Belli LS, et al. J Hepatol. 2018;doi:10.1016/j.jhep.2018.06.010
HCV-Positive Organs: A Viable Option for Uninfected Transplant Patients
The number of hepatitis C-infected organs viable for transplantation has increased in recent years in correlation with the increasing opioid epidemic. While it is common practice to offer HCV-positive organs to patients already infected, especially liver disease patients, researchers have started looking into their use in uninfected patients. This option has become viable thanks to the high success rate of treatment with direct-acting antivirals.
“We’ve been using HCV-positive organs since the early days of transplant, but we would always give them to HCV-positive individuals,” Norah Terrault, MD, from the University of California in San Francisco, told HCV Next. “Since we have a lot of patients on the waitlist with HCV, there has always been a home for those organs.”
The access to pangenotypic DAAs, in particular, is an advantage for HCV-positive organ transplantation. Without necessarily having to obtain the patient’s genotype, treatment can begin as soon as their physician chooses. Typically, physicians begin DAA therapy shortly after transplant, but graft function can affect the optimal time for treatment.
According to Terrault, the number of HCV-positive organs has increased in part due to increasing drug-overdose mortalities, which means that many of the organs are from young individuals. These organs are often of higher quality due to their age. This, she said, has implications for liver, kidney, and even heart transplants.
“The easy thing to do is to put those organs into HCV-infected individuals — and there are those cases — but now, because there are so many people whose HCV has been cured with treatment, there are fewer of those individuals on the waitlist who might be HCV infected,” Terrault said. “So, there is now the concept of putting HCV-positive organs in patients who are uninfected.”
So far, while research into HCV-positive organs for uninfected patients needing liver transplantation is sparse, there have been some published reports of uninfected patients receiving HCV-positive kidneys and hearts.
Currently, it is not uncommon for patients with HCV to undergo kidney transplantation with organs that are HCV viremic, either preceded or followed by DAA therapy. However, there remains a shortage of organs to ensure prompt transplantation.
According to a study published in the American Journal of Transplantation, many transplant centers are still averse to using HCV-positive organs at all, which can lead to a high discard rate in some regions. Proponents for HCV-positive organs, at least for infected patients, argue that recipients benefit from earlier transplantation with a potentially ideal organ. Additionally, the highly successful outcomes of DAA therapy nearly guarantee a cure posttransplant.
The researchers therefore sought to compare the timing of treating HCV in patients on the kidney waitlist. Results of a Markov medical decision analysis model showed that patients who received DAA therapy posttransplant were more likely to receive a transplant 1 year earlier than those who received DAA therapy prior to transplant. While patients who received DAA therapy prior to transplant did survive longer (0.43 life-years; 95% CI, 0.38-0.49), delayed DAA therapy was preferred in regions with greater access to HCV-positive organs or in patients with a low risk for HCV-related mortality.
“The main thing in terms of using HCV-positive organs is increasing the donor pool,” Monica Konerman, MD, director of the Michigan Medicine NAFLD Clinic, told HCV Next. “In the kidney transplant world, use of these organs would decrease the wait time which would therefore decrease the length of time people need to undergo dialysis.”
Two other recent studies from the American Journal of Transplantation looked at the cost-effectiveness of using HCV-positive kidneys in patients who were uninfected.
Matthew Kadatz, MD, from the University of British Columbia, designed a model using deceased donors infected with HCV that was confirmed with nucleic acid testing. Their primary analysis showed that the strategy was cost-effective and improved health outcomes compared with patients who remained on the waitlist for an additional 2 years or more to receive an organ without HCV.
The strategy was also cost-effective with an incremental ratio of $56,018 per quality-adjusted life year from the payer perspective and $4,647 per quality-adjusted life year from the societal perspective compared with patients who remained on the waitlist for an additional year. The projected savings to health care payers could approach $2.9 million over 10 years if approximately 20 such cases were performed, despite the cost of DAAs at market price.
Gaurav Gupta, MD, from the Virginia Commonwealth University School of Medicine, and colleagues found similar results in their 5-year cost-effectiveness decision model. The strategy of accepting an HCV-positive organ for an uninfected patient, followed by DAA therapy, resulted in an approximate total health care cost of $138,000 with an expected 4.8 years of life compared with an approximate cost of $329,00 and 4.7 years of life in patients who waited for an organ without HCV.
Further analysis showed that the HCV-positive strategy remained preferable after adjusting for kidney transplant-related mortality; acute rejection probabilities; expected cure rates from DAA therapy; and the cost of transplant, immunosuppressives, DAA therapy, dialysis or acute rejection.
“It’s still an area of ongoing research, as some of the studies in kidney transplant have shown the results were not always as good in patients who received HCV-positive kidneys,” Konerman said, “but I think as treatment has gotten better it’s not necessarily going to always be the case.”
