Cover Story

HCV-Positive, Recipient-Negative Transplant Solves Problems, Raises Questions

From its inception, the concept of organ transplantation has drilled down to the fundamental ethics of practicing medicine. From initial concerns about donating organs from individuals who died of a cardiac event to the advent of living donation, the medical community questioned if this practice violates the basic tenet of the Hippocratic Oath: do no harm. Now the HCV community is moving steadily toward donation of HCV-positive organs into HCV-negative recipients, and a new set of questions arises.

Raymond T. Chung, MD, vice chief of the gastrointestinal division and director of hepatology at Massachusetts General Hospital, laid out the terms of the discussion. “The notion of donor-positive, recipient-negative transplantation for HCV has been, until now, inconceivable because of the concerns about the natural history of the disease and our inability to completely control it following transplantation,” he said. “When you consider the notion of knowingly introducing an infection into an infection-naive recipient, there is a high bar that has to be surmounted in order to be acceptable.”

Raymond T. Chung

Chung said that the arguments against this practice were largely ethical. “This was a threat,” he said. “The potential for allograft disease and infection was high, in addition to the risks associated with less-than-perfect or poorly tolerated antiviral therapies. The notion was off the table.”

But now, with direct-acting antiviral agents, it is possible and worthy of discussion, according Robert S. Brown Jr., MD, MPH, Gladys & Roland Harriman professor of medicine and director of the center for liver disease and transplantation at Weill Cornell Medical College and New York-Presbyterian Hospital in New York. He suggested that a more comprehensive view is necessary when examining the ethical considerations involved.

“It depends on your interpretation of ‘do no harm,’” he said. “If you take the narrowest definition of the phrase, you would never give someone an organ that had a disease. However, if you take a broader definition, giving someone a life-saving organ transplant they might not otherwise receive and then treating them with drugs that have a cure rate of 97% to 99%, it likely can be justified.”

For Brown, it is simply a matter of numbers. “The failure rate of these drugs is 3%,” he said. “The risk of dying on the waiting list is greater than that. It is certainly not an ethical issue in terms of risk–benefit.”

This does not mean, however, one can ignore the ethical questions or those of finances and logistics. Wait times for donor organs need to be considered, as do directions for future research. HCV Next and the experts attempt to tackle these and other concerns related to donor-positive, recipient-negative liver transplantation.

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Setting the Stage

David S. Goldberg, MD, MSCE, assistant professor of Medicine and medical director for Living Donor Liver Transplantation at the Hospital of the University of Pennsylvania, and colleagues conducted a review of literature involving HCV-positive liver donation. They noted that HCV- positive organs are increasingly being used in HCV-negative recipients, but that clinical trials and prospective data sets remain sparse. “Future research should focus on the use of HCV-positive donor livers in HCV-negative liver transplant recipients,” they wrote.

David S. Goldberg

“To date there are no registered clinical trials of HCV-positive donation to HCV-negative recipients in liver transplantation,” Goldberg said in an interview with HCV Next. He noted that certain centers around the country, including groups at the University of Utah, Massachusetts General Hospital, Loma Linda and the University of Washington in Seattle, have been performing this procedure. “Our center is one of two centers that has an ongoing clinical trial doing positive-to-negative transplantations, but we are doing kidneys and not livers.”

The increasing use of HCV-positive livers is in part due to a growing number of young, comparatively healthy HCV-positive donors who have died in the opiate epidemic, according to Goldberg. “That’s the donor side,” he said. “On the recipient side, there are two factors to consider. One is that even though more and more patients are being treated for HCV, that doesn’t necessarily stave off the need for transplant. But the second point is that, with DAA therapies, we have a high degree of confidence that we will be able to cure them.”

Helen S. Te, MD, professor of Medicine and medical direct of Adult Liver Transplantation at the University of Chicago School of Medicine, outlined some of the obstacles that may potentially hinder the universal application of transplanting HCV-positive livers into HCV-negative recipients. “One is patient willingness to take the HCV-positive organ, which I think can be addressed by informed consent that should be carefully obtained and may require multiple discussions,” she said. “The discussion should include the possibility of failure of the current HCV therapy, which occurs in less than 5% of cases. As this is a real risk, should it occur, the patient’s post-transplant graft function and survival can be significantly impacted by the HCV infection.”

A second concern is the potential denial of insurance coverage for HCV therapy for this indication, particularly from insurance payers who are currently only committed to treatment of patients who demonstrate advanced hepatic fibrosis. “This can be overcome if the Centers for Medicare and Medicaid Services can create a pathway that allows programs to obtain a commitment for coverage for HCV therapy from the payers concomitantly with the commitment for coverage for the transplantation and the immunosuppression themselves,” Te said. “Advocacy to make HCV therapy more affordable for patients who have to pay a significant copay for medications is also direly needed.”

