Hepatitis C: 25 Years Old, and Fading
Hepatitis C: 25 Years Old, and Fading
Telaprevir (TPV) plus PEG/RBV remains the standard of care for chronic genotype 1 HCV infection in many regions. However, this regimen is associated with long treatment duration, suboptimal efficacy, and treatment-limiting adverse events related to PEG/RBV and exacerbated by TPV-associated rash and anemia.
Phase 3 studies of the 3D antiviral regimen (coformulated ombitasvir/paritaprevir/ritonavir and dasabuvir) with or without RBV have demonstrated high efficacy in patients with genotype 1 HCV infection, regardless of host, viral, or disease characteristics. As such, a multicenter trial was designed to directly compare the efficacy and safety of an all-oral, 3D antiviral regimen with TPV + PEG/RBV in treatment-naive patients without cirrhosis who had genotype 1 HCV infection.
Patients received the 3D regimen + RBV for 12 weeks, the 3D regimen alone for 12 weeks, or TPV + PEG/RBV for 12 weeks and PEG/RBV for an additional 12-36 weeks (total treatment duration of 24-48 weeks). Patients with genotype 1a HCV infection were randomly assigned in a 2:1 ratio to receive the 3D regimen + RBV or TPV + PEG/RBV. Patients with genotype 1b HCV infection were randomly assigned in a 2:2:1 ratio to receive the 3D regimen + RBV, the 3D regimen alone, or TPV + PEG/RBV.
For patients receiving the 3D regimen + RBV or the 3D regimen, SVR at 4 weeks (SVR4) and SVR12 rates were in the range of 97%-99%. SVR4 rates were 83%-85% for patients receiving TPV + PEG/RBV. Rates of common adverse events (ie, anemia, nausea, pruritus), related drug discontinuation or RBV dose modification, and serious events were significantly lower in patients receiving the 3D regimen with or without RBV compared with patients receiving TPV + PEG/RBV.
Reau and colleagues evaluated whether multiple negative predictors of response have a meaningful impact on SVR rates. A multivariate stepwise logistic regression analysis was performed on more than 2000 patients with genotype 1 HCV infection who were treated with the 3D regimen with or without RBV to identify factors associated with reduced response rates.
Lower SVR12 rates were associated with five independent variables: genotype 1a HCV, higher baseline body weight, IL28B TT genotype, Hispanic/Latino ethnicity, and higher baseline HCV RNA values. The overall SVR12 rate was 96%. SVR12 rates were 99% in patients with no or one negative predictor, and 97% and 95% in those with two or three negative predictors, respectively. SVR rates declined to 86% and 82% among patients with a combination of four or five negative predictors of response, respectively. Thus, the 3D regimen with or without RBV achieves high SVR rates across patient populations with multiple negative predictors regardless of host, viral, or disease characteristics.
Viral eradication in patients with chronic HCV infection and cirrhosis may result in improved hepatic synthetic function and reduced portal hypertension. Flamm and colleagues evaluated various noninvasive markers of liver function and fibrosis 48 weeks after treatment with the 3D regimen + RBV.
SVR12 rates were 92% and 97% in patients who were randomly assigned to receive 12 or 24 weeks, respectively, of the 3D regimen + RBV. Noninvasive estimates of liver fibrosis, laboratory surrogates for hepatic synthetic function, and alpha-fetoprotein values improved from baseline at 12 weeks after treatment and further improved at 48 weeks after treatment.
In patients who achieved SVR12, mean FibroTest scores improved at week 48. Conversely, mean FibroTest scores increased in patients who did not achieve SVR12. The investigators concluded that in the phase 3 trial of patients with genotype 1 HCV infection and cirrhosis, treatment with the 3D regimen + RBV improved surrogates of hepatic synthetic function, alpha-fetoprotein values, and FibroTest scores after completion of antiviral therapy.
Despite the availability of new treatment regimens, achieving high SVR rates in patients with HCV infection in whom treatment with PEG/RBV has failed remains a challenge. For example, patients with cirrhosis or prior null response to PEG/RBV currently require an extended 24-week treatment duration or a complex regimen to achieve high response rates.
