Several studies were presented to the recent Conference on Opportunistic Infections and Retroviruses (CROI) on the recently approved protease inhibitor tipranavir/ritonavir (Aptivus). This protease inhibitor is licensed for use by heavily pre-treated individuals and presentations to CROI demonstrated the drug’s virological potency compared to other boosted protease inhibitors when used in this population. There were also a number of studies looking at the pharmacokinetics of the tipranavir in both adults and children.
Durability of response to tipranavir/ritonavir
Patients with extensive prior experience of antiretroviral therapy who take tipranavir/ritonavir are significantly less likely than treatment-experienced patients who take an alternative boosted protease inhibitor to experience treatment failure, according to 48 weeks results from the RESIST 1 and 2 studies presented to CROI in early February.
Individuals were randomised to take tipranavir or a comparator ritonavir-boosted protease inhibitor along with a background of other antiretroviral drugs which were selected after resistance testing. All the patients were highly treatment experienced, and had previously taken drugs from all the three main classes of antiretrovirals, including two protease inhibitors. Baseline immunologic and virologic characteristics were comparable between the two arms of the study. Investigators wished to determine treatment response, defined as at least a one log reduction in viral load, according to the use of tipranavir or an alternative protease inhibitor.
The risk of treatment failure was 34% lower amongst patients taking tipranavir/ritonavir than that for individuals taking a comparator boosted protease inhibitor (p
Patients who were randomised to take tipranavir were more likely to have a response to treatment if they had a baseline viral load below 10,000 copies/ml (54% treatment response, versus 26% treatment response viral load above 100,000 copies/ml) and a higher baseline CD4 cell count (42% treatment response CD4 cell count between 200 – 350 cells/mm,sup>3 versus 18% CD4 cell count below 50 cells/mm3).
Tipranavir/ritonavir has an interaction with T-20
Doctors from Turin in Italy reported an unexpected interaction between tipranavir/ritonavir and the fusion of inhibitor T-20 (enfuvirtide, Fuzeon) to CROI.
Tipranavir and T-20 are often key components of ‘salvage’ regimens. Blood samples from 39 patients taking tipranavir/ritonavir were obtained eleven to thirteen hours after dosing to determine trough concentrations of the protease inhibitors. A total of 20 of these patients were also taking T-20.
Higher mean trough concentrations of tipranavir and ritonavir were observed in patients taking T-20. The investigators also found that the half-life of tipranavir was approximately nine and a half hours in patients taking T-20 but only four hours in individuals not taking the fusion inhibitor. A longer elimination half-life was also found for ritonavir amongst patients taking T-20 (four hours versus two and a half hours).
The Italian investigators call for further studies to determine the clinical significance of their findings.
Tipranavir dose for children
Investigators from the manufacturers of tipranavir, Boehringer Ingleheim, and the PACTG 1051 study presented data to CROI that showed that a paediatric dose of tipranavir/ritonavir 290/115mg/m2 had the same steady state pharmacokinetics as the 500/200mg adult dose.
Importance of tipranavir’s genotypic inhibitory quotient
Researchers from Turin also showed that the tipranavir genotypic inhibitory quotient, rather than trough concentrations of the drug, the number of mutations conferring resistance to tipranavir, or the use of T-20, was significantly associated with an early virologic response to treatment with the drug.
A total of 27 highly treatment-experienced individuals taking tipranavir/ritonavir, 14 of whom were also taking T-20 were studied. Early virologic and immunologic response to treatment was assessed after twelve weeks.
Individuals had a median baseline CD4 cell count of 226 cells/mm3 and a median baseline viral load of 50,000 copies/ml. After twelve weeks, median viral load had fallen to 400 copies/ml and eleven individual had a viral load below 50 copies/ml. Median CD4 cell count had increased by 8 cells/mm3.
Decrease in viral load was directly correlated with tipranavir genotypic inhibitory quotient (p = 0.001), but not trough concentrations of the drug (p = 0.085), number of tipranavir resistance mutations (p = 0.062), or use of T-20 (p = 97).
A tipranavir genotypic inhibitory quotient of 13,000 or above was associated with a 50% probability of an undetectable viral load at week twelve. Seven of the nine individuals with this value achieved this outcome, whereas only four of 18 patients with an inhibitory quotient below 13,000 had a viral load after three months below 50 copies/ml, a statistically different difference in outcome (p = 0.01).
Katlama C et al. Tipranavir achives twice the rate of treatment response and prolongs durability of response vs. comparator PI in ART-experienced patients, independent of baseline CD4 cell count or viral load: week 48 RESIST 1 and 2 combined analyses. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 520, 2006.
De Requena D et al. Unexpected drug-drug interaction between tipranavir/ritonavir and enfuvirtide. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 579, 2006.
Bonora S et al. Tipranavir genotypic inhibitory quotient predicts early virological response to TPV-based salvage regimens. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 577, 2006.
Sabo JP et al. Population pharmacokinetic assessment of systemic steady-state tipranavir concentrations for HIV+ pediatric patients administered tipranavir/ritonavir: BI 1182.14 and PACTG 1051 study team. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 687, 2006.