lactic acidemia (hyperlactatemia and pH<7.4) was 0.85 per 1,000 patient-years in another large cohort. The median lactate in these patients was 6.5 mmol/L, and the mortality was 33 % [63].…”

“…It is generally agreed that mitochondrial toxicity from NRTIs occurs after a threshold of mitochondrial dysfunction has occurred, but the timing of this is variable during the course of therapy. Cases have occurred from 1-20 months after the start of NRTI therapy [63]. The unpredictability of mitochondrial toxicity is attributed to a multitude of factors.…”

“…Supportive care is the mainstay of therapy. Some authors recommend administration of metabolic cofactors [63]. However, the evidence supporting these interventions is weak, the risk is very low as well.…”

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

“…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, …”

Mitochondrial dysfunction and human immunodeficiency virus infection

“…Lipoatrophy is a common manifestation of mitochondrial dysfunction, and less frequent complications include potentially fatal lactic acidosis, skeletal myopathy, cardiomyopathy, neuropathy, pancreatitis and nephro-toxicity that usually manifests as tubulopathy 2,[20][21][22][23][24][25][26][27] Although all NRTIs potentially affect mtDNA polymerase γ, didanosine (ddI) and stavudine (d4T) have repeatedly been implicated in the most severe cases of mitochondrial toxicity with fatal lactic acidosis. [28][29][30] Apart from their direct effect on mtDNA polymerase γ, nucleoside analogues may also compete with endogenous nucleosides for phosphorylation by mitochondrial thymidine kinase 2 and also for transport into the mitochondria.…”