GlaxoSmithKline (GSK) and Vertex Pharmaceuticals have announced preliminary results from their KLEAN study - a 48-week open-label head-to-head comparison of twice-daily ritonavir-boosted fosamprenavir (Telzir in Europe, Lexiva in North America) with twice-daily Kaletra (lopinavir/ritonavir) in treatment-naive individuals. The GSK-Vertex press release says that twice-daily ritonavir-boosted fosamprenavir is non-inferior to twice-daily ritonavir-boosted lopinavir, since an equal percentage of participants achieved the study's primary endpoint - a viral load under 400 copies/ml at 48 weeks.
KLEAN (ESS100732) was a phase IIIB, open-label, multicentre, international study designed to compare the efficacy and safety of twice-daily fosamprenavir 700mg plus twice-daily ritonavir 100mg to twice-daily lopinavir/ritonavir 400mg/100mg in combination with GSK's once-daily fixed dose combination nucleoside backbone pill (known as Kivexa in Europe, Epzicom in North America) containing 600mg abacavir and 300mg 3TC.
Between June, 2004 and January, 2005, 887 treatment-naive (or with less than two weeks of NRTI experience, and no prior NNRTI or protease inhibitor use) adults, from 130 sites in North America and Europe, with viral loads greater than 1000 copies/ml and any CD4 cell count, enrolled in the study. The primary endpoint was the proportion of individuals with viral load below 400 copies/ml after 48 weeks. The secondary endpoint was the proportion of participants who permanently discontinued randomised treatment due to adverse events.
The press release focuses on very basic data regarding the primary endpoint. It says that, in intent-to-treat analysis, 73% of participants receiving fosamprenavir/ritonavir achieved a viral load of less than 400 copies/ml after 48 weeks of dosing, compared with 71% on lopinavir/ritonavir.
The 95% confidence interval of the difference between the two arms was wide, from minus 3.26 to plus 5.47, meaning that the difference is not statistically significant. "Based on these results from this study," the press release goes on to say, "researchers have concluded that [twice-daily fosamprenavir/ritonavir] appears to be comparable to [twice-daily lopinavir/ritonavir] and has met the primary endpoints of this non-inferiority trial."
Last year, at the International AIDS Conference in Rio de Janeiro, an unplanned, interim, non-comparative analysis of suspected hypersensitivity reactions to abacavir (given once daily as part of a fixed dose combination) in all KLEAN participants was reported. They found that the incidence of suspected hypersensitivity reaction was 5.9% (2% for severe reactions; requiring hospitalisation in 1.4%) during the first six weeks, which is similar to previously published once- or twice-daily abacavir studies. The median time to the onset of suspected hypersensitivity symptoms was about eight days.
Comment
The study did not set out to prove that ritonavir-boosted fosamprenavir was superior to ritonavir-boosted lopinavir in treatment-naive individuals. Although the study has found that an equal amount of participants achieved a viral load below 400 copies/ml after 48 weeks, the information provided today is unlikely to be enough to persuade treatment guidelines committees to replace Kaletra with fosamprenavir as the favoured recommended first-line protease inhibitor.
After all, the current gold standard to measure efficacy is a viral load below 50 copies/ml after 48 weeks, and this can now be achieved in a high proportion of treatment-naive individuals using a once-daily boosted protease inhibitor. A recently reported open-label study of once-daily atazanavir 300mg with once-daily ritonavir 100mg in treatment-naive individuals found that, in intent-to-treat analysis, 86% of participants had viral loads below 400 copies/ml and 75% had viral loads below 50 copies/ml after 48 weeks.
Although fosamprenavir has been licensed in the United States to be taken in three possible ways in treatment-naive individuals - 1400mg twice daily; 1400mg with 200mg ritonavir once daily; or 700mg with 100mg ritonavir twice daily - the KLEAN study used the only dose currently licensed in the European Union; 700mg with 100mg ritonavir twice daily. The EU's Committee for Proprietary Medicinal Products were privy to preliminary 48 week results of the CONTEXT study, which compared once and twice daily dosing of ritonavir-boosted fosamprenavir with lopinavir/ritonavir in treatment-experienced individuals. Although this study suggested that the drugs were of similar efficacy, it also suggested that the degree of virologic suppression in fosamprenavir-treated participants was possibly inferior to those taking lopinavir, potentially indicating a higher risk of drug resistance.
The press release also provides scant information regarding issues of toxicity and tolerability - both of which are of paramount importance to patients - other than saying that "both regimens were generally well-tolerated," with 6% withdrawing from the study due to adverse events which "were consistent with those described in product information for [fosamprenavir] and [lopinavir/ritonavir]." However, there is no information on how many withdrew from each arm.
The jury will be out until more detailed results are presented at a scientific conference later this year.
Vertex Pharmaceuticals press release, May 16th, 2006.
Becker S et al. Reported incidence and severity of suspected abacavir hypersensitivity reactions (HSR) through at least 6 weeks in a large, controlled clinical trial using a once-daily (OAD) abacavir 600 mg/lamivudine 300 mg tablet (ABC/3TC FDC) dual nucleoside backbone with a boosted protease inhibitor: the KLEAN study. Third IAS Conference, Rio de Janeiro, TuPe2.4C08, 2005.