DAAs change liver transplant landscape, use of HCV-positive organs
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Direct-acting antivirals for hepatitis C have not only led to a cure for the virus — they’ve also changed the paradigm in liver transplantation. This includes the transplantation of HCV-positive organs into HCV-negative recipients.
Healio spoke with Nancy S. Reau, MD, FAASLD, AGAF, professor in the division of digestive diseases and nutrition, section chief of hepatology and associate director of organ transplantation at Rush University, about the current role for liver transplantation in HCV and in hepatology as a whole.
Healio: How have direct-acting antivirals changed the frequency of, and need for, liver transplant as a tool for managing HCV?
Reau: There are two big ways in which DAAs have changed transplants for HCV. The first is the ability to prevent the need for transplant by treating someone with HCV who has marginal liver dysfunction. Sometimes, after cure, their liver function improves to the point that they no longer require a transplant.
Unfortunately, sometimes, you improve their liver function enough that they are not eligible for a transplant, but they don’t have great quality of life. That is what we call MELD purgatory. Treatment has made these patients less competitive for transplant, but in reality, transplant remains important for them. It is hard to know if curing the virus will improve their quality of life or place them in purgatory. Now, we recognize that a MELD score around 20 is a reasonable threshold. Those below this score should do well after cure and avoid transplant with great long-term outcomes.
The other way in which DAAs have impacted transplant is in our organ allocation system. Early on, we were pretty open to giving a HCV-exposed liver to someone with HCV. Now, however, because DAAs are so effective and can be used in the perioperative period, we are able to offer HCV-exposed organs to recipients who are HCV-negative, knowing we can cure them quickly. That has been incredibly important.
Before DAAs, we could not treat post-transplant HCV without a risk of rejection and compromising the infected liver further. In addition to rejection and drug toxicity, the risk-benefit ratio also had to consider the incredibly low cure rates in the post-transplant population. We also recognized that post-transplant HCV was a more aggressive disease. No one would have willingly given HCV to a patient in these circumstances. Even in those with pre-transplant HCV, we would warn patients that HCV was universally recurrent, and they might end up with cirrhosis again in 5 to 10 years. Now, that message is incredibly different.
Healio: Is the standard of care for HCV different for individuals who are on the transplant list?
Reau: That will differ from center to center. In some centers, the standard of care is loosely defined, because most of our guidelines are truly just guidelines. You know there are patients that you probably would not treat before transplant — for example, someone with very decompensated liver disease or someone with liver cancer. In that case, I would probably forge ahead and try to get them a transplant, waiting to treat their HCV until after the transplant because of concerns about a drug-induced complication, lowering their MELD score or otherwise doing something that is a disservice to the patient. Our HCV transplant volume is really small, which is good, but it’s a direct reflection of the incredible effectiveness of DAA therapy.
Healio: Has the need for liver transplant decreased because DAAs changed liver transplantation overall?
Reau: DAAs did not magically erase liver disease in the United States, though they did decrease the need for transplant in those with HCV. Now the leading indications for transplant are alcohol and non-alcohol fatty liver disease and liver cancer. Management of alcohol-related liver disease is starting to evolve. Six months of sobriety is pretty consistent for alcohol-related cirrhosis but acute alcoholic hepatitis (AH) is a very different disease. A lot of programs now have protocols for acute AH that do not include a mandatory period of sobriety. This is an indication for transplant that probably would not even have been historically contemplated in many centers. NASH prevalence is increasing and these patients are developing liver cancer and decompensated cirrhosis. They are filling the transplant void that has been left by curing HCV.
Healio: Can you discuss transplanting HCV-positive organs into HCV-negative recipients?
Reau: Giving a HCV-positive organ to a HCV-negative patient has been demonstrated as safe and effective in multiple studies. It would be unfair to say that it is commonplace — a lot of centers would still consider it investigational — but it is certainly becoming less controversial for liver transplant and even in other solid organ transplant.
It was a small leap for us to go from giving HCV-positive organs to only HCV-positive recipients to the HCV-positive/HCV-negative transplant. We’ve been transplanting hepatitis B-exposed organs to HBV-negative recipients for a long time — not necessarily with highly active HBV infection, but certainly someone with HBV exposure. With these transplants, it is a matter of making sure the patient understands and consents appropriately.
The opioid epidemic has resulted in lot of donors now who are young with a risk factors for HCV exposure. These are incredibly sad circumstances and, for families, offer a wonderful opportunity to see their grief transplanted into life. These young donors are otherwise healthy. Yet, many centers would pass on these organ options, wasting incredibly effective organs. With DAA therapy, we can now use these organs with minimal long-term risk. That has really been a game changer for a lot of programs.
Healio: What are some of the challenges with HCV-positive to HCV-negative organ transplants?
Reau: First of all, we do not fully understand the protocols for post-transplant treatment. There are some very short protocols where patients are treated for a week or 10 days with HCV therapy that is started on the way out of the operating room. We use these entry blockers so that the virus cannot enter and infect the cells as easily; then we use a very short course of DAAs. That is in the very early investigational stages. It worked in a small study, but most centers that would use an HCV-positive organ for an HCV-negative recipient administer a standard course of therapy post-transplant.
There is a bit of a question about timing. Do you start therapy on day 0 or day 1? Or do you let the patient recover from a post-transplant status for a little while and then consider using it? The number of medications the patient is on and the immunosuppression is much more significant right after transplant, so perhaps you wait 2 or 3 months. However, if you do, you will almost certainly see an infection in an organ that would not otherwise become infected with HCV.
There are also very rare cases of extrahepatic manifestations of HCV or fibrosing cholestatic hepatitis (FCH), which is a very aggressive form of HCV. If you defer therapy until a point after transplant when the patient might be healthier, you risk giving them a chance to develop a complication that they otherwise would not have had.
These protocols are still investigational to some degree; we need to really understand exactly how long therapy needs to be, because you do not want to give treatment for longer than necessary. Most of us see optimal timing as very early. After that, most of the time, the drug-drug interactions can be managed. If you think about our HCV treatment now, it is not usually that onerous for a patient.
Healio: Are there any issues with stigma among HCV-negative donors who receive an HCV-positive organ?
Reau: A lot of the stigma comes from the transplant itself. There is still a lot of stigma regarding liver disease, but you do not have to advertise that you received a HCV-positive organ. The stigma is really internalized — or it occurs among your family members who know about the consenting process — but we can cure HCV. You are not stuck with something that is a ‘scarlet letter’ for the rest of your life, though you might have an HCV antibody that is positive if you ever get screened for something. Transplant is a brand each patient wears a little bit differently. However, when you tell a patient that, if they are willing to consider an HCV-positive or an HBV-exposed organ, which are diseases we can either control or cure, vs. delaying a transplant and running the risk for being too sick for transplant or having complications they otherwise may not have had, most patients understand.