CLINICAL STUDIES
HCV Patients
The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin tablets for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.
In study NV15801 (described as study 4 in the peginterferon alfa-2a package insert), patients were randomized to receive either peginterferon alfa-2a 180 mcg sc once weekly (qw) with an oral placebo, peginterferon alfa-2a 180 mcg qw with ribavirin tablets 1000 mg po (body weight <75 kg) or 1200 mg po (body weight ≥75 kg) or interferon alfa-2b 3 MIU sc tiw plus ribavirin 1000 mg or 1200 mg po. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin tablets or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (<50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with ribavirin tablets resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin (Table 1). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with ribavirin tablets compared to patients with other viral genotypes.
Table 1 Sustained Virologic Response (SVR) to Combination Therapy (Study NV15801 )
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Interferon alfa-2b + Ribavirin 1000 mg or 1200 mg
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Peginterferon alfa-2a + placebo
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Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg
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Difference in overall treatment response (peginterferon alfa-2a/ribavirin tablets - Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).
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All patients
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197/444 (44%) |
65/224 (29%) |
241/453 (53%) |
Genotype 1
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103/285 (36%) |
29/145 (20%) |
132/298 (44%) |
Genotypes 2-6
|
94/159 (59%) |
36/79 (46%) |
109/155 (70%) |
In study NV15942 (described as study 5 in the peginterferon alfa-2a package insert), all patients received peginterferon alfa-2a 180 mcg sc qw and were randomized to treatment for either 24 or 48 weeks and to a ribavirin tablet dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg/≥75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as >2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.
HCV Genotypes
HCV 1 and 4 - Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin tablets resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin tablets.
HCV 2 and 3 - Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin tablets resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin tablets (see Table 2).
The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.
Table 2 Sustained Virologic Response as a Function of Genotype (Study NV15942 )
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24 Weeks Treatment
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48 Weeks Treatment
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Peginterferon alfa-2a + Ribavirin Tablets 800 mg (N=207)
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Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg
(N=280)
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Peginterferon alfa-2a + Ribavirin Tablets 800 mg (N=361)
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Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg(N=436)
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Genotype 1 |
29/101 (29%) |
48/118 (41%) |
99/250 (40%) |
138/271 (51%) |
Genotypes 2, 3 |
79/96 (82%) |
116/144(81%) |
75/99(76%) |
117/153 (76%) |
Genotype 4 |
0/5 (0%) |
7/12 (58%) |
5/8 (63%) |
9/11 (82%) |
Other Treatment Response Predictors
Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.
Paired liver biopsies were performed on approximately 20% of patients in studies NV15801 and NV15942. Modest reductions in inflammation compared to baseline were seen in all treatment groups.
In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.
CHC and Coinfection with HIV (CHC/HIV): Study NR15961
In Study NR15961 (described as Study 6 in the peginterferon alfa-2a package insert), patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg sc once weekly (qw) plus an oral placebo, peginterferon alfa-2a 180 mcg qw plus ribavirin tablets 800 mg po daily or interferon alfa-2a, 3 MIU sc tiw plus ribavirin tablets 800 mg po daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. Ribavirin tablets or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count (200 cells/µL or CD4+ cell count (100 cells/µL but <200 cells/µL and HIV-1 RNA <5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 3.
Table 3 Sustained Virologic Response in Patients With Chronic Hepatitis C Coinfected With HIV (Study NR15961 )
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Interferon-a + Ribavirin Tablets 800 mg
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Peginterferon alfa-2a + Placebo
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Peginterferon alfa-2a + Ribavirin Tablets 800 mg
|
|
(N=289)
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(N=289)
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(N=290)
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All patients |
33 (11%)
|
58 (20%)
|
116 (40%)
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Genotype 1 |
12/171 (7%) |
24/175 (14%) |
51/176 (29%) |
Genotypes 2, 3 |
18/89 (20%) |
32/90 (36%) |
59/95 (62%) |
Treatment response rates are lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA >800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population.
Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2log10 reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and ribavirin tablets combination therapy, 2% (2/85) achieved an SVR.
In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with ribavirin tablets treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks posttreatment.
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