Putting the Pieces Together: HCV Therapy in Those With Chronic Kidney Disease

The prevalence of hepatitis C (HCV) in dialysis patients is higher than that of the general population, ranging from 1.8 to 8 percent in developed countries, with much higher rates in the developing world. Its prevalence correlates with the number of patient-years on dialysis. HCVinfected patients on maintenance dialysis experience increased mortality compared to uninfected patients due to progressive liver disease or the development of hepatocellular carcinoma (HCC). HCV is also associated with poor graft and patient outcomes after kidney transplantation, and is also implicated in the development and progression of chronic kidney disease. Patients with advanced chronic kidney disease or those on dialysis had low rates of treatment and sustained virologic response (SVR) when treated with interferon and ribavirin due to poor tolerability. The risk of rejection post-kidney transplantation also has limited the use of interferon in the past. In the initial trials of direct acting antiviral (DAA) therapy, patients with chronic kidney disease stages 4-5 were typically excluded from the clinical trial enrollment. However, DAA therapy use has now expanded into patients with chronic kidney disease.

In the RUBY-I trial, the paritaprevir/ ritonavir/ombitasvir/dasabuvir (PrOD) regimen was administered to 20 HCV genotype 1 patients, 70 percent of whom were on dialysis with favorable baseline patient characteristics (treatment naïve, non cirrhotics) for 12 weeks. 200 mg of Ribavirin daily was added to PrOD in only 13 patients with HCV genotype 1a; An overall SVR12 rate of 90 percent was achieved. Four patients had serious adverse events that were unrelated to treatment. Additionally, Ribavirin-related anemia was common, which led to the interruption of its use in nine patients, and erythropoietin was required in four patients but none needed blood transfusions. The PrOD regimen does not require dose adjustment in renal failure, however, Ribavirin does. This regimen is endorsed by the HCV guidelines from the American Association for the Study of Liver Diseases/Infectious Disease Society of America committee for patients with chronic kidney disease (hcvguidelines.org).

To date, the C-SURFER trial is the largest trial published on DAA therapy for HCV in patients with chronic kidney disease stage 4-5. In this trial, 224 patients with HCV genotype 1 were randomly assigned to two groups, immediate treatment (n=111) or deferred (n=113). The study population was comprised of 46 percent Whites, 46 percent African Americans, 80 percent diabetics, 76 percent hemodialysis patients and 6 percent overall with cirrhosis (metavir F4 fibrosis). An almost equal proportion of HCV genotypes 1a and 1b were present, and of those, 80 percent were treatment naïve. Grazoprevir, NS3/4 protease inhibitor and elbasvir, NS5A inhibitor (fixed dose combination pill) or placebo were administered once daily for 12 weeks at randomization. At week 16, the deferred treatment arm started the study drug for 12 weeks. HCV resistance testing was performed with population-based sequencing at baseline in almost half of the patients, which detected NS3/4A resistanceassociated variants in 32 percent and NS5A resistance-associated variants (RAVs) in 15 percent. No additional interventions were administered in those who harbored the resistance-associated variants. The primary efficacy outcome of SVR12 was achieved in 94 percent of the full analysis set and in 99 percent of the modified full analysis set (excluding those who failed to receive one or more doses of the drug due to events unrelated to treatment). Six patients discontinued the study for non virologic failure reasons and one non-cirrhotic patient with HCV genotype 1b with baseline L31M NS5A RAV had a true relapse. The SVR12 was 100 percent among African-American patients and in cirrhotics. None of the patients experienced on-treatment virologic breakthrough and the treatment had comparable adverse effects to the placebo. The regimen was ultimately approved by the U.S. Food and Drug Administration in January 2016 for HCV treatment even in the chronic kidney disease setting. Regarding other direct acting antivirals for chronic kidney disease patients, Sofosbuvir (NS5B nucleotide analogue) is not recommended in patients with a glomerular filtration rate below 30ml per minute, mainly due to concern regarding accumulation of its inactive metabolite. However, small case series from several groups have described its use in patients with chronic kidney disease stage 4-5. Although a half dose (200mg) of sofosbuvir plus ribavirin had low efficacy, an SVR of 40 percent was observed in an early report. The trial provided insight into the pharmacokinetics of the drug and its metabolite GS-331007. Subsequent studies with half or full dose sofosbuvir in combination with another direct acting antivirals, such as simeprevir, daclatasvir or ledipasvir, have shown encouraging efficacy and safety even with full dose medication.

There is emerging data from a few groups regarding kidney transplant recipients that show 100 percent SVR with sofosbuvir-based treatment. Such excellent results and the ease of administration in kidney transplant recipients has prompted the transplantation of kidneys from HCV-positive donors in HCV-positive recipients (HCV D+/R+) in some cases.

A recent report suggests that HCV-infected patients on the kidney transplant wait list derived the most benefit from this strategy as their wait time could be abbreviated to a few months rather than several years. The studies in this cohort are ongoing and the results are anticipated in the near future. In addition, another recent report also describes successful renal transplantation in a HCV-negative recipient who had accepted a kidney from an HCV-positive donor using direct acting antiviral therapy.

In conclusion, HCV therapy in chronic kidney disease, especially in stages 4-5, is now feasible and efficacious. Grazoprevir/ elbasvir or PrOD do not require any dose adjustments in severe renal impairment and can be safely administered even in dialysis patients. However, these protease-inhibitor based regimens in the advanced chronic kidney disease setting are endorsed only in HCV genotype 1 (possibly genotype 4) but those with genotypes 2, 3, 5 and 6 would still need to wait for newer direct acting antivirals. Sofosbuvir-based therapies, although not approved in the advanced chronic kidney disease setting, do show promising results in the post kidney transplant setting. Lastly, the acceptance of HCV-positive kidney grafts has now become become feasible for recipients who are already infected with HCV, aiding in the augmentation of the kidney donor pool and shortening recipient wait times. These exciting advances in HCV in the chronic kidney disease population in recent years help ensure that this complex patient population is no longer precluded from HCV therapy.

Dr. Bhamidimarri has served on scientific advisory boards for Gilead, AbbVie and Bristol-Myers Squibb.

Dr. Martin has served as a consultant and investigator for Gilead, Abbvie, Merck and Janssen.

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