Tipranavir (Aptivus) is able to reduce HIV viral loads by up to 1.5 log₁₀ when boosted with a low dose of ritonavir (Norvir). This small dose of ritonavir can substantially improve the drug’s pharmacokinetic profile and reduce the daily pill burden^[1]. However, tipranavir is only licensed for use in patients with substantial treatment experience and resistance to other protease inhibitors.

In study BI 1182.51, participants had experienced virological failure with at least two protease inhibitors, most commonly saquinavir (Invirase), nelfinavir (Viracept) and ritonavir, before receiving tipranavir. Forty-one people were initially randomised to receive either 1200mg tipranavir twice daily plus 100mg ritonavir, or 2400mg tipranavir twice daily plus 200mg ritonavir. All participants also received efavirenz (Sustiva) 600mg once daily and two nucleoside reverse transcriptase inhibitors (NRTIs). The tipranavir doses were reduced to 500 or 1000mg when a new formulation became available, and the ritonavir dose was reduced to 100mg.

After 48 weeks, 68% of the low-dose group and 41% of the high-dose group had viral loads below 50 copies/ml. A total of ten patients out of 41 discontinued treatment during this study, only two of whom discontinued due to side-effects^[2]. The poorer performance in the high-dose arm was due to poor tolerability of the hard fill capsules used in the earlier part of the study which reduced adherence.

Study BI 1182.52 further evaluated ritonavir-boosted tipranavir in 216 people who had failed at least two protease inhibitors and had evidence of protease inhibitor-associated resistance mutations. Dosage and the number of baseline protease inhibitor resistance mutations had a dramatic influence on treatment outcomes. People with more than two baseline protease inhibitor resistance mutations had a significantly poorer response after two weeks of treatment. Viral load fell by up to 1.4 log₁₀ in people with fewer than three protease inhibitor mutations who took 500mg tipranavir boosted with 200mg ritonavir twice a day, leading to selection of this dose for further study^[3][4].

The phase III RESIST-1 and 2 studies of treatment-experienced patients were pivotal in the drug’s approval. Patients with at least three months experience of each of the major drug classes, excluding fusion inhibitors were randomised to receive ritonavir-boosted tipranavir or a boosted protease inhibitor chosen with the aid of a genotypic resistance test. They also received a background regimen optimised by resistance testing. All of the patients had a resistance test showing evidence of at least one of the major protease inhibitor resistance mutations 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V and 90M, or at least two of the mutations at codons 33, 82, 84 and 90.

In RESIST-1, 25% of the tipranavir group had viral loads below 50 copies/ml, compared to 10% in the comparator group at week 24. Liver enzyme elevations were more common in the tipranavir group (7 vs. 1%)^[5].

In RESIST-2, 23% of the tipranavir group and 9% of the boosted protease inhibitor group had viral loads below 50 copies/ml at week 24. Twelve per cent of the patients were taking T-20 as part of their optimised background regimen^[6]. Liver enzyme and cholesterol elevations were more frequent in the tipranavir group but did not result in a higher rate of treatment discontinuation.

Taken together, year-long follow-up of the RESIST studies showed a greater percentage of patients taking tipranavir achieved a viral load fall of at least 1 log₁₀ than patients in the comparator protease inhibitor arm. More patients also achieved undetectable viral loads after 48 weeks. This was coupled with greater increases in CD4 cell counts, although the patients taking tipranavir were more likely to experience side-effects such as gastrointestinal problems, raised liver enzymes and altered blood fat levels^[7]. Analysis of the studies’ data has shown that patients with any number of protease inhibitor mutations at baseline had a better outcome than those in the comparator protease inhibitor arm, emphasising tipranavir’s strong position in salvage treatment^[8].

These studies have now provided evidence of tipranavir’s efficacy in salvage therapy over comparator protease inhibitors after a year’s treatment, with patients starting with a viral load below 10,000 copies/ml and those with a higher CD4 cell count having a better chance of viral suppression^[9].

Combining tipranavir with the fusion inhibitor T-20 (enfuvirtide, Fuzeon) allows viral loads to be suppressed to very low levels in highly treatment-experienced patients. A sub-analysis of the RESIST studies has shown that the addition of T-20 allowed viral loads to be suppressed by a further 0.91 log₁₀ on average, over the 1.25 log₁₀ brought about by ritonavir-boosted tipranavir itself after 24 weeks. This effect was greater in patients who had not taken T-20 before^[10]. A small study has found that tipranavir’s rate of clearance from the body may be slowed by T-20, although further studies are needed to determine whether this is responsible for its effects in clinical trials^[11].

The effectiveness of tipranavir is also increased by more active drugs in the treatment combination^[12].

Tipranavir was being studied in treatment-naive patient populations, but this study was stopped after ritonavir-boosted tipranavir was found to cause high rates of liver enzyme elevations at the licensed dose, and to be less effective at reducing viral loads than ritonavir-boosted lopinavir (Kaletra), when 100mg ritonavir was used to boost tipranavir. This means that it is unlikely that ritonavir-boosted tipranavir will become an option for first-line treatment of HIV infection.

Boehringer Ingelheim has agreed to continue to investigate the use of tipranavir in children, women and patients co-infected with hepatitis.