Monday, April 14, 2014

Hepatitis C cure on the Horizon: Implications for Nephrology

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.

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