Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.
Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.
Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.
Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.
It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list. It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.
During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube.
Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?
Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.
Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?
Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.
A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.
The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.
We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.
Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.
Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.
Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?
Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.
Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?
Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.