Once daily head to head shows efavirenz still top

The first comparison of once daily protease protease inhibitor dosing with efavirenz, the once daily NNRTI, shows that efavirenz is better tolerated and more likely to control viral load than saquinavir/ritonavir.

Twenty four week data from the FOCUS study were presented at this week’s 41st Interscience Conference on Antimicrobial and Antiviral Chemotherapy (ICAAC) in Chicago, by Dr Julio Montaner of the University of British Columbia, Vancouver. This is a 48 week study.

The study randomised 159 treatment-naïve patients to receive either efavirenz or saquinavir (1600mg boosted with 100mg of ritonavir) once daily, together with two nucleoside analogues, which were not dosed once daily. The average baseline viral load was 4.78 log (approximately 58,000 copies/ml) and the average CD4 cell count was around 350 in each group (in other words, a group of patients not strongly encouraged to start treatment under current UK treatment guidelines).

By intent to treat analysis (which measures the viral load of everyone who started treatment, regardless of whether they were still on the assigned treatment at week 24), 81% of those who received efavirenz had viral load below 50 copies (undetectable) at week 24, compared with 61% of those who received saquinavir. This difference was statistically significant (p=0.008).

The poorer performance of saquinavir was driven largely by discontinuations related to side effects and to the large number of pills (once daily saquinavir/ritonavir requires patients to take nine large capsules at one time, compared to three small efavirenz capsules). Nearly one third of those randomised to saquinavir/ritonavir stopped their original treatment in the first six months of the study (compared to 20% in the efavirenz arm). Eight patients stopped saquinavir due to adverse events compared to one discontinuation due to adverse events in the efavirenz arm. Thirty four per cent of all those who started saquinavir experienced nausea, vomiting or diarrhoea.

Interest in 48 week data from this study will focus on the long-term tolerability of once daily saquinavir/ritonavir and its effects on cholesterol and triglyceride levels.

Whilst these data will be disappointing for Roche, the manufacturer of saquinavir, which had hoped to build a new niche for saquinavir as a well tolerated once daily protease inhibitor, they do suggest that once daily saquinavir/ritonavir is a viable option. Although cross study comparisons should always be made with caution, it is worth noting that the virological perfomance of saquinavir/ritonavir in this study was considerably better than that of Bristol Myers Squibb’s new once daily protease inhibitor atazanavir in a recent comparison study (31% below 50 copies at 48 weeks in study AI424-008).

Once daily saquinavir with atazanavir

Atazanavir is being tested in combination with saquinavir in people who have experienced the failure of a first PI-containing regimen. Preliminary 24 week results from this study were also presented as a late breaker at ICAAC, and showed that patients who experienced triglyceride elevations as a result of their first PI regimen saw them fall after the switch to atazanavir and saquinavir. Cholesterol reductions were less pronounced.

Eighty five patients were randomised to receive either 400 or 600mg of atazanavir once daily together with 1200mg of saquinavir once daily, or to receive saquinavir/ritonavir (400/400mg) twice daily. This study was in effect comparing dual protease inhibitor treatment, since ritonavir was being dosed at a level known to have an antiviral effect.

At week 24, the average viral load reduction by on treatment analysis was –1.28 (n=29), -1.17 (n=22) and –1.5 log (n=13) respectively, a non-significant difference. However, triglyceride reductions of 23 and 21% in the atazanavir/saquinavir arm were not mirrored in the ritonavir/saquinavir arm, where triglyceride levels rose by an average of 90%. Cholesterol changes were less pronounced in each arm; while the average cholesterol level rose by 10% in the saquinavir/ritonavir group, total cholesterol fell by 1% and 9% respectively in the saquinavir/atazanavir arm.

One caution regarding the findings of this study relates to the high rate of discontinuations; 43% of those randomised to ritonavir/saquinavir had discontinued the assigned treatment by week 24, compared with 21 and 25% in the atazanavir/saquinavir arms. Discontinuation was driven by adverse events: gastrointestinal in the saquinavir/ritonavir group, jaundice and hyperbilirubinemia in the atazanavir group (13 and 19% discontinued due to jaundice at the respective atazanavir doses). However diarrhoea and nausea were not absent in the atazanavir/saquinavir groups; 31% of patients experienced these side effects in the atazanavir/saquinavir groups.

Also, the numbers evaluable for the purposes of measuring triglyceride levels were considerably smaller than those evaluable for cholesterol levels (15, 13 and 8 respectively for triglycerides, compared to samples for all participants on treatment at week 24 for total cholesterol). Intent to treat data on lipid levels and virological response from a larger group of patients will be awaited with interest, as will baseline resistance data and virologic response according to phenotypic and genotypic profile.