Long-Term Safety and Durable Antiretroviral Activity of
Long-Term Safety and Durable Antiretroviral Activity of
Objective: Combination antiretroviral therapy with lopinavir/ritonavir (LPV/r) has been highly effective in clinical trials. Results of long-term therapy with LPV/r-based regimens have not been previously reported. This study describes the 4-year (204-week) safety and antiretroviral activity of LPV/r-based treatment in antiretroviral-naive individuals.
Design: Long-term, open-label follow-up of a phase II, prospective, randomized, multicenter trial.
Methods: A group of 100 antiretroviral-naive HIV-infected patients were randomized to one of three blinded doses of LPV/r [200/100 mg (n = 16), 400/100 mg (n = 51), or 400/200 mg (n = 33)] with stavudine 40 mg and lamivudine 150 mg every 12 hours. After 48 weeks, LPV/r was dosed open-label at 400/100 mg every 12 hours with stavudine and lamivudine.
Results: Mean baseline plasma HIV-1 RNA and CD4 cell count were 4.9 log10 copies/ml and 338 × 10 cells/l, respectively. At week 204, 72 patients remained on study, 70 of whom had HIV-1 RNA < 50 copies/ml (70% by intent-to-treat analysis). Twenty-eight patients discontinued therapy prior to week 204 because of adverse events (n = 10), lost to follow-up (n = 9), or other reasons (n = 9). Of 15 patients who met protocol-defined criteria for virologic failure, seven remained on the study regimen and their HIV-1 RNA was re-suppressed to < 50 copies/ml at week 204. Genotypic analysis of rebound viral isolates was available from 10 patients, including all eight patients who discontinued the study prematurely. No isolate demonstrated primary or active site mutations in protease. The most common adverse events were gastrointestinal symptoms and lipid elevations.
Conclusions: LPV/r-based therapy provides durable antiretroviral response and is generally well tolerated through 204 weeks of therapy.
The introduction of potent antiretroviral agents into clinical practice has resulted in marked improvement in survival as a consequence of improved suppression of HIV-1 replication and consequent recovery of immune function. Among the most potent of such agents is lopinavir (a HIV-1 protease inhibitor) co-formulated with ritonavir (a cytochrome P450 3A4 enzyme inhibitor) to enhance its pharmacokinetic profile (LPV/r). The resulting mean trough concentrations of lopinavir are at least 75 times as high as the protein-binding corrected IC50 (concentration to inhibit 50% replication in vitro) for wild-type HIV. In a 48-week double-blind, randomized trial, conducted in antiretroviral-naive patients, LPV/r demonstrated superior virologic efficacy when compared with nelfinavir, both dosed with stavudine and lamivudine.
Despite numerous reports of the efficacy of various combinations of antiretroviral agents, there are few long-term virologic, immunologic, and tolerability data derived from prospective clinical trials of therapeutic regimens. This report describes a 4-year follow-up of individuals enrolled in the first trial of LPV/r in antiretroviral-naive, HIV-infected patients.
Objective: Combination antiretroviral therapy with lopinavir/ritonavir (LPV/r) has been highly effective in clinical trials. Results of long-term therapy with LPV/r-based regimens have not been previously reported. This study describes the 4-year (204-week) safety and antiretroviral activity of LPV/r-based treatment in antiretroviral-naive individuals.
Design: Long-term, open-label follow-up of a phase II, prospective, randomized, multicenter trial.
Methods: A group of 100 antiretroviral-naive HIV-infected patients were randomized to one of three blinded doses of LPV/r [200/100 mg (n = 16), 400/100 mg (n = 51), or 400/200 mg (n = 33)] with stavudine 40 mg and lamivudine 150 mg every 12 hours. After 48 weeks, LPV/r was dosed open-label at 400/100 mg every 12 hours with stavudine and lamivudine.
Results: Mean baseline plasma HIV-1 RNA and CD4 cell count were 4.9 log10 copies/ml and 338 × 10 cells/l, respectively. At week 204, 72 patients remained on study, 70 of whom had HIV-1 RNA < 50 copies/ml (70% by intent-to-treat analysis). Twenty-eight patients discontinued therapy prior to week 204 because of adverse events (n = 10), lost to follow-up (n = 9), or other reasons (n = 9). Of 15 patients who met protocol-defined criteria for virologic failure, seven remained on the study regimen and their HIV-1 RNA was re-suppressed to < 50 copies/ml at week 204. Genotypic analysis of rebound viral isolates was available from 10 patients, including all eight patients who discontinued the study prematurely. No isolate demonstrated primary or active site mutations in protease. The most common adverse events were gastrointestinal symptoms and lipid elevations.
Conclusions: LPV/r-based therapy provides durable antiretroviral response and is generally well tolerated through 204 weeks of therapy.
The introduction of potent antiretroviral agents into clinical practice has resulted in marked improvement in survival as a consequence of improved suppression of HIV-1 replication and consequent recovery of immune function. Among the most potent of such agents is lopinavir (a HIV-1 protease inhibitor) co-formulated with ritonavir (a cytochrome P450 3A4 enzyme inhibitor) to enhance its pharmacokinetic profile (LPV/r). The resulting mean trough concentrations of lopinavir are at least 75 times as high as the protein-binding corrected IC50 (concentration to inhibit 50% replication in vitro) for wild-type HIV. In a 48-week double-blind, randomized trial, conducted in antiretroviral-naive patients, LPV/r demonstrated superior virologic efficacy when compared with nelfinavir, both dosed with stavudine and lamivudine.
Despite numerous reports of the efficacy of various combinations of antiretroviral agents, there are few long-term virologic, immunologic, and tolerability data derived from prospective clinical trials of therapeutic regimens. This report describes a 4-year follow-up of individuals enrolled in the first trial of LPV/r in antiretroviral-naive, HIV-infected patients.
Source...