New protease inhibitors at Buenos Aires conference

Three new protease inhibitors were presented today at the First International AIDS Society Conference on HIV Pathogenesis and Treatment in Buenos Aires: mozenavir (formerly DMP-450), tipranavir and atazanavir (formerly BMS-232632).

Mozenavir is being developed by Triangle Pharmaceuticals. Its future looked uncertain when the drug was linked to QT prolongation in animal studies, but Dr Jose Sierra today reported no difference in QT scores between individuals randomised to mozenavir or to indinavir in a 48 weeks study.

Treatment naïve individuals with viral load above 10,000 copies/ml were randomised to one of three mozenavir doses or to indinavir three times daily, with a nucleoside analogue backbone of d4T/3TC in all arms.

After 48 weeks, mozenavir 1250mg twice daily showed equivalence to three times daily dosing of mozenavir or indinavir; by intent to treat (missing equals failure) analysis approximately 70% in each group had viral load below 400 copies at week 48.

Mozenavir also showed a lower rate of cholesterol elevation than indinavir; less than 20% of mozenavir recipients at all doses had cholesterol elevations, compared to 56% of indinavir recipients. A higher incidence of neturopenia was reported in the mozenavir 1250mg bid group compared to other treatment groups (20%).

Mozenavir is unusual among protease inhibitors in that its metabolism is not inhibited by other PIs, preventing the possibility of boosting its plasma levels by dosing with ritonavir, a dosing strategy being pursued with some other protease inhibitors such as tipranavir. The Cmin of mozenavir is approximately ten times higher than the IC90, but at this stage, data on the loss of drug susceptibility conferred by various genotypic resistance patterns is unavailable. Test tube studies suggest that the V82F mutation, commonly associated with indinavir or ritonavir treatment, is also associated with reduced mozenavir susceptibility.

The drug is likely to be dosed as one tablet twice daily.

Tipranavir

Dr Martin Markowitz presented long awaited data on the efficacy of tipranavir in protease inhibitor-experienced individuals. All participants had experienced virological failure with at least two protease inhibitors, most commonly saquinavir (>90%) and nelfinavir (53%-65% according to arm) or ritonavir (56% or 63% by arm).

Participants were initially randomised to receive either 1200mg of tipranavir twice daily plus 100mg of ritonavir, or 2400mg of tipranavir twice daily plus 200mg of ritonavir. All participants also received efavirenz 600mg once daily and two nucleoside analogues. The tipranavir doses were reduced to 500 or 1000mg when a new SEDDS formulation became available, and the ritonavir dose was reduced to 100mg at this time. Baseline viral load averaged 4.51 log in the 1200mg group and 4.46 log in the 2400 mg group.

Nineteen patients were randomised to the 1200mg arm and 22 to the 2400mg arm (there was no comparator arm in this study). At week 48, 68.4% of the 1200mg group and 40.9% of the 2400mg had viral load below 50 copies/ml. A total of ten patients out of 41 discontinued treatment during this study: four due to lack of efficacy, two due to adverse events and four lost to follow up or due to protocol violations.

No significant difference was reported in the rate of viral load reduction when participants were stratified by the number of baseline protease inhibitor mutations. Those with more than five mutations (qualifying mutations not reported) had comparable viral load reductions (-2.59 log vs 2.80 log) to those with five mutations or less by As Treated analysis.

The poorer performance in the 2400mg arm was due to poor tolerability of the hard fill capsules used in the earlier part of the study and consequent reduced adherence, according to Dr Markowitz, but of concern is the poorer bioavailability of the SEDDS formulation; average plasma concentrations lay just above the target concentration of 25 micromolar.

High rates of gastrointestinal side effects were reported; 59% of patients experienced dairrhoea and 31% of patients reported nausea, and around 20% of patients experienced substantial triglyceride elevations, suggesting that despite a different mode of action, tipranavir is similar to currently licensed protease inhibitors in its effects on lipids. No data on body fat changes were presented.

Atazanavir

In contrast, Bristol Myers Squibb continue to report a lack of cholesterol and triglyceride elevations in their ongoing study of BMS-232632, now known as atazanavir. This study is comparing 400mg or 600mg of atazanavir twice daily with nelfinavir 1250g twice daily. Four hundred and three treatment-naïve patients have now been followed for more than 24 weeks, with data available on 305 to week 32.

At week 24, 72% of the atazanavir 400mg group and 72% of the atazanavir 600mg group had viral load below 400 copies/ml by intent to treat (missing equals failure) analyis, compared with 63% of the nelfinavir group. This difference was non-significant. The proportions with viral load below 50 copies were substantially smaller, at around 40% for each group.

Dose reduction in the 600mg group was necessary in 19 patients due to grade 4 bilirubin elevations (although only 4 cases of clinical jaundice were reported in this arm). The risk of bilirubin elevations in individuals receiving atazanavir is related to genetic susceptibility, and not all patients are at risk of this side effect, but the incidence of grade 3 or 4 hyperbilirubinemia was high in both atazanavir groups (32% in the 400mg group and 52% in the 600mg group).

No significant triglyceride or cholesterol elevations were seen in the atazanavir groups; indeed, by week 32, the atazanavir groups showed a median 10-20mg/dL reduction in triglyceride levels, compared to a triglyceride elevation of approximately 40 mg/dL in the nelfinavir group.