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Fundamental Ethical Issues

Jeffrey Campsen, MD, assistant professor of Surgery and Pediatric Surgery in the Division of Transplantation and Advanced Hepatobiliary Surgery, surgical director of Adult Kidney and Pancreas Transplant and surgical director of Pediatric Kidney Transplant at the University of Utah Health Sciences Center, said that transplant has always been on the forefront of ethics. “When we are talking about live liver donation, right off the bat you are hurting someone to give someone else an organ,” he said. “When we started talking about giving people HCV-positive organs, we had already had some context for these discussions.”

It is important to note that a patient with kidney disease can live for a prolonged period with dialysis, which makes the conversation about transplanting that organ more nebulous. “The liver is a little more black and white,” Campsen said. “If a patient has a MELD score of 40, if they don’t get a liver, chances of that patient being alive in 40 days are small. We are talking about someone who is going to die.”

For Campsen, some other numbers also play into the ethical discussion. “Twenty-three people are dying on the transplant list every day,” he said. “There’s a mortality rate in waiting for organs. When we are looking that in the face of that, and when we understand that risk, we should consider using high-risk organs.”

This, then, raises questions about what constitutes a high-risk organ, according to Chung. “There are circumstances where we knowingly use organs from patients with long ischemic times or who experienced cardiac death rather than brain death,” he said. “In these cases, the outcomes are not as optimal as the more conventional brain death donor scenarios. Recipients who are not at the top of the wait list but who are doing very poorly may feel the need to accept extended criteria or more marginal donors.”

Donor age is also a component of the argument, according to Brown. “We use organs from elderly individuals, organs with a degree of fat or steatosis in them,” he said. “All organs carry some difference in risk that is higher than you would see in the idealized perfect donor.”

The opioid epidemic also has recently become a factor in the discussion. Young people are overdosing, and even if they are dying with HCV, they usually have not had the disease for nearly as long as a 60- or 70-year-old. Whether the younger liver is healthier is up for debate.

Brown is inclined to think yes, but others, including Lena Sibulesky, MD, assistant professor of surgery in the division of transplantation at the University of Washington Medical Center, believe the issue is not so clear. “A liver from a younger donor infected with HCV might be a better organ than a liver from an older person who is HCV-negative who died from a heart attack,” she said.

She offered a practical point to help make these kinds of determinations. “You have to look at various parameters, including a liver biopsy, to make this determination,” she said.

Patient psychology also plays into this discussion, according to Brown. “We explain these various factors to the patient, but it comes down to the risk that patients and physicians are willing to tolerate,” he said. “An older liver with a history of a cardiac event? A liver from a younger person who died of an opioid overdose? We have to let them know that there is always going to be a risk, so it is up to them to decide which of those risks they can live with.”

Robert S. Brown

Brown added another component to the psychological implications. “Patients don’t tolerate new diseases as well as they tolerate things that they already have,” he said.

Sibulesky offered a practical point. “If the donor is non-viremic (HCV Ab+ NAT-), the risk of transmission of the virus is very small,” she said. “Those are the people whose organs we are considering using in HCV-negative patients.”

Once these organs are in place, the main ethical issue is that the recipient incurs a new disease, according to Te. “This disease has the potential to cause significant liver dysfunction in the post-transplant period unless the infection is well-controlled or successfully eradicated,” she said. “In the past, when interferon-based therapy in liver transplant recipients had a success rate of 30% on average and was very poorly tolerated, doing this type of transplant just could not be justified. Today, when treatment for hepatitis C in liver transplant recipients is more than 95% successful and is well tolerated, there is so much more to gain from this approach in the setting of donor organ scarcity.”

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Informed Consent

It may be worthwhile to pause and analyze the idea of informed consent a bit further, according to Brown. “Do patients really understand what the risks and benefits are? In my experience, patients don’t always understand,” he said. “Some underestimate the risk and overestimate the benefit, and others do the opposite. There are plenty of situations where the benefit of accepting an HCV-positive organ and an earlier transplant would outweigh any risk associated with medications or lack of clearance.”

That said, Brown stressed that ethical considerations often get mixed up with litigious considerations. “There have been lawsuits with transmission-donor disease, including ones that were unknowable,” he said. “So, you can imagine in this case, where the disease is known, if the patient has an outcome they don’t wish, the patient could wonder whether the doctor informed them properly of risks and benefits.”