Recently, researchers from Vanderbilt University Medical Center in Nashville, Tennessee, published a study in the Journal of Heart and Lung Transplantation on preliminary results of transplanting HCV-positive hearts into uninfected patients.
“We don’t really know what the long-term outcomes of using these organs is going to be. Our preliminary results at Vanderbilt have been very promising,” Kelly H. Schlendorf, MD, lead author of the study told HCV Next. “Among the things we’ve noticed is that once we consult with patients about considering an HCV-positive donor, it seems that their waiting time is reduced, which is obviously a plus, particularly for patients who we think are at high risk for dying on the waitlist.”
According to Schlendorf, the few previous studies using this strategy in heart transplant patients suggested inferior outcomes to recipients. However, she noted that there were major caveats to these results. For one, these studies were performed prior to nucleic acid testing, so HCV-positivity was based solely on seropositivity, therefore making it difficult to extrapolate results that could be compared with the present day.
Secondly, these previous studies were performed in an era when standard of care for HCV was interferon-based, which was often poorly tolerated and associated with a lot of drug-drug interaction, particularly in immunosuppressed patients.
“Nowadays, we have the nucleic acid testing, so as soon as a donor heart is offered, we know if the organ is positive or negative,” Schlendorf said. “The direct-acting antivirals now available are associated with very few drug-drug interactions and are well-tolerated.”
In the study, Schlendorf and colleagues enrolled 12 HCV-naive patients and one patient whose HCV was cured prior to listing. These patients consented to undergo heart transplantation with HCV-positive organs, confirmed with nucleic acid testing.
Nine patients developed HCV viremia posttransplant and underwent subsequent treatment with DAAs. All nine patients received organs from donors with detectable HCV antibody and positive nucleic acid amplification test results. Median time from transplant to detection of viremia was 4 days (range, 2-13 days). As of October 2017, eight patients completed 12 weeks of DAA therapy and demonstrated sustained virologic response. One patient died due to pulmonary embolism during week 7 of treatment.
While these early results are promising, Schlendorf reiterated that it is still unclear what the long-term results will be.
“It seems like a great strategy for potentially increasing the donor pool; on the other hand, in about 5 years, we don’t know what patients who receive these hearts are going to look like and what implications they may suffer from,” she said.
The use of HCV-positive livers for nonviremic patients undergoing liver transplant is a rare occurrence, typically seen only in emergency cases or among patients who falsely tested negative for HCV viremia. So far, there are no published reports on the outcome of transplanting HCV-positive livers into HCV-naive patients.
However, much like recent cases of using positive organs in uninfected patients for kidney transplant or heart transplant, the strategy is gaining traction due to the efficacy of DAA therapy, persistent donor shortage, and the significant shift in available organs from young patients.
“All institutions are recognizing that this is an opportunity to expand the donor pool and that we can now use more donors. Every opportunity should be utilized,” Terrault said. “The American Transplant Society had a consensus conference and published results early this year stating that it’s quite reasonable to put HCV-positive organs into HCV-negative recipients, but it should be done under a protocol and with consent.”
A case study published in Liver Transplantation discussed the outcomes of a 57-year-old Caucasian woman with relatively well-compensated HCV-related cirrhosis who achieved SVR with DAA therapy but then developed hepatopulmonary syndrome and required a liver transplant. The patient consented to receive a liver that was anti-HCV negative but nucleic acid testing positive. After 24 weeks of treatment with Harvoni (sofosbuvir/ledipasvir, Gilead Sciences), starting on day 25 posttransplant, she achieved SVR.
In an editorial discussing the case study, Elizabeth C. Verna, MD, MSc, from Columbia University Medical Center in New York, and David S. Goldberg, MS, MSCE, from the University of Pennsylvania, stated that two important aspects in creating a plan for transplanting HCV-viremic donor livers into HCV-nonviremic recipients include treatment timing and appropriate selection of donors.
Additionally, Verna and Goldberg advocated that, given the current lack of data regarding the risks in such a case, use of this strategy should occur only in the context of a “rigorously informed consent process, both for clinical protocols or formal trials.”
“Centers should have a plan on how to do this and it should be done with full consent and documentation of that consent, and with a plan that ensures the patient has access to treatment after transplant,” Terrault explained. “When you’re going to give someone an HCV-infected organ, at some level you want to be confident that the patient can be cured after transplant with therapy. There has to be a discussion about what the risks are, what if treatment doesn’t work, and entertain the question of who is going to cover the cost of treatment. All of those things should be discussed with the patient before they are given the organ.”
Timing of DAA therapy
Studies have shown that since the introduction of DAAs, both liver transplant indications and HCV-related liver transplant outcomes have significantly improved. However, outcomes of transplantation involving HCV can vary based upon the timing of DAA therapy. Schlendorf explained that her center will not list a patient for transplant who is infected with HCV until the disease has been cured. The question of whether to treat prior to transplant or posttransplant becomes further varied in kidney and liver cases.
