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 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 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 people with creatinine clearance eGFR 46-60
(stage 3A), and 1643 people with creatinine clearance in the normal range (eGFR
>60).
In comparison, 122 study 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 which 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 people 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
Regimen
|
CKD stages 4/5
(eGFR<30)
(n = 19)
|
CKD stage 3b
(eGFR 31-45)
(n = 63)
|
Asymptomatic kidney disease or
normal function (n = 1643)
|
Sofosbuvir/PEG RBV
|
100%
|
33%
|
81%
|
Sofosbuvir/RBV
|
100%
|
80%
|
73%
|
Sofosbuvir/Simeprevir
|
80%
|
80%
|
87%
|
SOF/SIM/RBV
|
100%
|
100%
|
79%
|
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 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.