Stavudine (Zerit) may offer clinicians a new alternative for treatment of adults with advanced HIV infection.
Approved for marketing in June 1994, this nucleoside analogue is indicated for the treatment of patients who are intolerant to approved therapies for HIV infection, as well as for those who have experienced significant clinical or immunologic deterioration while receiving these therapies, or who have contraindications to their use.
“Clinical trial experience with stavudine indicates that it is an effective antiretroviral drug. It also appears to have some characteristics that may distinguish it from zidovudine, didanosine, and zalcitabine, although clearly more study is needed in an expanded patient population before any conclusive statements about relative safety and efficacy can be made,” commented Richard Pollard, MD, professor of internal medicine and microbiology, University of Texas Medical Branch at Galveston.
More than 800 patients are enrolled in an ongoing, phase III, multicenter, randomized, double-blind trial comparing stavudine and continued zidovudine in HIV-infected adults. These patients were able to tolerate zidovudine for at least 24 weeks prior to this treatment study. They also were required to have CD4 cell counts between 50 and 500 cells/mm3.
An interim analysis using the surrogate endpoint CD4 cell count was performed on data from 359 patients who had taken study medication for 12 weeks. The mean CD4 cell count among patients in the stavudine group increased 22 CD4 cells/mm3, while a decrease of 22 CD4 cells/mm3 was observed in the patients taking zidovudine. This blinded study is continuing, and complete evaluation of the data, including analysis of the incidences of opportunistic infections and death, is planned for December 1994.
“These results are very encouraging. While we have no head-to-head comparisons between stavudine and the other alternatives to zidovudine, the CD4 cell responses in stavudine-treated patients seem to be maintained for longer than those that have occurred when these other agents were introduced for treatment of advanced HIV infection, particularly in the early studies with didanosine,” noted Dr. Pollard.
Early experience with stavudine also suggests that the development of HIV-resistance may be less of a problem with this new agent compared with other antiretroviral drugs. “We must be very careful about drawing any conclusions at this point because stavudine hasn’t been used as long as zidovudine and the other agents. While resistance will no doubt increase as stavudine is used more widely, preliminary clinical findings and in vitro studies suggest that resistance may take longer to develop with stavudine use and may be of a lower level compared with the other antiretroviral drugs,” noted Dr. Pollard.
Prior to marketing, stavudine was used in a large number of HIV-infected patients as part of the Stavudine Parallel Track Program. During 20 months beginning October 1992, this study enrolled over 13,000 patients with CD4 cell counts below 300/mm3 who had not responded, were intolerant of, or had contraindications to therapy with zidovudine and didanosine. Patients were divided into three categories according to their weight and then randomized within each weight category to receive one of two different dosage regimens. Stavudine was provided to patients free of charge.
“The question often arises: ‘Why another nucleoside analogue?’ Looking at the high enrollment in the parallel track experience suggests that there are a lot of patients who need another therapeutic alternative and that there is definitely a role for an additional drug of this kind,” said Dr. Pollard.
Other studies evaluating the use of stavudine in patients with earlier HIV infection are expected to be underway soon. Two such studies will investigate stavudine in patients with CD4 cell counts of 300 to 600 cells/mm3 who have either no experience with antiretroviral treatment or have taken zidovudine for only a short duration. These studies will explore combinations of zidovudine and stavudine at currently recommended dosages.
Another study has been started to evaluate combined treatment with stavudine and didanosine.
The major clinical toxicity of stavudine has been peripheral neuropathy. In this respect it is similar to didanosine and zalcitabine. However, stavudine has not been associated with the hematologic toxicity that occurs with zidovudine, noted Dr. Pollard.
Self-limiting Side Effects
Peripheral neuropathy, characterized by numbness, tingling, or pain in the feet or hands, has occurred in 15 to 21% of patients who received stavudine in clinical trials. This side effect has generally been self-limiting if the treatment is withdrawn promptly. Therefore, patients should be cautioned to look for its potential signs. Stavudine can be reinitiated at a reduced dose of 20 mg bid if the symptoms resolve completely.
Due to its long intracellular half-life, stavudine is given only twice daily. Dr. Pollard pointed out that the stavudine dosage regimen makes it easier for patients to take than other drugs, which require either ingestion of more units per dose or more frequent administration.
Dr. Pollard is an investigator for clinical trials of stavudine funded by its manufacturer Bristol-Myers Squibb.