The question, then, is whether this should steer the clinical community away from moving forward with these transplantations. Brown says no. “But as we move further into this territory, this should be part of the clinical trial protocol, at least initially,” he said.

At Goldberg’s center, there is a multi-step consent process. “Many patients don’t even know what HCV is, so we have to start there,” he said. “A significant amount of education goes on before they are even in a position to give informed consent for the transplantation.”

Campsen noted that the team approach used by major transplant centers can help in ensuring as informed consent as possible. “In addition to the hepatologist, there is the patient’s primary care provider, we have nurses, patient advocates, pharmacists and, of course, the transplant surgeon. We have videos they can watch at home, literature and online resources at their disposal,” he said. “With the right kind of information infrastructure, they are going to get a lot of opinions.”

The method of decision-making is also critical, according to Campsen. “We don’t want them to sign to accept right away,” he said. “We want them to go home and consider all of this information.”

But even with all those resources available, Campsen acknowledged that some patients will simply hear, “infected organ,” and balk. “In that case, it’s fine, don’t give them the organ,” he said. “At a certain point, they have to be their own advocate.”

Campsen closed this discussion with something of a broader ethical point. “We are not going to waste any organs if we can help it,” he said. “This is why this is under consideration. If there were enough uninfected organs to go around, we would not be doing this, or doing living donation. But these organs can potentially save lives, so we should use every one we can.”

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Financial Concerns

While current DAA therapies, of course, have shown overwhelmingly strong sustained virologic response rates, the question becomes one of access. At Campsen’s center in Utah, the provider is also the insurer, so they can treat patients immediately as part of the protocol. Brown commented on this approach.

“In Utah, they made a decision that they were going to do this and that it was cost-effective for them,” he said. “They have a unique situation where they view that the cost of reducing admissions to their insurer justifies the cost of the medications and getting the patients to the transplant faster. I have no doubt that if we transplant sooner, we are going to offset more than just the cost of the medication.”

Clinical trials are the next best approach to ensuring treatment after transplantation, according to Brown. “The medications should be provided by a study so we know there won’t be any issues with approval,” he said.

Helen S. Te

For Te, it is worth looking at the big picture. “Although the cost of HCV therapy is undeniably high, many patients who are not served well by the MELD score allocation system have recurrent hospitalizations, for reasons such as exacerbations of hepatic encephalopathy despite optimal medical therapy, recurrent fluid overload despite being on diuretics, kidney dysfunction, hyponatremia, peritonitis or the need for repeated thoracentesis or paracentesis,” she said. “Avoidance of recurrent hospitalization in these patients with decompensated cirrhosis may even offset this cost.”

Chung built on this point. “We will be effectively increasing the donor pool,” he said. “We have to look at the numbers of actual donors and recipients. We have to look at the overall cost savings when you balance premature mortality against those individuals who receive an organ and return to productive lives. Of course, we will have to see if this savings is counter-balanced by the cost of antiviral therapy, which is considerable.”

Chung believes that, over the long run, this can offer potential savings. “It should also be noted that the price of these medications has seen a fairly steady decline, and it appears that that trend could continue,” he said.

For Goldberg, when dealing with real-world situations, the question returns to one of insurance coverage. “There are no guarantees that antiviral therapy will be approved,” he said. “Exposing someone to a virus without a treatment option in hand could lead to any number of costly downstream complications.”

The clinical community is becoming more adept at gaining approval for DAA therapies, Goldberg acknowledged. “Also, while it is expected that transmission of HCV would occur in nearly 100% of cases, the chance of having complications related to HCV in the first few months after transplantation is low,” he said. “But still, if we are going to be doing this, provisions should be in place for treatment within 3 to 6 months, if not sooner.”

The final consideration for cost is the possibility of failure of DAA therapy. Even with a 97% cure rate, the burden of dealing with those 3% of patients who acquire new HCV and are treated unsuccessfully remains unknown.

“We need to carefully consider what happens to those who can’t be cured,” Sibulesky said.

Brown offered a response to this. “In the 3% who fail post-transplant therapy, it is going to be very difficult for transplant centers and patients to accept that we gave them a new disease which we can’t cure,” he said. “The payer will say, ‘You did this to yourself, we’re not paying.’”

But there may be a silver lining to this somewhat bleak outlook. “This has always been an issue with donor-derived disease,” he said. “We have experience dealing with it.”

Goldberg urged caution. “This is why this practice is still experimental,” he said. “We need more information before it can become the standard of care.”

