Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia

doi:10.1016/S0140-6736(00)04579-7

The Lancet

Volume 357, Issue 9266, 5 May 2001, Pages 1412-1414

https://doi.org/10.1016/S0140-6736(00)04579-7 Get rights and content

Summary

Acute hepatitis with lactic acidosis is a life-threatening but reversible toxic effect on mitochondria of HIV-1 nucleosideanalogue treatment. We report fatal portal hypertension, liver failure, and persistent mitochondrial dysfunction in a man aged 65 years with HIV-1 infection who had recovered fromnucleoside-analogue-induced acute hepatitis and lactic acidaemia more than 18 months previously. We believe that symptomfree patients who receive nucleoside-analogue therapy should have hepatic function constantly monitored, especially those with past or present lactic acidaemia. Acute hepatitis with lactic acidosis is a toxic effect of HIV- 1 nucleoside analogues on mitochondria. 80% of patients with lactate greater than 10 mmol/L die. The longterm outcome of those who survive is unknown, but all reports have shown full recovery.

References (5)

B Fromenty et al.
Microvesicular steatosis and steatohepatitis: role of mitochondrial dysfunction and lipid peroxidation
J Hepatol
(1997)
G Pezeshkpour et al.
Ultrastructural characteristics and DNA immunocytochemistry in human immunodeficiency virus and zidovudine-associated myopathies
Hum Pathol
(1991)

There are more references available in the full text version of this article.

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Antiretroviral drugs, targeting the human immune deficiency virus, are the antivirals that more often cause drug-induced liver injury (DILI). DILI secondary to antiretroviral use is mostly asymptomatic and manifested only by elevation of liver enzymes. However, there are specific DILI syndromes associated with antiretroviral therapy: hypersensitivity reactions, lactic acidosis with hepatic steatosis, decompensation of cirrhotic liver, noncirrhotic portal hypertension, and nonalcoholic steatohepatitis. Although the exact pathogenic mechanisms for these forms of DILI may not be fully understood, risk factors have been recognized. Interferon, used for the treatment of hepatitis C and B viruses, can also cause decompensation of a cirrhotic liver. In addition, antivirals targeting Herpesviridae can cause liver enzyme elevations, albeit infrequently, and have occasionally been associated with liver failure.
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Citation Excerpt :
However, longer survival and long-term exposure to antiretroviral drugs are accompanied by changes in the morbidity and causes of death in HIV-infected patients, leading to the emergence of cancer, cardio-vascular and liver diseases [22,23]. A long-term hepatic toxicity of NRTI related to mitochondrial toxicity has long been suspected [24,25]. The recent identification of the clinical non-cirrhotic portal hypertension syndrome in HIV-infected patients, followed by the recognition of histopathological NRH lesions caused by microvascular portal venopathy were important steps in the understanding of this new body of severe liver diseases.
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Control patients and patients with NRH were similar at baseline regarding demographics and biological data with the exception of older age for patients with NRH (43.9 vs. 33.5 years, p = 0.044). At the time of NRH diagnosis, cases had a lower CD4 count (327 vs. 468/mm³, p = 0.013), a similar CD4 percentage (24 vs. 26.2%, p = 0.7), a lower platelet count (169 vs. 228 giga/L, p = 0.003) and a higher AST level (33 vs. 26 IU/L, p = 0.001) than controls. Univariate analysis demonstrated that patients with NRH had been exposed longer than controls to didanosine, stavudine, tenofovir, didanosine + stavudine, and didanosine + tenofovir. The age at baseline [OR 2.2 (1.0–5.0) per 10 years, p = 0.053] and didanosine + stavudine cumulative exposure [OR 3.7 (1.4–10.2) per year, p = 0.011] were independently associated with NRH. The age at baseline [OR 2.3 (1.0–5.3) per 10 years, p = 0.045], cumulative exposure to didanosine [OR 1.4 (1.1–1.9) per year, p = 0.023] and to tenofovir [OR 1.7 (1.0–2.8) per year, p = 0.04] were independently associated with NRH when didanosine + stavudine exposure was excluded from the model.
NRH in HIV-infected patients seems strongly related to age and the cumulative exposure to didanosine + stavudine, didanosine, and stavudine.
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Citation Excerpt :
Our results correspond to the findings of a previous study that showed a lactate level range of 5–10 mmol/l to be associated with a mortality rate of 7% and a lactate level range of 10–15 mmol/l to be associated with a mortality rate of >30%.4 Several studies have shown that the mortality rate of patients with a lactate level above 10 mmol/l is approximately 80%.4,6,21 Of note, total duration of drug exposure and female gender had previously been established as risk factors for mitochondrial toxicity.22
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A retrospective cohort study was conducted among patients who were diagnosed with symptomatic hyperlactatemia (lactate >2.5 mmol/l) between January 2004 and April 2006. All patients were followed until 3 months after the diagnosis.
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Research LettersFatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia

Summary

J Hepatol

Hum Pathol

Research Letters
Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia