Lactic acidosis-hepatic steatosis

Zalcitabine (ddC) Hivid (anticipated discontinuation of distribution in 2006) 0.375-, 0.75-mg tab 0.75 mg tid CrCI Dose (mL/minute) 10-40 0.75 mg bid less than 10 0.75 mg qday No data on hemodialysis None Peripheral neuropathy stomatitis, lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs) pancreatitis Renal excretion... 

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogs alone or in combination, including zalcitabine. In addition, rare cases of hepatic failure and death, considered possibly related to underlying hepatitis B and zalcitabine have been reported (see Warnings). 

As a class effect NRTIs are associated with lactic acidosis and hepatic steatosis, conditions which may occur more frequently in pregnant women. The individual NRTIs have their own adverse reactions. Pancreatitis is seen with lamivudine, stavudine, di-danosine and rarely with zalcitabine while the latter three agents can also induce peripheral neuropathy. 

A. The NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe hepatomegaly with hepatic steatosis. Risk factors associated with the development of this syndrome include female sex, obesity, alcoholism, and prolonged exposure to NRTIs. Peripheral neuropathy is a common side effect of some NRTIs (e.g., stavudine., didanosine, and zalcitabine) but not associated with these risk factors. Stevens-Johnson syndrome is rarely associated with NNRTIs, such as nevirapine, and not with these risk factors. Hyperuricemia is not associated with these risk factors. Hypersensitivity reaction may oc-... 

Adverse gastrointestinal symptoms (nausea, vomiting, anorexia, metallic taste, abdominal discomfort, and diarrhea) occur in up to 20% of individuals taking metformin this can be minimized by starting at a low dose and slowly titrating the dose upward with food. Like phenformin, metformin can cause lactic acidosis, but its occurrence is rare except when renal failure, hypoxemia, or severe congestive heart failure is present or when coadministered with alcohol. Metformin is also contraindicated in persons with hepatic dysfunction, but it appears to be safe for use in the hepatic steatosis that often occurs with fatty infiltration of the liver in poorly controlled type II diabetics. 

Lactic acidosis and hepatomegaly with steatosis. Severe acute exacerbations of hepatitis B have occurred in patients co-infected with HBV and HIV. 

All NRTI agents, as well as tenofovir, carry the risk of lactic acidosis with hepatic steatosis as a potential adverse event. 

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,... 

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). 

Adverse effects in clinical trials were mild, including fatigue, headache, abdominal pain, upper respiratory infection, increased creatine phosphokinase levels, and nausea and vomiting. A potential association with peripheral neuropathy is under evaluation. As with other nucleoside analogs, lactic acidosis and severe hepatomegaly with steatosis may occur during therapy as well as flares of hepatitis after discontinuation. 

In combination with other antiretroviral agents, stavudine has caused fatal lactic acidosis in some patients. It is also associated with motor weakness in which case it should be discontinued. Peripheral neuropathy is the most common toxicity associated with stavudine, which is more prevalent at high doses (4mg/kg per day). Neuropathy in these patients generally is associated with numbness, tingling or pain in feet or hands. Patients treated with the combination of stavudine and didanosine may also exhibit liver function abnormalities (hepatic steatosis) and pancreatitis. It may also be associated with the etiology of HIV lipodystrophy syndrome. 

Nucleoside analogue reverse transcriptase inhibitors can rarely cause lactic acidosis with hepatic steatosis and might potentiate the effect of metformin. 

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). 

DidanosineV idex EC (ddl) 125, 200, 250, orTOOmg enteric-coated capsules Body weight >60kg 400mg once daily <60kg 250mg once dahy Periphei al neuropatliy, pancreatitis, lactic acidosis witli hepatic steatosis 0.11... 

StavudmeSei it (d4T) 15, 20, 30, or 40mg capsules >60kg 40mg b.i.d. <60kg 30mg b.i.d. Peripheral neuropatliy, panaeatitis, lactic acidosis witli hepatic steatosis, neui omusculai weakness (rare) 0.58... 

Zalcitabme/Hivid (ddC) 0.375 or 0.75 mg tablets 0.75mg t.i.d. Periphei al neuropatliy, lactic acidosis witli hepatic steatosis 0.08... 

Acosta BS, Grimsley EW. Zidovndine-associated type B lactic acidosis and hepatic steatosis in an HIV-infected patient. Sonth Med J 1999 92(4) 421-3. 

The lactic acidosis seen with these drugs has ranged from mild and chronic to acute, severe, and fatal [95-106]. The acidosis generally develops after several months of therapy. Patients with NRTl-associated lactic acidosis present with symptoms of nausea, vomiting and abdominal pain. Other features often include elevated liver enzymes, hepatic steatosis, pancreatitis and elevated creatinine kinase with evidence of a myopathy, and liver failure. The lactic acidosis may persist for many weeks despite discontinuation of the NRTl [95-106]. NRTl-related mitochondrial toxicity may also present with rhabdomyolysis and acute kidney failure [110]. Mortality related to NRTl-induced acute lactic acidosis is high, in the range of 50% to 100%, despite drug discontinuation. 

Bleeker-RoversCP, Kadir SW, vanLeusen R, Richter C. Hepatic steatosis and lactic acidosis caused by stavudine In an HIV-Infected patient. Neth J Med 2000 57 190-193. 

Miiier KD, Cameron M, Wood LV, Daiakas MC, Kovacs JA. Lactic acidosis and hepatic steatosis associated with use of stavudine report of four cases. Ann intern Med 2000 133 192-196. 

As with other dideoxynucleosides and zidovndine, serious hepatic toxicity—with or without steatosis, hepatomegaly, and lactic acidosis—occurs very rarely but can be fatal. Risk factors for the lactic acidosis-steatosis syndrome include female sex, obesity, and prolonged exposure to the drag. 

No clinically important drug interactions are recognized, although drugs that reduce renal function or corrqretefor active tubular secretion could decrease adefovir clearance. An increased risk of lactic acidosis and hepatic steatosis may exist when adefovir is combined with antiretroviral agents. 

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... 

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