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Logistical Concerns

The logistics of transplantation — most notably, wait times — should be examined, according to Te. “Overall, there certainly is a significant benefit in utilizing HCV-positive organs to shorten waitlist times and lower waitlist mortality with little risk to the patient who is able to receive therapy for HCV,” she said. “This is particularly of utmost benefit to those patients who are disadvantaged on the waitlist for various reasons, whether it is for an unfavorable blood type, body habitus, debilitating symptoms such as hepatic encephalopathy or refractory ascites or hydrothorax that requires frequent paracentesis or thoracentesis despite placement of an intrahepatic shunt, or other circumstances that are not reflected well in the MELD score, which is the current allocation system for livers.”

Since data are limited for HCV-positive liver donation, other organs are forming the backbone of knowledge. Gallegos-Orozco and colleagues developed a protocol to treat HCV-positive potential kidney transplant recipients who had received HCV-positive organs. As per the protocol, patients were treated 3 to 6 months after transplantation. Between 2014 and 2015, 12 patients entered the protocol. Six have completed treatment and reached SVR12, while one patient is awaiting treatment. The transplantation yielded functioning kidneys in all seven patients. They noted that wait time for an organ decreased from an average of 1,350 days to 65 days.

Chung put these data sets into perspective. “A significant truncation of wait times is conceivable for all organs,” he said. “Assuming we can confirm the safety of the protocols, it might be unethical not to use these organs.”

“Looking at these data in the kidney, there are positives we can take away for liver, but there are also clinical and logistical concerns,” Goldberg said, namely, drug–drug interactions. “We are still learning about how these HCV drugs impact the kidneys. Some of them are contraindicated for kidney disease, so we have to be careful of renal failure.”

“People are also skittish because we don’t know how immunosuppressives interact with DAAs,” Campsen added. “Working from the example of HIV, experts in San Francisco have paved the way to manipulate immunosuppressive drug levels to make them tolerable, but this is still not widely understood.”

The clinical community may also benefit from observing experiences with similar diseases like hepatitis B, according to Sibulesky. “We put HBV core-positive livers into patients who were not immune to HBV and subjected them to lifelong treatment for this disease,” she said. “DAA regimens are 12 or 24 weeks of treatment, so it would have to be just as acceptable.”

Future Directions

It may be several years before the necessity of donor-positive, recipient-negative liver transplantation becomes pervasive, according to Chung. “We encounter this far less frequently because there are still so many HCV-positive patients ready, willing, and able to receive these organs,” he said. “As we successfully treat more and more people with DAAs, this need is going to rise.”

Brown suggested that this eventuality may come sooner than later. “The drive to put positive organs into negative patients exists because so many patients on the waiting list have been treated,” he said.

Still, however, these operations are largely being performed at individual centers rather than in multicenter trials. “We need to see this done in a large, multicenter trial with proper oversight,” Goldberg said.

In the absence of those trials, clinicians have had to be creative to ensure patients are treated with this life-saving procedure.

“We had a one-off situation of a patient with a profoundly disabling chronic liver disease, but the MELD score didn’t push him high enough onto the recipient list and there were no extended criteria offers forthcoming,” Chung said. “So, we designed an IRB protocol that applied just to him.”

The success of the situation depended on the ability to treat him immediately. “The IRB protocol allowed us to move forward with immediate treatment,” Chung said. “More importantly, we demonstrated that we could perform this procedure successfully under protocol.”

Brown’s team is also working on an IRB protocol, but warned that even with a clinical trial with proper oversight, the risk for performing these procedures is high from a public opinion perspective. “It would only take a few failures to generate a big outcry against this,” he said.

That said, Sibulesky remains optimistic. “I think things will change dramatically with time,” she said. “Currently, it is still a big deal to infect someone with HCV, people are still wary of this disease. But that is changing with current therapies. It is just going to be a very slow process.”

Brown, too, is hopeful. “What is clear is that this can be done,” he said. “What is clear is that it can be life-saving for HCV-negative patients to receive HCV-positive organs, just like it’s life-saving for HCV-positive patients to receive HCV- positive organs. It’s better to be transplanted than not.” – by Rob Volansky

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Disclosures: Brown reports associations with AbbVie, Bristol-Myers Squibb, Gilead, Janssen and Merck. Campsen reports no relevant financial disclosures. Chung reports receiving research grants paid to his institution from Bristol-Myers Squibb, Gilead Sciences, MassBiologics and Vertex Pharmaceuticals. Goldberg reports attending a funding event with Merck. Sibulesky reports no relevant financial disclosures. Te reports being a clinical investigator with AbbVie Pharmaceuticals and Gilead Sciences.

