The Impact of DAA in Changing the Face of Liver Transplantation_Juniper Publishers
Authored by John Fung
Opinion
The introduction of direct acting antiviral drugs
(DAA) directed to hepatitis C virus (HCV) is certainly one of the most
clinically significant breakthrough sin recent medical histories, with
the promise ofaffectinghundreds of millions of lives worldwide. In the
arena of liver transplantation (LT), the impact of the use of DAA can be
felt in 3 scenarios:
- Progressive reduction of the number of patients needing LT due to decompensated HCV-related cirrhosis;
- Eliminating the consequences of post-transplant HCV recurrence by way of clearing HCV viremia pre-transplant; and
- Safely and successfully treating LT patients developing post-transplant HCV recurrence.
Hopefully, decompensated HCV-related liver cirrhosis
as the primary indication for LT will disappear within the next two
decades. Considering the present distribution of liver diseases that are
indications for LT, the impact of DAA in the liver transplant arena has
the potential to eliminate 20% to 40% of the indications for LT.
In this setting, the liver transplant community
should consider how the reduced need for LT may impact the practice of
LT- Specifically, how will this void be filled in the future, supposing
that the proportion of donors that would otherwise be used for HCV
indications could be shifted to alternative indications? Secondarily,
could strategies of donor pool expansion and of organ preservation
change in front of a modification of this scenario?
Patients with hepatocellular carcinoma
Hepatocellular carcinoma arising in the cirrhotic
liver already represents a significant indication for LT and expected to
grow over the decade. Given the high association of HCC inpatients that
are HCV-positive in Western countries and the progressive aging of the
general population, patients with HCC that will be referred for LT are
likely to be at an increasingly advanced age. Therefore, a feature of a
candidate for LT for HCC in the next few years is likely to be that of a
patient older than 60-65 years, without active hepatitis virus
replication, and with possible age-related co-morbidities.Thus,
long-term posttransplant survival may be compromised by the risk of such
comorbidities (cardiovascular, metabolic, and oncological), posing a
challenge to our current complex and multidisciplinary care. In
addition, presentation of HCC at a very advanced age may preclude some
patients from being considered for LT due to a high risk of
postoperative morbidity and mortality. On the other hand, experiences
gained in the last ten years with neo adjuvant multi-modal treatment of
HCC, expansion of HCC beyond Milan criteria for LT, and strategies of
salvage transplantation after liver resection for HCC could reposition
the position of LT amongst therapies of HCC.
In fact, the shift away from donor utilization from
end-stage liver disease due to HCV may increase availability of liver
donors for HCC and lead to a further expansion of the still-restrictive
criteria for LT in HCC, possibly accepting a mild-to-moderate increase
of post-transplant tumor recurrence. In other words, more donors that
are available mayre-affirm the role of LT as a definitive and more
widely available curative treatment for HCC.
Live donors already represent a significant
proportion of grafts for patients with HCC worldwide, and they will
presumably be still necessary in the next years. The changing feature of
a typical candidate for liver transplant from a patient with
decompensate cirrhosis (frequently associated with HCV infection) to a
patient with better-preserved liver function and hepatic tumors,
cARGHies the possibility of maximizing living donor liver transplant by
taking advantage of less severe portal hypertension and less severe
liver disease. This in turn could reduce the risk to the living donor
and increase the likelihood of an obtaining a living donor. From the
organizational and governmental points of view, all the above assertions
will reinforce the principle that HCC should be treated in surgical
units with proficiency in both liver transplant and liver surgery, as
part of the multidisciplinary treatment of liver cancer and wARGHanting a
correct approach to living donor procedures based on a solid experience
of hepatic resections.
Donor pool expansion and conditioning of the donor liver
The persistent gap between the number of donors and
patients on the waiting list for LT has driven the increased utilization
of all possible means to expand the number of liver grafts over the
last 25 years. Donor livers with suboptimal function and/or structure,
older donors, partial grafts, and nonheart-beating donors now represent,
with appropriate inclusion criteria, a valid alternative to standard
deceased organs. Nevertheless, the so-called "Extended Criteria Donors”
(ECD), to which the above categories largely pertain, implies an
increased risk of suboptimal outcome in terms of graft function recovery
and post-transplant survival. In particular, the use of liver grafts
from older donors is still controversial, as some report poorer outcome
compared to transplants performed with younger donors.
