Steatosis–lactic acidosis syndrome associated with stavudine and lamivudine therapy

Johri, Shilpa; Alkhuja, Samer; Siviglia, Geraldine; Soni, Anita

doi:10.1097/00002030-200006160-00033

Cited by 30 publications

(9 citation statements)

References 6 publications

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“…Also the nature of NRTI might play a role. It is noteworthy that first reports of symptomatic HL were described during zidovudine or didanosine monotherapy [9–12], although recent reports focus on the involvement of stavudine, didanosine or a combination of both [4, 13–22]. Nevertheless, until a recent report, the experience of HL was based on observational, noncontrolled studies.…”

Section: Discussionmentioning

confidence: 99%

Prevalence, risk factors and outcome of hyperlactataemia in HIV‐infected patients*

et al. 2003

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ObjectiveWe describe the prevalence, risk factors and outcome of hyperlactataemia (HL) in a cohort of 140 HIV-infected patients. Patients and methodsPatients were enrolled consecutively within a 3-month period (July to September 1999) and followed until 31 October 2000. One hundred and forty HIV-infected patients had venous plasma lactate levels measured. HL was de®ned at baseline by two consecutive lactate levels > 2.1 mmol/L (upper limit of normal). We compared baseline demographic characteristics, immuno-virological parameters, antiretroviral therapy and outcome between patients with HL (cases) or without HL (controls). We described the clinical features of patients with HL. ResultsAmong 129 patients included in the analysis, HL was found in 11 patients (8.5%), all of whom were receiving nucleoside reverse transcriptase inhibitors (NRTIs). Cases were more likely than controls to receive didanosine or stavudine (82% vs. 19%, P 2.7 Â 10 À6 and 82% vs. 48%, P 0.03, respectively). Only 4/11 cases (36%) had symptoms consistent with HL. After a median follow-up of 15 months, lactate level returned to normal in all three patients who discontinued NRTIs, but in only 2/8 patients who did not (P 0.06). Only one case experienced lactic acidosis and died during followup. Mortality rate was similar in cases and controls. ConclusionHL is associated with NRTI use, in particular didanosine and stavudine, and discontinuation of NRTIs seems to be associated with rapid resolution of HL. Lactic acidosis remains rare and the long-term outcome of patients with HL does not seem to be poorer than controls.

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Section: Discussionmentioning

confidence: 99%

Prevalence, risk factors and outcome of hyperlactataemia in HIV‐infected patients*

et al. 2003

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“…This was observed both when ritonavir was administered as the sole PI and when it was combined with another PI. Several studies have described hepatotoxicity related to nucleoside reverse-transcriptase inhibitor use [19,20]. In particular, stavudine has been implicated [6,21], although this has not universally reported [17].…”

Section: Discussionmentioning

confidence: 99%

Hepatotoxicity Associated with Antiretroviral Therapy Containing Dual versus Single Protease Inhibitors in Individuals Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus

2002

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To determine the rates of patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who discontinued therapy as a result of protease inhibitor (PI)-related hepatotoxicity, a retrospective review was conducted. Baseline CD4 counts, plasma HIV RNA levels, and duration of therapy were comparable between single- and dual-PI-treated subjects and between subjects receiving ritonavir-containing therapy and those receiving ritonavir-sparing therapy. The proportions of patients with elevations in alanine aminotransferase level to > or =5 times the upper limit of normal (19% versus 26%) and hyperbilirubinemia (30% versus 38%) were similar between the dual-PI (n=27) and single-PI treatment groups (n=39), respectively. No difference in these characteristics was observed between ritonavir-containing (n=34) and ritonavir-sparing (n=32) treatment arms. Rates of treatment discontinuation due to hepatotoxicity were similar for single-PI and dual-PI therapy and for ritonavir-containing and ritonavir-sparing regimens. Dual-PI therapy and inclusion of ritonavir do not seem to increase the rates of hepatotoxicity in PI-treated, HIV-HCV coinfected subjects.