From its inception, the concept of organ transplantation has drilled down to the fundamental ethics of practicing medicine. From initial concerns about donating organs from individuals who died of a cardiac event to the advent of living donation, the medical community questioned if this practice violates the basic tenet of the Hippocratic Oath: do no harm. Now the HCV community is moving steadily toward donation of HCV-positive organs into HCV-negative recipients, and a new set of questions arises.

Raymond T. Chung, MD, vice chief of the gastrointestinal division and director of hepatology at Massachusetts General Hospital, laid out the terms of the discussion. “The notion of donor-positive, recipient-negative transplantation for HCV has been, until now, inconceivable because of the concerns about the natural history of the disease and our inability to completely control it following transplantation,” he said. “When you consider the notion of knowingly introducing an infection into an infection-naive recipient, there is a high bar that has to be surmounted in order to be acceptable.”

Raymond T. Chung

Chung said that the arguments against this practice were largely ethical. “This was a threat,” he said. “The potential for allograft disease and infection was high, in addition to the risks associated with less-than-perfect or poorly tolerated antiviral therapies. The notion was off the table.”

But now, with direct-acting antiviral agents, it is possible and worthy of discussion, according Robert S. Brown Jr., MD, MPH, Gladys & Roland Harriman professor of medicine and director of the center for liver disease and transplantation at Weill Cornell Medical College and New York-Presbyterian Hospital in New York. He suggested that a more comprehensive view is necessary when examining the ethical considerations involved.

“It depends on your interpretation of ‘do no harm,’” he said. “If you take the narrowest definition of the phrase, you would never give someone an organ that had a disease. However, if you take a broader definition, giving someone a life-saving organ transplant they might not otherwise receive and then treating them with drugs that have a cure rate of 97% to 99%, it likely can be justified.”

For Brown, it is simply a matter of numbers. “The failure rate of these drugs is 3%,” he said. “The risk of dying on the waiting list is greater than that. It is certainly not an ethical issue in terms of risk–benefit.”

This does not mean, however, one can ignore the ethical questions or those of finances and logistics. Wait times for donor organs need to be considered, as do directions for future research. HCV Next and the experts attempt to tackle these and other concerns related to donor-positive, recipient-negative liver transplantation.

PAGE BREAK

Setting the Stage

David S. Goldberg, MD, MSCE, assistant professor of Medicine and medical director for Living Donor Liver Transplantation at the Hospital of the University of Pennsylvania, and colleagues conducted a review of literature involving HCV-positive liver donation. They noted that HCV- positive organs are increasingly being used in HCV-negative recipients, but that clinical trials and prospective data sets remain sparse. “Future research should focus on the use of HCV-positive donor livers in HCV-negative liver transplant recipients,” they wrote.

David S. Goldberg

“To date there are no registered clinical trials of HCV-positive donation to HCV-negative recipients in liver transplantation,” Goldberg said in an interview with HCV Next. He noted that certain centers around the country, including groups at the University of Utah, Massachusetts General Hospital, Loma Linda and the University of Washington in Seattle, have been performing this procedure. “Our center is one of two centers that has an ongoing clinical trial doing positive-to-negative transplantations, but we are doing kidneys and not livers.”

The increasing use of HCV-positive livers is in part due to a growing number of young, comparatively healthy HCV-positive donors who have died in the opiate epidemic, according to Goldberg. “That’s the donor side,” he said. “On the recipient side, there are two factors to consider. One is that even though more and more patients are being treated for HCV, that doesn’t necessarily stave off the need for transplant. But the second point is that, with DAA therapies, we have a high degree of confidence that we will be able to cure them.”

Helen S. Te, MD, professor of Medicine and medical direct of Adult Liver Transplantation at the University of Chicago School of Medicine, outlined some of the obstacles that may potentially hinder the universal application of transplanting HCV-positive livers into HCV-negative recipients. “One is patient willingness to take the HCV-positive organ, which I think can be addressed by informed consent that should be carefully obtained and may require multiple discussions,” she said. “The discussion should include the possibility of failure of the current HCV therapy, which occurs in less than 5% of cases. As this is a real risk, should it occur, the patient’s post-transplant graft function and survival can be significantly impacted by the HCV infection.”

A second concern is the potential denial of insurance coverage for HCV therapy for this indication, particularly from insurance payers who are currently only committed to treatment of patients who demonstrate advanced hepatic fibrosis. “This can be overcome if the Centers for Medicare and Medicaid Services can create a pathway that allows programs to obtain a commitment for coverage for HCV therapy from the payers concomitantly with the commitment for coverage for the transplantation and the immunosuppression themselves,” Te said. “Advocacy to make HCV therapy more affordable for patients who have to pay a significant copay for medications is also direly needed.”

