Source: aidsmap.com Author: Keith Alcorn Published: 30 April 2015
Sofosbuvir-based direct-acting antiviral therapy for hepatitis C can be used safely and effectively in people with very advanced kidney disease, including people on dialysis, according to the findings of the HCV-TARGET international cohort study presented at the International Liver Congress last week in Vienna.
Hepatitis C increases the risk of chronic kidney disease, 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 people with hepatitis C are a low priority for transplant 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, sofosbuvir has proved problematic because the drug 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 – 21.7 fold in people undergoing dialysis). A safety and efficacy study presented at the American Liver Meeting in 2014 showed that a 24-week course of sofosbuvir, given at a reduced dose of 200mg, plus ribavirin at a reduced dose of 200 mg a day, cured four out of ten patients with severe kidney disease (CKD stage 4/5, eGFR >30 mL/min/1.73 m2) (Gane 2014). The lower dose of sofosbuvir used in this study is likely to explain the poor efficacy in this population.
HCV TARGET is a longitudinal cohort study monitoring responses to direct-acting antiviral regimens in patients receiving routine clinical care in clinics 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 study reported on 19 patients with severe kidney disease (Stages 4/5, creatinine clearance eGFR<30), 63 patients with creatinine clearance eGFR 31-45 (stage 3B), 168 with creatinine clearance eGFR 46-60 (stage 3A), and 1643 with creatinine clearance in the normal range (eGFR >60).
In comparison, 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 studied in the C-SURFER trial of grazoprevir / elbasvir, participants in the HCV-TARGET cohort with stage 4/5 kidney disease also had more advanced liver disease. 42% had cirrhosis, of which 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 and 45. 68% had cirrhosis, and of these 48% had a history of decompensation, 41% had a MELD score of 10 or above, and 54% had undergone a liver transplant. 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.
42% of the stage 4/5 group and 48% of the stage 3b group had genotype 1a hepatitis C infection, approximately 20% had genotype 1b and 16% of the stage 4/5 group had genotype 2 infection, 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.
Just over half of participants with chronic kidney disease (groups 3b and 4/5) received sofosbuvir and simeprevir, compared with 38% of the group with asymptomatic kidney disease or normal kidney function. The remainder received ribavirin-containing regimens. 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 ribavirin doses due to anaemia. Anaemia occurred more frequently among those with advanced kidney disease: 35% of the stage 4/5 group and 29% of the stage 3b developed anaemia, compared to 16% of the group with preserved kidney function.
Among those 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 renal 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, anaemia and other serious adverse events.
Saxena V et al. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C infected patients with reduced renal function: real-world experience from HCV-TARGET. J Hepatology 62 (50thInternational Liver Congress), S266, abstract LP08, 2015.
Gane E et al. Safety, antiviral efficacy, and pharmacokinetics of sofosbuvir in patients with severe renal impairment. AASLD, 2014.