You have probably noticed the
flurry of articles published this week in the NEJM, coinciding with the International
Liver Congress meeting in London, reporting incredible results with new direct-acting
antiviral agents
in Hepatitis
C. This is undoubtedly one of the biggest medical stories of the year and a
triumph for science, coming just 25 years after the discovery of the RNA virus. The
studies were in patients with genotype 1 HCV although apparently the response
is equally as good in other genotypes. The new agents interrupt viral replication which is vital for HCV to exist. Briefly, 2 different regimes have
demonstrated sustained viral responses of 94-99% within 12-24 weeks in chronic
Hepatitis C patients with and without cirrhosis and with and without previous treatment
failures with standard therapy. The agents were administered as once daily in pill form and were well tolerated overall. Ledipasvir and
sofosbuvir were the agents in one group of studies and ABT-450, ritonavir, dasabuvir and
ombitasvir in the other studies (latter group all had ribavirin; no additional benefit
with ribavirin in ledipasvir and sofosbuvir studies).
These new agents have shown
spectacular success in achieving a sustained viral response in patients with Hepatitis
C and will soon replace standard interferon-based therapy. There is a high
burden of renal disease in patients with Hepatitis C, largely glomerular disease
(mixed cryoglobulinemia, MPGN and less commonly membranous nephropathy). Treatment
of these diseases is primarily directed against the underlying HCV infection.
There are many issues with this:
Ribavirin is contraindicated at GFR <50mls/min.
Pegylated interferon is contraindicated at GFR<15mls/min (with the
added issue of assessing renal function in liver patients).
Renal transplant recipients who are anti-HCV positive pre-transplant
have increased proliferation of HCV, a significantly increased risk of post-transplant
chronic active hepatitis, de-novo glomerular disease and may have an increased
risk of death.
Interferon-alfa
is associated with aggressive renal allograft rejection that frequently leads
to graft loss, necessitating treatment pre-transplant if at all. Likely
mechanisms of this include upregulation of NK cells/cytotoxic T-cells, induction
of cytokine gene expression and cell surface expression of HLA antigens.
For nephrologists, we want to
know what role these agents will have in our patients. The first issue to note is that all these studies excluded patients with a creatinine
clearance <60mls/min (as per Cockcroft-Gault in ABT-450 based studies; unknown
method in the ledipasvir/sofosbuvir studies).
As per the manufacturer, sofosbuvir
has never been studied in patients with a creatinine clearance <30mls/min.
However, a trial is underway examining its use in this population. I could not find any
data on the other agents regarding renal function.
The incredible results of these
studies should have beneficial knock-on effects for nephrology, including a lower
incidence of HCV-related nephropathies, the ability to treat patients
post-transplant and maybe even less demand for combined liver-kidney transplant.
However, some uncertainty remains particularly regarding how to use these agents
in CKD/ESRD and predictably, economics. Estimated treatment costs of $90,000 will
preclude many in the developing world, in particular, from accessing these
curative agents. We await with interest how the story progresses from here.