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EASL 2015: Sofosbuvir-based Treatment Is Safe and Effective in Patients with Advanced Kidney Disease

Direct-acting antiviral therapy for hepatitis C that includes sofosbuvir (Sovaldi) can be used safely and effectively by people with very advanced kidney disease, including patients on dialysis, according to the findings of the HCV-TARGET international cohort study presented at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last week in Vienna.

[Produced in collaboration with Aidsmap.com]

Hepatitis C increases the risk of chronic kidney disease (CKD), and people with hepatitis C face more rapid progression of kidney disease once function begins to decline. As a consequence, they are likely to reach a point where they need dialysis and kidney transplantation sooner than other people with kidney disease. People with hepatitis C also have an increased risk of developing new onset diabetes after developing kidney disease.

If a kidney transplant is necessary, people with hepatitis C have a higher risk of transplant rejection (also known as graft failure) and poorer survival after transplantation. But for many people with hepatitis C who have severe kidney disease, a transplant will remain out of reach; poorer survival among HCV-infected transplant recipients means that these patients are generally a low priority for receiving donor organs.

For all these reasons, curing hepatitis C is an essential part of effective management of chronic kidney disease for people who have the virus. However, available treatments have been unsuitable for people with kidney disease.

In particular, Gilead Sciences' sofosbuvir has been thought be problematic because it is excreted through the kidneys, and diminished kidney function has been shown to result in very substantial increases in blood levels of the drug (13.8-fold to 21.7-fold in people undergoing dialysis). A safety and efficacy study presented at the 2014 AASLD Liver Meeting showed that a 24-week course of sofosbuvir, given at a reduced dose of 200 mg, plus ribavirin at a reduced dose of 200 mg/day, cured just 4 out of 10 patients with severe kidney disease. The lower dose of sofosbuvir used in that study likely explains the poor efficacy in this population.

HCV-TARGET is a longitudinal cohort study monitoring responses to direct-acting antiviral therapy in patients receiving routine clinical care in North America and Western Europe.

The HCV-TARGET investigators reported on responses to sofosbuvir-based treatment in people with chronic kidney disease and those with normal kidney function. The report included 19 chronic hepatitis C patients with stage 4-5 severe kidney disease (reduced creatinine clearance with eGFR <30 mL/min/1.73 m²), 63 patients with stage 3B kidney disease (eGFR 31-45), 168 with stage 3A kidney impairment (eGFR 46-60A), and 1643 with creatinine clearance within the normal range (eGFR >60).

In a related study, also presented at the Vienna conference, 122 participants with stage 4-5 kidney disease (eGFR <30) received active treatment in C-SURFER, a Merck-sponsored study of its investigational combination of the direct-acting antivirals grazoprevir and elbasvir.

In comparison to the population of patients with advanced kidney disease in C-SURFER, participants in the HCV-TARGET cohort with stage 4-5 kidney disease also had more advanced liver disease. 42% had cirrhosis, of whom 32% had a history of decompensation and 26% had a MELD score of 10 or above. 37% had undergone a liver transplant. The proportions in each of these categories were even higher among people with eGFR between 31-45: 68% had cirrhosis, 48% had a history of decompensation, 41% had a MELD score of 10 or above, and 54% had undergone liver transplantation. 25% of patients in this group had hepatocellular carcinoma. Diabetes was present in 37% of the stage 4-5 group and 48% of the stage 3B group.

Regarding HCV genotype, 42% of patients in the stage 4-5 group and 48% in the stage 3B group had genotype 1a HCV infection, approximately 20% had genotype 1b. 16% in the stage 4-5 group had genotype 2 compared to 13% in the stage 3B group. 58% of the stage 4-5 group and 56% of the stage 3B group had prior treatment experience, predominantly with pegylated interferon and ribavirin (PEG/RBV).

Treatment Response (SVR12) by Regimen and Kidney Disease Status

Just over half of participants with chronic kidney disease (stage 3B and 4-5) received sofosbuvir plus simeprevir (Janssen's Olysio), compared with 38% of the group with asymptomatic kidney disease or normal kidney function. The remainder received ribavirin-containing regimens.

Overall, 3%-6% of participants discontinued treatment due to drug-related adverse events, and 15% of participants in the CKD stage 3B group discontinued ribavirin due to poor tolerability. 38% in the stage 4-5 group and 30% in the stage 3B group had to reduce their ribavirin doses due to anemia. Anemia occurred more frequently among those with advanced kidney disease: 35% of the stage 4-4-5 group and 29% of the stage 3B group developed anemia, compared to 16% of patients with preserved kidney function.

Among participants not receiving ribavirin, renal function deteriorated during the course of treatment in 2 of 19 patients with stage 4-5 kidney disease and in 2 of 29 patients with stage 3B kidney disease. Changes in kidney function were not reported for participants receiving ribavirin.

The investigators concluded that although a high cure rate can be achieved in people with advanced kidney disease, close monitoring during treatment is essential to detect changes in kidney function, anemia, and other serious adverse events.

4/30/15

Reference

V Saxena, et al. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C infected patients with reduced renal function: real-world experience from HCV-TARGET. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract LP08.

E Gane, RA Robson, M Bonacini, et al. Safety, Antiviral Efficacy, and Pharmacokinetics of Sofosbuvir in Patients with Severe Renal Impairment. The Liver Meeting: 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Boston, November 7-12, 2014. Abstract 966.

Other Source

Merck. Merck Announces Results from Phase 2/3 Study of Investigational Chronic Hepatitis C Therapy Grazoprevir/Elbasvir in Patients with Advanced Chronic Kidney Disease. Press release. April 23, 2015.