Aptivus (Boehringer Ingelheim)
250 mg capsules
Approved indication: HIV
Australian Medicines Handbook section 5.4.3
Protease inhibitors can be used as components in combination regimens for HIV infection (see 'New developments in antiretroviral therapy for HIV infection', Aust Prescr 2005;28:146–9). As the virus can develop resistance there is a need to find treatments which work when these regimens fail. There are already eight protease inhibitors available in Australia, so tipranavir is reserved for patients who have viral replication with HIV strains that are resistant to multiple protease inhibitors.
Although tipranavir inhibits HIV production in the same way as other protease inhibitors it is not a peptide. In vitro it retains antiviral activity against strains that have decreased susceptibility to protease inhibitors.
Tipranavir is poorly absorbed so several doses would be needed to reach effective concentrations. However, a twice-daily dose is possible if ritonavir is also taken. Ritonavir inhibits cytochrome P450 3A and the P-glycoprotein pump, significantly increasing the plasma concentrations of tipranavir. In the presence of ritonavir there is very little metabolism of tipranavir and most of the dose is excreted in the faeces. The elimination half-life is approximately six hours.
In a dose-response study 31 untreated patients were randomised to take different doses of tipranavir, with or without ritonavir, for 14 days. All three regimens reduced viral RNA concentrations, but the greatest effect was in the two regimens containing ritonavir.1
Two open-label studies have assessed regimens including tipranavir and ritonavir in patients who had previously been treated with at least two protease inhibitors. Although the studies were not complete, tipranavir was approved on the basis of the results of 24 weeks treatment. A total of 1177 patients were randomised to take tipranavir with ritonavir or another protease inhibitor with ritonavir, in addition to other antiviral drugs. At 24 weeks 34% of the tipranavir group and 15% of the comparator group had less than 400 viral copies/mL. While only 9% of the comparator group had less than 50 copies/mL, 24% of the tipranavir group had reached this concentration. There was an increase of 34 CD4 cells/mm3 with tipranavir but only 4 cells/mm3 with the comparator drugs.
Although more patients responded to tipranavir it also caused more people (8% vs 4%) to discontinue treatment because of adverse events. The most common adverse reactions are diarrhoea, nausea, vomiting, fever, fatigue and headache. Altered liver function and dyslipidaemia are more frequent than with other protease inhibitors. Tipranavir is contraindicated if there is impaired liver function so frequent monitoring is needed. Patients should not be given drugs, such as midazolam, which are cleared by cytochrome P450 3A. There are many other drugs which may interact with tipranavir, particularly as it will be used in combination with ritonavir.
Preliminary data suggest that tipranavir will have a role in treating patients with resistant HIV. To define this role genotypic testing is recommended. At present the data about which mutations may have increased resistance to tipranavir are unclear.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- McCallister S, Valdez H, Curry K, MacGregor T, Borin M, Freimuth W, et al. A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 2004;35:376-82.