HIV Treatment Bulletin - Vol. 6, No. 1, December 2004 / January 2005
Simon Collins, HIV i-Base

One on the most anticipated studies at ICAAC was the 24-week results from tipranavir RESIST-1 study: Randomised Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir, presented by Charles Hicks from Duke University, North Carolina. RESIST-2, the European sister study in slightly more experienced and resistant patients will be presented a month later at Glasgow.

Entry criteria for this study include triple class experience including exposure to at least two PI-containing regimens. This required genotypic resistance with at least one primary resistant mutation from 30N, 46I/L, 48V, 50V, 82A/F/L/T. 84V or 90M but not more than two Universal Protease Associated Mutations (UPAMs): at positions 33, 82, 84, 90. The primary endpoint for treatment response was 1 log or greater reduction in viral load at 24 weeks, with additional secondary analysis related to changes in viral load and CD4.

The study design randomised just over 600 patients to optimised background regimen (OBR) plus either tipranavir/r or comparitor protease inhibitor (CPI). CPI (% patients) was LPV/r (61%), SQV (20%), APV (14%) and IDV (4%) with median baseline phenotypic sensitivity ranging from 76-fold (LPV/r) to 12-fold (APV). T-20 was used by 36% patients in the overall study.

Patients were generally advanced with median CD4 and viral load of 123 cells/mm³ (ranges, 1-860 and 1-1184) and viral load of 4.8 logs (range 2,3-6.1 and 2.0-6.3 logs) in the TPV and CPI arms respectively; with a median of 15 PI mutations in each arm. Gender and race balance was approximately 10% women/90% men ; 20% Black/ 80% White.

At week 4, by ITT analysis, approximately 60% and 40% of the patients in the TPV and CPI arms showed viral load reductions > 1 log, which by week 24 had fallen to 41% and 23% respectively (p-0.0001 from baseline to week 24). This highlights the difficulty of maintain responses in resistant patients without additional sensitive drugs. Median viral load change from baseline at week 24 was –0.88 and –0.28 log in the TPV and CPI arms respectively (p<0.001).

By ITT analysis, 34.7% vs 16.5% were <400 copies/mL and 25.1% vs 10.0% were <50 copies/mL in the TPV and CPI groups (both, p<0.001).

Virological failure drove the larger number of discontinuations in the CPI arm, when patients were then allowed roll-over access to tipranavir. 263/313 patient in the TPV arm remained on treatment at week 24, with 13 discontinuations due to virological failure and 25 due to side effects. 109/317 patients on the CPI arm discontinued due to failure and nine patients discontinued due to side effects.

Use of T-20 increased the chance of getting <400 or <50 copies/mL by up to 30% in either arm, with the additional increased benefit seen in patients using T-20 with tipranavir. 36% people in the study used T-20.

Median CD4 count increased by +36 cells/mm³ in the TPV and +6 cells/mm³ in the CPI arms at week 24 (P<0.001).

Side effects were evenly distributed between the two arms. Levels of grade 3/4 ALT (6.9 vs 1.3%), AST (4.6 vs 1.6%), triglyceride (22 vs 12%) and cholesterol (4 vs 0%) were all significantly higher in the TPV/r arms, but were mostly asymptomatic and resulted in few discontinuations.

The study concluded that tipranavir showed similar safety profile to other ritonavir-boosted PIs, with greater efficacy compared to CPI arms out to 24 weeks. The use of additional active drugs such as T-20 improved this virological response.

Ref: Hicks C et al. RESIST-1: a phase 3, randomised, controlled, open-labelled, multicenter trial comparing tipranavir/ritonavir (TPV/r) to and optimised comparator protease inhibitor (CPI/r) regimen in antiretroviral (ARV) experienced patients: 24-week data.

Comment

Results from the RESIST-2 study (in European patients) were presented at the Glasgow conference as this issue of HTB went to press, and were similar to this study. Only 11% patients used T-20 in either arm in RESIST-2.

Tipranavir is currently available in the UK through an expanded access programme. Doctors wishing to enroll patients in this programme or who have further questions should contact Sarah Jones at Boehringer Ingelheim 01344 741282 or 01344 742539.

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