General Information

Lexiva (formerly GW433908, or 908) is a new protease inhibitor (PI) for the treatment of HIV infection. It is a prodrug of amprenavir, an inhibitor of human immunodeficiency virus (HIV) protease.

Lexiva is indicated for the treatment of HIV infection in adults in combination with other antiretroviral agents.

The recommended dosage of Lexiva for therapy naïve patients is 1,400 mg twice daily. The recommended dosage of Lexiva for protease inhibitor-experienced patients is 700 mg twice daily.

Clinical Results

FDA approval of Lexiva was based on three pivotal phase III trials with both therapy naïve and experienced patients. The first trial was a randomized, open-label study called APV30001 (NEAT). It was designed to compare treatment with Lexiva (1,400 mg twice daily) against nelfinavir (1,250 mg twice daily) in 249 antiretroviral treatment-naive subjects. Both groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily). Results showed that the median increases of CD4+ cell counts from baseline were 201 cells/mm3 in the Lexiva group and 216 cells/mm3 in the nelfinavir group.

The second trial was a randomized, open-label study called APV30002 (SOLO). It was designed to compare treatment with Lexiva (1,400 mg once daily) plus ritonavir (200 mg once daily) versus nelfinavir 13 (1,250 mg twice daily) in 649 treatment-naive subjects. Both treatment groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily). Results showed that the median increases of CD4+ cell counts from baseline were 203 cells/mm3 in the Lexiva group and 207 cells/mm3 in the nelfinavir group.

The third trial was a randomized, open-label, multicenter study called APV30003 (CONTEXT). It was designed to compare Lexiva (700 mg twice daily) plus ritonavir (100 mg twice daily) or Lexiva (1,400 mg once daily) plus ritonavir (200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg twice daily) in 315 subjects who had experienced virologic failure to 1 or 2 prior protease inhibitor-containing regimens. Results showed that the time-averaged changes in plasma HIV-1 RNA from baseline were .1.4 log10 copies/mL for twice daily Lexiva/ritonavir and .1.67 log10 copies/mL for the lopinavir/ritonavir group. Data demonstrated that 58% of subjects taking Lexiva plus ritonavir twice daily achieved an HIV-1 RNA of under 400 copies/mL versus 61% of subjects taking lopinavir plus ritonavir. This study was not large enough to reach a definitive conclusion that Lexiva /ritonavir and lopinavir/ritonavir are clinically equivalent.

Mechanism of Action

Fosamprenavir is rapidly converted to amprenavir, an inhibitor of HIV-1 protease, by cellular phosphatases in vivo. Amprenavir binds to the active site of HIV-1 protease preventing the processing of viral Gag and Gag-Pol polyprotein precursors. This results in the formation of immature non-infectious viral particles.

Literature References

Bart PA et al. Immunological and virological responses in HIV-1-infected adults at early stage of established infection treated with highly active antiretroviral therapy. AIDS 14(13): 1887-97, 2000.

Blanche S et al. A phase II study of amprenavir in antiretroviral experienced children with HIV infection. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 695, 2000.

Kost RG et al. Open-label phase II trial of amprenavir, abacavir, and fixed-dose zidovudine/lamivudine in newly and chronically HIV-1--infected patients. Journal of Acquired Immune Deficiency Syndromes 26(4): 332-9, 2001.

Nadler J, Rodriguez-French A, Millard J, Wannamaker P. The NEAT Study: GW433908 Efficacy and Safety in ART-naive Subjects, Final 48-Week Analysis. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 10-14, 2003. Abstract 177.