Adverse Effects of Antiretroviral Drugs

Introduction

The following tables summarize the most common and most serious adverse events associated with antiretroviral medications used to treat HIV infection. For drug-drug interactions, see the Database of Antiretroviral Drug Interactions .

Tables

Nucleoside Reverse Transcriptase Inhibitors

• NRTIs are associated with lactic acidosis, hepatic steatosis, and body fat redistribution (lipodystrophy).

Drug Adverse Events Comments Abacavir Hypersensitivity syndrome (fever, myalgia, malaise, nausea, vomiting, symptoms suggestive of upper respiratory tract infection, anorexia); symptoms progressively worsen with each subsequent dose; rash occurs in about half of cases Rash Headache, nausea, vomiting, diarrhea Hypersensitivity reaction usually occurs in the first 6 weeks of treatment. Hypersensitivity reaction may be more severe with once-daily abacavir dosing. Risk of hypersensitivity related to certain genetic factors, particularly HLA B * 5701; consider screening for this before prescribing abacavir. Counsel patients on signs of hypersensitivity syndrome. In case of hypersensitivity syndrome, abacavir must be discontinued permanently. Didanosine Pancreatitis Peripheral neuropathy Nausea, diarrhea Concomitant alcohol use may increase risk of pancreatitis. Lower frequency of diarrhea with enteric-coated capsules. Increased risk of lactic acidosis and hepatic steatosis when combined with stavudine; this combination should be avoided when possible, especially during pregnancy. Increased risk of peripheral neuropathy when combined with stavudine. Adjust dosage for renal insufficiency or failure. Emtricitabine Headache, nausea, insomnia Hyperpigmentation of palms and soles (occurs most frequently in dark-skinned people) Active against hepatitis B virus (not approved by the U.S. Food and Drug Administration [FDA] for treatment of hepatitis B). In patients with HIV and hepatitis B coinfection, hepatitis may flare upon discontinuation of emtricitabine. Adjust dosage for renal insufficiency or failure. Lamivudine Headache, dry mouth Adverse effects occur infrequently. Active against hepatitis B virus. In patients with HIV and hepatitis B coinfection, hepatitis may flare upon discontinuation of lamivudine. Adjust dosage for renal insufficiency or failure. Stavudine Peripheral neuropathy Pancreatitis Dyslipidemia Diarrhea Of the NRTIs, stavudine appears to convey the greatest risk of lipodystrophy and other mitochondrial toxicity. Increased risk of lactic acidosis and hepatic steatosis when combined with didanosine; this combination should be avoided when possible, especially during pregnancy. Increased risk of peripheral neuropathy when combined with didanosine. Consider dosage adjustment for peripheral neuropathy. Adjust dosage for renal insufficiency or failure. Tenofovir Flatulence, nausea, diarrhea, abdominal discomfort Asthenia Acute renal insufficiency, Fanconi syndrome Chronic renal insufficiency Active against hepatitis B but not FDA approved for treatment of hepatitis B. In patients with HIV and hepatitis B coinfection, hepatitis may flare upon discontinuation of tenofovir. Gastrointestinal symptoms may be worse in lactose-intolerant patients; tenofovir is formulated with lactose. Case reports of renal insufficiency; association between tenofovir and renal insufficiency is not clear. Adjust dosage for renal insufficiency or failure. Zidovudine Anemia, neutropenia Fatigue, malaise, headache Nausea, vomiting Myalgia, myopathy Hyperpigmentation of skin and nails Twice-daily dosing preferred over thrice-daily dosing. Fatigue, nausea, headache, and myalgia usually resolve 2-4 weeks after initiation. Adjust dosage for renal insufficiency or failure.

Nonnucleoside Reverse Transcriptase Inhibitors

• NNRTIs are associated with rash, and may cause Stevens-Johnson syndrome and toxic epidermal necrolysis.
• All NNRTIs may have significant interactions with other drugs; dosage adjustment of interacting agents may be required.

Drug Adverse Events Comments Delavirdine Fatigue Elevations in liver function tests, hepatitis Nausea, diarrhea 100 mg tablets can be dissolved in water. Seldom used; less potent than other NNRTIs. Efavirenz Elevations in liver function tests Abnormal dreams, drowsiness, dizziness, confusion Hyperlipidemia Central nervous system symptoms are common; severity usually decreases within 2-4 weeks. Teratogenic in animal studies; contraindicated during pregnancy and for use by women who may become pregnant. Etravirine Elevations in liver function tests Tablets may be dissolved in water. Has significant interactions with many other drugs (may differ from those of first generation NNRTIs); screen carefully for drug interactions before prescribing. Does not interact with methadone. Nevirapine Elevations in liver function tests, hepatitis, liver failure Initial dose of 200 mg per day for first 14 days, then 200 mg twice daily, decreases frequency of rash. Most rash develops within first 6 weeks of therapy; rash is most common in women. Hepatotoxicity may be life threatening. It is more common at higher CD4 cell counts, in women, and in patients with hepatitis B or C. Nevirapine should not be initiated for women with CD4 counts of >250 cells/µL or men with CD4 counts of >400 cells/µL, unless the benefit clearly outweighs the risk. Monitor liver tests closely for the first 16 weeks of treatment.

