Taking T-20 (enfuvirtide, Fuzeon) with tipranavir (Aptivus) boosted by ritonavir increases trough levels of tipranavir, but this does not lead to liver toxicities, according to data from the large RESIST randomised controlled trial published in the September edition of AIDS.
A case had previously been reported of an HIV/hepatitis B coinfected patient who was receiving treatment with tipranavir/ritonavir and T-20 experiencing serious elevations in his transaminase levels. The patient’s physicians suggested that this liver toxicity was caused by the use of T-20 increasing blood levels of tipranavir/ritonavir. They therefore recommended that patients receiving tipranavir/ritonavir and T-20 should have blood levels of tipranavir and ritonavir closely monitored and that doses of these drugs should be adjusted if needed.
This case prompted investigators from the RESIST 1 and 2 studies, a randomised controlled trial comparing the safety and efficacy of tipranavir/ritonavir with comparator protease inhibitors in heavily treatment-experienced patients, to conduct an analysis to see if use of tipranavir/ritonavir with T-20 did increase plasma levels of tipranavir and if this resulted in more cases of liver toxicity.
The RESIST 1 and 2 studies involved 746 patients randomised to take tipranavir/ritonavir and 737 patients randomised to take a comparator protease inhibitor. T-20 was taken by 23% of patients in the tipranavir/ritonavir arm and 18% of patients in the comparator arm.
Measurements of plasma trough (Cmin,ss) were available for 661 of the tipranavir-treated patients. The investigators found that patients who received T-20 with tipranavir/ritonavir had 31% higher median trough tipranavir levels than patients who received tipranavir/ritonavir without the fusion inhibitor.
It was not just trough levels of tipranavir that were increased by administration of T-20. The investigators found similar results amongst patients in the comparator arm, with Cmin,ss levels of lopinavir increased by 19% and trough levels of saquinavir by 39%.
A tipranavir Cmin,ss above 120 mumol has previously been associated with an increased risk of developing grade 3 / 4 elevations in transaminase levels. In the RESIST studies, similarly small proportions of patients taking tipranavir/ritonavir with (1.3%) or without (1.2%) T-20 had transaminase increases of this level.
The average Cmin,ss for patients taking tipranavir/ritonavir with (73%) or without (69%) T-20 fell between 20 – 80 mumol.
Furthermore, over 96 weeks, grade 3 / 4 elevations in aminotransferase (ALT) levels occurred less frequently in the patients who took tipranavir/ritonavir with T-20 (7%) than without the fusion inhibitor (13%). Similarly, ALT elevation rates were lower in the comparator arm amongst patients treated with T-20 (1%) than amongst patients who did not receive this drug (3%).
When the investigators excluded patients with hepatitis B or C coinfection, the rate of ALT elevation remained marginally lower amongst patients who received T-20 with tipranavir (6%) than those who did not receive T-20 (12%). Broadly similar results were seen in the comparator arm (1% vs. 2%).
Patients who received tipranavir/ritonavir with T-20 also had lower rates of clinical liver side-effects than patients who only received tipranavir/ritonavir (six events per 100 patient years of follow-up vs. nine events per 100 patient years of follow up). However slightly higher rates of clinical hepatic events were seen in patients taking the comparator protease inhibitor with T-20 (four events per 100 person years of follow-up) than amongst those who did not take the fusion inhibitor (three events per 100 person years).
“These results indicate that the observed increases in Cmin,ss among RESIST participants who received enfuvirtide were not associated with an increased risk of hepatotoxicity”, comment the investigators.
They conclude, “on the basis of these results from a large clinical trial, the authors discourage any recommendations to alter ritonavir or tipranavir dosing in patients receiving tipranavir/ritonavir plus enfuvirtide as this may result in clinically significant underexposure to tipranavir and loss of the antiretroviral efficacy observed with this combination of therapeutic agents.”
Raffi F et al. Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub-analysis from RESIST. AIDS 21: 1977 – 1980, 2007.