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Double Protease Inhibitor Therapy
RITONAVIR + SAQUINAVIR
Abstract Th.B.934
At the Vancouver conference in July, Dr. William Cameron of the University of Ottawa reported preliminary results from a multi-center, open-label, exploratory study of ritonavir in combination with saquinavir in HIV+ individuals with CD4 counts between 100 to 500 cells/mm3.
The study was initiated based on laboratory and pre-clinical demonstration in animal models in which the combination of ritonavir and saquinavir achieved synergistic activity. Specifically, ritonavir has been shown to enhance and sustain saquinavir plasma levels in dogs and rats. In addition, data from laboratory experiments revealed that ritonavir and saquinavir non-overlapping viral resistance profiles.
The study objectives were to assess several dose combinations of ritonavir and saquinavir in HIV+ individuals and to evaluate long-term safety, tolerance and effectiveness of the combination therapy.
At study entry, all participants had discontinued nucleoside therapy and were randomized to receive 400 mg twice daily of ritonavir plus 400 mg twice daily of saquinavir (30 persons) or 600 mg twice daily of ritonavir plus 400 mg twice daily of saquinavir (30 persons) in Group I. After two weeks of safety assessment based on the doses in Group I, additional participants were enrolled in Group II and randomized to receive 400 mg three times daily of ritonavir plus 400 mg three times daily of saquinavir (30 persons) or 600 mg twice daily of ritonavir plus 600 mg twice daily of saquinavir (30 persons).
Dr. Cameron presented preliminary data from participants receiving the combined protease inhibitors in Group I. Among the 33 persons taking 400 mg twice daily ritonavir plus 400 mg twice daily saquinavir, the mean and median HIV RNA levels at baseline were 4.53 logs or 33,884 copies/mL and 4.63 logs or 42,657 copies/mL, respectively. And among the 30 persons taking 600 mg twice daily ritonavir plus 400 mg twice daily saquinavir, the mean and median viral load levels were 4.68 logs or 47,863 copies/mL and 4.65 logs or 44,668 copies/mL.
At baseline, mean and median CD4 counts were 274 and 249 cells/mm3, respectively, in the 400 mg twice daily ritonavir plus 400 mg twice daily saquinavir group. For the 600 mg twice daily ritonavir plus 400 mg twice daily ritonavir group, mean and median baseline CD4 counts were 299 and 255 cells/mm3, respectively.
Viral load levels were reduced by 1.6 , 2.1, and 2.2 logs below baseline after 2, 4 and 6 weeks of therapy with the 400 mg twice daily ritonavir plus 400 mg twice daily saquinavir. Similarly, viral load levels decreased by 1.6, 2.2, and 2.6 logs below baseline after 2, 4, and 6 weeks of therapy with 600 mg twice daily ritonavir plus 400 mg twice daily saquinavir, respectively.
CD4 counts were increased by 25, 50, 80 cells/mm3 above baseline after 2, 4, and 6 weeks of therapy with 400 mg twice daily ritonavir plus 400 mg twice daily saquinavir, respectively. Among those taking 600 mg twice daily ritonavir plus 400 mg twice daily saquinavir, CD4 count increases were 70, 85, and 100 cells/mm3 above baseline at week 2, 4, and 6, respectively.
Among the 33 persons taking 400 mg twice daily ritonavir plus 400 mg twice daily saquinavir, there were 25 episodes of circumoral paresthesia (tingling sensation around the mouth), 21 diarrhea, 14 fatigue, 12 nausea, and 7 flushing. Slightly higher frequency of , but not statistically significant, adverse symptoms were noted with the 600 mg twice daily ritonavir plus 400 mg twice daily saquinavir regimen. Among the 32 persons taking that regimen, there were 27 cases of circumoral paresthesia, 24 diarrhea, 14 fatigue, 12 nausea, and 17 flushing.
Few severe (grade 3 or 4) laboratory abnormalities were observed with the two dose regimens. However, higher number of increases in triglyceride levels (5) were associated with the 600 mg twice daily ritonavir plus 400 mg twice daily saquinavir, compared with those (2) in the 400 mg twice daily ritonavir plus 400 mg twice daily saquinavir group. Two persons had discontinued their participation in the study.
Dr. Cameron concluded that, based on these preliminary observations, therapy with ritonavir and saquinavir resulted in high and sustained plasma levels of the two protease inhibitors. Furthermore, the combination therapy rapidly produced a dramatic suppression of viral load and increase in CD4 cell counts. The study medications are generally well tolerated, he noted.
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