Protease Inhibitors

• All PIs are associated with metabolic abnormalities including dyslipidemia, hyperglycemia, insulin resistance, and lipodystrophy. (Atazanavir is less likely to cause dyslipidemia.)
• PIs may increase the risk of bleeding in hemophiliacs.
• PIs may have significant interactions with other drugs; dosage adjustment of interacting agents may be required.

Drug Adverse Events Comments Atazanavir Hyperbilirubinemia, jaundice Elevations in liver function tests PR interval prolongation Proton pump inhibitors interfere with atazanavir absorption and are contraindicated for use by patients receiving atazanavir. Other antacid medications and H2 blockers also interfere with absorption of atazanavir and should be used with caution by patients receiving atazanavir. Indirect hyperbilirubinemia; does not require discontinuation of atazanavir. May have less effect than other PIs on lipid levels. Darunavir Rash Elevations in liver function tests Increases pravastatin (and other statin) levels; no significant interaction with atorvastatin. Fosamprenavir Diarrhea, nausea, vomiting Elevations in liver function tests Rash Hyperlipidemia Prodrug of amprenavir. May cause rash in patients sensitive to or intolerant of sulfonamides. Indinavir Nephrolithiasis, flank pain Hyperbilirubinemia Elevations in liver function tests Alopecia, dry skin, ingrown nails Insomnia Taste perversion To reduce risk of nephrolithiasis, patients should drink at least 1.5 liters of fluid daily. When used as sole PI, should be taken on an empty stomach, 1 hour before or 2 hours after a meal, and should be taken every 8 hours (not 3 times per day). Lopinavir/ ritonavir Diarrhea, nausea, vomiting Dyslipidemia Elevations in liver function tests Taste perversion Available in tablets or oral solution. Tablets do not require refrigeration. Oral solution contains 42% alcohol. Avoid combining oral solution with metronidazole or disulfiram. Alcohol in the oral solution may cause disulfiram-like reaction. Nelfinavir Diarrhea Nausea, vomiting Elevations in liver function tests Fatigue Diarrhea is very common. It usually can be managed with antidiarrheals such as loperamide and diphenoxylate/atropine. Ritonavir Nausea, vomiting, diarrhea, abdominal pain Elevations in liver function tests Fatigue Circumoral or peripheral numbness Taste perversion Hyperuricemia Capsules are stable at room temperature for up to 30 days. Avoid combining oral solution with metronidazole or disulfiram. Alcohol in the oral solution may cause disulfiram-like reaction. Has significant interactions with many other medications. Saquinavir Nausea, vomiting, diarrhea Elevations in liver function tests Headache Oral ulcerations Available in hard-gel capsules and tablets Must be used in combination with low-dose ritonavir. Tipranavir Nausea, vomiting, diarrhea Elevations in liver function tests Increased total cholesterol and triglycerides Rash Intracranial hemorrhage Must be coadministered with ritonavir; should never be used without ritonavir boosting. Should be taken with food. May cause rash in patients sensitive to or intolerant of sulfonamides. Case reports of intracranial hemorrhage; association between tipranavir and intracranial hemorrhage is not clear. Many drug-drug interactions. Certain drug combinations should be avoided. Consult current information before prescribing.

Fusion Inhibitors

Drug Adverse Events Comments Enfuvirtide Injection site reactions; erythema, cysts, and nodules at injection sites Neutropenia Possible increased frequency of pneumonia Requires extensive patient counseling on injection technique, adherence, and management of possible side effects.

Chemokine Coreceptor Antagonists

Drug Adverse Events Comments Maraviroc Diarrhea, nausea Elevations in liver function tests, hepatitis Upper respiratory tract infections, cough Fatigue, dizziness, headache Joint pain, muscle pain Many drug-drug interactions; dose adjustment needed with many other antiretrovirals and/or other medications. Consult current information before prescribing.

Integrase Inhibitors

Drug Adverse Events Comments Raltegravir Nausea, diarrhea, flatulence Elevations in amylase and liver function tests Headache Dizziness, abnormal dreams Pruritus, rash Fatigue, muscle pain