Patients and clinicians demanded highly effective,
safe, all-oral therapy for HCV infection, and this challenge was met. As
a consequence, the conversation with our patients has shifted from how
to manage adverse events to how and when to deliver a cure. In response
to the rapid evolution of therapy, the AASLD/IDSA provides real-time guidance to facilitate clinicians with treatment nuances. Although we now have highly effective therapies for nearly all patients, subsets of patients still exist where treatment options remain less than optimal.
For example, last week I evaluated a 57-year-old patient who was considering renal transplantation. Dialysis, although not yet required, appeared to be inevitable. During his kidney transplant evaluation, he was found to have HCV infection and was referred to my practice for pretransplant clearance. However, the ensuing discussion elucidated the lack of straightforward treatment options and complex goals for viral eradiation in this patient and others like him.
Hepatitis C and Renal Disease: A Complicated RelationshipInfections, including HCV, can cause renal disease, and HCV infection is seen frequently in patients with chronic kidney disease. It would stand to reason that we should treat HCV infection in all patients with HCV and chronic kidney disease: HCV can initiate cryoglobulinemia-related mesangiocapillary glomerulonephritis, and a growing body of evidence suggests that the interaction extends well beyond these traditional extrahepatic manifestations. Dialysis is a potential source for HCV transmission, and HCV has a negative impact on survival in individuals on chronic dialysis and in kidney graft recipients.
Traditionally, HCV treatment options for patients with renal disease were limited both by adverse events and efficacy. Peginterferon and ribavirin were poorly tolerated and rarely effective—requiring dose modifications and even treatment disruption. In addition, many patients with chronic kidney disease are anemic, creating an even greater challenge to the use of ribavirin. All-oral options have eliminated the treatment gap for many special populations, yet renal patients continue to present challenges.
Today’s DilemmaMost individuals with HCV infection in the United States are infected with genotype 1 HCV. We currently have 3 FDA-approved all-oral treatment options for this genotype (all of which may have ribavirin added in certain situations to either decrease the interval of therapy or to improve efficacy): sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, and simeprevir in combination with sofosbuvir.
Notably, while the combination of daclatasvir and sofosbuvir was recently approved by the FDA for the treatment of genotype 3 HCV infection only, this regimen has also been evaluated for the treatment of genotype 1 HCV infection and is recommended by the AASLD/IDSA guidance in this population as well.
Although all 4 regimens are equally advocated for genotype 1 patients in the HCV guidance, patients with renal impairment are highlighted as a unique patient population requiring dose modifications. For example, no sofosbuvir-containing regimen is approved for those with creatinine clearance < 30 mL/min because it is renally metabolized. In these patients, reduced creatinine clearance leads to an increased area under the curve of sofosbuvir and its inactive metabolite GS-331007. Despite this, the observational cohort study HCV-TARGET included a small number of patients with severe renal impairment who received sofosbuvir-containing regimens. High SVR rates were reported in this group, but the small numbers and observational nature make it difficult to interpret safety data, and the AASLD/IDSA guidance recommends that sofosbuvir can be considered in the subgroup of these patients who are ribavirin intolerant or ineligible, but only in consultation with an expert.
Although daclatasvir requires no dose adjustment with any degree of renal impairment, it is subject to the same restrictions as other sofosbuvir-containing regimens in patients with severe renal impairment.
For patients with creatinine clearance < 30 mL/min (without cirrhosis) who require therapy and are not candidates for renal transplant, the AASLD/IDSA guidance recommends ombitasvir/paritaprevir/ritonavir plus dasabuvir based on limited data, although care must be taken to avoid anemia if ribavirin is added, such as in patients with genotype 1a HCV infection. Preliminary data from RUBY-1 supports this as a safe and effective alternative even in those on hemodialysis, although this combination has not been investigated in patients with concomitant cirrhosis and severe renal disease.
We also recognize that there are other options under investigation. Results of the C-SURFER trial showed high efficacy and safety in genotype 1 HCV–infected individuals with end-stage renal disease who were treated with grazoprevir/elbasvir, including a subset with cirrhosis.
Yet the story doesn’t stop there. Even if the therapeutic choices are straightforward, the timing of treatment remains controversial. Our patient was considering the option to receive an HCV-positive organ in order to decrease the wait time on the transplant list. With that goal, viral eradication should be deferred until after transplant to allow him a larger organ pool. In fact, the AASLD/IDSA guidance recommends treating HCV in patients with severe renal impairment only if treatment is urgent and renal transplant is not an option. However, this patient’s nephrologist was hoping that with viral eradication, his renal function might stabilize, thereby delaying—and possibly avoiding—the need for renal transplantation altogether.
Upcoming Discussions on Harder-to-Treat PopulationsDespite recent advances, managing HCV infection remains a challenge in selected populations such as those with renal disease. Next month, I and other colleagues, including Mark S. Sulkowski, MD, and Ira M. Jacobson, MD, will host a series of live case-based discussions on treatment decisions for challenging patients, including those with cirrhosis, genotype 3 HCV infection, reduced renal function, and HIV/HCV coinfection. I hope that you will join us for one of these exciting events, which you can prepare for by participating in my online CME-certified activity on these key patient populations.
