Fosamprenavir/ Ritonavir Once Daily in Treatment-naive HIV Patients Shows No PI Resistance at 48 Weeks

Fosamprenavir (GW433908; Lexiva) is a potent and durable HIV protease inhibitor (PI), the prodrug of amprenavir, with a favorable safety profile as demonstrated by two Phase III clinical trials in antiretroviral-naive patients.

Co-administration of fosamprenavir with low dose ritonavir (Norvir) boosts exposure of amprenavir (APV), which facilitates flexible dosing, including once daily (q.d.) dosing, and requires no food or fluid restrictions.

The purpose of the current study (The SOLO Study) was to investigate the emergence of resistance to fosamprenavir, a protease inhibitor (PI) with demonstrated antiviral efficacy, safety and tolerability, when administered once daily (q.d.) with low dose ritonavir (fosamprenavir/r).  Preliminary results of the SOLO Study were reported by HIV and Hepatitis.com in 2002. Final results are published in the March 5, 2004 issue of AIDS. Following is a brief summary of that review:

SOLO was a 48-week Phase III open-label study in which antiretroviral therapy-naive patients (n = 649) were treated with fosamprenavir/r, (1400 mg/200 mg, q.d.) or nelfinavir (Viracept) [1250 mg, twice daily (b.i.d.)] with two nucleoside reverse transcriptase inhibitors (NRTI), abacavir (Ziagen) 300 mg, b.i.d. and lamivudine (Epivir) 150 mg, b.i.d.  

Viral genotype and phenotype were analyzed at baseline and on treatment up to 48 weeks and beyond.   

Results    

Emergence of genotypic resistance was significantly different between the fosamprenavir/r q.d. and the nelfinavir b.i.d. treatment arms for both PIs (0 versus 50%; P < 0.001) and the NRTI (13% versus 69%; P < 0.001) received.   

In the nelfinavir arm the key protease mutations D30N and/or L90M were frequently observed. The absence of protease resistance mutations and reduced incidence of NRTI resistance mutations in the fosamprenavir/r q.d. arm was confirmed by phenotyping, which showed a lack of PI cross-resistance.  

The absence of resistance to fosamprenavir or cross-resistance to other PIs, and reduced NRTI resistance, following a fosamprenavir/r q.d. regimen supports the use of this boosted PI early in therapy. 

Discussion

Analysis of the virological failure samples from patients in SOLO have revealed significantly lower incidence of the emergence of resistance to both the PI and NRTI components of the regimen in the fosamprenavir/r q.d. arm compared with the NFV b.i.d. arm. No PI cross-resistance was observed except in patient 1, where archival resistance mutations contributed to phenotypic resistance to the six PIs tested.

Evaluation of the viral load profiles in the NFV b.i.d. and fosamprenavir/r q.d. arms revealed differences associated with the slopes of virological failure, and acquisition of mutations.

This suggested that rapid rebounds which possibly result from stopping therapy are more frequently associated with few or no mutations, whereas gradual rebound or ongoing replication, possibly due to prolonged suboptimal drug exposure, are associated with acquisition of mutations.

The high drug exposure of the fosamprenavir/r regimen would be consistent with the greater genetic barrier producing a delay in the emergence of resistance to both PIs and NRTI.

Questionnaire adherence data showed that the fosamprenavir/r q.d. regimen had higher overall adherence than the NFV b.i.d. regimen, but that the fosamprenavir/r q.d. virological failures were more frequently associated with poor adherence than the NFV b.i.d. virological failures, suggesting a lower barrier to resistance of the NFV arm.

In conclusion, the authors write, “The absence of emergent protease resistance to fosamprenavir or cross-resistance to other PI and reduced NRTI resistance during treatment with a fosamprenavir/r q.d. regimen supports the use of this boosted PI early in the treatment continuum.”

Note: The HIV protease inhibitor fosamprenavir (Lexiva) was approved by the FDA for the treatment of HIV infection in October 2003.

03/26/04

Reference
S MacManus and others. GW433908/ritonavir once daily in antiretroviral therapy-naive HIV-infected patients: absence of protease resistance at 48 weeks. AIDS 18(4): 651-655. March 5, 2004.