“The question has come up a lot within the hepatology world, when we’re considering people who are actively listed for liver transplant: Does it make sense to treat them for their hepatitis C before they get transplanted or after?” Konerman said. The problem, she explained, was that treatment can affect MELD scores. On one hand, a patient with a very low MELD score who receives treatment prior to transplant might improve enough to no longer need the operation, whereas another patient may have their MELD improve enough to drop lower on the waitlist after cure but still require the transplant.
“There was a study that looked at cost-effectiveness in treating liver transplant candidates pre vs. post and they looked at MELD cut-offs,” she continued. “They showed when the MELD score is 21 or lower, it was more cost-effective to treat pre-transplant, whereas a score of 22 or higher, it was more cost-effective to treat after. So, within liver transplant candidates, it really has to do with MELD score.”
Regarding other organ transplants, she was optimistic about the flexibility that DAA therapy can offer and the choice to treat before or after transplant will likely depend on the patient’s access to an HCV-positive organ.
“As we expand those options for patients, we will have different approaches as far as timing of treatment,” she said. “That’s more of a moving target.”
“It’s difficult to start treatment pre-transplant, because you’re not always sure who will be receiving the organ, but I do believe that if we’re going to do this, we should treat as early as possible,” Terrault said. “Early could mean in a day or two or as long as a week or more. The idea is that you want a patient who is stable and then you can start therapy early.” Terrault added that in transplant cases, it has been the standard to treat for a full 12 weeks, as no testing has been done on the shorter 8-week course of some DAAs.
While it is often an individualized decision and delaying HCV treatment can allow a patient access to HCV-positive organs, it is also important to minimize the length of time that a patient is infected. The decision can often weigh between stabilizing their disease and preventing HCV-related mortality while on the waiting list vs. stabilizing their MELD score and lower their access to transplant.
All new methods of treatment in medicine come with the same question: what are the long-term outcomes? As centers begin using HCV-positive organs for uninfected patients, the most important thing will be to follow the patients and look for risk factors that clarify the strategy’s benefits or complications.
“The known unknown is we don’t know yet what are the risks for the patient,” Terrault said. “That hasn’t been quantified yet. To advance to a point where this becomes a standard of care, or that we have a policy on how this is done broadly across the U.S., we have to get more data first. I think we’re suffering from an actual void of data. What is the actual failure rate of therapy? How many patients will develop progressive disease?”
According to Terrault, with the number of studies currently underway, it is likely that within a year there will be enough data to allow more national policies to be developed and to lead the development of clinical protocols.
The next step, Konerman said, was to have individual centers develop a clear protocol in terms of what patients will consider; how DAA therapy will be a part of it; and how to educate patients, physicians and providers. Once individual centers develop their protocols, they can each perform pilot studies with a small number of patients, iron out the strategy’s details, and then begin planning for larger studies.
Schlendorf added to the conversation on the topic of heart transplant that patients who receive an HCV-positive organ may be at an increased risk for cardiac allograft vasculopathy, as suggested by previous literature. “We don’t know for sure in the current era,” she said, “but it’s something we’re mindful of. At our institution, our clinical protocol stipulates that patients who undergo transplant with an HCV-positive donor and go on to develop infection, will undergo vascular ultrasounds at baseline and again at 1 year to see if they may be developing cardiac allograft vasculopathy at an accelerated rate.”
It is clear, however, that the opportunity to increase transplant donor pools with available HCV-positive organs is one that physicians are eager to explore, given the high likelihood of successful cure in the DAA era.
- Belli LS, et al. J Hepatol. 2018;doi:10.1016/j.jhep.2018.06.010.
- Crespo G, et al. J Hepatol. 2018;doi:10.1016/j.jhep.2018.02.012.
- Gupta G, et al. Am J Transplant. 2018;doi:10.1111/ajt.15054.
- Kadatz M, et al. Am J Transplant. 2018;doi:10.1111/ajt.14929.
- Kiberd BA, et al. Am J Transplant. 2018;doi:10.1111/ajt.14891.
- Saberi B, et al. Liver Transpl. 2018;doi:10.1002/lt.24838.
- Schlendorf KH, et al. J Heart Lung Transplant. 2018;doi:10.1016/j.healun.2018.01.1293.
- Verna EC, Goldberg DS. Liver Transpl. 2018;doi:10.1002/lt.24985.
- For more information:
- Monica Konerman, MD, MSc, can be reached at email@example.com.
- Norah Terrault, MD, can be reached at firstname.lastname@example.org.
- Kelly H. Schlendorf, MD, can be reached at email@example.com.
Disclosures: Konerman, Schlendorf and Terrault report no relevant financial disclosures.