The once-daily combination of grazoprevir and elbasvir cured hepatitis C in 99% of people with advanced chronic kidney disease, researchers reported at the International Liver Congress last week in Vienna, Austria.
The findings are the first evidence that people with chronic kidney disease stand a very high chance of being cured of hepatitis C if treated with an interferon-free regimen, and will offer hope to a group of people with hepatitis C until now left behind by recent advances in antiviral treatment.
Hepatitis C increases the risk of chronic kidney disease, although the mechanisms by which the virus causes kidney damage are still unclear. People with hepatitis C face more rapid progression of kidney disease once kidney function begins to decline, and 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.
Ribavirin exacerbates the anaemia suffered by many people with chronic kidney disease.
Sofosbuvir must be used with caution in kidney disease because the drug is cleared through the kidneys. Poorer kidney function leads to much higher levels of the drug in the blood, and there are very limited safety data on the use of sofosbuvir in people with advanced kidney disease (creatinine clearance eGFR >30 ml/min/1.73 m2). A pharmacokinetic study has shown that sofosbuvir metabolite levels increased 5.5-fold in people with severe kidney disease, and 13.8-fold to 21.7-fold in people undergoing dialysis, depending on whether the drug was dosed before or after 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, 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.
Grazoprevir (an NS3/4 protease inhibitor) and elbasvir (an NS5A inhibitor) are being developed by Merck. The combination is being studied as a once-daily, single-tablet regimen, with or without ribavirin. The two drugs are active against multiple genotypes of hepatitis C.
Grazoprevir and elbasvir are not excreted through the kidneys, but broken down in the liver, so these drugs can be used without dose adjustment.
The C SURFER study recruited people with genotype 1 hepatitis C who had chronic kidney disease (stages 3/4) with creatinine clearance below 30 ml/min/1.73 m2. Three-quarters of participants were dependent on dialysis. The study population was evenly divided between people with genotype 1a and 1b (52% vs 48%) and approximately 80% were previously untreated. Approximately 7% had cirrhosis, defined by non-invasive testing (the study excluded people with decompensated cirrhosis).
Reflecting the higher prevalence of chronic kidney disease among African Americans, the study population comprised 46% African Americans, 48% Caucasians and 6% Asian and other ethnic groups. Approximately 75% of participants were men.
The study population was randomised to immediate treatment with grazoprevir 100mg / elbasvir 50mg for 12 weeks (n = 122) or a deferred treatment arm in which participants received placebo for 12 weeks followed by 12 weeks of treatment with grazoprevir 100mg / elbasvir 50mg (n = 113).
In the immediate treatment group, six people discontinued treatment for reasons unconnected with the study medication (one death due to cardiovascular disease, one participant withdrew consent, one participant was discontinued from the study due to violent behaviour at the dialysis centre, two participants were lost to follow-up and one participant was non-adherent). In the full analysis set which included discontinuations, the rate of sustained virological response was 94%. In the modified on-treatment analysis, the SVR12 rate was 99%, with one case of viral relapse after treatment. (SVR12 means sustained virological response at 12 weeks after the end of treatment.)
Sub-group analyses showed no significant variation in virological response by genotype, ethnicity, treatment experience, stage of chronic kidney disease, diabetes or dialysis.
Treatment was well tolerated, with no significant difference in reports of headache, nausea, fatigue, insomnia, dizziness and diarrhoea between the placebo group and the active treatment group. One serious adverse event in the active drug group (lipase elevation) was considered to be related to treatment.
Elevations in ALT, AST and total bilirubin were more frequent in the placebo group than in the active treatment group.
The baseline prevalence of anaemia in the study population was not reported, but 23% of participants receiving active study drug required erythropoietin (EPO) during the study in order to manage anaemia, compared to 35% of the placebo group.
Applications for approval of the grazoprevir / elbasvir combination pill will be submitted shortly in the United States and European Union and the product could receive marketing approval by the end of 2015. In the US the Food and Drug Administration (FDA) has granted Breakthrough Status to the combination for the treatment of people with end-stage renal disease on haemodialysis, which means that the application should be reviewed within 60 days.
Gane E et al. Safety, antiviral efficacy, and pharmacokinetics of sofosbuvir in patients with severe renal impairment. The Liver Meeting, the 65th annual meeting of the American Association for the Study of Liver Diseases (AASLD), 2014.
Roth D et al. C-SURFER: grazoprevir plus elbasvir in treatment-naïve and treatment-experienced patients with hepatitis C virus genotype 1 infection and chronic kidney disease. J Hepatology 62 (50th International Liver Congress), S263, abstract LP02, 2015.