Kwo and colleagues evaluated the efficacy and safety of the once-daily, fixed-dose combination tablet of grazoprevir (GZR) and elbasvir (EBR), with or without twice-daily RBV, in cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 HCV in whom prior PEG/RBV therapy had failed. Patients were randomly assigned to receive GZR/EBR, with or without RBV, for 12 or 16 weeks. Randomization was stratified according to cirrhosis status and prior PEG/RBV treatment response.
Of 420 enrolled patients, 65% were male, 35% were cirrhotic, 5% were HIV-coinfected, 18% were black, and 9% were Hispanic. Previous responses to PEG/RBV were relapse, partial response, and null response.
Overall SVR12 rates were 92% after 12 weeks of GZR/EBR without RBV, 94% after 12 weeks with RBV, 92% after 16 weeks without RBV, and 97% after 16 weeks with RBV. For patients with genotype 1a HCV infection, SVR12 rates were 90% after 12 weeks of GZR/EBR without RBV, 93% after 12 weeks with RBV, 94% after 16 weeks without RBV, and 95% after 16 weeks with RBV.
The SVR12 outcomes for patients with genotype 4 disease were somewhat lower: 78% after 12 weeks of GZR/EBR without RBV, 93% after 12 weeks with RBV, 80% after 16 weeks without RBV, and 100% after 16 weeks with RBV. Response in patients with cirrhosis was 89% after 12 weeks of treatment with GZR/EBR with RBV.
Common adverse events were fatigue, headache, and nausea. In this ongoing phase 3 study of patients with genotype 1, 4, or 6 HCV infection in whom prior PEG/RBV therapy had failed, SVR rates of 92%-99% were achieved with a simple once-daily, fixed dose combination of GZR/EBR, with or without RBV, for 12-16 weeks.
The Three-Direct-Acting (3D) Antiviral Regimen
3D Regimen vs Telaprevir
Telaprevir (TPV) plus PEG/RBV remains the standard of care for chronic genotype 1 HCV infection in many regions. However, this regimen is associated with long treatment duration, suboptimal efficacy, and treatment-limiting adverse events related to PEG/RBV and exacerbated by TPV-associated rash and anemia.
Phase 3 studies of the 3D antiviral regimen (coformulated ombitasvir/paritaprevir/ritonavir and dasabuvir) with or without RBV have demonstrated high efficacy in patients with genotype 1 HCV infection, regardless of host, viral, or disease characteristics. As such, a multicenter trial was designed to directly compare the efficacy and safety of an all-oral, 3D antiviral regimen with TPV + PEG/RBV in treatment-naive patients without cirrhosis who had genotype 1 HCV infection.
Patients received the 3D regimen + RBV for 12 weeks, the 3D regimen alone for 12 weeks, or TPV + PEG/RBV for 12 weeks and PEG/RBV for an additional 12-36 weeks (total treatment duration of 24-48 weeks). Patients with genotype 1a HCV infection were randomly assigned in a 2:1 ratio to receive the 3D regimen + RBV or TPV + PEG/RBV. Patients with genotype 1b HCV infection were randomly assigned in a 2:2:1 ratio to receive the 3D regimen + RBV, the 3D regimen alone, or TPV + PEG/RBV.
For patients receiving the 3D regimen + RBV or the 3D regimen, SVR at 4 weeks (SVR4) and SVR12 rates were in the range of 97%-99%. SVR4 rates were 83%-85% for patients receiving TPV + PEG/RBV. Rates of common adverse events (ie, anemia, nausea, pruritus), related drug discontinuation or RBV dose modification, and serious events were significantly lower in patients receiving the 3D regimen with or without RBV compared with patients receiving TPV + PEG/RBV.
SVR Rates in Patients With Negative Predictors of Response
Reau and colleagues evaluated whether multiple negative predictors of response have a meaningful impact on SVR rates. A multivariate stepwise logistic regression analysis was performed on more than 2000 patients with genotype 1 HCV infection who were treated with the 3D regimen with or without RBV to identify factors associated with reduced response rates.
