Tipranavir and ART-Experienced Patients
Tipranavir and ART-Experienced Patients
Recent data suggest that tipranavir is going to be an important drug for our antiretroviral-experienced patients. Who is likely to benefit most from this drug and how do you think it should optimally be used?
Brian Conway, MD, FRCPC
Associate Professor, Department of Pharmacology & Therapeutics, University of British Columbia; Coordinator, Downtown ID Clinic, Vancouver, Canada
Effective treatment for the antiretroviral drug-experienced patient is often challenging and problematic. The goal of highly active antiretroviral therapy (HAART) is to produce maximal virologic suppression for as long as possible; however, achievement of this goal is often impossible in HIV-infected individuals who have received a number of different treatment regimens because of the development of drug resistance. It may be that there are just not 3 agents to which a given set of isolates remains sensitive and that can be used to construct a viable regimen. Nonnucleoside reverse transcriptase inhibitors are rarely useful in highly treatment-experienced patients. At best, a single nucleoside reverse transcriptase inhibitor might retain activity. This agent is often tenofovir ( Viread ), as it was initially shown to be a relatively potent "add-on" drug in this setting. Enfuvirtide ( Fuzeon ) also may play an important role, as most HIV-infected patients have not yet received fusion inhibitors, and its use has been quite beneficial in persons with an extensive antiretroviral treatment history. But that still leaves us with the need to identify a third drug to complete the regimen.
Traditionally, this third drug had been lopinavir/ritonavir ( Kaletra ) as the protease inhibitor (PI) with the highest barrier to resistance. However, this approach has its limitations, especially in patients with prior exposure to multiple PIs. In one study of PI-experienced patients in whom the number of mutations conferring reduced susceptibility to lopinavir were considered, virologic response was observed in 91% (21/23), 71% (15/21), and 33% (2/6) of subjects with 0-5, 6-7, and 8 such mutations, respectively. Thus, in some individuals, lopinavir/ritonavir is not an effective option.
Tipranavir is a nonpeptidic PI currently in late phase 3 clinical development. On the basis of available clinical and in vitro data, it appears to remain active against viral strains that are resistant to all commercially available PIs. It has been evaluated in a comprehensive way within the RESIST ( R andomized E valuation of S trategic I ntervention in Multi-Drug Re S istant Patients with T ipranavir) clinical trial program that included patients previously treated with multiple antiretroviral drug regimens. Within this program, RESIST-1 was conducted in 620 patients in the United States, Canada, and Australia. Patients enrolled in this study were randomized to receive a 500 mg/200 mg twice-daily dose of tipranavir combined with ritonavir, or another PI combined with ritonavir at its standard boosting dose. In addition to the PI, patients received an optimized-background regimen selected on the basis of treatment history and baseline genotypic resistance testing. The use of enfuvirtide was allowed, if chosen prior to randomization. At 24 weeks, more patients on tipranavir had a -1.0 log10 copies/mL decrease in plasma viral load (41.5% vs 22.3%; P < .0001) or a plasma viral load < 400 copies/mL (34.7% vs 16.5%; P < .001). Although the study was not designed in this way, the main comparator PI turned out to be lopinavir/ritonavir. Further, it should be noted that among patients who received enfuvirtide and tipranavir, fully 47.1% had maximal virologic suppression (< 400 copies/mL), and 32.8% even exceeded the more rigorous standard of viral load < 50 copies/mL.
This study (and a companion study conducted in Europe, RESIST-2) clearly shows the benefit of tipranavir in highly experienced patients (especially if it is combined with enfuvirtide). This is the setting in which it is likely to find its most effective use in clinical practice.
Question
Recent data suggest that tipranavir is going to be an important drug for our antiretroviral-experienced patients. Who is likely to benefit most from this drug and how do you think it should optimally be used?
Response From Expert
Brian Conway, MD, FRCPC
Associate Professor, Department of Pharmacology & Therapeutics, University of British Columbia; Coordinator, Downtown ID Clinic, Vancouver, Canada
Effective treatment for the antiretroviral drug-experienced patient is often challenging and problematic. The goal of highly active antiretroviral therapy (HAART) is to produce maximal virologic suppression for as long as possible; however, achievement of this goal is often impossible in HIV-infected individuals who have received a number of different treatment regimens because of the development of drug resistance. It may be that there are just not 3 agents to which a given set of isolates remains sensitive and that can be used to construct a viable regimen. Nonnucleoside reverse transcriptase inhibitors are rarely useful in highly treatment-experienced patients. At best, a single nucleoside reverse transcriptase inhibitor might retain activity. This agent is often tenofovir ( Viread ), as it was initially shown to be a relatively potent "add-on" drug in this setting. Enfuvirtide ( Fuzeon ) also may play an important role, as most HIV-infected patients have not yet received fusion inhibitors, and its use has been quite beneficial in persons with an extensive antiretroviral treatment history. But that still leaves us with the need to identify a third drug to complete the regimen.
Traditionally, this third drug had been lopinavir/ritonavir ( Kaletra ) as the protease inhibitor (PI) with the highest barrier to resistance. However, this approach has its limitations, especially in patients with prior exposure to multiple PIs. In one study of PI-experienced patients in whom the number of mutations conferring reduced susceptibility to lopinavir were considered, virologic response was observed in 91% (21/23), 71% (15/21), and 33% (2/6) of subjects with 0-5, 6-7, and 8 such mutations, respectively. Thus, in some individuals, lopinavir/ritonavir is not an effective option.
Tipranavir is a nonpeptidic PI currently in late phase 3 clinical development. On the basis of available clinical and in vitro data, it appears to remain active against viral strains that are resistant to all commercially available PIs. It has been evaluated in a comprehensive way within the RESIST ( R andomized E valuation of S trategic I ntervention in Multi-Drug Re S istant Patients with T ipranavir) clinical trial program that included patients previously treated with multiple antiretroviral drug regimens. Within this program, RESIST-1 was conducted in 620 patients in the United States, Canada, and Australia. Patients enrolled in this study were randomized to receive a 500 mg/200 mg twice-daily dose of tipranavir combined with ritonavir, or another PI combined with ritonavir at its standard boosting dose. In addition to the PI, patients received an optimized-background regimen selected on the basis of treatment history and baseline genotypic resistance testing. The use of enfuvirtide was allowed, if chosen prior to randomization. At 24 weeks, more patients on tipranavir had a -1.0 log10 copies/mL decrease in plasma viral load (41.5% vs 22.3%; P < .0001) or a plasma viral load < 400 copies/mL (34.7% vs 16.5%; P < .001). Although the study was not designed in this way, the main comparator PI turned out to be lopinavir/ritonavir. Further, it should be noted that among patients who received enfuvirtide and tipranavir, fully 47.1% had maximal virologic suppression (< 400 copies/mL), and 32.8% even exceeded the more rigorous standard of viral load < 50 copies/mL.
This study (and a companion study conducted in Europe, RESIST-2) clearly shows the benefit of tipranavir in highly experienced patients (especially if it is combined with enfuvirtide). This is the setting in which it is likely to find its most effective use in clinical practice.
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