PAGE BREAK

Fundamental Ethical Issues

Jeffrey Campsen, MD, assistant professor of Surgery and Pediatric Surgery in the Division of Transplantation and Advanced Hepatobiliary Surgery, surgical director of Adult Kidney and Pancreas Transplant and surgical director of Pediatric Kidney Transplant at the University of Utah Health Sciences Center, said that transplant has always been on the forefront of ethics. “When we are talking about live liver donation, right off the bat you are hurting someone to give someone else an organ,” he said. “When we started talking about giving people HCV-positive organs, we had already had some context for these discussions.”

It is important to note that a patient with kidney disease can live for a prolonged period with dialysis, which makes the conversation about transplanting that organ more nebulous. “The liver is a little more black and white,” Campsen said. “If a patient has a MELD score of 40, if they don’t get a liver, chances of that patient being alive in 40 days are small. We are talking about someone who is going to die.”

For Campsen, some other numbers also play into the ethical discussion. “Twenty-three people are dying on the transplant list every day,” he said. “There’s a mortality rate in waiting for organs. When we are looking that in the face of that, and when we understand that risk, we should consider using high-risk organs.”

This, then, raises questions about what constitutes a high-risk organ, according to Chung. “There are circumstances where we knowingly use organs from patients with long ischemic times or who experienced cardiac death rather than brain death,” he said. “In these cases, the outcomes are not as optimal as the more conventional brain death donor scenarios. Recipients who are not at the top of the wait list but who are doing very poorly may feel the need to accept extended criteria or more marginal donors.”

Donor age is also a component of the argument, according to Brown. “We use organs from elderly individuals, organs with a degree of fat or steatosis in them,” he said. “All organs carry some difference in risk that is higher than you would see in the idealized perfect donor.”

The opioid epidemic also has recently become a factor in the discussion. Young people are overdosing, and even if they are dying with HCV, they usually have not had the disease for nearly as long as a 60- or 70-year-old. Whether the younger liver is healthier is up for debate.

Brown is inclined to think yes, but others, including Lena Sibulesky, MD, assistant professor of surgery in the division of transplantation at the University of Washington Medical Center, believe the issue is not so clear. “A liver from a younger donor infected with HCV might be a better organ than a liver from an older person who is HCV-negative who died from a heart attack,” she said.

She offered a practical point to help make these kinds of determinations. “You have to look at various parameters, including a liver biopsy, to make this determination,” she said.

Patient psychology also plays into this discussion, according to Brown. “We explain these various factors to the patient, but it comes down to the risk that patients and physicians are willing to tolerate,” he said. “An older liver with a history of a cardiac event? A liver from a younger person who died of an opioid overdose? We have to let them know that there is always going to be a risk, so it is up to them to decide which of those risks they can live with.”

Robert S. Brown

Brown added another component to the psychological implications. “Patients don’t tolerate new diseases as well as they tolerate things that they already have,” he said.

Sibulesky offered a practical point. “If the donor is non-viremic (HCV Ab+ NAT-), the risk of transmission of the virus is very small,” she said. “Those are the people whose organs we are considering using in HCV-negative patients.”

Once these organs are in place, the main ethical issue is that the recipient incurs a new disease, according to Te. “This disease has the potential to cause significant liver dysfunction in the post-transplant period unless the infection is well-controlled or successfully eradicated,” she said. “In the past, when interferon-based therapy in liver transplant recipients had a success rate of 30% on average and was very poorly tolerated, doing this type of transplant just could not be justified. Today, when treatment for hepatitis C in liver transplant recipients is more than 95% successful and is well tolerated, there is so much more to gain from this approach in the setting of donor organ scarcity.”

PAGE BREAK

Informed Consent

It may be worthwhile to pause and analyze the idea of informed consent a bit further, according to Brown. “Do patients really understand what the risks and benefits are? In my experience, patients don’t always understand,” he said. “Some underestimate the risk and overestimate the benefit, and others do the opposite. There are plenty of situations where the benefit of accepting an HCV-positive organ and an earlier transplant would outweigh any risk associated with medications or lack of clearance.”

That said, Brown stressed that ethical considerations often get mixed up with litigious considerations. “There have been lawsuits with transmission-donor disease, including ones that were unknowable,” he said. “So, you can imagine in this case, where the disease is known, if the patient has an outcome they don’t wish, the patient could wonder whether the doctor informed them properly of risks and benefits.”

