1	Potential Utility of Tipranavir in Current Clinical Practice Daniel R. Kuritzkes, MD Director of AIDS Research Brigham and Woman’s Hospital Division of AIDS Associate Professor of Medicine Harvard Medical School Boston, MA
2	Current medical need for tipranavir Growing number of patients with highly drug-resistant HIV-1 Durable success of salvage therapy regimens depends on the number of active drugs Many patients and clinicians are holding back on use of drugs such as enfuvirtide while awaiting other active drugs Maintaining patients on active antiretroviral therapy delays AIDS progression and AIDS-related mortality
3	Increasing prevalence of drug resistance Prevalence of resistance increasing in treatment-naïve and experienced patient populations HCSUS cohort1 showed 43% prevalence of PI resistance in samples from 1099 viremic patients CDC surveillance of recently infected treatment-naïve patients2 showed 15.2% prevalence of resistance-associated mutations CHIC study showed 25% risk of resistance over 6 years in patients starting 3-drug antiretroviral therapy
4	Clinical impact of treatment failure Pursuing Later Treatment Options (PLATO) Collaboration 13 HIV cohorts from Europe, N.A., and Australia Retrospective evaluation of patients with 3-class virologic failure Time from 3-class failure to new AIDS event, death, or combined AIDS or death N=15,214 pts of whom 2488 experienced virologic failure 276 (11%) died 66% of deaths with known cause attributed to HIV (median CD4 at time of death was 12) Overall mortality rate: 5.5 per 100 person-years Rate was ~22 per 100 person-years in pts with baseline CD4 < 50 Relative hazard for death 2.85-fold higher for patients not on antiretroviral therapy Conclusion: Maintaining viral load < 10,000 copies/ml and CD4 > 200 prevented mortality
5	Goals of ARV therapy in treatment-experienced patients Complete suppression of plasma HIV-1 RNA remains the goal of ARV therapy Achieving this objective requires availability of active drugs to construct fully potent ARV regimens The broad activity of tipranavir against PI-resistant viruses makes it an important new ARV for clinicians seeking to construct regimens for treatment-experienced patients
6	Tipranavir Efficacy Summary Potent activity against PI resistant viruses Immune reconstitution commensurate with viral load decrease Associated with reduction in AIDS progression events (though not statistically significant) Durability requires additional active drugs in the BR
7	Grade 3 or 4 Elevated LFTs on Boosted PIs Background 6-30% of pts receiving ART develop significant LFT elevations Greater risk in those with hepatitis co-infection High-dose ritonavir (1200 mg/day) associated with increased risk Hopkins HIV clinic cohort 1161 PI-naïve patients receiving an initial PI-containing regimen 148 (12.7%) developed severe (Grade 3-4) AST/ALT increases
8	Clinical Implications of Hyperlipidemia on TPV/r Increases in cholesterol and triglycerides could increase risk of atherosclerosis with longer term exposure High triglycerides could result in pancreatitis although this has been seen infrequently with ritonavir-boosted PI regimens
9	Role of TPV/r in Treatment-Experienced Patients TPV/r has shown significant antiviral activity in patients with PI-resistant virus resulting in virologic and immunologic superiority to the CPI/arms in the RESIST trials. Increased rates of lipid elevation and hepatotoxicity were seen in the RESIST trials for TPV/r compared with CPI/r, but these risks can be managed with appropriate medical and laboratory monitoring. Use of TPV/r should be based on an assessment of the resistance profile of a patient’s virus, risk of toxicity, and availability of additional drugs with which to construct a potent ARV regimen.
10	Conclusion: Where should TPV/r be used? TPV/r, like any new drug to treat HIV-1, requires additional active drugs to obtain a durable response. For patients like those evaluated in the RESIST program, enfuvirtide may be the only remaining active drug to combine with TPV/r Use of TPV/r in populations with less extensive resistance or treatment experience than the RESIST population expands the number of active drugs available to combine with TPV/r, and therefore may increase the likelihood of achieving a durable response. TPV/r should be used in those PI-experienced patients for whom it represents the best choice of boosted PI in order to construct a maximally potent ARV regimen.