Lamivudine (Page 6 of 7)

14 CLINICAL STUDIES

The use of lamivudine is based on the results of clinical studies in HIV-1-infected patients in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-l RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

14.1 Adults

Clinical Endpoint Study: NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of patients] or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-l-infected adults with 25 to 250 CD4+ cells/mm 3 (median = 122 cells/mm 3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on study was 12 months. Results are summarized in Table 8.

Table 8. Number of Patients (%) With at Least One HIV-1 Disease Progression Event or Death

Endpoint Current Therapy (n= 460) Lamivudine plus Current Therapy (n=896) Lamivudine plus an NNRTI a plus Current Therapy (n=460)
HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%)
Death 27 (5.9%) 23 (2.6%) 14 (3.0%)

a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States
Surrogate Endpoint Studies: Dual Nucleoside Analogue Studies: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These studies demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple- drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.
Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive Adults: EPV20001 was a multi-center, double-blind, controlled study in which patients were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm 3 (median = 362 cells/mm 3), and median baseline plasma HIV-1 RNA of 4.66 log 10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9. Figure 2. Virologic Response Through Week 48, EPV20001 ab (Intent-to-Treat)

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a Roche AMPLICOR HIV-1 MONITOR.
b Responders at each visit are patients who had achieved and maintained
HIV-1 RNA<400 copies/mL without discontinuation by that visit. Table 9. Outcomes of Randomized Treatment Through 48 Weeks (Intent-to- Treat)

Outcome Lamivudine300mg Once Daily plus Zidovudine plus Efavirenz (n = 278) Lamivudine150mg Twice Daily plus Zidovudine plus Efavirenz (n = 276)
Responder a 67% 65%
Virologic failure b 8% 8%
Discontinued due to clinical progression <1% 0%
Discontinued due to adverse events 6% 12%
Discontinued due to other reasons c 18% 14%

a Achieved confirmed plasma HIV-1 RNA <400 copies/mL and maintained through 48 weeks.
b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through
Week 48.
c Includes consent withdrawn, lost to followup, protocol violation, data outside the study-defined schedule, and randomized but never initiated treatment.
The proportions of patients with HIV-l RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for patients receiving lamivudine 300 mg once daily and 63% for patients receiving lamivudine 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm 3 at Week 48 in patients receiving lamivudine 300 mg once daily and 146 cells/mm 3 for patients receiving lamivudine 150 mg twice daily. A small, randomized, open-label pilot study, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm 3 , median plasma HIV-1 RNA 4.8 log 10 copies/mL) were enrolled. Two of the treatment arms in this study provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-l RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice- daily group; and the median increases in CD4+ cell counts were 166 cells/mm 3 in the once-daily lamivudine group and 216 cells/mm 3 in the all-twice-daily group.

14.2 Pediatric Patients

Clinical Endpoint Study: ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of lamivudine plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (≤56 days of antiretroviral therapy) pediatric patients were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm 3 (mean: 1,060 cells/mm3 and range: 0 to 4,650 cells/mm3 for patients ≤5 years of age; mean: 419 cells/mm 3 and range: 0 to 1,555 cells/mm 3 for patients >5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies/mL. The median duration on study was 10.1 months for the patients receiving lamivudine plus zidovudine and 9.2 months for patients receiving didanosine monotherapy. Results are summarized in Table 10.

Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or-Death)

Endpoint Lamivudine plus Zidovudine (n = 236) Didanosine (n = 235)
HIV-1 disease progression or death (total) 15 (6.4%) 37 (15.7%)
Physical growth failure 7 (3.0%) 6 (2.6%)
Central nervous system deterioration 4 (1.7%) 12 (5.1%)
CDC Clinical Category C 2 (0.8%) 8 (3.4%)
Death 2 (0.8%) 11 (4.7%)

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