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Trizivir & ACTG 5095: GSK Response
  This GlaxoSmithKline Press Release was issued following the publication of ACTG 5095 yesterday in the New England Journal of Medicine.
Research Triangle Park, NC (April 28, 2004) -- Preliminary results of ACTG 5095 are published in the April 29 issue of the New England Journal of Medicine, following presentation of these data at the International AIDS Society meeting in July 2003. GlaxoSmithKline provides the following information as background for journalists and others on the development of its antiretroviral drug TRIZIVIR‚ (abacavir sulfate, lamivudine and zidovudine), which was one of the medications evaluated in this study.
The components of TRIZIVIR have been researched and refined for nearly a decade, involving more than 1,700 patients in 14 clinical trials testing the combined three nucleoside components. TRIZIVIR, or a combination of its three individual components, has been prescribed alone or with other antiretrovirals for many thousands of patients since 1999. TRIZIVIR is indicated alone or in combination with other antiretroviral agents for the treatment of HIV-1 infection. The indication for TRIZIVIR is based on two controlled trials with abacavir of 16 and 48 weeks in duration that evaluated suppression of HIV RNA and changes in CD4 cell count. At present, there are no results from controlled trials evaluating the effect of abacavir on clinical progression of HIV. There are limited data on the use of this triple-combination regimen in patients with higher viral load levels (>100,000 copies/mL) at baseline.
The dose of one tablet taken twice daily alone or in combination with other antiretrovirals, with no food and water restrictions, offers patients the benefit of dosing simplicity. Based on sound clinical research, GlaxoSmithKline continues to support the use of TRIZIVIR.
"We believe TRIZIVIR has a valuable role in the continuum of HIV care," said Doug Manion, M.D., GSK vice president of clinical development and medical affairs. "We also believe it is important to put the interim preliminary results from ACTG 5095 into context with data reported in other controlled, clinical evaluations of TRIZIVIR."
ACTG 5095, a placebo-controlled, double-blinded study conducted by the Adult AIDS Clinical Trials Group (ACTG), compared a treatment arm involving TRIZIVIR alone to two other regimens: Combivir‚ (lamivudine/zidovudine) + efavirenz, and TRIZIVIR + efavirenz. The National Institute of Allergy and Infectious Diseases (NIAID) Data and Safety Monitoring Board (DSMB), which oversees ACTG 5095, announced in a Notice to Physicians March 10, 2003, that the treatment arm containing only TRIZIVIR met predefined criteria related to virologic failure when TRIZIVIR was compared to each of the efavirenz containing arms. This required the discontinuation of the arm. The two arms containing efavirenz continued; patients taking only TRIZIVIR whose viral loads were suppressed, could elect to continue with the regimen and are being provided the drug off study.
The preliminary data that prompted the DSMB action was related to one of the study's primary endpoints -- time to virologic failure (HIV-1 RNA <200 copies/mL); and a secondary endpoint -- a comparison of the proportion of patients who achieved HIV-1 RNA <200 copies/mL at 48 weeks. After a median time period of 32 weeks into the 96-week study, a greater proportion of the 167 antiretroviral-naïve patients who experienced virologic failure were in the treatment group taking TRIZIVIR alone (21 percent) than in the other two treatment groups combined (10 percent). At the same time, among 33 percent of patients who reached 48 weeks, 74 percent of patients in the group taking TRIZIVIR alone had a viral load of <200 copies/mL, compared to 89 percent in the other groups combined.
GSK provides the following information for context:
Viral Suppression
  • 43 percent of the patients in the arm taking TRIZIVIR alone entered with a viral load >100,000 copies/mL. There are limited data on the use of this triple-combination regimen in patients with higher viral load levels >100,000 copies/mL at baseline.

  • 74 percent of the naïve patients treated with TRIZIVIR alone achieved viral suppression of <200 copies/mL, which is clinically acceptable and consistent with other published data on TRIZIVIR.

  • While lower than in the other two treatment arms, the 74 percent success rate is actually high when considered against the strict criterion for virologic failure. In ACTG 5095 virologic failure was defined as a confirmed HIV RNA >=200 copies/mL at least 16 weeks after starting the study treatment.

