Lactic acidosis zidovudine

NRTls are structural analogues of the natural nucleotides that form the building blocks of RNA and DNA in human cells. Their use as part of HAART has dramatically modified the natural history of HIV infection. They, however, cause a range of drag- or tissue-specific toxicides zidovudine (AZT) causes myopathy zalcitabine (ddC), didanosine (ddl), and lamivudine (3TC) cause neuropathy stavudine (d4T) causes neuropathy or myopathy and lactic acidosis (Dalakas 2001). During phase 1 and 11 trials, the dose-limiting toxicity of didanosine, zalcitabine, and stavudine was identified as peripheral neuropathy (Dalakas 2001). 

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination, including zidovudine and other antiretrovirals (see Warnings). 

Caution [B (D if near term), M] Contra Sulfonamide or salicylate sensitivity, porphyria, GI/GU obst avoid in hepatic impair Disp Tabs SE GI upset discolors urine dizziness, HA, photosens, oligospermia, anemias, Stevens-Johnson synd Interactions T Effects OF oral anticoagulants, oral hypoglycemics, MTX, pheny-toin, zidovudine X effects W/ antibiotics X effects OF digoxin, folic acid, Fe, procaine, proparacaine, sulfonylureas, tetracaine EMS T Effects of anticoagulants monitor EGG and BP for signs of hypovolemia and electrolyte disturbances d/t D skin urine may become yellow-orange may stain contact lenses T risk of photosensitivity Rxns OD May cause NA, drowsiness, HA, abd pain, skin Rxns, lactic acidosis, and jaundice symptomatic and supportive... 

Chariot, P. et al. (1999) Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. Journal of Hepatology, 30 (1), 156-160. 

The adverse effects with which stavudine is most frequently associated are headache, diarrhea, skin rash, nausea, vomiting, insomnia, anorexia, myalgia, and weakness. Peripheral neuropathy consisting of numbness, tingling, or pain in the hands or feet is also common with higher doses of the drug. Significant elevation of hepatic enzymes may be seen in approximately 10 to 15% of patients. Lactic acidosis occurs more frequently with stavudine than with other NRTIs. Viral resistance to stavudine may develop, and cross-resistance to zidovudine and didanosine may occur. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

Antiretroviral nucleoside analogues have been associated with hepatic steatosis and lactic acidosis. These compounds require phosphorylation to active triphosphate derivatives by cellular phosphokinases. The triphosphate nucleotide inhibits the growing proviral DNA chain, but it also inhibits host DNA polymerases, and this can result in compensatory glycolysis and lactic acidosis. Abnormal mitochondrial oxidation of free fatty acids causes the accumulation of neutral fat in liver cells, and this manifests as hepatomegaly with macrovesicular steatosis. Hepatic steatosis and lactic acidosis have been reported previously with zidovudine, didanosine, zalcita-bine, Combivir (zidovudine plus lamivudine), and lamivudine. Of 349 Australian patients studied for 18 months (516 patient-years) taking NRTIs only two had severe lactic acidosis (847). 

Adverse reactions early in treatment may include anorexia, nausea, vomiting, headache, dizziness, malaise and myalgia, but tolerance develops to these and usually the dose need not be altered. More serious Eire anaemia and neutropenia which develop more commonly when the dose is high, and with advanced disease. A toxic myopathy (not easily distinguishable from HIV-associated myopathy) may develop with long-term use. Rarely, a syndrome of hepatic necrosis with lactic acidosis may occur with zidovudine (and with other reverse transcriptase inhibitors). 

Initially, most of the adverse effects seen with zidovudine use (in particular hematological effects) were attributed to interference with cellular DNA replication. However, DNA replication also occurs in mitochondria. Mitochondrial DNA encodes some of the enzymes used for oxidative phosphorylation. Only recently has it been hjrpothesized that inhibition of this pathway could lead to mitochondrial toxicity and be responsible for most of the toxicity seen with NRTIs, including polyneuropathy, myopathy, cardiomyopathy, steatosis, lactic acidosis, exocrine pancreas failure, bone marrow failure, and proximal tubular dysfunction (11). These adverse effects are also a compilation of the clinical features seen in several genetic mitochondrial cytopathies. 

A well-documented case has shown that zidovudine can cause type B lactic acidosis and acute respiratory and hepatic failure (33). 

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, and didanosine which has also been attributed to mitochondrial DNA toxicity [95-106]. There are five types of DNA polymerase in human cells that catalyze the synthesis of new complementary DNA from the original DNA template (HIV encodes a reverse transcriptase DNA polymerase which uses RNA as the template). The active triphosphate metabolites of zidovudine, didanosine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [91-93,101,105-108]. The link between NRTl effects on mitochondrial DNA and lactic acidosis is not entirely clear but is most likely related to disturbances of oxidative phosphorylation and impaired pyruvate metabolism leading to lactate accumulation. 

Sundar K, Suarez M, Banogon PE, Shapiro JM. ZIdovudIne-Induced fatal lactic acidosis and hepatic failure In patients with acquired Immunodeficiency syndrome report of two patients and review of the literature. Crit Care Med 1997 25 1425-1430. 

Coinfection with HIV is common in patients with HCV given the shared risk factors for transmission. Patients coinfected with these viruses have a more accelerated progression of their HCV disease. Most trials to date have excluded patients with HIV or limited them to patients with stable HTV infection. Combination therapy using ribavirin is considered to be superior however, enhancement of antiretroviral adverse events such as lactic acidosis limits therapy. Concurrent use of ribavirin therapy with didanosine, stavudine, or zidovudine is relatively contraindicated. ... 

The most common adverse effect with stavudine is peripheral neuropathy which occurs in -12% of patients. Combining stavudine with zidovudine leads to increased risk and severity of peripheral neuropathy and potentially fatal pancreatitis, and these drugs shorrld not be used together under most circumstances. Lactic acidosis and hepatic steatosis also have been seen and are more common with stavudine than with zidovudine or abacavir. Of aU the nucleoside analogs, stavudine is most strongly linked to the HIV lipodystrophy syndrome, perhaps due to toxic effects on adipocytes. 

Chabrol B, Mancini J, Chretien D, Rustin P, Munnich A, Pinsard N (1994) Valproate-induced hepatic failure in a case of cytochrome c oxidase deficiency. Eur J Pediatr 153 133-135 Chariot P, Drogou I, de Lacroix-Szmania I, Ehezer-Vanerot MC, Chazaud B, Lombes A, Schaeffer A, Zafrani ES (2000) Zidovudine-indueed mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol 32 364-365 Chen CH, Cheng YC (1989) Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeflcieney vims compound 2, 3 -dideoxycytidine. J Biol Chem 264 11934-11937... 

Interferon alfa does not alter the pharmacokinetics of didanosine or lamivudine to a clinically relevant extent. Interferon alfa and, particularly, interferon beta can cause an increase in the serum levels of zidovudine. HIV-positive patients infected with hepatitis C and treated with interferon alfa and ribavirin may be at special risk of NRTI-associated lactic acidosis. Interleukin-2 appears not to interact significantly with zidovudine. 

---