Studies of double-boosted protease inhibitors, where two PIs, both boosted by ritonavir, are taken together, generated interest this week at the Seventh International Conference on Drug Therapy in HIV Infection in Glasgow.
This interest follows from a previously reported study at London’s Chelsea and Westminster (C&W) Hospital, where saquinavir and atazanavir, both boosted by ritonavir, were found to have a synergistic effect on each other’s plasma levels. In this small thirty-day study of 18 patients, the addition of two different doses of atazanavir (150mg and 200mg) at different times during the study period further boosted saquinavir trough levels by 92 and 99%.
The C&W study suggested that double-boosted PIs might be a good salvage therapy for patients with resistance to all nucleosides or who had moderate PI resistance, and the first results from a clinical trial using boosted saquinavir/atazanavir as the sole HIV therapy was presented at Glasgow.
The ATSAQ study gave saquinavir, atazanavir and ritonavir at doses of 1000, 300 and 100mg respectively as the sole HIV therapy to 40 patients who were protease-inhibitor experienced (though not atazanavir-experienced) and failing on their current regimen.
The mean age of the patients, six of who were women, was 44 and 50% had an AIDS diagnosis. Their median CD4 count at baseline was 288 cells/mm3 and their median viral load was 3700 copies/ml
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They had taken an average of three previous protease inhibitors and eight previous regimens.
After a median follow-up of 32 weeks, 85% of patients had a viral load under 400 on an intent-to-treat analysis, and 60% (24 patients) below 50 copies/ml.
Three patients discontinued, two due to atazanavir-related jaundice, and one due to virological failure; 92.5% of those remaining on treatment achieved viral loads under 400 copies/ml.
The baseline viral load influenced patients’ results. The median viral load at 32 weeks with those with a baseline under 100,000 copies/ml was less than 50 copies/ml by week 12. In patients starting at over 100,000 copies/ml (most of whom were among the 15 who had taken treatment breaks before the study), median viral load was 800 copies/ml at week 12 and 90 copies/ml by week 24.
The C&W’s Marta Boffito presented findings from a substudy of her original study in which the intracellular levels of saquinavir and atazanavir were measured in twelve of the 18 patients. The mean peak level of saquinavir inside cells was found to be 4.9 times that observed in plasma, at 10,600ng/ml, and the level 24 hours after dosing was 12.6 times the plasma level, at 1,760ng/ml. The cellular half-life of saquinavir also longer than the plasma half life, at 6.9 hours versus 4.8 hours.
Atazanavir trough concentration in cells was 61% higher than plasma concentration, though peak levels and half-life were very little different.
During her presentation of these results, Boffito commented that the saquinavir boosting and cell-concentration effects were not understood. One theory was that atazanavir inhibited the pGp molecules that ‘pumps’ protease inhibitors out of cells, but measurements of pGp expression were unchanged.
At a Roche satellite meeting, the C&W’s Anton Pozniak said there were three other studies named StARS, 1-2-3 and ASK500 under way, testing various doses of boosted atazanavir/saquinavir with and without nucleoside analogues.
He also reviewed other possible double-PI combinations. Some pairs, such as lopinavir and fosamprenavir, and most PIs combined with tipranavir, are antagonistic; the PIs lower rather than raise each others’ levels. Others, such as saquinavir/lopinavir and saquinavir/fosamprenavir are additive, while saquinavir and nelfinavir are slightly synergistic, with a poster at the recent ICAAC conference finding that combining the two increased levels of the active metabolite of nelfinavir.
A preliminary study by Charles Farthing of the AIDS Healthcare Foundation found that atazanavir and fosamprenavir might have a mildly synergistic effect. And a case study of two patients by Clifford Leen of Western General Hospital, Edinburgh found that it might be possible to combine tipranavir and indinavir without the decrease in drug levels seen when tipranavir is combined with other PIs.
Rottman C et al. Atazanavir/ritonavir/saquinavir without any other antiretroviral drugs in protease inhibitor experienced patients with no reverse transcriptase inhibitor options: a 24 week cohort analysis. 7th International Congress on Drug Therapy in HIV Infection, Glasgow. 2004. Abstract P21.
Ford J, Boffito M et al. Effect of atazanavir on intracellular and plasma pharmacokinetics of saquinavir and ritonavir administered once daily in HIV infected patients. 7th International Congress on Drug Therapy in HIV Infection, Glasgow. 2004. Abstract PL6.3 (The original C&W study was also presented as abstract P272).
Khanlou H, Farthing C. Favorable interaction between atazanavir and fosamprenavir with and without ritonavir in the treatment of HIV-infected patients. 7th International Congress on Drug Therapy in HIV Infection, Glasgow. 2004. Abstract P288.
Leen C.L.S et al. Pharmacokinetics of indinavir when co-administered with tipranavir/ritonavir. 7th International Congress on Drug Therapy in HIV Infection, Glasgow. 2004, Abstract 299.