Sofosbuvir-based treatment safe and effective in advanced kidney disease

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, Austria.

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 transplant recipients with hepatitis C 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 to 21.7-fold in people undergoing dialysis). A safety and efficacy study presented at The Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), in 2014, showed that a 24-week course of sofosbuvir, given at a reduced dose of 200mg, plus ribavirin at a reduced dose of 200mg a day, cured four out of ten people 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 people 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 people with severe kidney disease (stages 4/5, creatinine clearance eGFR<30), 63 people 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. Forty-two per cent had cirrhosis, of whom 32% had a history of decompensation and 26% had a MELD score of 10 or above. Thirty-seven per cent had undergone a liver transplant. The proportions in each of these categories were even higher among people with eGFR between 31 and 45. Sixty-eight per cent 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. Twenty-five per cent 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.

Forty-two per cent 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. Fifty-eight per cent of the stage 4/5 group and 56% of the stage 3b group had prior treatment experience, predominantly with pegylated interferon and ribavirin.

Treatment response by regimen and kidney disease status

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. Three to six per cent 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. Thirty-eight per cent 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 participants 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.