The Body PRO Covers: The 8th European Conference on Clinical Aspects and Treatment of HIV-Infection

Managing HIV-1 Infection Today (Satellite Symposium)

October 28, 2001

  • Tipranavir: The First Non-Peptidic Protease Inhibitor
    Presented by P. Yeni
Despite the success of highly active antiretroviral therapy (HAART), many patients still fail that therapy and an increasing number are exhausting or have exhausted all treatment options.

Thus, clinicians and HIV-infected patients are looking forward to the development of new antiretrovirals with unique resistance profiles that do not render them cross-resistant to currently available antiretrovirals. One of these drugs, tipranavir, has been in development for quite a while, and is finally beginning to enter more advanced stages of clinical development and assessment. In a satellite symposium sponsored by Boehringer-Ingelheim, Patric Yeni gave a review of the recent data and discussed the current state of knowledge regarding tipranavir.

Tipranavir is a non-peptidic protease inhibitor (PI). It appears to be highly potent in vitro and to be synergistic with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and other protease inhibitors. Tipranavir appears to be effective against all HIV quasispecies that are resistant to a single protease inhibitor. Further, in patients with HIV harboring multiple-protease inhibitor resistance, 90% remain fully and 8% remain partially sensitive to tipranavir and only 2% are fully resistant. The precise combination of mutations for tipranavir resistance has not been elucidated at this point.

Due to pharmacokinetic problems, 200mg twice daily of ritonavir is used to boost tipranavir levels by blocking cytochrome p450. This dose of ritonavir may be responsible for, or at least add to, the common side effects associated with tipranavir, which tend to be gastrointestinal in nature with a relatively high rate of nausea, vomiting and diarrhea. It was hoped that the new formulation of tipranavir would improve bioavailability and perhaps decrease side effects, but those familiar with the tipranavir trial presented at the International AIDS Society Meeting in July, 2001 (discussed below) will remember the significant pharmacokinetic problems associated with switching from the hard fill capsules (HFC) to the soft-emulsion formulation (SEDDS).1

A prior dose ranging study was reviewed by Dr. Yeni. It used the soft-gel formuation (SEDDS) in treatment-naive patients and found that tipranavir/ritonavir decreased viral load by between 1.4 to 1.7 log10 copies/mL over 15 days of therapy. A further finding was that there was a significant difference in virologic suppression between tipranavir alone and tipranavir boosted with ritonavir.

The second trial mentioned was a trial that enrolled 41 patients (mean baseline CD4+ cell count 300 cells/mm3 and viral load 4.5 log10 copies/mL) that had clinically failed two or more protease inhibitor-containing regimens, but were non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive. The enrolled patients either received tipranavir (HFC 1,200mg BID followed by SEDDS 500mg BID) plus ritonavir (RTV) 100mg BID, efavirenz 600mg QD and 1 new nucleoside reverse transcriptase inhibitor (NRTI) or tipranavir (HFC 2,400mg BID followed by SEDDS 1,000mg BID) plus RTV (initially 200mg BID but changed to 100mg BID when tipranavir SEDDS were started), efavirenz 600mg QD and one new NRTI.

At the end of 48 weeks of therapy, the two arms were statistically equivalent in most respects regarding virologic outcome, but the trends favored the lower tipranavir-dose group. Using an intent to treat, last observation carried forward, analysis, the mean decreases in viral load for the two groups were between 1.5 and 2 log10 copies/mL. Between 41% and 68% of the patients were able to achieve a viral load less than 50 copies/mL. The mean CD4+ cell count increased by 149 to 184 cells/mm3 in the two groups.

These results are obviously not bad for a very heavily experienced group, but they are not clearly superior to the results obtained in the Abbott 957 trial that used Kaletra (lopinavir/ritonavir), efavirenz and NRTIs in an effort to salvage patients that had failed more than one PI. Furthermore, one of the significant issues involved in this study involved the change, after the study had started, from tipranavir HFC to SEDDS. This change was supposed to improve bioavailability; however, it proved to be problematic, since the trough levels of tipranavir achieved with the HFC were significantly higher than those achieved with the SEDDS. Thus, there are some significant pharmacokinetic, drug interaction and possibly adherence issues that remain to be resolved.

Even with the problems mentioned above, it appears that tipranavir has the potential to be a significant and important addition to the drug armamentarium needed to fight HIV. As mentioned by the speaker, due to its unknown resistance profile, twice-daily dosing and problematic side effects, it will most likely be used initially for salvage in patients with few other antiretroviral options. Hopefully, issues regarding dosing, resistance profile, and side effect management will be clarified as studies move forward.


  1. M. Markowitz et al. Safety and Efficacy of Tipranavir, a Non-Peptidic Protease Inhibitor, in Multiple PI-Failure Patients (BI 1182.2). 1st IAS Conference on HIV Pathogenesis and Treatment. Oral Abstract 3.


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