Tipranavir approved for use in combination HIV therapy

July 2005

The FDA granted accelerated approval of the investigational HIV protease inhibitor (PI) tipranavir (Aptivus, Boehringher Ingelheim) for HIV treatment in drug-resistant patients, making tipranavir the second non-peptidic PI currently available for adult patients.

The decision was made based on the FDA’s Antiviral Drugs Advisory Committee recommendation in May. The committee reviewed phase-3 clinical trial safety and efficacy data of RESIST-1 and RESIST-2, two 24-week ongoing studies.

As reported in June’s Infectious Disease News, the decision to recommend accelerated approval passed by an 11 to 3 vote; however, those who voted for approval expressed caution and stressed that further studies, specifically longer-term data, will be needed before the FDA can consider traditional approval. The committee specifically highlighted the need for studies that focus on how to monitor and manage adverse events, such as long-term liver toxicities.

There are no study results demonstrating tipranavir’s effect on clinical progression of HIV-1.

The approved dose is 500 mg administered twice a day with food, boosted by low-dose (200 mg) ritonavir (Norvir, Abbott). Tipranavir must be used with other antiretrovirals.

Treatment of tipranavir boosted by ritonavir (tipranavir/r) is indicated for adult HIV patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple PIs.

The FDA suggests physicians consider the following points when initiating tipranavir/r therapy:

• The use of other active agents with tipranavir/r is associated with a greater likelihood of treatment response.
• Genotypic or phenotypic testing and/or treatment history should guide treatment use. The number of baseline primary PI mutations affects the virologic response.
• Liver function testing should be performed at initiation of therapy with tipranavir/r and monitored frequently throughout the duration of treatment.
• Use caution when prescribing tipranavir/r to patients with elevated transaminases, hepatitis B or C coinfection or other underlying hepatic impairments.
• The extensive drug-drug interaction potential of tipranavir/r when coadministered with multiple classes of drugs must be considered prior to and during tipranavir/r use.
• The risk-benefit of tipranavir/r has not been established in treatment-naive adult or pediatric patients.

Pivotal data – RESIST trials

Tipranavir’s approval was based on the two controlled RESIST trials, which examined treatment response of tipranavir/r compared with a comparator group at 24 weeks.

Patients in the comparator group received one of several marketed ritonavir-boosted PIs. Investigators selected a comparator PI that offered patients the best opportunity for treatment response based on resistance testing.

According to the FDA, the results of the RESIST studies showed that “a statistically significant greater percentage of HIV-positive patients taking Aptivus/ritonavir achieved a treatment response versus the comparator group (40% vs. 18%).”

In addition, a significantly greater proportion of patients receiving regimens that contain boosted tipranavir achieved undetectable HIV levels than in the boosted comparator group.

At 24 weeks, 34% of patients in the tipranavir/r group and 16% of patients in the boosted comparator group achieved a viral load of less than 400 copies/mL, and 23% compared with 9% achieved less than 50 copies/mL.

Patients treated with tipranavir/r also experienced greater increases in their immune cells than the comparator group. Average change from baseline in CD4+ cell count at week 24 was +34 cells/mm³ in patients receiving tipranavir/r (n=582) compared with +4 cells/mm³ in the comparator group (n=577).

The most commonly reported adverse events of at least moderate intensity include diarrhea (10.9%), nausea (6.7%), vomiting (3.4%) and abdominal pain (2.8%). Fever (4.6%), fatigue (4%), headache (3.1%), bronchitis (2.9%), depression (2%) and rash (2%) also occurred.

The tipranavir label includes a black box warning regarding hepatoxicity, due to reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C coinfection, FDA officials said.

For more information:

• To view the Antiviral Drugs Advisory Committee meeting presentation agenda from May 19, 2005, visit the FDA’s Web site at www.fda.gov/ohrms/dockets/ac/05/slides/2005-4139-Web-Slide-Index.htm.
• Or visit Boehringer Ingelheim’s Web site at http://us.boehringer-ingelheim.com.
• RESIST-1 results. AIDS patient care STDs. 2005;19(1):58-61.
• Tipranavir favored in RESIST-2. AIDS patient care STDs. 2005;19(1):59.