We are interested in hearing what questions you might want addressed during upcoming meetings on harder-to-treat populations. Please leave a comment below.
For example, last week I evaluated a 57-year-old patient who was considering renal transplantation. Dialysis, although not yet required, appeared to be inevitable. During his kidney transplant evaluation, he was found to have HCV infection and was referred to my practice for pretransplant clearance. However, the ensuing discussion elucidated the lack of straightforward treatment options and complex goals for viral eradiation in this patient and others like him.
Hepatitis C and Renal Disease: A Complicated RelationshipInfections, including HCV, can cause renal disease, and HCV infection is seen frequently in patients with chronic kidney disease. It would stand to reason that we should treat HCV infection in all patients with HCV and chronic kidney disease: HCV can initiate cryoglobulinemia-related mesangiocapillary glomerulonephritis, and a growing body of evidence suggests that the interaction extends well beyond these traditional extrahepatic manifestations. Dialysis is a potential source for HCV transmission, and HCV has a negative impact on survival in individuals on chronic dialysis and in kidney graft recipients.
Traditionally, HCV treatment options for patients with renal disease were limited both by adverse events and efficacy. Peginterferon and ribavirin were poorly tolerated and rarely effective—requiring dose modifications and even treatment disruption. In addition, many patients with chronic kidney disease are anemic, creating an even greater challenge to the use of ribavirin. All-oral options have eliminated the treatment gap for many special populations, yet renal patients continue to present challenges.
Today’s DilemmaMost individuals with HCV infection in the United States are infected with genotype 1 HCV. We currently have 3 FDA-approved all-oral treatment options for this genotype (all of which may have ribavirin added in certain situations to either decrease the interval of therapy or to improve efficacy): sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, and simeprevir in combination with sofosbuvir.
Notably, while the combination of daclatasvir and sofosbuvir was recently approved by the FDA for the treatment of genotype 3 HCV infection only, this regimen has also been evaluated for the treatment of genotype 1 HCV infection and is recommended by the AASLD/IDSA guidance in this population as well.
Although all 4 regimens are equally advocated for genotype 1 patients in the HCV guidance, patients with renal impairment are highlighted as a unique patient population requiring dose modifications. For example, no sofosbuvir-containing regimen is approved for those with creatinine clearance < 30 mL/min because it is renally metabolized. In these patients, reduced creatinine clearance leads to an increased area under the curve of sofosbuvir and its inactive metabolite GS-331007. Despite this, the observational cohort study HCV-TARGET included a small number of patients with severe renal impairment who received sofosbuvir-containing regimens. High SVR rates were reported in this group, but the small numbers and observational nature make it difficult to interpret safety data, and the AASLD/IDSA guidance recommends that sofosbuvir can be considered in the subgroup of these patients who are ribavirin intolerant or ineligible, but only in consultation with an expert.
Although daclatasvir requires no dose adjustment with any degree of renal impairment, it is subject to the same restrictions as other sofosbuvir-containing regimens in patients with severe renal impairment.
For patients with creatinine clearance < 30 mL/min (without cirrhosis) who require therapy and are not candidates for renal transplant, the AASLD/IDSA guidance recommends ombitasvir/paritaprevir/ritonavir plus dasabuvir based on limited data, although care must be taken to avoid anemia if ribavirin is added, such as in patients with genotype 1a HCV infection. Preliminary data from RUBY-1 supports this as a safe and effective alternative even in those on hemodialysis, although this combination has not been investigated in patients with concomitant cirrhosis and severe renal disease.
We also recognize that there are other options under investigation. Results of the C-SURFER trial showed high efficacy and safety in genotype 1 HCV–infected individuals with end-stage renal disease who were treated with grazoprevir/elbasvir, including a subset with cirrhosis.
Yet the story doesn’t stop there. Even if the therapeutic choices are straightforward, the timing of treatment remains controversial. Our patient was considering the option to receive an HCV-positive organ in order to decrease the wait time on the transplant list. With that goal, viral eradication should be deferred until after transplant to allow him a larger organ pool. In fact, the AASLD/IDSA guidance recommends treating HCV in patients with severe renal impairment only if treatment is urgent and renal transplant is not an option. However, this patient’s nephrologist was hoping that with viral eradication, his renal function might stabilize, thereby delaying—and possibly avoiding—the need for renal transplantation altogether.
Upcoming Discussions on Harder-to-Treat PopulationsDespite recent advances, managing HCV infection remains a challenge in selected populations such as those with renal disease. Next month, I and other colleagues, including Mark S. Sulkowski, MD, and Ira M. Jacobson, MD, will host a series of live case-based discussions on treatment decisions for challenging patients, including those with cirrhosis, genotype 3 HCV infection, reduced renal function, and HIV/HCV coinfection. I hope that you will join us for one of these exciting events, which you can prepare for by participating in my online CME-certified activity on these key patient populations.
We are interested in hearing what questions you might want addressed during upcoming meetings on harder-to-treat populations. Please leave a comment below.
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