GlaxoSmithKline's Trizivir (abacavir sulfate, lamivudine, and zidovudine) has received traditional approval from the FDA for the treatment of HIV. Trizivir, approved for adults with HIV who weigh over 40 kg, is a fixed-dose combination regimen of 3 nucleoside reverse transcriptase inhibitors. Traditional approval requires extended clinical trials lasting at least 48 weeks. Accelerated approval, which requires data from clinical trials lasting only 24 weeks, was granted to Trizivir in 2000. GlaxoSmithKline promotes Trizivir's fixed-dose regimen to increase patient compliance through a simplified twice-a-day administration without regard to food or water.1
Abacavir, a carbocyclic synthetic nucleoside analogue, is converted to an active metabolite that inhibits HIV- 1 reverse transcriptase activity. Lamivudine and zidovudine are both synthetic nucleoside analogues that are converted intracellularly to active metabolites. These metabolites inhibit reverse transcriptase activity through DNA chain termination.2
A 48-week clinical trial involved the individual components of Trizivir. In a multicenter, double-blind, controlled study, 562 HIV-infected therapy-naïve adults were randomized into 2 groups: one group received abacavir 300 mg twice daily and Combivir (lamivudine 150 mg and zidovudine 300 mg) twice daily, while the other group received indinavir 800 mg 3 times a day plus Combivir twice daily. At the end of the study, both treatment groups displayed similar efficacy. These results suggest that treatment with the components of Trizivir is as effective as treatment with a protease inhibitor.3
Abacavir has been associated with severe and often fatal hypersensitivity reactions in about 3% to 5% of patients who use it. Trizivir should never be used in patients with a history of hypersensitivity to abacavir; upon reintroduction, more severe symptoms may develop within hours and possibly result in death.4 Symptoms of abacavir hypersensitivity include 2 or more of the following: fever; rash; gastrointestinal upset, such as nausea, vomiting, diarrhea, or abdominal pain; constitutional symptoms, such as generalized malaise, fatigue, or aches; and respiratory symptoms, such as dyspnea, cough, or pharyngitis.
Patients must be aware of the potential for hypersensitivity to abacavir and educated to identify a hypersensitivity reaction. GlaxoSmithKline provides patients with a summary of the symptoms of hypersensitivity on a Medication Guide and Warning Card. Patients should carry the Warning Card at all times.2
Hematologic toxicity, such as neutropenia and anemia, has been linked to zidovudine, especially in patients with advanced HIV.2
Antiretrovirals, including abacavir, lamivudine, and zidovudine, have been associated with severe hepatomegaly with steatosis and lactic acidosis, often with fatal results.2 Hepatic function should be monitored closely in HIV patients with concomitant infection with hepatitis B virus who have discontinued lamivudine, which is a component of Trizivir.2 Trizivir should not be used in patients with impaired hepatic function or creatinine clearance less than 50 mL/min.2
Trizivir should be used cautiously in patients with bone marrow suppression (granulocytes less than 1000 cells/m3 or hemoglobin less than 9.5 g/dL).2
Myopathy and myositis have been observed with zidovudine therapy and may result with Trizivir as well.2
The following drugs may alter one or more of the components of Trizivir: nelfinavir, trimethoprim/sulfamethoxazole, atovaquone, fluconazole, methadone, probenecid, ritonavir, valproic acid, and ethanol.2
The most commonly reported side effects include nausea; vomiting; malaise; fatigue; headache; diarrhea; fever; depressive disorders; rash; anxiety; ear, nose, and throat infections; and viral respiratory infections.2-4
Dr. Holmberg is a pharmacist with Phoenix Children's Hospital, Phoenix, Ariz.
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