Fast track — ArticlesDurable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials
Introduction
Current antiretroviral regimens for HIV-infected individuals have improved the durability of treatment responses for a substantial proportion of patients; however, for some patients, therapy fails and viral rebound occurs with the development of resistance.1 Data have shown that 21% of treatment-experienced patients and 11% of treatment-naive patients experienced triple drug class virological failure 6 years after starting highly active antiretroviral therapy.2 Furthermore, once patients have triple class virological failure, their treatment options are extremely limited and they are at increased risk of death.3 In fact, 15% of patients who fail treatment with the three main antiretroviral drug classes die within 3 years.3 Thus, there is a need for new, potent antiretroviral agents to construct active treatment regimens for patients with drug resistant HIV-1 strains who have experienced triple class treatment failure.
Tipranavir (Aptivus) is a novel non-peptidic protease inhibitor with potent in-vitro activity against most HIV-1 strains resistant to currently available protease inhibitors.4, 5, 6 Additionally, in-vitro data have shown that resistance to tipranavir develops slowly.7 When co-administered with ritonavir, the drug has shown potent antiviral activity in both treatment-naive and treatment-experienced patients.8, 9, 10, 11, 12
In the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1 and RESIST-2) studies, the efficacy and safety of tipranavir-ritonavir (500 mg/200 mg twice daily) in 1509 highly treatment-experienced HIV-1-positive patients is being assessed over 96 weeks. The 24-week analyses of each of these open-label trials showed that tipranavir-ritonavir with an optimised background antiretroviral regimen significantly improved virological responses and increased the CD4-positive T-lymphocyte (CD4) count compared with an investigator-selected, ritonavir-boosted standard-of-care comparator protease inhibitor (CPI-ritonavir) plus optimised background regimen.11, 12 Data from the combined RESIST studies showed that at the week 24 analyses, 41% of patients treated with tipranavir-ritonavir had a reduction in viral load of greater than 1 log10 copies per mL, versus 19% of participants on the standard-of-care comparator (p<0·0001). Since the inclusion criteria and study designs of RESIST-1 and RESIST-2 were similar, the 48-week data from both clinical trials could be subjected to a combined analysis. We present the pooled efficacy and safety results.
Section snippets
Patients
Patients were HIV-1 infected male and female adults (aged ≥18 years) with 3 months or longer of previous treatment with all three classes of antiretroviral drug (nucleoside reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs], and protease inhibitors), including two or more protease-inhibitor-based regimens (one being the regimen at screening) and had a viral load of 1000 copies per mL or greater of HIV-1 RNA in the plasma at baseline; there were no
Results
The trials took place between January, 2003, and April, 2004. Figure 1 shows the combined trial profile. After randomisation, 26 patients did not receive study treatment, ten because they withdrew their consent; others were lost to follow-up or did not meet inclusion criteria. Thus, the pooled efficacy population consisted of 1483 patients. Demographic and baseline characteristics, including previous use of antiretroviral drugs, were similar between the two groups in the pooled population (
Discussion
The results from this 48-week combined analysis of the two RESIST studies confirm and extend the findings of the RESIST-1 and RESIST-2 24-week analyses, showing that tipranavir-ritonavir (500 mg/200 mg twice daily) provides better viral suppression and immunological responses than an alternative comparator protease inhibitor (both in combination with an optimised background regimen) in this population with advanced disease and poor prognosis. Importantly, most patients who had a successful
References (23)
- et al.
Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes
Lancet
(2004) - et al.
Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir
Antiviral Res
(2005) Determinants of virological response to antiretroviral therapy: implications for long-term strategies
Clin Infect Dis
(2000)- et al.
Time to virological failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group
J Infect Dis
(2004) - et al.
Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class
J Med Chem
(1998) - et al.
Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor
Antimicrob Agents Chemother
(1997) - et al.
In-vitro tipranavir susceptibility of HIV-1 isolates with reduced susceptibility to other protease inhibitors
Aids
(2000) - et al.
A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients
J Acquir Immune Defic Syndr
(2004) - et al.
Pharmacokinetic characterization of different dose combinations of coadministered tipranavir and ritonavir in healthy volunteers
HIV Clin Trials
(2004) - Gathe J, Kohlbrenner V, Pierone G. Tipranavir/ritonavir demonstrates potent efficacy in multiple protease inhibitor...