Lower SVR12 rates were associated with five independent variables: genotype 1a HCV, higher baseline body weight, IL28B TT genotype, Hispanic/Latino ethnicity, and higher baseline HCV RNA values. The overall SVR12 rate was 96%. SVR12 rates were 99% in patients with no or one negative predictor, and 97% and 95% in those with two or three negative predictors, respectively. SVR rates declined to 86% and 82% among patients with a combination of four or five negative predictors of response, respectively. Thus, the 3D regimen with or without RBV achieves high SVR rates across patient populations with multiple negative predictors regardless of host, viral, or disease characteristics.
Improvements in Liver Tests and Liver Fibrosis
Viral eradication in patients with chronic HCV infection and cirrhosis may result in improved hepatic synthetic function and reduced portal hypertension. Flamm and colleagues evaluated various noninvasive markers of liver function and fibrosis 48 weeks after treatment with the 3D regimen + RBV.
SVR12 rates were 92% and 97% in patients who were randomly assigned to receive 12 or 24 weeks, respectively, of the 3D regimen + RBV. Noninvasive estimates of liver fibrosis, laboratory surrogates for hepatic synthetic function, and alpha-fetoprotein values improved from baseline at 12 weeks after treatment and further improved at 48 weeks after treatment.
In patients who achieved SVR12, mean FibroTest scores improved at week 48. Conversely, mean FibroTest scores increased in patients who did not achieve SVR12. The investigators concluded that in the phase 3 trial of patients with genotype 1 HCV infection and cirrhosis, treatment with the 3D regimen + RBV improved surrogates of hepatic synthetic function, alpha-fetoprotein values, and FibroTest scores after completion of antiviral therapy.
Pangenotypic Efficacy and Safety of Grazoprevir/Elbasvir
Despite the availability of new treatment regimens, achieving high SVR rates in patients with HCV infection in whom treatment with PEG/RBV has failed remains a challenge. For example, patients with cirrhosis or prior null response to PEG/RBV currently require an extended 24-week treatment duration or a complex regimen to achieve high response rates.
Kwo and colleagues evaluated the efficacy and safety of the once-daily, fixed-dose combination tablet of grazoprevir (GZR) and elbasvir (EBR), with or without twice-daily RBV, in cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 HCV in whom prior PEG/RBV therapy had failed. Patients were randomly assigned to receive GZR/EBR, with or without RBV, for 12 or 16 weeks. Randomization was stratified according to cirrhosis status and prior PEG/RBV treatment response.
Of 420 enrolled patients, 65% were male, 35% were cirrhotic, 5% were HIV-coinfected, 18% were black, and 9% were Hispanic. Previous responses to PEG/RBV were relapse, partial response, and null response.
Overall SVR12 rates were 92% after 12 weeks of GZR/EBR without RBV, 94% after 12 weeks with RBV, 92% after 16 weeks without RBV, and 97% after 16 weeks with RBV. For patients with genotype 1a HCV infection, SVR12 rates were 90% after 12 weeks of GZR/EBR without RBV, 93% after 12 weeks with RBV, 94% after 16 weeks without RBV, and 95% after 16 weeks with RBV.
The SVR12 outcomes for patients with genotype 4 disease were somewhat lower: 78% after 12 weeks of GZR/EBR without RBV, 93% after 12 weeks with RBV, 80% after 16 weeks without RBV, and 100% after 16 weeks with RBV. Response in patients with cirrhosis was 89% after 12 weeks of treatment with GZR/EBR with RBV.
Common adverse events were fatigue, headache, and nausea. In this ongoing phase 3 study of patients with genotype 1, 4, or 6 HCV infection in whom prior PEG/RBV therapy had failed, SVR rates of 92%-99% were achieved with a simple once-daily, fixed dose combination of GZR/EBR, with or without RBV, for 12-16 weeks.
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