Reports

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XVI International AIDS Conference

Toronto, Ontario / August 13-18, 2006

The comparative non-inferiority study on the ritonavir-boosted protease inhibitors (PIs) fosamprenavir (FPV/r) and lopinavir (LPV/r), called the KLEAN (Kaletra Versus Lexiva with Epivir and Abacavir in ART-Naive Patients) trial, provided important support for the new guidelines identifying this as a first-line therapy in antiretroviral (ARV) treatment-naive patients. The KLEAN study demonstrated that FPV/r twice daily provides similar efficacy and tolerability as LPV/r when each is combined with a once-daily combination pill of abacavir (ABC) and lamivudine (3TC).

“Similar results were observed when patients were stratified by baseline characteristics, such as a viral load >100,000 HIV RNA copies/mL or <50 CD4+ cells/mm3,” reported Dr. Joseph Eron, Associate Professor of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill. Senior author of the KLEAN trial, which was published just prior to the International AIDS Society (IAS) conference (Eron et al. Lancet 2006; 368:476-82), Dr. Eron reported that this study had a 90% power to confirm non-inferiority, but the proportion of patients achieving viral suppression was almost identical in the two arms of the study. On intent-to-treat-exposed-population (ITT-E) analysis, the primary end point of <400 HIV RNA copies/mL at 48 weeks was achieved in 73% of those randomized to FPV/r vs. 71% of those randomized to LPV/r.

Study Design and Results

In the KLEAN study, 878 ARV-naive patients were randomized to FPV 700 mg or LPV 400 mg, each boosted by ritonavir 100 mg and administered twice daily. Both groups received ABC 600 mg and 3TC 300 mg in a co-formulation once-daily pill. The open-label trial was conducted over 48 weeks and the treatment arms were monitored for efficacy, safety and tolerability. Treatment centres were located in the US, Canada and Europe. About 20% of the study participants were women, 40% were non-Caucasian, 11% had a previous AIDS diagnosis and slightly more than half had some form of hepatitis.

The efficacy of the two boosted regimens was remarkably similar on both ITT-E and observed treatment outcomes. In addition to the similar rates of ITT-E virologic suppression, the observed rates of virologic suppression <400 HIV RNA copies were 97% for those in the FPV/r arm and 96% for those randomized to LPV/r. The ITT-E results for <50 copies/mL were 66% for FPV/r and 65% for LPV/r. Observed rates at this level of viral suppression were 89% and 88% for FPV/r and LPV/r, respectively. The median increase in CD4+ cell counts over 48 weeks was also comparable with 176 cells/mm3 in the FPV/r arm and 191 cells/mm3 in the LPV/r arm. Virologic failure was observed in 4% of FPV/r patients and 5% of LPV/r patients.

Similarly, both regimens were well tolerated. Premature discontinuation for adverse events was recorded in 12% of those in the FPV/r arm and 10% in the LPV/r arm. After diarrhea (reported in grade 2 to 4 in 13% of FPV/r and 11% of LPV/r patients) and nausea (reported in 6% of the FPV/r arm and in 5% of LPV/r patients), the most common adverse event for both cohorts was ABC hypersensitivity reaction, which was observed in 6% of FPV/r patients and 4% of LPV/r patients.

Laboratory abnormalities were nearly identical with 11% of FPV/r and 9% of LPV/r patients demonstrating elevations in fasting cholesterol and 8% of each group demonstrating elevations in fasting triglycerides. There was about a 40% increase in HDL-C in both study arms. Liver enzyme elevations were observed in 6% of FPV/r patients and 5% of LPV/r patients, while creatine kinase was elevated in 4% of FPV/r patients and 6% of LPV/r patients. Neutrophil counts were increased in 4% of FPV/r patients and 5% of LPV/r patients. Glucose was elevated in 1% of FPV/r patients and 2% of LPV/r patients.

Adherence was excellent in both arms of the study, with 98.4% of FPV/r and 98% of LPV/r patients who remained on therapy demonstrating good compliance at the end of 48 weeks. There were two major PI-associated mutations in each arm of the study, but no patient developed reduced phenotypic susceptibility to either compound. A median time to virologic failure using the Kaplan-Meier method could not be calculated because of the very low number of virologic failures.

Characterizing this study as “a large, well-powered comparison,” Dr. Eron concluded that results demonstrate that a triple combination therapy with boosted FPV provides a degree of potency and safety that is comparable to that provided by a triple combination with boosted LPV.

IAS-USA Panel Guidelines

Reinforcing the latest IAS-USA Panel guidelines, Dr. Eron stated, “FPV/r can now be added to the list of agents that can be administered with two nucleosides for initial therapy, including in patients with high viral loads and very low CD4+ cell counts.”

The authors of the IAS-USA Panel guidelines, anticipating the results of KLEAN, indicated that the data on FPV/r “support its use in initial regimens,” but relied on previous studies to draw the conclusion that this boosted PI appeared effective and safe. They relied on similar studies to suggest that boosted atazanavir and boosted saquinavir are also acceptable choices for first-line therapy, although they warned that comparative studies “will be important.”

In the case of boosted atazanavir, they noted that evidence of a lower risk of hyperlipidemia relative to LPV/r is a potential advantage, but the asymptomatic hyperbilirubinemia with which atazanavir has been associated is a potential liability. The IAS-USA guideline panel also indicated that comparable efficacy and safety cannot be assumed without a direct comparison. In the case of saquinavir, they noted that a direct comparison has been performed, and results found boosted lopinavir preferable to boosted saquinavir. However, they stressed that this comparison was conducted with the soft-gel formulation of saquinavir which appears to have disadvantages to the currently available hard-gel formulation when each is boosted with ritonavir.

Summary

The goal of HIV therapy is to maintain viral loads below a level at which replication can generate resistance mutations. This depends both on antiviral potency and on tolerability that permits patients to remain on full doses of their regimen indefinitely. While LPV/r was identified as a preferred initial treatment in several previously published treatment guidelines based on double-blind, randomized trials, a direct comparison showing non-inferiority of FPV/r has provided objective evidence on which to expand choice.

“These data support the new guidelines and reinforce the efficacy and safety of boosted FPV as a first- line therapy in treatment-naive patients,” Dr. Eron stated.

Questions and Answers

The following section is based on discussions with Dr. Joseph Eron, Associate Professor of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill, during the scientific sessions.

Q: What is unique about this study? A: No large, randomized clinical trials have been previously undertaken comparing two ritonavir-enhanced PIs such as LPV/r and FPV/r in ARV-naive patients.

Q: What is the significance of the results? A: Our findings are likely to be useful for patient management because well-done, large randomized trials are important for clinical decisions.

Q: Ten years after the development of potent combination ARV regimens, do PI-based therapies remain a reasonable first-line regimen in treatment-naive patients? A: Triple combination therapies containing a PI have produced important reductions in HIV-related morbidity and mortality and remain a standard of care for initial treatment.