Study Evaluates ABC, 3TC and EFV versus ZDV, 3TC and EFV

Newswise — At a Glance

* In this study, combination therapy with 3TC/ABC/EFV was shown to be non-inferior to ZDV/3TC/EFV.

* 70 percent of subjects in the 3TC/ABC/EFV group and 69 percent of subjects in the ZDV/3TC/EFV group achieved viral load <50 copies/mL.

* Patients in the 3TC/ABC/EFV group had a change from baseline of +209 CD4+ cells/mm3 compared to +155 CD4+ cells/mm3 in the ZDV/3TC /EFV group.

* Safety profiles were comparable.

A treatment regimen of Ziagen® (abacavir sulfate) (ABC), Epivir® (lamivudine) (3TC) and efavirenz (EFV) has been shown to be non-inferior to the often prescribed regimen of Retrovir® (zidovudine) (ZDV) and 3TC and EFV in a large Phase III clinical trial comparing virologic response in treatment-naïve HIV+ adults. The 48-week data from the trial (CNA30024) were reported here today at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

Study CNA30024 enrolled therapy-naïve adults and randomized them to treatment with (1) ABC 300mg twice daily plus 3TC 150mg twice daily plus EFV 600mg once daily or (2) ZDV 300mg twice daily plus 3TC 150 mg twice daily plus EFV 600mg once daily. Abacavir is currently approved for twice daily dosing and lamivudine is approved for both once daily and twice daily dosing.

CNA30024 Results

Virologic failure was infrequent and similar between the treatment groups at 48-weeks, but subjects in the ABC/3TC/EFV group had a significantly better immunologic response (+209 CD4+cells/mm3) compared to subjects in the ZDV/3TC/EFV group (+155 CD4+cells/mm3). Safety profiles were comparable and both regimens were generally well tolerated over 48 weeks of randomized treatment.

"In this study, the three-drug combination of abacavir, lamivudine and efavirenz provided a potent antiretroviral response over 48 weeks and was shown to be non-inferior to zidovidine, lamivudine and efavirenz," said Edwin DeJesus, M.D., Infectious Disease Consultants, Altamonte Springs, Fla., lead investigator on the study.

In the international, multicenter trial of 649 patients, 70 percent of subjects in the ABC/3TC/EFV group and 69 percent of subjects in the ZDV/3TC/EFV group achieved an undetectable viral load (VL) level below 50 copies/mL at 48 weeks. Among all the patients, median VL at baseline was approximately 62,000 copies/mL and 39 percent had baseline VL >100,000 copies/mL. Median baseline CD4+ cell count was 264 cells/mm3.

The rate of suspected abacavir hypersensitivity reported by investigators in this double-blind study was 9 percent in the ABC/3TC/EFV group and 3 percent in the ZDV/3TC/EFV group.

"According to these results, the combination of ABC/3TC/EFV shows promise as a dosing combination that may provide an additional therapeutic option for physicians and patients," said Doug Manion, M.D., GSK vice president of clinical development.

Product Information

HIV medicines do not cure HIV infection/AIDS or prevent passing HIV to others. Ziagen Tablets and Oral Solution, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection. This indication is based on two controlled trials of 16 and 48 weeks duration that evaluated suppression of plasma HIV-1 RNA and changes in CD4+ cell count. At present, there are no results from controlled trials evaluating the effect of Ziagen on clinical progression of HIV.

When used as part of a combination regimen, abacavir is a potent nucleoside reverse transcriptase inhibitor (NRTI). The most serious adverse event associated with abacavir administration is a hypersensitivity reaction occurring in approximately 5 percent of patients and which 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. 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 healthcare 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, abacavir 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, but generally resolve following permanent discontinuation of abacavir. Patients experiencing these symptoms should stop taking abacavir and contact a physician immediately.

Patients experiencing this reaction must not take abacavir again as restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening and fatal reactions. When therapy with abacavir 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 abacavir must be provided by pharmacists to patients with each new and refilled prescription in order to provide further information to the patient on this drug.

Epivir in combination with other antiretroviral agents is indicated for the treatment of HIV infection. Epivir should be used with caution in pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis. Patients with HIV or coinfected with HIV and hepatitis B should only receive the recommended HIV dosage of Epivir (300mg/day) and not Epivir-HBV® (100mg/day). Epivir has not been adequately studied for treatment of chronic hepatitis B in coinfected patients. Clinical and laboratory exacerbations of hepatitis B have occurred after discontinuation of lamivudine and may be severe in patients with decompensated liver disease.

Retrovir in combination with other antiretroviral agents is indicated for the treatment of HIV infection. Retrovir 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. 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, lamivudine, zidovudine and other antiretrovirals.

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 side effects with Ziagen are nausea, vomiting, tiredness, headache, diarrhea and loss of appetite. The most common side effects with Epivir are headache, upset stomach, tiredness, and nasal signs and symptoms. The most common side effects with Retrovir are headache, tiredness, nausea, loss of appetite and vomiting.

The recommended dose of Ziagen is 300mg twice a day. The recommended dose of Epivir is 150mg twice a day or 300mg once a day. The recommended dose of Retrovir is 300mg twice a day. The recommended dose of Combivir is one tablet (3TC 150mg/ZDV 300mg) twice a day.

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 healthcare companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.