AIDS drugs and adverse events (side effects)

Adverse Events of Antiretroviral Drugs
Author: Ian R. McNicholl, PharmD, University of California San Francisco

August 2004; Updated July 2006

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 HIV InSite Database of Antiretroviral Drug Interactions.

Tables

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Agent	Adverse Events	Comments
NRTIs are associated with lactic acidosis, hepatic steatosis, and body fat redistribution (lipodystrophy).
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. Counsel patient 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 in pregnant women. Adjust dosage for renal insufficiency or failure.
Emtricitabine	Headache, nausea, insomnia Hyperpigmentation of palms and soles (occurs most frequently in dark-skinned patients)	Active against hepatitis B virus (not approved by 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 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 in pregnant women. Consider dose adjustment for peripheral neuropathy. Adjust dosage for renal insufficiency or failure.
Tenofovir	Flatulence, nausea, diarrhea, abdominal discomfort Asthenia Acute renal insufficiency, Fanconi syndrome	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. GI symptoms may be worse in lactose intolerant patients (tenofovir 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)

Agent	Adverse Events	Comments
All NNRTIs may have significant interactions with other drugs; dosage adjustment of interacting agents may be required.
Delavirdine	Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis 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	Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis 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 in pregnancy or in women at risk of pregnancy.
Nevirapine	Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis 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 in women with CD4 >250 cells/µL or men with CD4 >400 cells/µL, unless the benefit clearly outweighs the risk. Monitor liver tests closely for the first 16 weeks of treatment.

Protease Inhibitors (PIs)

Agent	Adverse Events	Comments
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.
Amprenavir	Diarrhea, nausea, vomiting Elevations in liver function tests Rash	May cause rash in patients sensitive to or intolerant of sulfonamides. Capsule formulation no longer available in adult dosage; consider fosamprenavir. The oral solution should not be combined with metronidazole or disulfiram; it contains propylene glycol and may cause disulfiram-like reaction. The dosage of the capsule and oral solution formulations is not interchangeable.
Atazanavir	Hyperbilirubinemia, jaundice Elevations in liver function tests PR interval prolongation	Proton pump inhibitors interfere with atazanavir absorption and are contraindicated in patients receiving atazanavir. Other antacid medications and H2 blockers, also interfere with absorption of atazanavir and should be used with caution in patients receiving atazanavir. Indirect hyperbilirubinemia; does not require discontinuation of atazanavir. May have less effect on lipid levels than do the other PIs.
Darunavir	Nausea Diarrhea Headache Rash	May cause rash in patients sensitive to or intolerant of sulfonamides. May also cause hyperamylasemia and hypernatremia. Must be coadministered with ritonavir.
Fosamprenavir	Diarrhea, nausea, vomiting Elevations in liver function tests Rash	Prodrug of amprenavir. (See amprenavir adverse effects above.)
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 or 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 disulfuram-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. Hard-gel capsule and tablet formulations should be used in combination with low-dose ritonavir.
Tipranavir	Nausea, vomiting, diarrhea Elevations in liver function tests Increased total cholesterol and triglycerides Rash	Must coadministered with ritonavir; should never be used without ritonavir boosting. Should be taken with food. May cuse rash in patients sensitive to or intolerant of sulfonamides. Many drug-drug interactions. Certain drug combinations should be avoided. Consult up-to-date information before prescribing.

Fusion Inhibitors

Agent	Adverse Events	Comments
Enfuvirtide, T-20	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 side effects.

Abbreviations:

FDA = U.S. Food and Drug Administration

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