Tuesday, August 16, 2016

The patient perspective: Waiting for the liver

Waiting for “The Liver” – No Longer?
Gregory T. Everson
University of Colorado School of Medicine, CO, USA See Article, pages 524–531

Journal Of Hepatology
September 2016 Volume 65, Issue 3, Pages 467–469
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References
DOI: http://dx.doi.org/10.1016/j.jhep.2016.06.013

The new issue of the Journal of Hepatology is online! Read it here.

Editorial

The patient perspective: Waiting for the liver
Vladimir and Estragon, both afflicted with chronic hepatitis C, met while attending support group and became companions engaged in endless conversation concerning their plight. Despite treatments with interferon (IFN), pegylated interferon (PegIFN), and PegIFN plus ribavirin, the hepatitis C virus persisted and progressively damaged and scarred their livers to the final stage of cirrhosis. Vladimir noticed swellings about the ankles and protuberance of his abdomen; Estragon’s thoughts had become confused and muddled – the time had come to list for liver transplantation. The two were listed. They waited and shared the horrors of interferon, waited and discussed their doctors, nurses, and surgeons, waited and bemoaned the many medications to treat their ailments, … and, waited for the liver that had not come today but surely would tomorrow. Then, in the midst of the waiting – something changed, dramatically!

The alternative: Direct-acting antiviral therapy for hepatitis C virus infection
Direct-acting antiviral drugs (DAAs) for the treatment of the hepatitis C virus have arrived and now promise to potentially change the paradigm of “Waiting for the Liver”. These highly effective and well tolerated drugs have revolutionized therapy for patients infected with hepatitis C virus (HCV). Rates of sustained virological response (SVR) are 95% or higher in patients with compensated cirrhosis and 80 to 90% in patients with decompensated cirrhosis [[1], [2], [3]]. Encouraged by the tolerability of DAAs and the high rates of SVR in these cirrhotic populations, transplant physicians have begun to treat many of the patients on waiting lists for liver transplantation.

The study
The study by Belli and colleagues in this issue of the Journal of Hepatology, suggests that transplant candidates with chronic hepatitis C may have an alternative to “Waiting for the Liver”. They report the outcomes of 103 transplant candidates with HCV genotypes 1 through 4, without hepatocellular carcinoma, who were treated with a variety of DAA regimens between 2014 and 2015  [4. Fifty percent received sofosbuvir (SOF)/ribavirin (RBV), 34% SOF/daclatasvir (DAC), 7% SOF/simeprevir (SMV), and 9% SOF/ledipasvir (LDV) and 97/103 (94%) achieved SVR. Baseline median model for end-stage liver disease (MELD) score was 16, and 86% had MELD scores <20. Despite the relatively low MELD scores all were classified as Child-Pugh (CP) B or C. In post-treatment follow-up 41 were transplanted. Of the remaining 62 patients, 34 experienced hepatic improvements sufficient to be inactivated for liver transplantation, and 21 of these 34 remained stable or sufficiently improved on further follow-up to warrant delisting. Approximately, 1/3 of these waiting list patients could be inactivated and 1/5 delisted for liver transplantation.

The observed rates of inactivation or delisting were compared to rates derived from a model of inactivation and delisting due to spontaneous hepatic improvement. This comparison indicated a positive effect of DAA treatment and SVR. In multi-variable analyses, patients with baseline MELD <16, greater Δ MELD (decrease), and greater Δ albumin (increase) were most likely to be inactivated or de-listed.

Although, the report is largely an observational study, the authors are to be congratulated for providing the first evidence of a potentially major clinical benefit of treating waitlist patients with HCV – reduction in need for liver transplantation. Of course, long-term follow-up will be required to be certain that the inactivated and delisted remain stable, have improved clinical outcomes, and do not require relisting

Reasons for listing patients with HCV for liver transplantation
The two main indications for listing patients with HCV for liver transplantation are hepatocellular carcinoma (HCC) and decompensated cirrhosis. The HCV patient with HCC will either undergo the transplant, or be delisted for HCC progression. Achieving SVR with DAA treatment will not affect these outcomes.

In contrast to the HCV patient with HCC, the HCV patient with decompensated cirrhosis has theoretically reached the “point of no return”. Presumably, the accumulated damage is so extensive and irreversible that liver transplantation would be required for restoration of liver health. In the IFN era of HCV treatment, these patients were either too sick to treat, or had extremely low rates of SVR in response to treatment. DAAs have changed this paradigm – even the sickest patients can tolerate treatment, and have an excellent chance to achieve SVR. Thus, for the first time, we can now examine the clinical and economic impact of achieving SVR in patients with decompensated disease on transplant waiting lists.

Anticipated benefits of achieving SVR in waitlist patients
There are two expected benefits of achieving SVR in decompensated patients on the waiting list: prevention of post-transplant recurrence of HCV infection, and stabilization or improvement of liver disease. Improvement in liver function and the hepatic and portal circulations could reduce risk for liver-related complications, decrease waitlist mortality, and potentially eliminate the need for liver transplantation. Recent studies have proven that treating HCV patients with DAAs prior to liver transplantation can reduce post-transplant recurrence [5.  But the goal of reversal of liver disease to the point of reducing waitlist mortality and eliminating the need for liver transplantation remains elusive. The report by Belli and colleagues demonstrates that patients on liver transplant waiting lists who achieve SVR with DAAs may experience hepatic improvement and be inactivated or delisted for transplantation. These findings seem to imply that mortality and rates of liver transplantation will decrease in the HCV patients achieving SVR, but this remains to be proven.

