The Body Covers: The XV International AIDS Conference
July 13, 2004
In the past year, 2 new protease inhibitors (PIs), atazanavir (ATV, Reyataz) and fosamprenavir (908, Lexiva, Telzir), have dramatically increased practical treatment options for persons with HIV infection. Fosamprenavir was approved by the U.S. Food and Drug Administration in October 2003 and by the European Medicines Agency in July 2004. Fosamprenavir has been previously shown to be a well-tolerated PI that has efficacy similar to nelfinavir (NFV, Viracept) and, when dosed twice daily, is similar to lopinavir/ritonavir (LPV/r, Kaletra) in treatment-experienced patients. There is no dietary requirement to taking fosamprenavir, in contrast to other PIs that either require food or fasting with doses.References Abstract: GW433908 (908)/Ritonavir (r): 48 Week Results in PI-Experienced Subjects: A Retrospective Analysis of Virological Response Based on Baseline Genotype and Phenotype (Oral MoOrB1055
As with all new medications, it is important to have a detailed description of fosamprenavir's short- and long-term safety. Several presentations given at the XV International AIDS Conference, from both clinician investigators and the scientists at GlaxoSmithKline, confirm and extend our understandings of fosamprenavir.
Long-Term Follow-Up of Therapy-Naive Studies
Several presentations provided follow-up to the pivotal NEAT and SOLO clinical trials.1-3 These studies evaluated the responses of treatment-naive persons to unboosted or boosted fosamprenavir (both with abacavir [ABC, Ziagen] and lamivudine [3TC, Epivir]). The rollover study of these patients was termed protocol APV30005. Jeffery Nadler (University of South Florida, poster TuPeB4506) presented the 96-week follow-up of patients receiving unboosted fosamprenavir in the NEAT study. These results demonstrated continued sustained virologic suppression in the study population: 85% of the patients (observed) had a viral load less than 50 copies/mL and a median increase in CD4+ cell count of 255 cells/mm3 (compared to baseline).
The adverse event profile was similar in the second year of the clinical study -- significantly few moderate or severe laboratory abnormalities were reported. Interestingly, there was a sustained increase in high-density lipoprotein (HDL) cholesterol (+11 mg/dL) and a return to baseline in triglyceride levels. A total of 7 subjects met the study criteria for virologic failure between weeks 48 and 96 of treatment.
Joseph Gathe (Therapeutic Concepts, Houston, Texas), a clinician actively involved in innovative PI research, presented long-term follow-up data on patients who received first-line, once-daily, boosted fosamprenavir from the SOLO and APV30005 studies (poster TuPeB4507). Similar to the presentation results from Jeffrey Nadler, patients who had reached 48 weeks on this treatment regimen continued to have excellent efficacy and tolerability in the second year of treatment. Virologic suppression was sustained in 86% of the patients (<50 copies/mL; observed data) and there was a continued increase in CD4+ cell count. Additionally, while 41% of the patients reported some drug-related side effect through the 2 years of observation, in the second year of the study only 1 new subject reported nausea and there were no new cases of mild to severe diarrhea or hypersensitivity. Mirroring the results of NEAT/APV30005, HDL cholesterol increased (+12 mg/dL) over baseline; there were no additional increases in total cholesterol or triglycerides in the second year of follow-up.
Switch From Amprenavir to Fosamprenavir
The results of a study on the efficacy and safety of switching patients from amprenavir (APV, Agenerase) to fosamprenavir were presented by Alan Rodriguez (University of Miami, poster TuPeB4504). There is clinical interest in confirming the safety of this treatment simplification because the improved pill burden of fosamprenavir (2 tablets twice a day versus 8 capsules twice a day) should prove to be attractive to patients currently receiving amprenavir. The current study evaluated patients in the CLASS study who had initiated treatment with amprenavir (with abacavir and lamivudine) and who were later switched to fosamprenavir.
