Tipranavir in the Protease Inhibitors Arena

Highly active antiretroviral therapy (HAART) has become the standard for treating HIV infection. HIV protease inhibitors (PIs) have been used as amajor component of theHAART regimens over the past 10 years, along with nucleoside and non-nucleoside reverse transcriptase inhibitors. The introduction of these regimens resulted in an appreciable decline in morbidity and mortality due to HIV infection. Tipranavir (TPV) is a nonpeptidic PI, approved by the US FDA and the European Medicines Agency for the treatment of HIV infection. The structure of this molecule is a sulfonamidesubstituted dihydropyrone. Similar to other PIs, TPV binds directly to HIV aspartyl protease, disrupting the catalytic site of the enzyme and preventing protease-dependent cleavage of HIV gag and gag-pol polyproteins into smaller functional proteins. For this reason, the chance to develop resistance is not so easy. TPV is active against PI multidrug resistant viruses and it has been very difficult to corner HIV to mutate through subsequent in vitro passages. TPV plus lowdose ritonavir (TPV/r) is used in combination with other antiretroviral (ARV) drugs. The advantages of this approach include raising trough drug concentrations, minimizing inter-patient variability, prolonging drug elimination half-life, and reducing pill burden. Results in the efficacy of the selected dose of TPV/r (500/200mg twice daily) were quite encouraging in extensively treated HIVinfected patients. TPV is generallywell tolerated; the most frequent adverse events were in the gastrointestinal system and laboratory abnormalities, such as alteration of the lipid profile and liver function. Darunavir (DRV) is another new-generation nonpeptidic HIV protease inhibitor approved by the FDA, used with low doses of ritonavir (600/100mg twice daily) for pharmacologic enhancement (boosting). It has demonstrated potent activity against multidrug-resistant HIV in heavily treatment-experienced patients with HIV infection. Like TPV, DRV needs multiple mutations in the HIV protease for the virus to build a significant resistance to these drugs. For this reason, TPV and DRV exhibit a high genetic barrier to the emergence of novel resistant strains. Boosted DRV is generally well tolerated, with a lower incidence of diarrhea and modification of the lipid profile. The aim of the POTENT trial was the headto-head comparison of the safety and efficacy of TPV versus DRV plus a low dose of ritonavir, eachwith an optimized background regimen (OBR) in triple-class-experienced HIV-infected patients, being resistant to more than one PI. This study was designed in 2007 (20 September) to enroll and treat 800 HIV-1-positive patients, randomly assigned (1 : 1) to one of the two arms: TPV/r (500/200mg twice daily) or DRV/r (600/100mg twice daily), with a treatment period of 50 weeks. Both drugs were administered in combination with another selected ARV, based on patient therapeutic history (and virtual phenotype screening results). The major shortcoming of the POTENT trial was the very low enrollment numbers: only 39 patients (5% of the planned number) were randomized and received drugs prior to early termination of the study (1 July 2008). The data from the trial, due to poor patient enrollment and premature termination, are insufficient to assess primary and secondary previously established endpoints. For this reason, statistical tests were not applied to this collected observational data. COMMENTARY Drugs R D 2011; 11 (4): 291-293 1179-6901/11/0004-0291