Antiviral drugs are used for a variety of infections, including herpesvirus, hepatitis B (HBV), hepatitis C (HCV), and influenza. Antiviral drugs that target human immunodeficiency virus (HIV) are referred to as antiretrovirals. A wide variety of antiviral and antiretroviral agents from different mechanistic classes are now available (Table II-12). These agents are often given in combination to treat HCV and HIV infections. Combined formulations decrease the number of pills taken per day and increase adherence to treatment regimens.

The mechanism underlying toxic effects varies with the agent and is usually an extension of its pharmacologic effect.

1. Neurotoxicity may be the result of inhibition of mitochondrial DNA polymerase and altered mitochondrial cell function.
2. Hepatic steatosis, severe lactic acidosis, and lipodystrophy may be due to inhibition of mitochondrial DNA polymerase-gamma, depletion of mitochondrial proteins, and disruption of the electron transport chain. Mitochondrial dysfunction leads to impaired fatty acid utilization, lactate production, and acidemia.
3. Acyclovir crystal deposition in the tubular lumen leading to an obstructive nephropathy may cause acute renal failure. Indinavir is poorly water soluble and can precipitate in the kidney, causing kidney stones and interstitial nephritis.
4. Chronic use of many of these agents can cause serious toxicity including bone marrow depression, diabetes mellitus, hepatotoxicity, lactic acidosis, lipodystrophy, lipoatrophy, myopathies, rhabdomyolysis, pancreatitis, peripheral neuropathy, renal failure, and seizures.
5. Antiviral/retroviral drugs that are metabolized mainly via the hepatic cytochrome P450 isoenzyme system may be associated with clinically significant interactions with other drugs and dietary supplements (eg, St. John wort, garlic).

Acute single ingestions are infrequent, and toxicity has been generally mild. Chronic toxicity, however, commonly occurs.

Gastrointestinal symptoms are common after therapeutic doses and are more remarkable after an acute overdose. Specific features of toxicity are described in Table II-12.

1. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs) can cause mitochondrial toxicity leading to myopathy, lipoatrophy, neuropathy, and lactic acidosis (with or without hepatic steatosis). Lactic acidosis, often severe, most commonly occurs with the use of zidovudine, lamivudine, stavudine, and didanosine.
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have fewer adverse effects compared with NNRTIs and NtRTIs. All NNRTIs are known to cause rashes, the most severe of which include Stevens-Johnson syndrome and toxic epidermal necrolysis.
3. Protease inhibitors can cause diarrhea, nausea, vomiting, and metabolic complications including insulin resistance, hyperlipidemia, and lipodystrophy with abnormal central fat accumulation and localized loss of fat tissue.

Is usually based on the history of exposure.

1. Specific levels. Serum levels are not commonly available for these agents and have not been particularly useful for predicting toxic effects.
2. Other useful laboratory studies include CBC, electrolytes, glucose, BUN, creatinine, liver function tests, creatine kinase, urinalysis, and ECG monitoring. Plasma lactate levels and venous or arterial blood gases are recommended if lactic acidosis is suspected.
3. Genetic polymorphisms. Individuals who have the HLA-B*5701 genotype are at risk for developing Stevens-Johnson syndrome and toxic epidermal necrolysis with abacavir. The prevalence rate of this mutation is highest among Caucasians and Africans, and is rare among Asians. Testing is available through reference laboratories.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat coma, seizures, hypotension, torsade de pointes, rhabdomyolysis, and anaphylaxis if they occur.
   3. Replace fluid losses resulting from gastroenteritis with IV crystalloids.
   4. Maintain steady urine flow with IV fluids to alleviate crystalluria and reverse renal dysfunction.
   5. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug.
2. Specific drugs and antidotes. There are no specific antidotes for these agents. Anecdotal reports suggest that vitamin deficiency may be a contributor to the development of NRTI-associated lactic acidosis. Riboflavin (50 mg/d) and/or thiamine (100 mg twice a day) may be beneficial if levels are low.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination. The few reported overdoses with these agents have been benign or associated with mild toxicities. Hemodialysis may remove 60% of the total body burden of acyclovir, 50% of ganciclovir, and approximately 30% of emtricitabine over 3-4 hours. Enhanced elimination, however, has yet to be evaluated or employed after acute overdoses.