CD4 Cell Count
  • 48 percent of the patients in the arm taking TRIZIVIR alone entered with a CD4 count of 200 or below.

  • There were no significant differences between treatment arms with respect to CD4 cell count change from baseline. At week 48, the mean change was 174 cells/mm3 in the arm taking TRIZIVIR alone and 173 cells/mm3 in the pooled efavirenz arms.

  • Although data on CD4+ T cell counts were not available at the time of the interim analysis, the DSMB (National Institute of Allergy and Infections Diseases' Data and Safety Monitoring Board) felt that they would not reverse the outcome.

Dosing Convenience
TRIZIVIR is approved to be dosed as one tablet taken twice a day alone or in combination with other antiretrovirals with no food or water restrictions. Dosing simplicity offered by TRIZIVIR is an important factor when considering antiretroviral therapy.
As stated in the letter from the NIAID Division of AIDS to health care providers: "It is important to consider this interim study finding in the context of published results, particularly those from prior studies that investigated either triple nucleoside regimens or efavirenz-based regimens. The risk of virologic failure is clearly an important factor in selecting an initial antiretroviral regimen. Other factors such as safety, toxicity, adherence, preservation of future treatment options, access, cost and other issues also remain important in selecting the optimal first regimen for an individual patient."GlaxoSmithKline has informed health care professionals who treat HIV/AIDS patients of these details to clarify the study parameter, and also has posted this and other information on clinical trials involving TRIZIVIR on the web site www.treathiv.com.
Product Information
HIV medicines do not cure HIV infection/AIDS or prevent passing HIV to others.
There are limited data on the use of this triple-combination regimen in patients with higher viral load levels (>100,000 copies/mL) at baseline.
The most serious adverse event associated with abacavir (a medicine in TRIZIVIR and Ziagen) is a hypersensitivity reaction that can be life threatening and has been fatal in some cases. 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. In clinical studies, hypersensitivity reaction has been observed in approximately 5 percent of patients. 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 and health care professionals should also watch for respiratory symptoms such as shortness of breath, sore throat or cough.
To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, TRIZIVIR or Ziagen should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory disease, gastroenteritis, or reactions to other medication). Rechallenge is contraindicated after a diagnosis of hypersensitivity. Symptoms of this reaction usually occur within the first six weeks of treatment although these reactions can occur at any time during therapy. The symptoms of this reaction get progressively worse with continued treatment with abacavir (TRIZIVIR or Ziagen), but generally resolve following permanent discontinuation of TRIZIVIR or Ziagen. Patients experiencing these symptoms should stop taking TRIZIVIR or Ziagen and contact a physician immediately. Patients experiencing this reaction must not take TRIZIVIR or Ziagen again as restarting the drug after a hypersensitivity reaction has resulted in cases of life- threatening and fatal reactions. When therapy with TRIZIVIR and Ziagen has been discontinued and reinitiation of therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have a hypersensitivity reaction. A Medication Guide and Warning Card for TRIZIVIR and Ziagen must be provided by the pharmacists to the patient with each new and refill prescription in order to provide further information to the patient on this drug.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, zidovudine, lamivudine and other antiretrovirals.
Zidovudine has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV disease. Prolonged use of zidovudine has been associated with symptomatic myopathy.
Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. The causal relationship, mechanism and long-term consequences of these events are currently unknown.
The most common adverse events associated with the use of Trizivir > 5 percent include nausea, vomiting, diarrhea, loss of appetite, weakness or tiredness, headache, dizziness, pain or tingling of the hands or feet, and muscle and joint pain.
Recombinant laboratory strains of HIV-1 (HXB2) containing multiple reverse transcriptase mutations conferring abacavir resistance exhibited cross-resistance to lamivudine, didanosine, and zalcitabine in vitro.
GlaxoSmithKline is one of the world's leading research-based pharmaceutical and health care companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs to investigate new targets to treat HIV.
For full prescribing information please go to www.treathiv.com.
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