Patients with end-stage renal disease (ESRD) have limited options for
concomitant treatment of hepatitis C. Standard therapies, such as
interferon, ribavirin, and pegylated interferon, have been successfully
used in patients with normal renal function. Patients with ESRD,
however, have not benefited from these therapies, primarily because of
their toxic effects.
Patients with ESRD and hepatitis C have higher mortality than those without co-occurring infection, and renal transplant recipients have lower graft survival rates in the presence of untreated hepatitis C.[1] These statistics have heightened the urgency of developing novel agents to treat hepatitis C in this selected and highly susceptible population.
The current study (C-SURFER) looked at the safety and efficacy of two novel antiviral agents against hepatitis C: grazoprevir and elbasvir. Both drugs inhibit viral protein activity, and neither drug is excreted through the kidneys. In theory, these medications should have the same therapeutic effectiveness in patients with advanced or end-stage kidney disease as they have been shown to have in patients without renal disease.
The second study was observational in design. Four weeks after the end of the randomized treatment, patients in the placebo arm of the study were given grazoprevir 100 mg and elbasvir 50 mg once daily. These patients were followed for an additional 12 weeks to determine the degree to which they achieved a sustained viral response (SVR12). The investigators hypothesized that this combination therapy would result in a greater percentage of patients with kidney disease achieving an SVR12 than similar patients who received interferon monotherapy (39%) or patients without kidney disease who received pegylated interferon plus ribavirin (40%). They defined successful therapy as achieving an SVR12 in greater than 45% of patients. Merck, the manufacturer of these medications, funded this study.
In the randomized controlled portion of the study, the frequency of adverse events was similar between the treatment and placebo arms. In the observational portion, approximately 95% or more of patients showed an SVR12 in every subgroup analyzed. More than 98% of patients with advanced kidney disease achieved an SVR12 in the treatment arm.
It is not clear why the investigators chose the observational design to study SVR12 when they had already randomly assigned patients into treatment and placebo arms. Why study adverse events in a randomized fashion, but not therapeutic effectiveness as well? Could this be because conventional therapy against hepatitis C is more or less contraindicated in patients with advanced kidney disease? Perhaps placebo is not the best comparator against grazoprevir and elbasvir, but the act of randomization itself could have balanced some confounders that influenced the results of the observational study design. Also, dividing the observational data into subgroups could increase the confounding that commonly plagues observational studies and make the results less reproducible in subsequent studies.
Despite these concerns, it looks like physicians have a legitimate therapy against hepatitis C in the ESRD population. We can be optimistic about the C-SURFER results: that a combination of drugs can help patients with advanced kidney disease achieve SVRs at rates similar to those among patients with normal kidney function receiving conventional therapy.
Patients with ESRD and hepatitis C have higher mortality than those without co-occurring infection, and renal transplant recipients have lower graft survival rates in the presence of untreated hepatitis C.[1] These statistics have heightened the urgency of developing novel agents to treat hepatitis C in this selected and highly susceptible population.
The current study (C-SURFER) looked at the safety and efficacy of two novel antiviral agents against hepatitis C: grazoprevir and elbasvir. Both drugs inhibit viral protein activity, and neither drug is excreted through the kidneys. In theory, these medications should have the same therapeutic effectiveness in patients with advanced or end-stage kidney disease as they have been shown to have in patients without renal disease.
Study Design
C-SURFER was actually two studies in one. The first was a randomized trial to assess the safety of these agents in patients with chronic kidney disease stage 4 and dialysis-dependent patients. Patients were randomly assigned in a 1:1 fashion to receive grazoprevir 100 mg plus elbasvir 50 mg once daily or placebo. Adverse effects were observed over the 12-week treatment period. An elevation in aminotransferase levels was the primary adverse event that was monitored.The second study was observational in design. Four weeks after the end of the randomized treatment, patients in the placebo arm of the study were given grazoprevir 100 mg and elbasvir 50 mg once daily. These patients were followed for an additional 12 weeks to determine the degree to which they achieved a sustained viral response (SVR12). The investigators hypothesized that this combination therapy would result in a greater percentage of patients with kidney disease achieving an SVR12 than similar patients who received interferon monotherapy (39%) or patients without kidney disease who received pegylated interferon plus ribavirin (40%). They defined successful therapy as achieving an SVR12 in greater than 45% of patients. Merck, the manufacturer of these medications, funded this study.
Study Results
A total of 235 patients were included in this study, of whom 111 were randomly assigned to the treatment arm and 113 to the placebo arm. An additional 11 patients were included in a third "intensive" arm, in which they received the study drugs and had more frequent blood tests than patients in the treatment arm.In the randomized controlled portion of the study, the frequency of adverse events was similar between the treatment and placebo arms. In the observational portion, approximately 95% or more of patients showed an SVR12 in every subgroup analyzed. More than 98% of patients with advanced kidney disease achieved an SVR12 in the treatment arm.
Analysis and Commentary
This is an exciting study that nonetheless needs to be interpreted cautiously. Having new medications to treat hepatitis C in a high-risk population (such as patients with advanced or end-stage kidney disease) is refreshing and long overdue. Unfortunately, the study design is questionable and puzzling.It is not clear why the investigators chose the observational design to study SVR12 when they had already randomly assigned patients into treatment and placebo arms. Why study adverse events in a randomized fashion, but not therapeutic effectiveness as well? Could this be because conventional therapy against hepatitis C is more or less contraindicated in patients with advanced kidney disease? Perhaps placebo is not the best comparator against grazoprevir and elbasvir, but the act of randomization itself could have balanced some confounders that influenced the results of the observational study design. Also, dividing the observational data into subgroups could increase the confounding that commonly plagues observational studies and make the results less reproducible in subsequent studies.
Despite these concerns, it looks like physicians have a legitimate therapy against hepatitis C in the ESRD population. We can be optimistic about the C-SURFER results: that a combination of drugs can help patients with advanced kidney disease achieve SVRs at rates similar to those among patients with normal kidney function receiving conventional therapy.
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