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
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
A natural hormone made in the kidneys to stimulate the production of red blood cells by the bone marrow.
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 who have 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
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
The C SURFER study recruited people with genotype 1 hepatitis
C with 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 genotype 1a and 1b (52% vs 48%) and
approximately 80% were previously untreated.
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.
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
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 United States, the Food and Drug Administration has granted Breakthrough
Status to the combination for the treatment of patients with end-stage renal
disease on haemodialysis, which means that the application should be reviewed
within 60 days.