This is Part 1 of a 2-part series on Hepatitis C and kidney transplantation, highlighting some of the exciting breakthroughs impacting this field that have come about as a result of promising antiretroviral therapy.
Part 1: Hepatitis C and Kidney Transplantation
In 1989, Dr. Michael Houghton and his colleagues published two papers in Science describing their work in identifying and cloning the Hepatitis C virus (HCV) and developing a test to diagnose HCV. It took almost 20 years for this mystery virus, previously called “non-A, non-B hepatitis,” and the culprit for most blood transfusion-associated hepatitis cases in the 70s and 80s, to be identified. Almost 30 years after HCV was discovered, approximately 71 million persons worldwide remain chronically infected with HCV. In the United States, approximately 3.5 million persons have HCV: 2.7 million in the general population, plus another 800,000 in the incarcerated population.
HCV greatly impacts patients with kidney disease as it is not only highly prevalent but also associated with inferior outcomes. Among ESRD patients, a DOPPS study quantified the prevalence at a mind-boggling 13.5% and this varied between 2.6% to 22.9% across 8 countries. In the kidney transplant population, the prevalence has been reported to be 6.8%.
HCV is associated with inferior outcomes not only in ESRD patients but also in kidney transplant recipients. Historically, HCV+ kidney transplant recipients have had inferior patient and allograft survivals compared to HCV- counterparts. Several reasons implicated include an increase in:
- Cardiovascular disease
- Liver disease and uncontrolled viral replication
- Rejection episodes
- Glomerular disease
- Transplant glomerulopathy
- New onset diabetes after transplant
- Post-transplant lymphoproliferative disease
Despite these inferior outcomes and complications, kidney transplantation has been pursued because of superior patient survival compared to remaining on the waiting list. This is the same rationale for transplanting older patients or those with diabetes, i.e. even if older patients don’t do as well as younger counterparts, or diabetic patients don’t do as well as non-diabetic patients, transplantation is pursued as it still confers these higher risk patients a survival advantage compared to the alternative of remaining on dialysis.
The Past: The Interferon Era
Up until a few years ago, the available treatment for patients with HCV was pegylated interferon (IFN) + ribavirin (RBV). Unfortunately, this drug regimen had suboptimal efficacy (approximately 50% cure rate), particularly in patients with renal failure (approximately 30-40% and even lower in genotype 1). Pegylated IFN was also poorly tolerated as the drug in and of itself was implicated in a variety of nephrotoxic mechanisms. It is not surprising that during the IFN era, a study using the DOPPS cohort found that HCV was very rarely treated among hemodialysis patients (approximately 1% received a prescription for IFN or RBV) and this was also true even among waitlisted patients (3.7%).
During the IFN era, patients pursuing a kidney transplant had the option of being treated for HCV pre-transplantation but not post-transplantation due to the high rates of acute rejection attributed to IFN. HCV+ transplant candidates who were not treated or who did not respond to therapy pre-transplantation had the option of listing for a HCV+ kidney. The individual benefit to be gained from this is that it reduced one’s waiting time on the deceased donor waiting list due to the relatively few patients competing for a HCV+ kidney. In a study of the UNOS database from 1995-2009, Kucirka et al found that recipients of HCV+ kidneys waited 310 days fewer than the average waiting times at their center and 395 fewer days than counterparts who waited for HCV- kidneys.
From a societal perspective, there is a benefit to increasing organ utilization, something that is badly needed due to the ever growing demand for kidneys that are in short supply. Reese et al reported that from 2005-2014, only 37% of available HCV+ kidneys were transplanted (discard rate of 67% compared to the usual discard rate of 20%). However, these aforementioned individual and societal benefits must be weighed against several concerns for transplanting HCV+ kidneys into HCV+ recipients. These concerns include the nearly universal transmission of the virus and possible genotype superinfection and also inferior patient and graft survival in patients who receive HCV+ compared to HCV- kidneys.
The Present: The DAA Era
In the last few years, the options and outlook for kidney transplant candidates and recipients have changed dramatically with the emergence of direct acting antiviral (DAA) therapy.
- Patients with HCV can be treated effectively and safely pre-transplantation with DAA if they have genotypes 1 or 4. This was demonstrated in the C-SURFER study where treatment with elbasvir/grasoprevir of HCV+ patients with a GFR <30 mL/min afforded a 99% cure rate and similar rates of adverse events between the placebo and study groups. In addition to elbasvir/grasoprevir, drug development continues to advance and it is anticipated that in the near future, DAAs will become available for all genotypes.
- Patients with HCV post-transplantation can also be treated with DAA without the risk of rejection that is seen with IFN. Several case series have reported cure rates close to 100% in this new DAA era. For example, Sawinski et al reported on their experience of treating 43 patients with 4 different DAA regimens where ALL patients were cured (defined as a sustained virologic response 12 weeks after completing therapy). Notably, the DAA drugs have generally been well-tolerated. There is, however, some indication that calcineurin inhibitor levels may be affected, and so judicious monitoring during DAA therapy may be warranted.
The overall effects of treating HCV post-transplantation on patient and graft survival are not yet known. The ability to treat HCV post-transplantation, however, strengthens the argument for delaying DAA treatment and listing for a HCV+ kidney. In the study by Sawinski mentioned earlier, patients who received HCV+ kidneys waited approximately 484 days (1.3 years) fewer than those who received HCV- kidneys. At our Nashville VA center where 20% of our transplants since December 2014 (implementation of the new Kidney Allocation System) have been HCV+ donors to HCV+ recipients, HCV+ recipients waited approximately 4.4 years fewer than HCV- recipients of HCV- kidneys (2.6 years versus 7 years).
Taking into account the benefits of a reduced waiting time and an increase in organ utilization associated with listing for a HCV+ kidney, an algorithm in managing pre-transplantation patients with HCV was recently published in a review by Sawinski and Bloom. In summary:
- Kidney transplantation candidates who are HCV RNA+ should continue to undergo liver biopsy (current practice) to exclude cirrhosis and the need for simultaneous liver-kidney transplantation. If they are not cirrhotic (Fibrosis Stage 0-3), patients with living donors should be treated with DAAs pre-transplantation.
- In the absence of a living donor, these patients have two options. The first is to be treated with DAAs pre-transplantation and list for a HCV- kidney like everyone else. The second option is to delay treatment and list for both HCV+ and HCV- kidneys, then receive HCV treatment with DAAs after transplantation (of note, the authors recommend consideration of the delayed treatment approach only for patients with genotype 1).
- The delayed treatment approach may be particularly beneficial for patients who expect to have a prolonged waiting time on the deceased donor list (listed in a center with a long waiting time, blood type O or B) or those who are at high risk for health deterioration on the waiting list (patients who are elderly or diabetic).
- For patients with advanced liver disease (Fibrosis Stage 3), HCV treatment pre-transplantation may be prudent.
Read about the future of HCV and kidney transplantation in Part 2 of this 2-part series.