Feature

HCV on the Transplant List: Weighing Options and Making Clinical Decisions

Direct-acting antiviral therapies have had far-reaching consequences in the treatment of hepatitis C, and that has extended to patients awaiting potentially life-saving liver transplant.

At the moment, these drugs are so well tolerated that we can safely treat HCV in many decompensated patients and bring about meaningful improvement in MELD score. This improvement may in some cases even trigger removal from the transplant list. But despite these improvements, these patients may continue to experience diminished quality of life.

So before empirically and reflexively treating them, thought should be given to the downstream consequences of curative treatment. We need to ask ourselves whether we may, in fact, be doing patients a disservice by treating HCV in patients on transplant waiting lists.

Raymond T. Chung

There are a number of clinically relevant question for caregivers with patients who require liver transplantation. For the purposes of this discussion, this population may be divided into two groups: those who have HCV and are awaiting transplantation, and those who have successfully undergone liver transplantation with HCV. It may be helpful to consider component parts and address issues pertaining to disparities in transplantation wait times from region to region; so-called ‘tweener’ cases, which include patients without obviously low or high MELD scores; quality of life issues; consideration of HCV-positive liver donors; and the possibility of developing guidelines for this patient group.

Setting the Stage

Increasingly, as the benefits of DAA therapies diffuse out to additional patient groups, including those who have historically been viewed as difficult-to-treat, we are seeing the treatment of patients post-liver transplantation becoming more and more straightforward.

With this being the case, the major question pivots to the management of patients who are on the liver transplant waiting list. Clinical trials of DAAs have demonstrated that in a majority of these cases — as many as two-thirds to three-quarters of patients — experience improvement in clinical status. This finding has implications for transplant list management.

Patients with severe disease who are high on the transplant list and have very high MELD scores are unlikely to see their status on the transplant list appreciably change. Moreover, we should consider that there may be an undue risk in treating these severely advanced patients with DAAs, since in trials, deterioration was observed in a higher frequency of patients with more advanced MELD scores.

Therefore, the burden and the risk-benefit calculus would argue against treating those patients with very high MELD scores (>30) who are close to a donor organ offer. A companion point that needs to be raised is that by treating those high MELD score patients prior to transplantation, we effectively remove an option that has become increasingly viable — receiving an organ from an HCV-positive donor. This will be discussed further below.

Conversely, patients with a lower MELD score are looking at a long wait for a donor organ, so the question is whether that patient would benefit from successful treatment of HCV. As noted, a fairly high percentage will experience clinical stabilization or improvement. One possible additional benefit of treatment will be that it will move some of those patients off the transplant list. Thus, it would seem that treating patients on the list with low MELD scores would be associated with a favorable cost-benefit calculus as viral clearance may move some of those patients off the list.

‘Tweener’ Cases

But what about the ‘tweeners,’ those patients who have a MELD score that is neither particularly high nor particularly low? With ‘tweeners,’ there are arguments to be marshalled in either direction. Viral clearance could in many instances improve their symptoms. However, in some patients, even if we improve their MELD scores by two points, we won’t necessarily obviate the transplant. They are still sick and will still have an impaired quality of life. Many, for instance, will still have significant ascites and/or encephalopathy despite the improved MELD score. In a sense, we may be relegating them to something of a purgatory where we have reduced their priority for, but not eliminated the need for transplantation.

The concern, then, is simple: we just don’t know what constitutes the sweet spot for drawing a distinction or threshold for who should be treated and who shouldn’t be treated in this context. For now, the choice to treat is a highly individualized approach based on considerations of the patient’s projected wait time and quality of life.

Our obligation as caregivers is to eliminate all causes of suffering wherever we can, but we have been thrust into a very interesting dilemma. The decision to treat HCV in some instances may be countered by the potentially adverse consequences of putting a patient further down the priority list for transplantation, when the transplantation is really needed to preserve quality of life and life expectancy.

Donation Concerns

These decisions are further complicated by regional disparities in donor allocation, which is something that individual clinicians need to take into consideration, depending on where they are practicing.

Another factor to consider is that depending on the severity of their symptoms, these patients may benefit from organs from marginal donors, including those with HCV. This could be an option for stabilizing the transplantation list.