The question, then, is whether this should steer the clinical community away from moving forward with these transplantations. Brown says no. “But as we move further into this territory, this should be part of the clinical trial protocol, at least initially,” he said.

At Goldberg’s center, there is a multi-step consent process. “Many patients don’t even know what HCV is, so we have to start there,” he said. “A significant amount of education goes on before they are even in a position to give informed consent for the transplantation.”

Campsen noted that the team approach used by major transplant centers can help in ensuring as informed consent as possible. “In addition to the hepatologist, there is the patient’s primary care provider, we have nurses, patient advocates, pharmacists and, of course, the transplant surgeon. We have videos they can watch at home, literature and online resources at their disposal,” he said. “With the right kind of information infrastructure, they are going to get a lot of opinions.”

The method of decision-making is also critical, according to Campsen. “We don’t want them to sign to accept right away,” he said. “We want them to go home and consider all of this information.”

But even with all those resources available, Campsen acknowledged that some patients will simply hear, “infected organ,” and balk. “In that case, it’s fine, don’t give them the organ,” he said. “At a certain point, they have to be their own advocate.”

Campsen closed this discussion with something of a broader ethical point. “We are not going to waste any organs if we can help it,” he said. “This is why this is under consideration. If there were enough uninfected organs to go around, we would not be doing this, or doing living donation. But these organs can potentially save lives, so we should use every one we can.”

PAGE BREAK

Financial Concerns

While current DAA therapies, of course, have shown overwhelmingly strong sustained virologic response rates, the question becomes one of access. At Campsen’s center in Utah, the provider is also the insurer, so they can treat patients immediately as part of the protocol. Brown commented on this approach.

“In Utah, they made a decision that they were going to do this and that it was cost-effective for them,” he said. “They have a unique situation where they view that the cost of reducing admissions to their insurer justifies the cost of the medications and getting the patients to the transplant faster. I have no doubt that if we transplant sooner, we are going to offset more than just the cost of the medication.”

Clinical trials are the next best approach to ensuring treatment after transplantation, according to Brown. “The medications should be provided by a study so we know there won’t be any issues with approval,” he said.

Helen S. Te

For Te, it is worth looking at the big picture. “Although the cost of HCV therapy is undeniably high, many patients who are not served well by the MELD score allocation system have recurrent hospitalizations, for reasons such as exacerbations of hepatic encephalopathy despite optimal medical therapy, recurrent fluid overload despite being on diuretics, kidney dysfunction, hyponatremia, peritonitis or the need for repeated thoracentesis or paracentesis,” she said. “Avoidance of recurrent hospitalization in these patients with decompensated cirrhosis may even offset this cost.”

Chung built on this point. “We will be effectively increasing the donor pool,” he said. “We have to look at the numbers of actual donors and recipients. We have to look at the overall cost savings when you balance premature mortality against those individuals who receive an organ and return to productive lives. Of course, we will have to see if this savings is counter-balanced by the cost of antiviral therapy, which is considerable.”

Chung believes that, over the long run, this can offer potential savings. “It should also be noted that the price of these medications has seen a fairly steady decline, and it appears that that trend could continue,” he said.

For Goldberg, when dealing with real-world situations, the question returns to one of insurance coverage. “There are no guarantees that antiviral therapy will be approved,” he said. “Exposing someone to a virus without a treatment option in hand could lead to any number of costly downstream complications.”

The clinical community is becoming more adept at gaining approval for DAA therapies, Goldberg acknowledged. “Also, while it is expected that transmission of HCV would occur in nearly 100% of cases, the chance of having complications related to HCV in the first few months after transplantation is low,” he said. “But still, if we are going to be doing this, provisions should be in place for treatment within 3 to 6 months, if not sooner.”

The final consideration for cost is the possibility of failure of DAA therapy. Even with a 97% cure rate, the burden of dealing with those 3% of patients who acquire new HCV and are treated unsuccessfully remains unknown.

“We need to carefully consider what happens to those who can’t be cured,” Sibulesky said.

Brown offered a response to this. “In the 3% who fail post-transplant therapy, it is going to be very difficult for transplant centers and patients to accept that we gave them a new disease which we can’t cure,” he said. “The payer will say, ‘You did this to yourself, we’re not paying.’”

But there may be a silver lining to this somewhat bleak outlook. “This has always been an issue with donor-derived disease,” he said. “We have experience dealing with it.”

Goldberg urged caution. “This is why this practice is still experimental,” he said. “We need more information before it can become the standard of care.”

