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Update on Merck's Indinavir
INDINAVIR + AZT + 3TC
Abstract Th.B.931
Dr. Trip Gulick of New York University detailed the extended 48-week follow-up data from the study (protocol 035) evaluating indinavir plus AZT and 3TC. The 24-week data were first presented publicly last January at the Third Conference on Retroviruses and Opportunistic Infections held in Washington, D.C.
The primary study objective is to assess the safety and tolerability of indinavir plus AZT and 3TC. The secondary objectives are to evaluate the magnitude and duration of anti-HIV activity of the triple therapy and to assess the development of resistance to all 3 study medications.
A total of 97 individuals with at least 6 months of prior AZT therapy and CD4 counts of between 50 to 400 cells/mm3 and 20,000 copies/mL or greater of serum HIV RNA were enrolled in the study. All participants had no previous use of any protease inhibitor or 3TC at study entry and had a median duration of prior AZT therapy of 29.7 months.
Participants were randomized to receive 800 mg three times per day of indinavir plus 200 mg three times per day of AZT plus 150 twice per day of 3TC, or indinavir alone, or AZT plus 3TC.
Seven of 97 participants had dis-continued after up to 60 weeks of therapy; one person withdrew due to nausea, one due to lost to follow-up, two due to concurrent use of non-study medications (rifampin and cytotoxic chemotherapy), and three due to patient's own request (declining CD4 cell counts).
At baseline, median CD4 counts were 131.5, 156.5, and 144 cells/mm3 in the triple therapy group (32 persons), indinavir alone group (28 persons), and AZT/3TC group (31 persons), respectively. After 36 weeks of therapy, the median CD4 counts increased by 131 cells/mm3 above baseline for the 26 persons taking triple therapy at that point, compared to a 121 cells/mm3 increase among 24 persons in the indinavir alone group and a 14 cells/mm3 increase among 27 in the AZT/3TC group. At week 44, estimated median CD4 cell increases were 215, 160, and 20 cells/mm3 above baseline in the triple (7 persons), monotherapy (9 persons), and double groups (9 persons), respectively.
At baseline, median serum HIV RNA levels were 4.59 logs (39,320 copies/mL), 4.57 logs (37,335 copies/mL), and 4.64 logs (43,490 copies/mL) in the triple therapy group (32 persons), indinavir alone group (28 persons), and AZT/3TC group (31 persons), respectively.
At 36 week, the median viral load decrease was about 2 logs below baseline among the 26 participants taking the triple therapy. Among the 24 participants taking indinavir monotherapy, the median decrease was 1 log at week 36. And among the 27 participants receiving AZT/3TC at week 36, the median viral load decrease was 0.5 log.
After 48 weeks, the median viral load reduction was 2.3 logs below baseline among the 7 participants taking the triple combination. Among the 9 participants receiving indinavir monotherapy, the median decrease was 1.6 logs at 48 weeks. And among the 8 still taking AZT/3TC at the same time point, the median viral load decrease was 0.4 log. A higher proportion of participants (6 of 7 persons or 86%) receiving triple therapy for 48 weeks had fewer than 500 HIV RNA copies/mL, compared with 5 of 9 (56%) in the indinavir alone group and none of 8 (0%) in the AZT/3TC group.
The study medications were generally safe and well tolerated for up to 48 weeks of follow-up. There have been 9 cases of nephrolithiasis, two of which required dose reductions of indinavir. None of these participants had to withdrawn from the study because of nephrolithiasis. Thus far, a total of 22 elevations in total bilirubin (2.5 to 5.1 mg/dL) were observed; 12 in the triple therapy group, 9 in the indinavir alone group and 1 in the AZT/3TC group. None of these elevations were associated with clinical symptoms.
INDINAVIR + AZT
Abstract: I109 (ICAAC)
Dr. Randi Leavitt of Merck Research Laboratories presented data from interim analyses of two ongoing studies (protocol 028 and 033) comparing 800 mg three times per day of indinavir in combination with 200 mg three times per day of AZT to indinavir alone or AZT alone in antiretroviral-naive HIV+ persons. Protocol 028 is a clinical endpoint study in Brazil and protocol 033 is a one-year surrogate marker study in North America and Europe.
Both studies had similar entry criteria including exclusion for prior use of AZT and any protease inhibitor, except that CD4 entry criteria were 50 to 500 cells/mm3 for one study (protocol 033) and 50 to 250 cells/mm3 for another (protocol 028).
Mean baseline CD4 counts for the participants in both studies were 204 cells/mm3 in the indinavir alone group (161 persons), 200 cells/mm3 in the AZT alone group (166 persons), and 210 cells/mm3 in the combination group (163 persons). Mean serum viral load levels were 22,323 copies/mL in the indinavir group (155 persons), 19,917 copies/mL in the AZT group (160 persons), and 23,416 copies/mL in the combination group (161 persons).
Pooled data from both studies on mean CD4 increases for the indinavir alone, AZT alone, and indinavir/AZT combination groups were 91.2, 28.3, and 85.1 cells/mm3 above baseline after 24 weeks of therapy, respectively. The CD4 responses between either indinavir group and AZT alone group were statistically significant (p = 0.0001). No difference was noted between indinavir alone and the combination groups.
Mean viral load decreases below baseline at week 24 were 0.88 log among the 108 persons taking indinavir alone, 0.20 log among the 115 persons taking AZT alone, and 1.03 logs among the 110 persons taking indinavir/AZT group. The difference between either indinavir group and AZT alone group was statistically significant (p = 0.0001). Similarly, the difference between the indinavir alone group and the combination group was statistically significant (p = 0.024).
The proportion of participants with HIV RNA below assay detection limit after 24 weeks was 39% in the indinavir group, 4% in the AZT group, and 43% in the combination group. Individuals with high baseline viral load levels were more likely to have undetectable HIV RNA after 24 weeks when receiving combination therapy than indinavir monotherapy.
The combination of indinavir with AZT also significantly reduced the incidence of AZT associated mutations compared to AZT monotherapy over 24 weeks of therapy.
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IDV + AZT vs. AZT (p < 0.001) IDV + AZT vs. IDV (p = 1.000) IDV vs. AZT (p = 0.001) |
Dr. Leavitt concluded that the results from interim analyses of both studies showed that the addition of AZT provides small, but statistically significant, viral load suppression to indinavir therapy and that no evidence of benefit by CD4 counts was observed through the first 24 weeks of therapy.
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