# Presentation: 758080

## Potential Utility of Tipranavirin Current Clinical Practice

**Daniel R. Kuritzkes, MD**
- Director of AIDS ResearchBrigham and Woman’s HospitalDivision of AIDS
- Associate Professor of MedicineHarvard Medical SchoolBoston, MA

## 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

## 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

- 1. Richman, D et al.  AIDS 2004; 18: 1393; 2. Bennett D, et al. 12th CROI 2005, Abstract #674.

## 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

- The PLATO Collaboration.  *Lancet* 2004; 364: 51.

## 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

## 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

## Grade 3 or 4 Elevated LFTs on Boosted PIs

**Background**
- 630% of pts receiving ART develop significantLFT 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

- Sulkowski MS, et al.  AIDS 2004; 18: 2277.

## 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

## 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.

## 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.