If this is not your name, click here.
| | If this is not your name, click here. | | |
| | Contact Us | Order Now | Journals | Bookstore | Register a colleague | | |
| |  Ziagen And Combivir Effective In HIV And Have Simple Dosing Schedules SAN FRANCISCO, CA -- February 3, 2000 -- Immune system and resistance data from a study comparing a triple nucleoside regimen of Ziagen(R) (abacavir sulfate) and Combivir(R) (lamivudine/zidovudine) to a regimen of indinavir sulfate (Merck) in combination with Combivir were presented at a major scientific meeting in San Francisco. These data build on previous efficacy and safety results (Study CNA3005) presented at the 1999 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Ziagen, in combination with other antiretroviral agents, is currently approved for use in adults and children to treat HIV-1 infection. This indication is based on analyses of surrogate markers in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV-RNA or disease progression with Ziagen in the product labeling.
The randomized, double-blind, 96 week, international trial enrolled 562 patients who had not previously received antiretroviral therapy (35 patients did not receive study drug). Using an 'intent-to-treat' analysis, at 48 weeks the study showed that 51 percent of patients in each arm -- 133 of 262 on the Ziagen arm, and 136 of 265 on the indinavir arm -- experienced a reduction in viral load to less than 400 copies (Roche Amplicor MONITOR(TM) assay). There was no significant difference in discontinuations due to adverse events: 17 percent (44/262) of patients treated with Ziagen and 21 percent (55/265) of patients treated with indinavir withdrew due to adverse events. There was also no significant difference in the overall rate of discontinuations: 40 percent (106/262) of patients treated with Ziagen and 43 percent (115/265) of patients treated with indinavir withdrew from the study. In this blinded study, patients on both treatment arms were asked to adhere to the stricter, three times-a-day indinavir dosing regimen, taking a mixture of medicine and placebo equal to the dosage of all medications in the study, a total of 16 pills per day. The indicated dose for Ziagen is one 300 mg tablet twice daily with no food restrictions or oral fluid requirements. Indinavir is dosed as two 400 mg capsules every eight hours, and must be taken on an empty stomach or with a low-fat snack, and has a hydration requirement of at least 48 ounces of water per day. (In this trial, indinavir was provided by Merck as four 200 mg capsules every eight hours.) "Ziagen and Combivir offer simple, two tablets, twice-daily dosing," said Lynn Smiley, M.D., vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome. "We are firmly committed to developing medications and evaluating regimens that simplify the effective, yet often complex, regimens that HIV patients take. In addition to the efficacy and safety data in this trial, we planned to investigate the impact of this regimen on some of the measures of immune restoration and resistance." At baseline, the median CD4 cell count was 359 and 360 cells/mm3 in the Ziagen and indinavir-containing arms, respectively. The median increase in CD4 cell count at 48 weeks for the Ziagen-containing arm was 149 cells/mm3 while patients receiving the indinavir regimen had a median increase of 142 cells/mm3. In addition to CD4 cell counts, changes were observed in the two treatment arms in some other markers of immune restoration including favorable changes in the T-cell receptor repertoire and specific molecular markers of new T-cells (T-cell Receptor Excision Circles or TRECs). In a subgroup analysis, median TREC levels on the Ziagen arm increased from 3.8 microliters blood at baseline (N=13) to 20.5 microliters at 36 to 52 weeks (N=6). Patients on the indinavir arm rose from 9.0 microliters (N=8) to 20.8 microliters (N=6) over the same time period. The immune system is complex and other factors are involved. Additional studies are needed. In one of the earlier, pivotal studies of Ziagen (CNA3003), at 16 weeks the median CD4 increases from baseline were 47 cells/mm3 in the group receiving Ziagen and 112 cells/mm3 in the control group. "Results of these analyses of two markers of immune system restoration involving triple nucleoside therapy with Ziagen plus Combivir provide important information regarding HIV therapy," said Phil Keiser, M.D., of University of Texas Southwest Medical Center, a principal investigator of the study comparing Ziagen and Combivir to the standard-of-care-regimen. A subanalysis of patients with two consecutive viral RNA measurements >400 copies/mL between week 16 and 48 found that the Ziagen arm selected for mutations in 18/24 subjects (12 M184V only, six M184V + other NRTI-associated mutation). The indinavir arm selected for mutations in 12/20 subjects (nine M184V only, two M184V + PI-associated mutation). Overall, these subjects maintained > 1log10 decrease in viral RNA from baseline regardless of emergent mutations. Virologic failure occurred in approximately 5 percent (14/262) of patients in the Ziagen and Combivir arm and 5 percent (12/265) of patients in the indinavir and Combivir arm. The clinical relevance of genotypic and phenotypic changes associated with Ziagen therapy has not been established. In clinical trials to date, the most commonly reported adverse events were headache, nausea, vomiting, malaise and diarrhea when Ziagen was taken, primarily with Epivir(R) (lamivudine) and Retrovir(R) (zidovudine) but also to a limited extent with all marketed and most investigational compounds. Lactic acidosis and severe hepatomegly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, zidovudine, lamivudine, stavudine, didanosine and zalcitabine. Zidovudine in Retrovir and Combivir has been associated with anemia and neutropenia, especially in patients with advanced disease, and with symptomatic myopathy after prolonged use. The most serious adverse event associated with Ziagen is a hypersensitivity reaction that can be life threatening and has been fatal in some cases. In the thousands of patients who have taken Ziagen in clinical trials, hypersensitivity reaction has been observed in approximately 5 percent of patients. It is characterized by fever, skin rash, fatigue and gastrointestinal symptoms, such as nausea, vomiting, diarrhea or abdominal pain. Respiratory symptoms such as dyspnea, pharyngitis or cough may also occur. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, flu-like illness) are possible. Therefore, patients should also watch for respiratory symptoms such as shortness of breath, sore throat or cough. Rechallenge is contraindicated after a diagnosis of hypersensitivity. Symptoms of this reaction usually occur within the first six weeks of treatment. The symptoms of this reaction get progressively worse during treatment, but generally resolve following permanent discontinuation of Ziagen. Patients experiencing these symptoms should stop taking Ziagen and contact a physician immediately. Patients experiencing this reaction must not take Ziagen again as restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening and fatal reactions. A medication guide for Ziagen is available to provide further information on optimizing care with this drug. Ziagen has a low likelihood of interactions with antiretroviral drugs that are metabolized by the cytochrome P450 enzyme system. This is a favorable factor for Ziagen when trying to prescribe the multi-drug regimens required to treat HIV. Related Links: Ziagen (abacavir sulfate), Combivir (lamivudine/zidovudine), Crixivan (indinavir sulfate), Epivir (lamivudine), Retrovir (zidovudine), Merck and Glaxo Wellcome.
|