At present, in most regions, at least 5% of donor organs are HCV-positive. In some procurement areas, those numbers may be considerably higher. There has been a well publicized sharp rise in overdose deaths as a direct consequence of the opioid crisis. These events, generally speaking, involve young donors who have not had a long duration of HCV infection. Therefore, the donor liver quality is fairly preserved, and such donor livers may be offered to particularly needy recipients who sit further down the list.

However, those prospective recipients who have been treated for HCV as they await transplantation may no longer be eligible for these otherwise high-quality organs. These are the unintended consequences of a perfectly valid and well-intentioned effort to eliminate the underlying cause of hepatic deterioration. Thus, when contemplating treating patients on the list, this complex scenario merits full discussion with the patient about the benefits and risks of embarking on antiviral therapy.

Many institutions have taken the position that unless there is a compelling reason to treat HCV at that moment — if they are highly symptomatic or very low priority on the transplant list — treatment should be delayed. However, this position must be weighed against the observation that successful treatment can yield clinical benefit for most patients. This is an area of active investigation that demands additional studies to help us clarify the best management for this group of patients.

Guidelines

At the moment, clinical decisions are primarily made by the hepatologist and the patient and not by an entire transplant team or committee. We have not developed an across-the-board policy because there is not yet enough data to fully justify an algorithmic approach as to whether or when a patient should be treated while on the transplant list.

It would be desirable to have guidance on this. We want to optimize the outcome for all patients. Can there be a flat MELD threshold below which patients should be treated? Possibly, but regional allocation differences may need to factor into the equation. In a shorter wait time region, where donor organs are offered at lower MELD scores, the MELD threshold for DAA treatment could be lower than in a long wait time region.

Until substantial real-world data are accrued, to define this threshold will likely require projections and assumptions that are fed into more sophisticated models.

At our center, based on early models, we have deferred on treating patients with MELD scores greater than 26 and have considered treating each patient below this threshold.

Parting Shots

The introduction of DAAs has produced an unexpected bounty of options for the patient with advanced HCV liver disease awaiting transplantation. There are many factors that enter decision-making surrounding the treatment of these patients, including projected wait time, quality of life and safety of the regimen. The development of guidance on prudent thresholds at which to initiate DAA therapy in these patients will be very important, but ultimately, there is no substitute for a balanced discussion of the pros and cons of therapy with the individual patient.

Direct-acting antiviral therapies have had far-reaching consequences in the treatment of hepatitis C, and that has extended to patients awaiting potentially life-saving liver transplant.

At the moment, these drugs are so well tolerated that we can safely treat HCV in many decompensated patients and bring about meaningful improvement in MELD score. This improvement may in some cases even trigger removal from the transplant list. But despite these improvements, these patients may continue to experience diminished quality of life.

So before empirically and reflexively treating them, thought should be given to the downstream consequences of curative treatment. We need to ask ourselves whether we may, in fact, be doing patients a disservice by treating HCV in patients on transplant waiting lists.

Raymond T. Chung

There are a number of clinically relevant question for caregivers with patients who require liver transplantation. For the purposes of this discussion, this population may be divided into two groups: those who have HCV and are awaiting transplantation, and those who have successfully undergone liver transplantation with HCV. It may be helpful to consider component parts and address issues pertaining to disparities in transplantation wait times from region to region; so-called ‘tweener’ cases, which include patients without obviously low or high MELD scores; quality of life issues; consideration of HCV-positive liver donors; and the possibility of developing guidelines for this patient group.

Setting the Stage

Increasingly, as the benefits of DAA therapies diffuse out to additional patient groups, including those who have historically been viewed as difficult-to-treat, we are seeing the treatment of patients post-liver transplantation becoming more and more straightforward.

With this being the case, the major question pivots to the management of patients who are on the liver transplant waiting list. Clinical trials of DAAs have demonstrated that in a majority of these cases — as many as two-thirds to three-quarters of patients — experience improvement in clinical status. This finding has implications for transplant list management.

Patients with severe disease who are high on the transplant list and have very high MELD scores are unlikely to see their status on the transplant list appreciably change. Moreover, we should consider that there may be an undue risk in treating these severely advanced patients with DAAs, since in trials, deterioration was observed in a higher frequency of patients with more advanced MELD scores.

Therefore, the burden and the risk-benefit calculus would argue against treating those patients with very high MELD scores (>30) who are close to a donor organ offer. A companion point that needs to be raised is that by treating those high MELD score patients prior to transplantation, we effectively remove an option that has become increasingly viable — receiving an organ from an HCV-positive donor. This will be discussed further below.