Interestingly, a growing appreciation of the studies
on this topic have clearly shown that most of the detrimental effect of
grafts from old donors emerged when they were transplanted into
HCV-positive recipients related to the dramatic impact of an earlier,
more rapid and severe post-transplant HCV infection recurrence when
using older donors. In fact, when the results obtained in
non-HCV-positive patients were considered separately, they were
comparable to those achieved with younger donors in most of the recent
studies. Thus, the absence of active HCV replication in LT candidates
may further encourage the use of older donors and/or, in a larger
perspective, of ECDs in general.
In this light, the possible conditioning of marginal
grafts with different techniques and may take on grater importance than
in the recent past. For example, the use of machine oxygenated perfusion
in a hypo- or normothermic state, has already successfully adopted in
clinical setting, and could be expanded with less apprehension
considering that the most dreadful recipient-related variable (disease
recurrence) will not impact negatively on the functional recovery and
survival outcome. Other techniques, such as ischemic preconditioning,
either remote, or pharmacological, or even the use of regenerative
medicine approaches may be better applied.
Immunotolerance induction
While immunosuppression protocols aimed at achieving
tolerance of the transplanted live rare still in its infancy, this goal
remains the holy grail of solid organ transplantation. One of the
factors limiting the expansion of this approach has been the
demonstration of high failure rates in attempts to wean immune
suppression in HCV positive recipients, as well as concern for
accelerated HCV recurrence with induction therapy. Therefore, it is
intuitive that pro-tolerant strategies with induction immune suppression
regimens may be more successful with the elimination of HCV before or
after LT.
Patients with metabolic disorders
Non-alcoholic steatohepatitis (NASH) as a feature of
dysmetabolic syndrome represents a progressively increasing indication
to LT in most Western countries, and the reduction of HCV-related
decompensated cirrhosis will further increase the proportion of
dysmetabolic patients listed for LT. The medical and surgical challenges
faced in treating this category of patients is already significant,
considering the higher prevalence of obesity, diabetes and
cardiovascular diseases when compared with non- NASH patients.
Nutritional awareness and surgical procedures aiming at reducing obesity
and diabetes are increasingly utilized, which may curb the growth of
patients with NASH. In addition, bariatric procedures during or after
transplant, may reduce the long-term negative impact of obesity in these
patients.
Other indications for liver transplant
One of the most intriguing consequences ofthe
disappearance of HCV-related decompensated cirrhosis is the void, which
may be filled by patients with tumors currently judged as unsuitable for
LT. With strict selection criteria, patients with hepatic metastases
from neuroendocrine tumors or with hilar cholangiocarcinoma (Klatskin
tumor) already represent an accepted indication for LT. There is
increasing interest to consider patients with non-resectable, liver-only
metastases from colorectal cancer for LT, based on promising results
obtained in Norway. The combination of the generally improved results of
LT in the last few decades, the higher efficacy of chemotherapy for
metastatic colorectal cancer, and the use of immunosuppressive drugs
with anti-proliferative effects (e.g. mTOR inhibitors), may explain the
5-year post-transplant survival of 60% in selected candidates with
colorectal carcinoma liver metastases. This outcome may be further
improved if patients demonstrate objective response to chemotherapy
prior to LT. This degree of long-term survival provides a benefit
comparable to that achieved by other malignant indications.
Interestingly, the ethical dilemma of providinga liver graft to such
patients, while patients in other currently acceptable categories are
waiting for LT could be mitigated by the use of extended criteria grafts
in patients with colorectal metastasis, including small size partial
and living donor grafts, based on the absence of cirrhosis and portal
hypertension.
Conclusion
With the exception of mandatory hepatitis B
vaccination and the development of nucleotide and nucleoside analogs for
the treatment of HBV, no other clinical development except DAA for the
cure of HCV has the potential of reducing the burden of end- stage liver
disease on LT waiting lists throughout the world. In this setting,
there is an opportunity to strategically define how the LT community
will react to the changing indications and opportunities to increase the
utilization of LT.
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