Elsevier

The Lancet

Volume 368, Issue 9534, 5–11 August 2006, Pages 466-475
The Lancet

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Durable 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

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Summary

Background

Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients.

Methods

We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log10 copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2).

Findings

3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65·1%) patients on tipranavir-ritonavir and 192 (26·1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33·6%] vs 113 [15·3%]; p<0·0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0·0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group.

Interpretation

Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

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

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