The Non-peptidic HIV Inhibitor Tipranavir Modulates Pneumocystis in vitro Growth

Italian researchers have already demonstrated that most therapeutically used HIV Protease Inhibitors (PIs), at clinically achievable concentrations, exert an anti-Pneumocystis effect in vitro, offering a potential additional anti-opportunistic benefit to the antiviral activity.

The objective of the current study was to evaluate the modulation of in vitro P. carinii (Pc) growth in presence of tipranavir (TPV), the first of a new class of non-peptidic HIV PIs that has demonstrated potent activity against multiple HIV strains, both wild-type or PI-resistant.

Monolayers of HEL 299 were infected with rat-derived Pc trophozoites. Microrganisms were allowed to grow untreated or treated with 7-3.5-0.7-0.35 mM TPV or 250 mg/mL cotrimoxazole (positive control). Multiwell plates were maintained in 10% CO2 and 5% O2 for 7 days, 4 wells/drug in at least 3 separate experiments.

On days 1,3,5 and 7, 10 mL of supernatant were collected from each well and microscopically scored. Data were reported as number of trophozoites per field and statistical analyzed with a 2-way ANOVA test and Bonferroni as post-hoc test.

Results

On day 7 a significant dose-independent Pc count reduction was seen in presence of 7 and 3.5 µM TPV (p<0.01 vs Pc untreated) but not at lower concentrations.

Pc growth inhibition reached 50-60%.

"Despite of the fact that TPV is not a peptide like other HIV PIs, for which we have already demonstrated an anti-Pneumocystis activity, it also exerted in vitro an unexpected inibitory effect on this opportunistic infection at plasmatic concentrations achievable during HAART.

"During clinical practice TPV/r reaches Ctrough values exceeding concentrations detected as inhibitory in vitro against Pc.

"Our observations suggest that it could be useful to clinically explore TPV anti-opportunistic properties in addition to its potent antiviral effect. Interestingly, in our laboratory TPV/r was detected in epithelial lining fluid at concentrations clearly exceeding EC90 in HIV patients."

L. Sacco Hospital, II Dep of Infectious Diseases, Milan, Italy.

08/18/06

Reference
F Mazza, E Tronconi, A Valerio, and others. The non-peptidic HIV inhibitor tipranavir modulates pneumocystis in vitro growth. 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract THPE0051.