Tipranavir (Aptivus): approval cautiously recommended.

Tipranavir (brand name Aptivus), a protease inhibitor that usually works against HIV that is resistant to other protease inhibitors, was recommended for approval by the FDA's Antiviral Drugs Advisory Committee at a meeting on May 19, 2005. The drug, manufactured by Boehringer Ingelheim, is widely expected to be approved in June 2005.

The advisory committee recommended approval by a vote of 11-3, because of the great need for the drug, and its demonstrated efficacy (greater percentage of patients achieving a treatment response, defined for this study as at least a one log [10 fold] viral load reduction) compared with a non-tipranavir regimen, for multiple-PI resistant volunteers. But the entire committee was cautious about tipranavir, mainly because of safety "signals"--indications that there might be problems when the drug is widely used for longer times and with less physician expertise and monitoring than in the clinical trials or expanded-access program. Also, drug interactions with tipranavir can be unusually complex, making correct dosing of both tipranavir, and certain other drugs used at the same time, more difficult.

Physicians and interested patients will benefit from following the recommendations and practices of leading HIV physicians regarding tipranavir. Current information will be free and accessible to anyone at Web sites such as http://www.clinicaloptions.com/hiv, http://www.thebodypro.com, http://www.medscape.com/hiv-aidshome, and http://www.aidsmeds.com (aidsmeds.com is primarily for patients; the other three are written mainly for medical professionals).

The recommendation for approval was based on 24 weeks of data in two clinical trials, called RESIST-I and RESIST-2. These trials together tested tipranavir in well over 1,000 patients who had taken a median of 12 antiretroviral drugs and were heavily resistant (97% tested resistant to at least one protease inhibitor). These volunteers had a background regimen of approved drugs (NRTIs, NNRTIs, and/or Fuzeon [enfuvirtide, also known as T-20]) designed for them based on genotypic resistance tests, and then were randomized to receive with it boosted tipranavir or with a comparator boosted protease inhibitor. Note that based on genotypic resistance testing, 87% of the volunteers were possibly or definitely resistant to the comparison protease inhibitor. The main goal of these trials was to see if tipranavir combined with the usually inadequate background regimen helped more patients achieve at least a one-log drop in viral load. More than twice the percentage of patients achieved this drop in the tipranavir arm than in the comparison protease inhibitor arm, so tipranavir was deemed to have proven efficacy.

When considering tipranavir, here are some aspects to keep in mind (at least for the near future). Always check for recent information, because it will change due to new results from clinical trials, and new physician experience.

1. Combination with Fuzeon (enfuvirtide): Tipranavir worked much better in reducing HIV viral load in highly treatment experienced patients when combined with Fuzeon. Probably this happened not because of anything special about Fuzeon, but because HIV treatment works best when at least two drugs in a regimen are highly active against the patient's virus--and the volunteers in the two large phase III tipranavir trials from which most data are available (the trials are named RESIST I and RESIST 2) already had substantial resistance to almost all antiretrovirals available. But they had much less resistance to tipranavir because of its different resistance pattern. They also had little or no enfuvirtide resistance because this drug is in a different class--fusion inhibitors--from all other approved antiretrovirals (so there is no cross resistance), and 88% of these volunteers had no prior exposure to enfuvirtide itself.

Fuzeon is very expensive, and inconvenient to use because it is injected twice a day. When "small molecule" fusion inhibitors are available--or drugs in new classes, with different mechanisms of action--patients largely resistant to currently available antiretrovirals will have alternative choices.

2. Liver toxicity: In the RESIST 1 and 2 trials together, 10% of volunteers taking tipranavir developed new grade 3 or 4 ALT or AST elevations (compared to 3% taking a comparison boosted protease inhibitor). Very few of these volunteers had clinical symptoms of liver problems (as opposed to blood-test results) so far, after at least 24 weeks of tipranavir use. But experts are concerned, because they cannot rule out the possibility that, if patients are left with such high ALT or AST values for long periods, permanent damage might be done before symptoms develop. Monitoring will be recommended, although it is not clear what will happen if these patients have no satisfactory alternative to using tipranavir.

More studies will be necessary to determine the safety of tipranavir in patients with hepatitis B or C co-infection.

3. Cholesterol and triglyceride elevations: In the RESIST 1 and 2 trials, more volunteers taking tipranavir developed grade 3 or 4 cholesterol or triglycerides than did volunteers in the comparison arm without tipranavir.

4. Skin reactions, especially in women: In a phase I study, 53% of healthy, HIV-negative women developed a skin rash while taking tipranavir combined with an oral contraceptive. In the RESIST trials, 8.5% of HIV-positive women compared with 6.54% of HIV-positive men experienced a rash. No grade 3 or 4 rashes have been reported.

Could tipranavir be like nevirapine (another antiretroviral, coincidentally made by the same company) in that it causes a potentially serious rash that is more common in women than in men--and more common in people with a high CD4 count than in those with more advanced HIV disease (probably because this particular kind of rash depends on immune functions that are partly suppressed by HIV)? No one knows, because not enough women or people with high CD4 counts have taken tipranavir in clinical trials (where the data is collected and recorded most thoroughly than in medical practice). Boehringer Ingelheim has fully enrolled a trial of tipranavir for treatment-naive volunteers, but since only about 20% of them are women, and this trial enrolled people with advanced HIV disease, it is unlikely to give definitive answers about who is most likely to get the rash.

5. Drug interactions: We noted above that these can be complex and difficult when tipranavir is combined (either with HIV treatments or with other drugs). And the thinking at this time is that tipranavir is NOT suitable for the double-boosted protease inhibitor strategy. Here as elsewhere it will be important to watch what expert consensus develops regarding tipranavir.

Note: AIDS Treatment News did not attend the Advisory Committee hearing because of a schedule conflict. The above summary is mostly from a 43-page briefing paper prepared by FDA staff for the Antiviral Drugs Advisory Committee (dated April 22, 2005 and available at www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-01-fda.pdf and from activist reports from the meeting.

What is known about tipranavir will change rapidly, over the next few months especially. Be sure to check publication dates, and use current information.