Does Enfuvirtide Interact With Other Antiretrovirals

A review of:
Unexpected drug-drug interaction between tipranavir/ritonavir and enfuvirtide. Daniel Gonzalez de Requena, Andrea Calcagno, Stefano Bonora, Laura Ladetto, Antonio D'Avolio, Mauro Sciandra, Marco Siccardi, Olivia Bargiacchi, Alessandro Sinicco, Giovanni Di Perri. AIDS. October 3, 2006;20(15):1977-1979.

In summary, these Italian investigators looked at the concentrations of tipranavir (TPV, Aptivus) and ritonavir (RTV, Norvir) in HIV-infected patients, half of whom were also receiving enfuvirtide (T-20, Fuzeon). To their surprise -- and to mine -- they found that the levels of tipranavir + ritonavir were higher among the patients who were concomitantly receiving enfuvirtide. These elevations were significant, at approximately 50% above the values observed in patients not on enfuvirtide, which could have at least two clinical implications for tipranavir + ritonavir administration in combination with enfuvirtide: (1) increased antiretroviral activity and (2) increased toxicity.

The Bottom Line

Many studies have shown that the addition of enfuvirtide to optimized background regimens increases the probability of a virologic response in patients with multi-drug resistance. It has always been thought that this was due to the potent antiretroviral activity of enfuvirtide. This study suggests that increased concentrations of some antiretrovirals in the presence of enfuvirtide might also play a role in virologic suppression. Moreover, treatment with tipranavir + ritonavir has been associated with increases in liver enzyme levels and sometimes hepatotoxicity. Since tipranavir + ritonavir is almost always used in conjunction with enfuvirtide, these problems may be caused by increased protease inhibitor exposure resulting from drug-drug interactions between tipranavir + ritonavir and enfuvirtide.

No major clinical implications should be drawn from this study until the results are confirmed. The main, and very significant, limitation of this report is that the analysis was not a formal pharmacokinetic study; the investigators used samples that were collected for other reasons, and then the pharmacokinetics were retrospectively modeled. The authors also had difficulty finding a biologically plausible mechanism to explain the drug-drug interaction.

Other studies looking at enfuvirtide have not found significant interactions with other antiretrovirals. My feeling after reading this article is that I want to hear more about potential drug-drug interactions with enfuvirtide. However, at this point, I am not going to change my practice as a consequence of these preliminary findings