Sixty-six patients were followed for a median of 175 days on amprenavir and 570 days on fosamprenavir. After a combined 96 weeks of therapy, 79% of the study subjects who had a viral load <400 copies/mL prior to the PI switch maintained viral suppression. There was no significant change in either the side effect or laboratory abnormality profile seen following the switch, and none of the patients needed to change to an alternative PI because of side effects. These data provide strong, if not unexpected, support for the clinical utility in switching patients from the cumbersome amprenavir formulation to fosamprenavir.
Resistance to Fosamprenavir
Resistance to fosamprenavir was the topic of several analyses. Previous reports have shown that the emergence of new protease gene mutations was not observed in people experiencing failure of first-line, boosted fosamprenavir-containing treatment. For people initiating unboosted fosamprenavir, new protease resistance mutations were observed, though susceptibility to other PIs was, in general, preserved.
In Gathe's presentation of the SOLO/APV30005 study patients, 5 patients met criteria for virologic failure between weeks 48 and 96 of observation. In HIV that was isolated from this group of patients, there were no primary protease gene mutations and only 1 patient had a mutation (M184M/V) in the reverse transcriptase gene. Phenotypic analysis of these viral isolates showed no measurable resistance to any PI and only borderline resistance to lamivudine in the single patient with the 184 mutation.
Additional analysis of the resistance mutations in the NEAT/APV30005 study showed the emergence of amprenavir-associated resistance mutations in 3 new patients. Phenotypic studies confirmed the presence of limited or no resistance to other PIs.
An oral presentation by virologist Rob Elston (GlaxoSmithKline, United Kingdom, oral MoOrB1055) provided insight into the genetic factors that influence the response treatment-experienced patients have to fosamprenavir. Persons enrolled in the CONTEXT clinical trial were included for this analysis. Previous reports of the CONTEXT study showed that, in treatment-experienced patients, boosted fosamprenavir (dosed twice daily) and boosted lopinavir/ritonavir reduced viral loads to undetectable levels in similar proportions of patients. In this patient population, viruses harboring protease gene mutations D30N (associated with nelfinavir resistance), M46I/L and L90M (a multidrug resistance mutation) were common. Fosamprenavir and lopinavir/ritonavir performed similarly in patients with D30N, M46I/L and L90M virus, but notably, the presence of virus with the 46- or 90 mutations were less likely to respond to either drug. Unfortunately, there was insufficient data from this study cohort to draw a statistically valid conclusion of the phenotypic cutoff for resistance to fosamprenavir.
New, better-tolerated PIs have clearly impacted most HIV clinicians' prescribing habits, with a growing number of treatment-naive persons electing to start HIV treatment with boosted PIs. The absence of treatment-emergent protease resistance among first-line patients who experience highly active antiretroviral therapy (HAART) failure, first reported by Kemp and colleagues at Abbott Laboratories in patients taking lopinavir/ritonavir, has been validated by Elston's analyses of patients taking fosamprenavir in the SOLO clinical trial.
The extended data on fosamprenavir adds to our knowledge base and increases confidence in using this new PI, particularly among treatment-naive persons or among persons who are receiving first-line amprenavir therapy. With the exception of patients who are currently receiving amprenavir with lopinavir/ritonavir, I believe that it is reasonable, if not recommended, to switch from amprenavir to fosamprenavir.
For treatment-experienced patients, resistance patterns and predictors of response are my primary basis for selecting antiretroviral agents -- the Elston analysis provides important genotypic information but falls short of giving us the elusive phenotypic cutoff for response to fosamprenavir.
Authored by: R C Elston, P Yates, M Tisdale, N Richards, S White, E DeJesus
Abstract: Efficacy and Safety of Switch to GW433908/Ritonavir 200mg (908/r) QD in Subjects Initiating Therapy With Amprenavir/Ritonavir 200mg (APV/r) QD: ESS40001(CLASS)
Abstract: Sustained Antiviral Efficacy and Tolerability Over 96 Weeks in ART Naive Subjects: Long-Term Follow-Up on Unboosted GW433908 (908) BID (Poster TuPeB4506)
Abstract: Long-Term Follow-Up on GW433908/Ritonavir (908/r) QD: Sustained Virologic and Immunologic Response in Antiretroviral Treatment Naive Subjects Over 96 Weeks (Poster TuPeB4507)
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