Limitations of the study
Small sample size
Although 11 EU centers were included, only 103 patients are reported and 41 of the 103 patients underwent transplantation leaving just 58 for possible inactivation and delisting. As stated above, 34 of the 58 were inactivated and 21 of the 34 delisted. Inactivated and delisted patients had lower baseline MELD (median 14), greater decrease in MELD, and greater increase in albumin. All of these predictors are available to treatment providers in real-time and could indicate significant hepatic improvement sufficient to warrant inactivation or delisting. However, in MELD-based organ allocation, a baseline low MELD score and further decline in MELD score while waiting would eliminate the possibility of liver transplantation.

No uniform criteria for inactivation or delisting
The criteria for improvement sufficient to warrant inactivation or delisting was left to the individual liver transplant teams, based on “clinical judgment”. In MELD-based organ allocation, “clinical judgment is based heavily on MELD score”. Indeed, baseline MELD and Δ MELD were two of the three main predictors of inactivation and delisting – suggesting a key role of MELD in the centers’ decision-making regarding listing status. Is it possible that at least some of the patients who were inactivated or delisted in response to low baseline MELD and Δ MELD still had clinical manifestations or features of significant portal hypertension – MELD Purgatory? In my own experience, many cirrhotic patients with advanced disease will continue to experience manifestations or complications of portal hypertension, even years after achieving SVR.

In the multi-variable analysis, MELD score and Δ MELD, but not CP score or Δ CP, were associated with inactivation and delisting. This suggests that MELD and not clinical assessment was main criteria for inactivation and delisting.

Inactivation and delisting was limited to cases with MELD <20
The rate of inactivation and delisting in the Belli study, may not be translatable to all transplant centers. The median MELD score was 16 for the whole group, and 14 for the patients who were inactivated or delisted. Patients with MELD >20 were considered too sick and were not inactivated or delisted. This is relevant to liver centers in the US where liver transplantation is driven by high MELD scores. In fact, many US centers don’t currently list liver candidates until MELD >20. If the Belli study is correct, and MELD >20 is too sick to inactivate or delist, then the newly listed US candidates for liver transplantation will not be inactivated or delisted after SVR. [6. However, there is a backlog of HCV cases on the US liver transplant waiting list. Over half of HCV patients are listed at MELD <20 and about one-third of all waiting list deaths occur in this low-MELD group

Even though curing HCV in low-MELD patients might not alter liver transplant rates, it certainly could reduce waitlist mortality. If the patient is cured and survives longer, will that translate into sustained survival benefit, reduction in liver decompensation, reduction in risk of HCC, and improved liver function and physiology. Or, will the positive effect of reduction in immediate mortality rates only be a transient short-term effect? In long-term follow-up will the inactivated and delisted patients still die of liver decompensation or HCC or get re-listed for transplantation? In the latter case, one could argue that inactivation and delisting might actually be harmful.

Limited period of follow-up
The period of follow-up in the Belli study was very short and, therefore, could not determine the impact of inactivation or delisting on subsequent clinical outcomes. Ongoing clinical stability with reductions in decompensation, HCC, and mortality would confirm the wisdom and benefit of inactivation or delisting. However, on the other hand, if long-term follow-up were to demonstrate ongoing liver decompensation, HCC, or death from liver disease, one could question the wisdom or benefit of inactivation or delisting.

Phases of liver recovery after SVR
There are three phases of hepatic improvement during and after DAA treatment of cirrhotic patients with HCV. Data from nearly every DAA clinical trial demonstrate rapid clearance of HCV and rapid decline in alanine aminotransferase (ALT) within the first month of initiation of treatment. These events are consistent with reduction in inflammation and liver cell injury. Over the next few months, hepatocellular functions, such as international normalized ratio, bilirubin, and albumin, improve. The SOLAR-1 and SOLAR-2 trials documented improvement in at least some of these hepatocyte functions over the 6 months of post-treatment follow-up.

The last and slowest phase of healing of the liver requires remodeling of portal fibrosis, improvement in the portal circulation, and reduction in portal hypertension. A long-term study of patients with portal hypertension treated with SOF/RBV demonstrated non-significant changes in portal pressure at year 1 but significant improvement by year 2 [[7], [8]].  Additionally, a dual cholate test of liver function and physiology demonstrated early improvement at 1 month due to resolution of inflammation and liver cell injury, but no additional improvement up to 1 year [9.

Concluding remarks

Unlike Beckett’s Godot and the somewhat equivalent icon of transplantation, “The Liver”, the new DAAs have arrived and have begun to change the landscape of treatment and management of the HCV transplant candidate on the waiting list. The study of Belli et al. indicates that low-MELD patients are likely to achieve the greatest potential benefit of SVR – eradication of HCV coupled with significant hepatic improvement leading to inactivation and delisting. In contrast, patients with MELD >20 may not experience hepatic improvement despite SVR and should remain active on the list for liver transplantation. The overall success of treating the waiting list patients will depend on the results of long-term studies of clinical outcomes, such as liver-related complications, HCC, and death from liver disease.

Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Article Outline
The patient perspective: Waiting for the liver
The alternative: Direct-acting antiviral therapy for hepatitis C virus infection
The study
Reasons for listing patients with HCV for liver transplantation
Anticipated benefits of achieving SVR in waitlist patients
Limitations of the study
Small sample size
No uniform criteria for inactivation or delisting
Inactivation and delisting was limited to cases with MELD <20
Limited period of follow-up
Phases of liver recovery after SVR
Concluding remarks
Conflict of interest
References

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