Two studies compare triple nucleoside therapy Ziagen® + Combivir® with protease inhibitorplus Combivir® regimens in therapy-naive patients

July 12, 2000

Preliminary data on triple nucleoside regimen compared to PI-containing regimen presented in Durban, South Africa.

Patients reported on their adherence to the regimens.

Durban, South Africa -- July 12, 2000 -- Two studies comparing the triple nucleoside regimen of Ziagen® (abacavir sulfate) plus Combivir® (lamivudine/zidovudine) with triple-drug regimens containing protease inhibitors (PI) as first-line antiretroviral therapy (ART) were presented here today at the 13th International AIDS Conference in Durban, South Africa.

Preliminary 24-week data from two open-label randomized trials assess Ziagen/Combivir as first line ART. Further, one study evaluated adherence to Ziagen/Combivir compared to the PI-containing regimen.

The Ziagen/Combivir regimen consisted of taking one Ziagen tablet and one Combivir tablet twice a day without dietary restriction. Patients on the nucleoside plus PI regimen took two indinavir tablets every eight hours and one Combivir tablet twice a day in one study and three nelfinavir tablets every eight hours and one Combivir tablet twice a day in the second study. The patients taking indinavir were required to take the tablets 1 hour before or 2 hours after a meal and drink one-and-a-half quarts of water a day.

"We are pleased to have these additional, preliminary data that compare the Ziagen plus Combivir regimen of just two tablets twice a day to a protease-containing regimen," said Lynn Smiley, M.D., vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome.

Ziagen/Combivir vs Indinavir/Combivir

In this open-label multi-center study (CNAB3014) of 342 antiretroviral therapy-naive patients, patients were randomized to receive Ziagen/Combivir or indinavir/Combivir for 48 weeks. Patients were stratified according to baseline plasma viral load (VL), with 63 percent having a VL greater than 5,000 copies/ml but less than 100,000 copies/ml, and 37 percent having a VL greater than 100,000 copies/ml. The median baseline VL of patients on the Ziagen/Combivir regimen was 59,402 copies/ml and the median CD4+cell count was 323 cells/ml. Patients on indinavir/Combivir had a median baseline VL of 66,386 copies/ml and a CD4+ cell count of 300 cells/ml. Viral loads were measured using <400 and <50 copies> At 24-weeks, in an intent to treat analysis, 68 percent (112/164) of patients on Ziagen/Combivir had VL <400 copies>Adherence was self-reported by patients, using the Treatment Assessment and Satisfaction Questionnaire (TraSQ), which is a validated measure of adherence. Preliminary analysis of the data indicated that 74 percent (108/145) of subjects on Ziagen/Combivir and 45 percent (66/146) on indinavir/Combivir reported taking all antiretroviral doses over the previous four weeks or missed less than one dose per week.

Thirty-eight percent (55/145) of patients on indinavir/Combivir indicated that their triple regimen was difficult to take as scheduled compared to 6 percent (9/146) on Ziagen/Combivir.

"These early data offer important information about this triple nucleoside regimen," said Pedro Cahn, M.D., director, Fundacion Huesped, Buenos Aires and principal investigator of the study.

Adverse events were experienced by a total of 127 patients on Ziagen/Combivir, 98 of which were considered drug-related. The most common included nausea (45 percent), vomiting (22 percent), headache (16 percent), dizziness (10 percent), fatigue (10 percent) and abdominal pain (8 percent). A total of 133 patients had adverse events (123 drug-related) in the indinavir/Combivir group. The most common included nausea (58 percent), vomiting (41 percent), headache (11 percent), dizziness (10 percent) and abdominal pain (8 percent).

Ziagen/Combivir vs Nelfinavir/Combivir

In a second study (CNAF3007) conducted by French researchers at 61 sites, 195 ART-naive adults were randomized to receive Ziagen/Combivir or nelfinavir/Combivir for 48 weeks.

"Our preliminary 24 week data provide further information concerning the use of the triple nucleoside regimen of Ziagen plus Combivir," said Sophie Matheron, M.D., Hopital Bichat, Paris.

