Tipranavir for HIV Infection

Abstract & Commentary

By Dean L. Winslow, MD, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center and Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert

Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron and is on the speaker’s bureau for Pfizer/Agouron.

Synopsis: In May 2005, the Antiviral Drug Products Advisory Committee recommended to the FDA the approval of tipranavir (TPV) for treatment of HIV infection. This new antiretroviral agent has significant activity against many strains of HIV resistant to other HIV protease inhibitors.

Source: Valdez H, et al. Tipranavir (TPV) Excretion Mass Balance and Metabolite Profile When Co-administered with Ritonavir. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. 2004. Abstract A-455.

We are now over 10 years into the era of haart (highly active antiretroviral therapy). The use of potent HIV protease inhibitors (or non-nucleoside reverse transcriptase inhibitors), generally used in combination with a background of 2 nucleoside/nucleotide analog reverse transcriptase inhibitors, almost overnight changed the natural history of HIV disease. Even individuals presenting with advanced immunosuppression and opportunistic infections when started on HAART generally demonstrated positive responses with at least partial restoration of cellular immunity. This has eliminated HIV infection as a leading cause of death in young people in the developed world.

Unfortunately, in some cases, patients have developed virologic failure due to development of HIV drug resistance. Despite the availability of HIV drug resistance testing, especially in cases where patients have failed on more than one antiretroviral regimen, it remains difficult to construct effective salvage therapy regimens due to extensive cross-resistance between drugs of the same class. The addition of the fusion inhibitor, enfuvirtide (Fuzeon), has been helpful, but seldom produces a durable antiretroviral effect unless a backbone regimen of antiretroviral agents with some activity against the patient’s virus can be constructed.

Tipranavir is a nonpeptidic HIV protease inhibitor that shows in vitro activity against many HIV isolates resistant to previously available PIs. Tipranavir is both an inducer and a substrate of the CyP3A/4 isoform of cytochrome P450, and its pharmacokinetics are significantly enhanced by co-administration with ritonavir, which acts as a potent cytochrome P450 inhibitor. Tipranavir is normally dosed in adults at 500 mg along with ritonavir 200 mg twice daily (TPV/r). Absorption, distribution, metabolism, and excretion studies1 show the following: 1) main route of elimination of 14C-labeled TPV was via the feces (82.3%); 2) primary form of circulating and excreted TPV was unchanged; 3) TPV steady state plasma concentration was achieved by day 7 of administration; 4) most common adverse effects were loose stools and mild nausea.

Drug interaction studies of TPV/r demonstrated significant increases in Cmax and AUC of rifabutin, which will necessitate reducing rifabutin dosing to 3 times per week when coadministered with TPV/r.2 Co-administration of TPV/r and clarithromycin shows moderate increases in AUC of both clarithromycin and TPV, but the increased exposure is not expected to be clinically relevant.3 In combination with fluconazole, TPV/r resulted in no significant change in fluconazole PK parameters but did result in minimal increases in TPV AUC and Cmax, which should not necessitate dose modification.4

Clinical efficacy data from the ongoing Tipranavir RESIST trials were most recently presented at this Februrary’s CROI meeting.5 This study randomized 1483 treatment experienced HIV patients to TPV/r or best comparator protease inhibitor boosted with ritonavir (CPI/r) along with optimized best background regimen, as determined by resistance testing obtained at screening. Patients were also stratified by particular CPI/r and by use of enfuvirtide. By week 24, 34.2% of TPV/r patients had HIV RNA below 400 copies/mL vs 14.9% for CPI/r. By viral load below 50 copies/mL, the percentages were 23.9% vs 9.4%, respectively. Looking at the subgroup analysis comparing TPV/r to Lopinavir/ritonavir (LPV/r), 23.9% of patients on the TPV/r arm had HIV RNA below 50 copies/mL vs 18.3% on the LPV/r arm.

Not surprisingly, the efficacy of both TPV/r and CPI/r was progressively enhanced by the number of active drugs included in the optimized background regimen. TPV/r was always superior to CPI/r, regardless of the number of background ARVs. Addition of enfuvirtide to both TPV/r and CPI/r resulted in greater treatment response, however, TPV/r was superior to CPI/r with or without enfuvirtide.

Grade 3 or 4 elevations of transaminases and of triglycerides were seen more frequently in the TPV/r arm than in the CPI/r arm.

Commentary

Tipranavir represents a significant advance in the treatment of HIV infection, and appears to be effective in many patients when included in a salvage therapy regimen. Clinicians need to remember the importance HIV resistance testing to optimize background antiretrovirals in treatment-experienced patients whether TPV/r or any other agent is used. The hefty dose of ritonavir needed to improve the pharmacokinetics of TPV is the most likely factor contributing to the gastrointestinal side effects, liver function abnormalities, and hyperlipidemia seen in TPV/r treated patients. For now, it seems prudent to hold TPV/r in reserve and use primarily when needed to construct a salvage therapy regimen, since little is known about the activity of older antiretroviral agents against TPV-resistant viruses or the ability to construct salvage therapy regimens in patients who have developed virologic failure on TPV. Consideration should be given to including enfuvirtide as part of the salvage therapy regimen, especially in patients who have failed more than one antiretroviral regimen.

References

  1. Valdez H, et al. Tipranavir (TPV) Excretion Mass Balance and Metabolite Profile When Co-administered with Ritonavir. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. 2004. Abstract A-455.
  2. Van Heeswijk R, et al. The Pharmacokinetic Interaction Between Single-Dose Rifabutin and Steady-State Tipranavir/Ritonavir 500mg/200mg (TPV/r) in Healthy Volunteers. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. 2004. Abstract A-456.
  3. Van Heeswijk R, et al. The Effect of Tipranavir/Ritonavir (TPV/r) 500 mg/200 mg on the Pharmacokinetics of Clarithromycin (CLR) in Healthy Volunteers. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. 2004. Abstract A-457.
  4. Van Heeswijk R, et al. The Effect of Tipranavir/Ritonavir 500 mg/200 mg bid (TPV/r) on the Pharmacokinetics of Fluconazole in Healthy Volunteers. 5th International Workshop on Clinical Pharmacology in HIV Therapy. 2004. Poster 4.8.
  5. Cooper D, et al. 24-Week RESIST Study Analyses: The Efficacy of Tipranavir/Ritonavir (TPV/r) is Superior to Lopinavir/Ritonavir (LPV/r), and the TPV/r Treatment Response is Enhanced by Inclusion of Genotypically Active Antiretrovirals in the Optimized Background Regimen (OBR). 12th Conference on Retroviruses and Opportunistic Infections. 2005. Poster 560.