Conversely, patients with a lower MELD score are looking at a long wait for a donor organ, so the question is whether that patient would benefit from successful treatment of HCV. As noted, a fairly high percentage will experience clinical stabilization or improvement. One possible additional benefit of treatment will be that it will move some of those patients off the transplant list. Thus, it would seem that treating patients on the list with low MELD scores would be associated with a favorable cost-benefit calculus as viral clearance may move some of those patients off the list.

‘Tweener’ Cases

But what about the ‘tweeners,’ those patients who have a MELD score that is neither particularly high nor particularly low? With ‘tweeners,’ there are arguments to be marshalled in either direction. Viral clearance could in many instances improve their symptoms. However, in some patients, even if we improve their MELD scores by two points, we won’t necessarily obviate the transplant. They are still sick and will still have an impaired quality of life. Many, for instance, will still have significant ascites and/or encephalopathy despite the improved MELD score. In a sense, we may be relegating them to something of a purgatory where we have reduced their priority for, but not eliminated the need for transplantation.

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The concern, then, is simple: we just don’t know what constitutes the sweet spot for drawing a distinction or threshold for who should be treated and who shouldn’t be treated in this context. For now, the choice to treat is a highly individualized approach based on considerations of the patient’s projected wait time and quality of life.

Our obligation as caregivers is to eliminate all causes of suffering wherever we can, but we have been thrust into a very interesting dilemma. The decision to treat HCV in some instances may be countered by the potentially adverse consequences of putting a patient further down the priority list for transplantation, when the transplantation is really needed to preserve quality of life and life expectancy.

Donation Concerns

These decisions are further complicated by regional disparities in donor allocation, which is something that individual clinicians need to take into consideration, depending on where they are practicing.

Another factor to consider is that depending on the severity of their symptoms, these patients may benefit from organs from marginal donors, including those with HCV. This could be an option for stabilizing the transplantation list.

At present, in most regions, at least 5% of donor organs are HCV-positive. In some procurement areas, those numbers may be considerably higher. There has been a well publicized sharp rise in overdose deaths as a direct consequence of the opioid crisis. These events, generally speaking, involve young donors who have not had a long duration of HCV infection. Therefore, the donor liver quality is fairly preserved, and such donor livers may be offered to particularly needy recipients who sit further down the list.

However, those prospective recipients who have been treated for HCV as they await transplantation may no longer be eligible for these otherwise high-quality organs. These are the unintended consequences of a perfectly valid and well-intentioned effort to eliminate the underlying cause of hepatic deterioration. Thus, when contemplating treating patients on the list, this complex scenario merits full discussion with the patient about the benefits and risks of embarking on antiviral therapy.

Many institutions have taken the position that unless there is a compelling reason to treat HCV at that moment — if they are highly symptomatic or very low priority on the transplant list — treatment should be delayed. However, this position must be weighed against the observation that successful treatment can yield clinical benefit for most patients. This is an area of active investigation that demands additional studies to help us clarify the best management for this group of patients.

Guidelines

At the moment, clinical decisions are primarily made by the hepatologist and the patient and not by an entire transplant team or committee. We have not developed an across-the-board policy because there is not yet enough data to fully justify an algorithmic approach as to whether or when a patient should be treated while on the transplant list.

It would be desirable to have guidance on this. We want to optimize the outcome for all patients. Can there be a flat MELD threshold below which patients should be treated? Possibly, but regional allocation differences may need to factor into the equation. In a shorter wait time region, where donor organs are offered at lower MELD scores, the MELD threshold for DAA treatment could be lower than in a long wait time region.

Until substantial real-world data are accrued, to define this threshold will likely require projections and assumptions that are fed into more sophisticated models.

At our center, based on early models, we have deferred on treating patients with MELD scores greater than 26 and have considered treating each patient below this threshold.

Parting Shots

The introduction of DAAs has produced an unexpected bounty of options for the patient with advanced HCV liver disease awaiting transplantation. There are many factors that enter decision-making surrounding the treatment of these patients, including projected wait time, quality of life and safety of the regimen. The development of guidance on prudent thresholds at which to initiate DAA therapy in these patients will be very important, but ultimately, there is no substitute for a balanced discussion of the pros and cons of therapy with the individual patient.