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Logistical Concerns

The logistics of transplantation — most notably, wait times — should be examined, according to Te. “Overall, there certainly is a significant benefit in utilizing HCV-positive organs to shorten waitlist times and lower waitlist mortality with little risk to the patient who is able to receive therapy for HCV,” she said. “This is particularly of utmost benefit to those patients who are disadvantaged on the waitlist for various reasons, whether it is for an unfavorable blood type, body habitus, debilitating symptoms such as hepatic encephalopathy or refractory ascites or hydrothorax that requires frequent paracentesis or thoracentesis despite placement of an intrahepatic shunt, or other circumstances that are not reflected well in the MELD score, which is the current allocation system for livers.”

Since data are limited for HCV-positive liver donation, other organs are forming the backbone of knowledge. Gallegos-Orozco and colleagues developed a protocol to treat HCV-positive potential kidney transplant recipients who had received HCV-positive organs. As per the protocol, patients were treated 3 to 6 months after transplantation. Between 2014 and 2015, 12 patients entered the protocol. Six have completed treatment and reached SVR12, while one patient is awaiting treatment. The transplantation yielded functioning kidneys in all seven patients. They noted that wait time for an organ decreased from an average of 1,350 days to 65 days.

Chung put these data sets into perspective. “A significant truncation of wait times is conceivable for all organs,” he said. “Assuming we can confirm the safety of the protocols, it might be unethical not to use these organs.”

“Looking at these data in the kidney, there are positives we can take away for liver, but there are also clinical and logistical concerns,” Goldberg said, namely, drug–drug interactions. “We are still learning about how these HCV drugs impact the kidneys. Some of them are contraindicated for kidney disease, so we have to be careful of renal failure.”

“People are also skittish because we don’t know how immunosuppressives interact with DAAs,” Campsen added. “Working from the example of HIV, experts in San Francisco have paved the way to manipulate immunosuppressive drug levels to make them tolerable, but this is still not widely understood.”

The clinical community may also benefit from observing experiences with similar diseases like hepatitis B, according to Sibulesky. “We put HBV core-positive livers into patients who were not immune to HBV and subjected them to lifelong treatment for this disease,” she said. “DAA regimens are 12 or 24 weeks of treatment, so it would have to be just as acceptable.”

Future Directions

It may be several years before the necessity of donor-positive, recipient-negative liver transplantation becomes pervasive, according to Chung. “We encounter this far less frequently because there are still so many HCV-positive patients ready, willing, and able to receive these organs,” he said. “As we successfully treat more and more people with DAAs, this need is going to rise.”

Brown suggested that this eventuality may come sooner than later. “The drive to put positive organs into negative patients exists because so many patients on the waiting list have been treated,” he said.

Still, however, these operations are largely being performed at individual centers rather than in multicenter trials. “We need to see this done in a large, multicenter trial with proper oversight,” Goldberg said.

In the absence of those trials, clinicians have had to be creative to ensure patients are treated with this life-saving procedure.

“We had a one-off situation of a patient with a profoundly disabling chronic liver disease, but the MELD score didn’t push him high enough onto the recipient list and there were no extended criteria offers forthcoming,” Chung said. “So, we designed an IRB protocol that applied just to him.”

The success of the situation depended on the ability to treat him immediately. “The IRB protocol allowed us to move forward with immediate treatment,” Chung said. “More importantly, we demonstrated that we could perform this procedure successfully under protocol.”

Brown’s team is also working on an IRB protocol, but warned that even with a clinical trial with proper oversight, the risk for performing these procedures is high from a public opinion perspective. “It would only take a few failures to generate a big outcry against this,” he said.

That said, Sibulesky remains optimistic. “I think things will change dramatically with time,” she said. “Currently, it is still a big deal to infect someone with HCV, people are still wary of this disease. But that is changing with current therapies. It is just going to be a very slow process.”

Brown, too, is hopeful. “What is clear is that this can be done,” he said. “What is clear is that it can be life-saving for HCV-negative patients to receive HCV-positive organs, just like it’s life-saving for HCV-positive patients to receive HCV- positive organs. It’s better to be transplanted than not.” – by Rob Volansky

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Disclosures: Brown reports associations with AbbVie, Bristol-Myers Squibb, Gilead, Janssen and Merck. Campsen reports no relevant financial disclosures. Chung reports receiving research grants paid to his institution from Bristol-Myers Squibb, Gilead Sciences, MassBiologics and Vertex Pharmaceuticals. Goldberg reports attending a funding event with Merck. Sibulesky reports no relevant financial disclosures. Te reports being a clinical investigator with AbbVie Pharmaceuticals and Gilead Sciences.