INDICATIONS AND USAGE
CRIXIVAN in combination with antiretroviral agents is indicated for the treatment of HIV infection.
This indication is based on two clinical trials of approximately 1 year duration that demonstrated: 1) a reduction in the risk of AIDS-defining illnesses or death; 2) a prolonged suppression of HIV RNA.
Description of Studies
In all clinical studies, with the exception of ACTG 320, the AMPLICOR HIV MONITOR assay was used to determine the level of circulating HIV RNA in serum. This is an experimental use of the assay. HIV RNA results should not be directly compared to results from other trials using different HIV RNA assays or using other sample sources.
Study ACTG 320 was a multicenter, randomized, double-blind clinical endpoint trial to compare the effect of CRIXIVAN in combination with zidovudine and lamivudine with that of zidovudine plus lamivudine on the progression to an AIDS-defining illness (ADI) or death. Patients were protease inhibitor and lamivudine naive and zidovudine experienced, with CD4 cell counts of 200 cells/mm3. The study enrolled 1156 HIV-infected patients (17% female, 28% Black, 18% Hispanic, mean age 39 years). The mean baseline CD4 cell count was 87 cells/mm3. The mean baseline HIV RNA was 4.95 log10 copies/mL (89,035 copies/mL). The study was terminated after a planned interim analysis, resulting in a median follow-up of 38 weeks and a maximum follow-up of 52 weeks. Results are shown in Table 4 and Figures 1
& 2.
Table 4: ACTG 320
Number (%) of Patients with AIDS-defining Illness or Death
Endpoint
IDV+ZDV+L
(n=577)
ZDV+L (n=579)
IDV = Indinavir, ZDV = Zidovudine, L = Lamivudine
HIV Progression or Death
35 (6.1)
63 (10.9)
DeathThe number of deaths is inadequate to assess the impact of Indinavir on survival.
10 (1.7)
19 (3.3)
Study ACTG 320: Figure 1 - Indinavir Protocol ACTG 320 Zidovudine Experienced Plasma Viral RNA - Proportions Below 400 copies/mL
Study ACTG 320: Figure 2 - ACTG 320 Zidovudine Experienced CD4 Cell Counts - Mean Change from Baseline
Study 028, a double-blind, multicenter, randomized, clinical endpoint trial conducted in Brazil, compared the effects of CRIXIVAN plus zidovudine with those of CRIXIVAN alone or zidovudine alone on the progression to an ADI or death, and on surrogate marker responses. All patients were antiretroviral naive with CD4 cell counts of 50 to 250 cells/mm3. The study enrolled 996 HIV-1 seropositive patients [28% female, 11% Black, 1% Asian/Other, median age 33 years, mean baseline CD4 cell count of 152 cells/mm3, mean serum viral RNA of 4.44 log10 copies/mL (27,824 copies/mL)]. Treatment regimens containing zidovudine were modified in a blinded manner with the optional addition of lamivudine (median time: week 40). The median length of follow-up was 56 weeks with a maximum of 97 weeks. The study was terminated after a planned interim analysis, resulting in a median follow-up of 56 weeks and a maximum follow-up of 97 weeks. Results are shown in Table 5 and Figures 3 and 4.
Table 5: Protocol 028
Number (%) of Patients with AIDS-defining Illness or Death
Endpoint
IDV+ZDV(n=332)
IDV(n=332)
ZDV(n=332)
HIV Progression or Death
21 (6.3)
27 (8.1)
62 (18.7)
DeathThe number of deaths is inadequate to assess the impact of Indinavir on survival.
8 (2.4)
5 (1.5)
11 (3.3)
Study 028: Figure 3 - Indinavir Protocol 028 Zidovudine Naive Viral RNA - Proportions Below 500 Copies/mL in Serum
Study 028: Figure 4 -Indinavir Protocol 028 Zidovudine Naive CD4 Cell Counts - Mean Change from Baseline
Study 035 was a multicenter, randomized trial in 97 HIV-1 seropositive patients who were zidovudine-experienced (median exposure 30 months), protease-inhibitor- and lamivudine-naive, with mean baseline CD4 count 175 cells/mm3 and mean baseline serum viral RNA 4.62 log10 copies/mL (41,230 copies/mL). Comparisons included CRIXIVAN plus zidovudine plus lamivudine vs. CRIXIVAN alone vs. zidovudine plus lamivudine. After at least 24 weeks of randomized, double-blind therapy, patients were switched to open-label CRIXIVAN plus lamivudine plus zidovudine. Mean changes in log10 viral RNA in serum, the proportions of patients with viral RNA below 500 copies/mL in serum, and mean changes in CD4 cell counts, during 24 weeks of randomized, double-blinded therapy are summarized in Figures 5, 6, and 7, respectively. A limited number of patients remained on randomized, double-blind treatment for longer periods; based on this extended treatment experience, it appears that a greater number of subjects randomized to CRIXIVAN plus zidovudine plus lamivudine demonstrated HIV RNA levels below 500 copies/mL during one year of therapy as compared to those in other treatment groups.
Study 035: Figure 5 - Indinavir Protocol 035 Zidovudine Experienced Viral RNA - Mean Log10 Change from Baseline in Serum
Study 035: Figure 6 - Indinavir Protocol 035 Zidovudine Experienced Viral RNA - Proportions Below 500 Copies/mL in Serum
Study 035: Figure 7 - Indinavir Protocol 035 Zidovudine Experienced CD4 Cell Counts - Mean Change from Baseline
Genotypic Resistance in Clinical Studies
Study 006 (10/15/93-10/12/94) was a dose-ranging study in which patients were initially treated with CRIXIVAN at a dose of <2.4 g/day followed by 2.4 g/day. Study 019 (6/23/94-4/10/95) was a randomized comparison of CRIXIVAN 600 mg every 6 hours, CRIXIVAN plus zidovudine, and zidovudine alone. Table 6 shows the incidence of genotypic resistance at 24 weeks in these studies.
Table 6: Genotypic Resistance at 24 Weeks
Treatment Group
Resistance to IDV n/NN - includes patients with non-amplifiable virus at 24 weeks who had amplifiable virus at week 0.
Resistance to ZDV n/N
IDV
<2.4g/day
31/37 (84%)
2.4g/day
9/21 (43%)
1/17 (6%)
IDV/ZDV
4/22 (18%)
1/22 (5%)
ZDV
1/18 (6%)
11/17 (65%)
image of study ACTG 320 figure 1
image of study ACTG 320 Figure 2
image of study 028 figure 3
image of study 028 figure 4
image of study 035 figure 5
image of study 035 figure 6
image of study 035 figure 7