The median baseline VL was comparable in both treatment groups (4.2log10 copies/ml in the Ziagen/Combivir group and 4.2 log10 copies/ml in the nelfinavir/Combivir group). Median CD4+cell counts at baseline were 387 cells/ml for the Ziagen/Combivir group and 449 cells/ml for the nelfinavir/Combivir group.

In an intent to treat analysis that included all randomized patients and where any changes to randomized medications was considered a failure, 67 percent (66/98) of patients in the Ziagen/Combivir group had VL below 50 copies/ml and 72 percent (71/98) had VL below 400/copies/ml, compared to 66 percent (64/97) below 50copies/ml, and 71 percent (69/97) below 400 copies/ml in the nelfinavir/Combivir group. In an as treated analysis, where only patients with data on randomized medication are included, the percentage of patients with a VL below 50 copies/ml was 90 percent (63/70) and 86 percent (62/72) for the nelfinavir/Combivir and Ziagen/Combivir groups respectively. The median change from baseline VL was -2.4log10 in both groups (ITT switch included). The median CD4+ cell count increase was 91 cells/mm3 in the Ziagen/Combivir group and 65 cells/mm3 in patients on nelfinavir/Combivir (ITT switch included).

Fourteen patients (7 percent) experienced serious adverse events (SAEs); 10 patients on Ziagen/Combivir (10 percent), including 4 cases of hypersensitivity to abacavir, and 4 on nelfinavir/Combivir. SAEs of those on Ziagen/Combivir were 1 neutropenia; 1 anemia; 1 post traumatic pleural effusion; 1 retinal detachment; 1 alcoholic pancreatitis; 1 acute confusional psychosis. SAEs for patients on nelfinavir/Combivir included: 1 person with depression, diarrhea, hepatic cytolysis, viral respiratory infection; 1 person with hepatic cytolysis; 1 person with viral respiratory infection; 1 person with erythematous skin condition.

In the registration clinical trial in therapy-naive adults, the most commonly reported adverse events observed when Ziagen was taken in combination with Epivir® (lamivudine) and Retrovir® (zidovudine) were nausea (47 percent), nausea and vomiting (16 percent), diarrhea (12 percent), loss of appetite/anorexia (11 percent) and insomnia and other sleep disorders (7 percent). Only 2 percent of the occurrences of these adverse events were severe (grade 3 and 4) and these were in patients experiencing nausea, and nausea and vomiting. Lactic acidosis and severe hepatomegly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone, including abacavir, zidovudine, lamivudine, stavudine, didanosine and zalcitabine, or in combination. 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 has been observed in approximately 5 percent of patients. Symptoms of hypersensitivity reaction usually occur in the first six weeks of treatment and get progressively worse, but generally resolve following permanent discontinuation of Ziagen. The reaction 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 also may occur, and patients should watch for symptoms such as shortness of breath, sore throat or cough. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute respiratory disease, even if other respiratory diagnoses such as pneumonia, bronchitis or flu-like illnesses are possible. Patients experiencing these symptoms should stop taking Ziagen and contact their physician immediately. After a diagnosis of hypersensitivity, patients must not take Ziagen again. Restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening hypotension and fatal reactions.

Ziagen in combination with other antiretroviral agents is indicated for the treatment of 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.

Combivir in combination with other antiretroviral agents is indicated for the treatment of HIV infection.
-end-
Ziagen was discovered and developed by Glaxo Wellcome. The rights to related compounds and technology, including intermediates used in the manufacture of Ziagen, resulting from the research by Dr. Robert Vince, et. al, were licensed to Glaxo Wellcome by the University of Minnesota.

Glaxo Wellcome is a pharmaceutical industry leader in HIV research and therapies. In addition to Ziagen and Combivir, Glaxo Wellcome also manufactures and markets the protease inhibitor Agenerase® (amprenavir). The company is engaged in basic research programs designed to investigate new targets to treat HIV.

Following are the abstracts of the research presented at Durban. Complete prescribing information for Combivir and Ziagen follows. For additional information, please go to
http://www.treathiv.com ,
http://www.ziagen.com ,
http://www.combivir.com ,
http://www.retrovir.com ,
http://www.epivir.com ,
http://www.agenerase.com

00-045
Mary Faye Dark
919-483-8580

Public Communications Inc.

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