A subanalysis of the RESIST studies has shown that addition of the fusion inhibitor T-20 (enfuvirtide, Fuzeon) to a drug combination including ritonavir (Norvir)-boosted tipranavir (Aptivus) allows viral loads to be suppressed to low levels in patients with very limited antiretroviral treatment options. These findings were presented at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro on July 27th.
Tipranavir recently received accelerated marketing approval in the United States for the treatment of highly treatment-experienced individuals with evidence of ongoing HIV replication. The dose of the drug is 500mg, boosted by 200mg of ritonavir, twice daily. It is a non-peptidic protease inhibitor with activity against multidrug resistant HIV.
Investigators from Boehringer Ingelheim, tipranavir’s manufacturers, randomly selected 450 samples from individuals participating in the RESIST clinical trials that compared tipranavir to other protease inhibitors. The investigators calculated the tipranavir inhibitory quotient from trough drug concentrations measured at weeks 2 and 4 in the patients, and analysed 24-week virologic responses to treatment according to inhibitory quotient and use of T-20.
The patients were highly treatment-experienced, having previously received a median of twelve antiretrovirals, including four protease inhibitors. Median baseline CD4 cell count was 155 cells/mm3 and median baseline viral load was 63,000 copies/ml.
The inhibitory quotient is a measure of the amount of drug present in a patient’s blood relative to the minimum concentration needed for the drug to have an effect. A higher inhibitory quotient means there is enough drug in the body to inhibit the virus, while a low inhibitory quotient means that drug levels are low or resistance to the drug is high.
A total of 58% of the patients who used tipranavir / ritonavir with T-20 achieved at least a 1 log10 reduction in their viral load by week 24.
Inhibitory quotient was determined for 99 patients, with a total of 57 (58%) having an inhibitory quotient above 60. After 24 weeks of treatment with tipranavir / ritonavir in combination with T-20, 81% of patients with an inhibitory quotient above 60 had achieved a reduction in their viral load of at least 1 log10 and 37% had a viral load below 50 copies/ml.
The investigators calculated that adding T-20 to tipranavir in these patients allowed viral load to be suppressed by an average of 0.91 log10 (p 10 suppression brought about by tipranavir / ritonavir itself (p
Other significant factors included having an active drug available in the optimised background regimen (-0.24 log10; p 10 (p
The investigators also found that 70% of the patients who took tipranavir / ritonavir and were previously naïve to T-20 achieved a reduction in their viral load of this magnitude after 24 weeks of treatment. However, only 31% of T-20-experienced patients achieved this outcome.
“Most protease inhibitor experienced patients who received a tipranavir / ritonavir-containing regimen achieved an inhibitory quotient of 60”, conclude the investigators. They add, “with this inhibitory quotient, 81% of patients who also included a new class of drug in their regimen achieved a week 24 viral load reduction of 1 log10 or more. Nearly 60% of these hard-to-treat patients achieved a week 24 viral load below 400 copies/ml."
The benefit of adding T-20 to a protease inhibitor-based regimen in highly treatment-experienced patients has also been observed in other studies, including trials investigating ritonavir-boosted lopinavir (Kaletra) and the investigational protease inhibitor TMC114.
Valdez H et al. Tipranavir/ritonavir 500mg/200mg BID drives 24 week viral load below 400 copies/ml when combined with a second active drug (T-20) in protease inhibitor experienced HIV-positive patients. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WeOa0205, 2005.