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Update on Roche's Saquinavir
SAQUINAVIR + ddC
Abstract Mo.B.410
Dr. Jay Lalezari of Mt. Zion Hospital in San Francisco presented final clinical endpoint data and early surrogate marker analysis from a study (protocol NV14256) comparing three different regimens of 600 mg three times per day of saquinavir (the "original" formulation), 0.75 mg three times per day of ddC, and the combination of saquinavir and ddC in HIV+ people with CD4 count of 50-300 cells/mm3 who were intolerant to or had greater than or equal to 4 months of prior AZT therapy and had discontinued AZT. All participants had no prior ddC nor protease inhibitor therapy.
At study entry, participants' median CD4 counts ranged from 160 to 180 cells/mm3 across the three treatment groups. Median baseline viral loads were 5.2 to 5.3 logs (about 158,500 to 199,500 copies/mL). The median duration of previous AZT use was lower in the saquinavir plus ddC group (15.7 months) than in the saquinavir alone group (17.3 months) and the ddC alone group (17 months).
Median duration on initial treatment was slightly shorter for the 314 people on ddC (11.1 months) as compared to the 318 people on saquinavir (12.9 months) and the 308 people on saquinavir plus ddC (13 months). Slightly more people in the saquinavir plus ddC group than in the two monotherapy groups successfully completed the study. People who stopped therapy due to toxicity were the highest in the ddC group. About 6 to 8% of all study participants were lost to follow up.
People in the saquinavir plus ddC group had developed significantly fewer AIDS-defining events or death (46 events) as compared to people in the ddC group (85 events) and those in the saquinavir group (77 events). The combination treatment reduced the overall risk of progression of disease by 53%. In addition, there were significantly fewer deaths in the saquinavir plus ddC group (9 deaths) as compared to the ddC group (28 deaths) and the saquinavir group (34 deaths). Treatment with saquinavir plus ddC reduced the risk of death by 72% compared with ddC alone.
Based on the analysis of data derived from the first 423 participants, people in the saquinavir plus ddC group had a higher and more sustained increase in CD4 counts, as measured by the difference from baseline averaged over 16 weeks (DAVG16), compared to those in the ddC group and in the saquinavir group. There were no significant differences in CD4 cell response between ddC and saquinavir. The median DAVG16 values were 26 cells/mm3 for the combination group, 10 cells/mm3 for the saquinavir group, and 3 cells/mm3 for the ddC group.
Similarly, combination therapy produced a greater and more sustained decrease in viral load than either monotherapy. The median DAVG16 values were -0.6 log for the saquinavir plus ddC group, -0.1 log for the saquinavir group, and -0.3 log for the ddC group.
Analysis of safety in the first 423 people showed that saquinavir was well tolerated alone or in combination with ddC after 1 year of therapy with no increase in ddC toxicities. Of the first 423 people, 3.4% had moderate to severe diarrhea in the combination group compared to 3.8% and 1.4% in the saquinavir alone group and ddC alone group, respectively. Buccal mucosa ulceration, headache, and peripheral neuropathy were also observed with the highest percentages of occurrence in the ddC group.
Dr. Lalezari concluded that the combination of saquinavir and ddC was associated with greater increases in CD4 count and greater reductions in HIV RNA than either saquinavir or ddC monotherapy. Clinical progression to new or recurrent AIDS defining event or death, and survival alone, were prolonged in the combination group compared to those on ddC alone.
SAQUINAVIR + AZT + 3TC
Abstract Mo.B.172
Dr. Alice Baurch, working at Hoffmann-La Roche during the trial, presented preliminary data from an exploratory, open-label study designed to assess the safety and effectiveness of triple combination therapy with saquinavir plus AZT and 3TC in HIV+ people with CD4 counts of 150-500 cells/mm3.
A total of 33 treatment naive, HIV+ people were enrolled with mean baseline CD4 counts of 326 cells/mm3 and mean baseline HIV RNA, as measured by the Roche RT-PCR assay, of 4.77 logs or 60,000 copies/mL. Twenty-three of the 33 participants had greater than 20,000 HIV RNA copies/mL at baseline.
All participants received triple combination therapy with 600 mg three times per day of saquinavir (the "original" formulation) plus 200 mg three times per day of AZT plus 150 mg twice per day of 3TC for 4 weeks after last patient enrollment.
The triple combination produced a mean decrease from baseline of HIV RNA of 1.96 logs or 99% reduction at week 4 in 30 people with an average maximum reduction of 2.10 logs or 99% reduction. Nineteen of the 32 evaluable participants had at least a 2 log reduction in viral load of which 15 of these people had greater than 20,000 HIV RNA copies/mL at baseline. There was a mean increase of CD4 counts of 107.5 cells/mm3 from baseline at week 4 with a maximum increase of 152.5 cells/mm3.
The triple combination was generally well tolerated. None of the participants experienced a serious adverse event or withdrawn early from the study due to an adverse event or laboratory toxicity. The most common drug-related events were asthenia, nausea, headache, and abdominal pain. Five persons experienced a severe adverse event (nausea, chest pain, fever, headache, gingivitis, and maculopapular rash). The two cases of severe nausea were deemed by the study investigator as probably related to the study medications. In terms of laboratory toxicity, one patient had an increase in liver function enzyme (grade 3 ALT and AST) which was attributed to a concomitant medication.
In conclusion, the triple combination produced a mean decline in HIV RNA of 1.96 logs and mean increase of 107.5 cells/mm3 at week 4. The observed mean maximum changes in HIV RNA and CD4 counts were 2.1 logs and 152.5 cells/mm3. No serious adverse events were reported.
SAQUINAVIR + d4T
Abstract Th.B.945
Dr. Olivier Rutschmann and his colleagues at the University Hospital in Geneva, Switzerland, reported preliminary observations on the impact of adding saquinavir to d4T in advanced HIV+ people on changes in CD4 counts and viral load.
Saquinavir (the "original" formulation) was added at a dosage of 600 mg three times per day to the regimens of 14 HIV+ individuals who had been receiving 40 mg twice per day of d4T for an average of 120 days. All patients were intolerant to or had failed therapy with the other nucleoside analogs. Twelve patients had previous AIDS defining illnesses.
Eight weeks after saquinavir was added, a median decline of 0.9 log below the median baseline viral load of 5.2 logs or about 158,000 copies/mL was achieved. The median CD4 counts increased from 33 to 90 cells/mm3 over 8 weeks, and the median CD8 counts rose from 449 to 696 cells/mm3 over the same time point.
Dr. Rutschmann noted that the combination of saquinavir and d4T was well tolerated. Two patients, however, had their treatment temporarily interrupted due to severe neuropathy.
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