Crixivan, under the provisions of the FDA's accelerated approval process, was approved as a treatment for HIV infection in adults when antiretroviral therapy is warranted. This indication is based on analyses of surrogate endpoints in studies of up to 24 weeks in duration.
Crixivan, a potent inhibitor of the HIV protease enzyme that is critical to replication of the virus that causes AIDS, can be taken in combination with other anti-HIV therapies or alone.
In clinical trials, treatment with Crixivan caused improvements in the surrogate markers for HIV disease--CD4 cell counts and viral load, the indicators of disease status in people with HIV. Crixivan was also generally well tolerated. It produced increases in CD4 cell counts, an important measure of immune system function, and significant reductions in viral load, or levels of HIV in the bloodstream. However, the clinical relevance of changes in viral load induced by Crixivan is not a cure for AIDS, and its effect on the development of opportunistic infections and survival has not yet been shown, although such studies are under way.
Crixivan has been studied in more than 2,000 people in 14 studies to date, including several ongoing studies. One recent multicenter trial studied Crixivan alone and in combination with two other antiviral drugs, zidovudine and lamivudine (Retrovir and Epivir) in subjects who had previously been treated with zidovudine. At 24 weeks in this "triple-therapy" trial, mean decreases observed in viral load were 98% in 22 subjects taking the triple combination of Crixivan with zidovudine and lamivudine. The clinical relevance of changes in viral load effected by Crixivan has not been established.
At 24 weeks, 20 of 22 subjects (91%) taking Crixivan with zidovudine and lamivudine had HIV levels in their blood below the limit of detection of the test used. In the same study, seven of 20 subjects (35%) taking Crixivan alone, and zero of 19 (none) of the subjects taking zidovudine and lamivudine had HIV levels below the limit of detection of the test used. Subjects receiving the triple combination and subjects taking Crixivan alone had mean increases at 24 weeks of 100 cells/mm3, compared to mean increases of 33 cells/mm3 in subjects taking zidovudine and lamivudine.
Crixivan has been generally well tolerated in clinical trials. Nephrolithiasis (defined as flank pain, blood in the urine or kidney stones) occurred in approximately 4% of subjects. People who take Crixivan are encouraged to drink at least 48 ounces of water every day to maintain hydration and help avoid nephrolithiasis. In phase II clinical studies, less than 6% of subjects taking Crixivan alone discontinued therapy due to drug-related adverse experiences. Among the most common side of moderate or severe intensity reported in greater than or equal to 2% of subjects on Crixivan alone in clinical trials are: nausea, abdominal pain, headache, diarrhea, vomiting, weakness/fatigue, insomnia, flank pain, taste changes, acid regurgitation, and back pain. Crixivan is contraindicated in subjects with clinically significant hypersensitivity to any of its components.
HIV destroys CD4 cells, which orchestrate the body's immune response--its natural defense against infection and disease. The number of CD4 cells in the blood, or CD4 cell counts, are an indicator of the health of the immune system. Viral load is a measure of the amount of HIV circulating in the bloodstream.
Although not specifically studied, the prescribing information for Crixivan contains a warning against taking terfenadine, astemizole, cisapride, triazolam, or midazolam with Crixivan because their use in combination may create the potential for serious and/or life threatening events (i.e. cardiac arrhythmias, prolonged sedation). In drug interaction studies, no clinically significant interactions were seen with Crixivan and zidovudine, d4T, lamivudine, fluconazole, clarithromycin, trimethoprim/sulfamethoxazole, isoniazid, Ortho-Novum 1/35, cimetidine, and quinidine.