Interim analysis comparing TDF to EFV in combination with 3TC + ABC

September 16, 2003

Chicago, Sept. 16, 2003 - An unplanned interim analysis of a study comparing tenofovir disoproxil fumarate (TDF) to efavirenz (EFV) - both given in combination with a fixed-dose investigational co-formulation of Epivir® (lamivudine) (3TC) and Ziagen® (abacavir sulfate) (ABC) - for the treatment of HIV showed that subjects in the TDF- containing arm experienced an unacceptably high rate of early virologic non-response compared with the EFV-containing arm. The finding led to the protocol being amended to terminate the TDF arm in the study, ESS30009, according to data reported here today at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The precise nature of the interaction leading to non-response in this study is not yet known.

In both study arms, ABC and 3TC were administered in a fixed-dose investigational co-formulation and all drugs were administered once a day (QD). Virologic non-response was defined as <2.0 log10 drop in viral load (VL) by week 8, or a rebound from nadir of 1.0 log10 or greater. The protocol was amended and patients in the TDF arm could discontinue the study or continue the study on an alternative regimen.

The randomized, open-label multicenter study includes 345 antiretroviral treatment-naïve patients with HIV infection. A total of 194 patients with 8 weeks or more of VL data were included in the interim analysis. The mean baseline VL was 4.63 log10 copies/mL and the mean CD4+ cell count was 290 cells/mm3 among the patients analyzed. Virologic non-response occurred in 50 of 102 patients (49 percent) taking the TDF combination, compared to 5 of 92 subjects (5 percent) taking the EFV combination. After 8 weeks, VL <400 copies> "Preliminary resistance data also demonstrated the presence of both K65R and MI84V mutations in 23 of 36 patients (64 percent) of patients experiencing virologic non-response in the TDF group at 12 weeks. The K65R mutation was much more common in patients failing this combination than has been reported with failure of other tenofovir-containing regimens," said Joel Gallant, M.D., MPH, associate professor of medicine and epidemiology, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

"This study is part of GlaxoSmithKline's ongoing effort to provide options that fit the needs of individual patients by exploring fixed dose co-formulations that provide flexibility while reducing pill burden and dosing frequency," said Doug Manion, M.D., vice president of clinical development, GSK. "The study arm using the investigational co-formulation of ABC/3TC with EFV showed good virologic responses and it is continuing unchanged. GSK is committed to pursuing this further to better understand the findings of ESS30009." Abacavir is currently approved for BID dosing and lamivudine is approved for both QD and BID dosing. GSK is developing a co-formulation of lamivudine and abacavir for once daily dosing. This co-formulation is in late-stage 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.

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 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 recommended dose of Ziagen is 300mg twice a day. The recommended dose of Epivir is 150mg twice a day or 300mg once 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.
At a Glance

  • In a study comparing TDF vs. EFV (both given with 3TC and ABC), 49 percent of patients in the TDF arm experienced early virologic non-response, compared with 5 percent of patients in the EFV arm at week 8.
  • 90 percent of patients in the EFV arm achieved viral loads <400 copies> The study protocol was amended to terminate the 3TC/ABC/TDF arm.
  • The precise nature of any interaction leading to non-response in this study is not yet known.

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