Adverse Effects of Antiretroviral Drugs

Adverse Effects of Antiretroviral Drugs

Author: Ian R. McNicholl, PharmD, University of California, San Francisco

Source: AETC National Resource Center and UCSF Center for HIV Information
Date: October 19, 2012

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. 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	Abnormal dreams, drowsiness, dizziness, confusion Mood changes Elevations in liver function tests Hyperlipidemia	Central nervous system symptoms are common; severity usually decreases within 2-4 weeks. Teratogenic in animal studies; contraindicated during the first trimester of 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 (immediate-release formulation) or 400 mg once daily (extended-release formulation), 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.
Rilpivirine	Insomnia Depression Elevations in liver function tests Elevations in serum creatinine	May be less potent if baseline HIV RNA >100,000 copies/mL Requires acidic gastric environment for adequate absorption: Must be taken with food. Contraindicated with proton pump inhibitors. Other antacid medications and H2 blockers require specific timing if used by persons taking rilpivirine.

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
Elvitegravir/cobicistat	Insomnia, abnormal dreams Rash	Do not initiate combination of elvitegravir/cobicistat/tenofovir/emtricitabine if ClCr <70 ml/min. Discontinue if ClCr decreases to <50 mL/min. Discontinuation should be considered if the serum Cr increases 0.4 mg/dL or more.

Pharmacokinetic Enhancers

Drug	Adverse Events	Comments
Cobicistat	Increased serum creatinine, proteinuria Nausea, diarrhea Headache	Do not initiate combination of elvitegravir/cobicistat/tenofovir/emtricitabine if ClCr <70 ml/min. Discontinue if ClCr decreases to <50 mL/min. Discontinuation should be considered if the serum Cr increases 0.4 mg/dL or more. Cobicistat can inhibit renal tubular secretion of creatinine; clinicians will need to differentiate cobicistat effects and tenofovir-induced nephrotoxicity. Multiple drug interactions; consult a reliable drug interaction resource.