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“…The d4T treatment can cause mild to transient Raghu and Karthikeyan, 2016;Raghu et al, 2015;Banerjee et al, 2013;Brinkman et al, 1998;Dubin and Braffman, 1989 Stavudine Elevation of liver toxicity marker enzymes, lactic acidosis, inhibition of mitochondrial oxidation of FFA -macrovesicular steatosis van Griensven et al, 2010;Gerschenson et al, 2001;Johri et al, 2000;Lea and Faulds, 1996 Lamivudine Elevation in serum ALT levels in patients co-infected with chronic HBV, elevation of hepatotoxic and lipid marker enzymes in serum and plasma Jesudas et al, 2016;Johri et al, 2000 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine Jaundice, hepatitis, hepatic necrosis, hepatic failure, elevation of liver marker enzymes (AST/ALT) in chronic therapy Ajulo et al, 2015;Bera et al, 2012;Hitti et al, 2004 Efavirenz Retention of bile constituents in hepatocytes -cholestasis -hepatocytes apoptosis, inhibits bile acid transport in human/rat hepatocytes, high levels of elevation of AST/ALT, hepatic steatotic changes, mitochondria and ER stress Thamrongwonglert et al, 2016;Patil et al, 2015;Apostolova et al, 2013;McRae et al, 2006 Protease inhibitors (PIs) Ritonavir Induction of hepatocytes apoptosis through caspase-3 cascade system Inhibits bile acid transport in human/rat hepatocytes Increased risk of hepatotoxicity in HIV+TB infected patients with rifampicin treatment Mchunu et al, 2016;Kuang et al, 2014;Schmitt et al, 2009 Nelfinavir elevation in liver marker enzymes due to hepatotoxicity which occurs in up to 50% of patients and lactic acidosis is often reported in these patients with high mortality rate (van Griensven et al, 2010;Lea and Faulds, 1996). In primates, chronic exposure of d4T has been reported to induce mitochondrial toxicity and there was a significant destruction of hepatocytes mitochondrial DNA found in the liver of d4T-exposed monkeys (Gerschenson, et al, 2001).…”

Section: Stavudine (D4t)mentioning

confidence: 99%

“…In primates, chronic exposure of d4T has been reported to induce mitochondrial toxicity and there was a significant destruction of hepatocytes mitochondrial DNA found in the liver of d4T-exposed monkeys (Gerschenson, et al, 2001). Like other ARV drugs, d4T also interferes with mitochondrial catabolic beta-oxidation of free fatty acids causing the infiltration of lipid droplets in liver cells, manifesting as severe macrovesicular steatosis with hepatomegaly (Johri et al, 2000).…”

Section: Stavudine (D4t)mentioning

confidence: 99%

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HAART and Hepatotoxicity

2017

J App Pharma Sci

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Antiretroviral (ARV) drugs are given in combination to treat the human immunodeficiency virus (HIV)infection and to prolong the life expectancy of the patient. The increase in the levels of hepatotoxicity due to the use of above drugs has been the concern till date. Lactic acidosis, hepatocytes fatty infiltration and oxidative stress are the commonly associated hepatotoxic effects with the administration of nucleoside reverse transcriptase inhibitors. Non-nucleooside reverse transcriptase inhibitors such as nevirapine and efavirenz inhibit bile acid transport causing cholestasis which in turn causes apoptosis to the hepatocytes. Furthermore, hepatitis C and B virus co-infection and Tuberculus bacilli in HIV infected patients remains a vital risk factor for the development of hepatotoxicity associated with highly active antiretroviral therapy (HAART). Overwhelming evidences clearly shows that the ARV drugs mediated hepatotoxicity has been attributed due to their mitochondrial interference. Although a low grade of hepatotoxicity resolves, high levels of toxicity leads to discontinuation of the therapy. Hence, careful observation is necessary especially during and after HAART to study the drug-induced liver diseases.

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Steatosis–lactic acidosis syndrome associated with stavudine and lamivudine therapy

Cited by 30 publications

References 6 publications

Prevalence, risk factors and outcome of hyperlactataemia in HIV‐infected patients*

Prevalence, risk factors and outcome of hyperlactataemia in HIV‐infected patients*

Hepatotoxicity Associated with Antiretroviral Therapy Containing Dual versus Single Protease Inhibitors in Individuals Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus

HAART and Hepatotoxicity

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