Lamivudine clinical studies

# Clinical Studies
The use of EPIVIR 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-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

## Adults
Clinical Endpoint Study: NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone  or zidovudine with didanosine or zalcitabine ) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells/mm3 (median = 122 cells/mm3) 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.
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 EPIVIR 300 mg once daily or EPIVIR 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/mm3 (median = 362 cells/mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9.
a Roche AMPLICOR HIV-1 MONITOR.
bResponders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit.
The proportions of patients with HIV-1 RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for patients receiving EPIVIR 300 mg once daily and 63% for patients receiving EPIVIR 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in patients receiving EPIVIR 300 mg once daily and 146 cells/mm3 for patients receiving EPIVIR 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/mm3, median plasma HIV-1 RNA 4.8 log10 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-1 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/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group.

## Pediatric Patients
Clinical Endpoint Study: ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR 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/mm3 (mean: 1,060 cells/mm3 and range:  0 to 4,650 cells/mm3 for patients 5 years of age; mean: 419 cells/mm3 and range: 0 to 1,555 cells/mm3 for patients >5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration on study was 10.1 months for the patients receiving EPIVIR plus RETROVIR and 9.2 months for patients receiving didanosine monotherapy. Results are summarized in Table 10.