The Body PRO Covers: The 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment

The Inhibitory Quotient in Tipranavir/Ritonavir

July 14, 2003

Many patients with HIV infection have multi-drug resistant virus and/or medication intolerances and have few viable treatment options. New medications are urgently needed to fill this treatment gap. One candidate agent that is moving through clinical trials and coming closer to approval is the protease inhibitor (PI) tipranavir (TPV) boosted with low-dose ritonavir (RTV, Norvir).

Previous work has shown that tipranavir/ritonavir (TPV/r) possesses good antiviral activity against virus resistant to all currently available PIs. The study reported here was funded by the maker of TPV/r, Boehringer-Ingelheim, and was presented by one of their senior scientists.

This new presentation on TPV/r was an expanded analysis of data obtained in the phase 2 trial previously reported at the February 2003 Retrovirus meeting held in Boston. In the original study (BI 1182.52), patients had to be triple-class experienced and failing therapy on a PI-based regimen. Additionally, they had to have at least one primary resistance mutation to a PI, but not more than one of the 82L/T, 84V or 90M mutations (these mutations are sometimes called UPAMs, or universal PI-associated mutations). TPV/r was substituted for the PI and following two weeks of functional monotherapy, the background regimen was optimized.

The result of this study was that TPV/r produced an approximate 1 log reduction in viral load in these highly treatment-experienced patients. This study showed that TPV/r is a promising agent for the treatment of patients with HIV infection and multi-drug resistant virus. The magnitude of antiretroviral activity in this short term evaluation was similar to that of T-20 (enfuvirtide, Fuzeon). TPV/r will soon become available on a limited basis through expanded access programs. One potential strategy for heavily treatment-experienced patients with drug-resistant virus may be the combined use of TPV/r with T-20.

This current study expanded the previous information on this compound by determining the inhibitory quotient (IQ) of TPV/r. The IQ for TPV/r may be expressed by the formula IQ = Cmin/(3.75 x 0.058 x fold WT IC50). The protein binding adjustment factor, determined by two different models of estimation, is 3.75. The 0.058 factor in the equation is derived from the TPV IC50 for wild-type virus, which is 0.058 mM. The last factor in the equation is the fold change in sensitivity of virus to TPV.

As this formula shows, IQ depends on the minimum drug concentration, protein binding correction, inherent sensitivity of virus to TPV and specific viral resistance to TPV. Thus, the IQ calculation involves the integration of viral sensitivity data and drug levels to allow predictions about the probable activity of TPV.

In this study, 134 patients had IQ determinations greater than 30 and had, on average, more than a 1 log reduction in viral load. In contrast, 34 patients with an IQ less than 30, on average, did not demonstrate a reduction in viral load. The primary conclusion of this study was that an IQ of 30 was a meaningful clinical cut-off that predicted virologic success of TPV/r in patients with PI-resistant virus.

This current study may also have broader implications for the management of HIV drug resistance. Therapeutic drug monitoring (TDM) has not yet become a standard of care for the management of HIV infection in the United States, primarily because of the paucity of studies linking drug levels with virologic outcome. This study showed that IQ calculation by use of TDM and phenotypic resistance testing was a valuable predictor of virologic response. If confirmed by future studies, TDM and IQ determination may become part of the new model for the management of HIV drug resistance.

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