Until recently, the ritonavir (Norvir) dose approved for providing pharmacological boosting of once-daily fosamprenavir (Lexiva) was 200 mg. However, pharmacokinetic analyses support the use of 100 mg ritonavir to provide therapeutic plasma concentrations of amprenavir [1], and 100 mg dosing has now been approved in the U.S. on this basis.

To date, there have been no prospective studies comparing long-term safety and efficacy of 100 mg versus 200 mg ritonavir boosting of once-daily fosamprenavir-based regimens. Thus, a 96-week study was initiated to evaluate efficacy and safety of the 100 mg dose in comparison to 200 mg of ritonavir.

Results of the study were presented by Chuck Hicks, MD, at the recent 11th European AIDS Conference (EACS) in Madrid, Spain (October 24-27, 2007).

The study enrolled 115 subjects. Baseline characteristics are shown in Table 1 in the poster, and have previously been described [2].

COL100758 is a 96-week, open-label, multicenter study that enrolled antiretroviral-naive adult HIV patients with HIV RNA > 1000 copies/mL who were randomized to receive once-daily 600 mg abacavir (Ziagen) plus 300 mg 3TC (lamivudine (Epivir) plus 1400 mg fosamprenavir boosted with 100 mg versus 200 mg of ritonavir.

The objectives were to evaluate efficacy, immunological and metabolic responses, safety, and tolerability of the 100 mg ritonavir versus the 200 mg ritonavir regimen, as well as to evaluate adherence, over 24, 48, and 96 weeks.

The primary efficacy endpoint was the proportion of subjects with plasma HIV RNA < 400 copies/mL at Week 48. Results from the intent-to-treat, missing equals failure (ITT, M=F) and observed (Obs) analyses for the efficacy endpoints are presented. The study was not powered, and p-values are descriptive only.

Results

• Baseline data for the fosamprenavir/ritonavir 100 mg and fosamprenavir/ritonavir 200 mg groups, respectively, were as follows:
• median HIV RNA: 4.7 vs 4.9 log₁₀ copies/mL;
• median CD4 count: 259 vs 179 cells/mm³;
• total/HDL cholesterol ratio: 4.6 vs 4.6;
• male sex: 81% in both groups;
• non-white: 63% vs 55%.
• In the observed analysis, the proportions of subjects with HIV RNA < 400 copies/mL were 98% vs 84% (P=0.02) in the 100 mg vs 200 mg ritonavir arms.
• The proportions were 92% vs 80% (P=0.10), respectively, for viral load < 50 copies/mL.
• In the fosamprenavir/ritonavir 100 mg arm, the median CD4 T-cell count change from baseline at Week 48 was +183 cells/mm³.
• In the fosamprenavir/ritonavir 200 mg arm, the median change was +195 cells/mm³.
• Treatment-related grade 2-4 adverse events (AEs) observed in ≥ 5% of subjects were:
• diarrhea: 14% vs 18%;
• headache: 9% vs 4%;
• suspected abacavir hypersensitivity reaction: 10% vs 2%;
• abdominal pain: 7% vs 0%;
• nausea: 3% vs 5%;
• fatigue: 5% vs 2%;
• rash: 5% vs 2%.
• There were no differences between the 2 arms in terms of tolerability or lipid parameters.

The higher virological efficacy rate, but absence of tolerability or lipid advantages observed with fosamprenavir/ritonavir 100 mg in this study may in part be related to the greater adherence to ritonavir and abacavir/3TC in the lower ritonavir dose group, as well as to differences in baseline characteristics compared with the fosamprenavir/ritonavir 200 mg arm (fewer CDC class C patients, lower median overall baseline viral load, and higher CD4 cell count).

There was a higher study discontinuation rate in the fosamprenavir/ritonavir 200 mg arm, but given the small sample size, it is difficult to determine whether this was related to the regimen.

In conclusion, the study authors wrote, “fosamprenavir/ritonavir 100-treated patients generally had better virologic responses and similar CD4 T-cell count improvements compared to fosamprenavir/ritonavir 200-treated patients.”

In addition, they wrote, “In this study, efficacy through 48 weeks favored the fosamprenavir/ritonavir 1400 mg/100 mg arm, perhaps due to baseline characteristics and adherence. Both arms showed similar improvements in CD4 cell count and total/HDL cholesterol ratio.”

Finally, they noted, “Better regimen adherence was observed in patients taking 100 mg ritonavir as compared with 200 mg ritonavir.”

Duke Univ. Med. Ctr., Infectious Diseases, Durham, USA, Orlando Immunology Ctr., Orlando, USA, University of North Carolina at Chapel Hill, Chapel Hill, USA, 4GlaxoSmithKline, Research Triangle Park, USA.

11/02/07

Source                                                                                                                                    

C Hicks, E DeJesus, D Wohl, and others.  Once-Daily Fosamprenavir (FPV) Boosted with Either 100mg or 200mg of Ritonavir (r) Along with Abacavir (ABC)/Lamivudine (3TC): 48 Week Safety and Efficacy Results from COL100758. 11th European AIDS Conference (EACS). Madrid, Spain. October 24-27, 2007. Abstract (poster) P5.7/01.

References

1. RJ Ruane, AD Luber, MB Wire MB, and others. Plasma amprenavir pharmacokinetics and tolerability following administration of 1,400 milligrams of fosamprenavir once daily in combination with either 100 or 200 milligrams of ritonavir in healthy volunteers. Antimicrobial Agents and Chemotherapy 51: 560-565. 2007.

2. Hicks, C, E DeJesus, L Sloan, and others. Once-Daily Fosamprenavir (FPV) with a Reduced Dose of Ritonavir (RTV), Given with Fixed-Dose Abacavir (ABC)/Lamivudine (3TC): A Planned Week 24 Interim Analysis. 8th International Congress on Drug Therapy in HIV Infection. November 12-16, 2006. Glasgow, UK. Abstract (poster) P2.