There is some emerging “in vitro” evidence that CyA may  exert an antiviral effect on HCV, requiring concomitant administration of  interferon; this may be explained by the inhibition of the binding of NS5B to  cyclophilin B, a functional regulator of the NS5B-RNA-dependent RNA  polymerase[38]. While at present there are no elements to prefer either  CyA or Tac in HCV patients, some authors propose a two step immunosuppression in  which Tac could be used as initial treatment, better preventing cellular  rejection, for its greater immunosuppressive potency. A possible switch to CyA  may be adopted later during interferon-based antiviral therapy, taking advantage  of cyclophilin-inhibiting properties of this latter drug[39].

Antimetabolites
The impact of the antimetabolites on HCV recurrence after LT remains an open issue. Many studies have shown an antiviral and antifibrotic effect of  mycophenolate mofetil (MMF)[40-44]. Faola et  al[45]  reported decreased 3 month HCV-RNA levels after induction with MMF in HCV  positive liver  transplant recipients.

In 2005, Bahra et al[46] evidenced that patients treated with MMF and  CNI taper presented a significantly decelerated impairment of  liver graft  histology compared to a matched control group on CNI only, without any  difference in terms of viral load. Similar findings have recently been reported  by our group on a small population of HCV positive recipients switched
from CNI  to MMF compared with a control group of recipients remaining on CNI. The CNI  group presented a significant increase of fibrosis with a yearly  fibrosis  progression rate of 0.33 ± 0.24 vs 0.05 ± 0.44 in the MMF  group  (P = 0.04)[46].
These data are in contrast with a previous report showing a  significant impairment of liver histology after MMF treatment without tapering   of CNIs[47]. MMF can be beneficial for liver inflammation and fibrosis because  it allows CNI reduction and therefore a reduction of immunosuppression, without increasing the risk of acute rejection; however, a direct effect, mediated by  the inhibition of lymphocyte proliferation through the block of the guanine  nucleotides necessary for DNA synthesis, along with an antiviral effect, may  also explain the decreased inflammatory activity and, therefore, the beneficial  impact on fibrosis progression.
Furthermore, MMF, added to Tac and steroids, has been associated with an improved survival in patients with HCV compared to those treated with Tac and steroids alone, as shown in 2005 by the analysis of the Scientific Registry of Transplant Recipients database[48].

Regarding azathioprine, its impact on HCV recurrent disease has been recently evidenced by Manousou and co-authors who analyzed 103 recipients, randomized to Tac monotherapy (n = 54) or triple therapy with Tac, azathioprine and steroids (n = 49); those on triple therapy had a slower onset of histologically proven severe fibrosis and portal hypertension in  comparison with those on monotherapy.

The beneficial effect of the triple  therapy in this study may be attributed to the long-term azathioprine therapy, as suggested by the authors[49].

Two large randomized trials comparing MMF to azathioprine in a maintenance immunosuppressive regimen showed no significant differences in  either rates of recurrence of hepatitis C or outcomes in HCV infected patients  in the study vs controls[47].

Other immunosuppressants
T-cell depleting therapies, such as Alemtuzumab (Campath)are very effective in the treatment of refractory acute rejection, although caution should be used in patients who are HCV positive[50,51]. Interleukin-2 receptor antibody-based  therapy does not seem to be associated with a deleterious effect on HCV  recurrence[52].

Complete weaning of immunosuppression
Some authors speculated that progression of HCV disease may be more  related to excessive administration of immunosuppressant post LT, rather than  the long-term effect of a specific immunosuppressive agent[37]. With this perspective, in our center we attempted the complete withdrawal of immunosuppression in thirty HCV recipients. Complete weaning was feasible only in eight (25%) patients. These subjects, however,  exhibited a slower rate of fibrosis progression, a lower necro-inflammatory score, improved liver tests and lower HCV-RNA levels compared to those who did 
 not achieve sustained immunosuppression withdrawal[53]. While 6.5  years follow-up data showed a less marked impact of the immunosuppression free  state on the progression of HCV disease, a reduction of IS-related morbidity and  an increase
of the quality of life was recorded[54].

EXTENDED CRITERIA  DONORS

The rising demand for LT along with the shortage of organs is a critical issue in the liver transplant field. In order to expand the donor pool,  livers from extended criteria donors (ECD), including older donors, fatty livers, longer ischemia time and donation after cardiac death (DCD), have been increasingly utilized. Grafts of reduced quality from ECD may show an increased 
sensitivity toward additional damaging events such as ischemia/reperfusion injury, acute rejection episodes or recurrent hepatitis C.

Donor age
Donor age is an established risk factor for severity of HCV recurrence and reduced graft and patient survival[7,55,56]. In 2005,  the analysis of the US Scientific Registry of Transplant Recipients, including  3463 patients with hepatitis C, evidenced that donor age between 41 years and 50  years was associated with a 67% increase in the risk of graft loss; the risk  increased to 86% for donors between 51 years and 60 years of age and was more  than 2-fold greater when donors were older than 60 years[57].  Interestingly, Selzner et al[58] showed that younger HCV positive patients  with older grafts had better long-term results when compared with older HCV  positive recipients receiving older grafts. 

Ideally, HCV-infected transplant  recipients should not receive organs from older donors; however, considering the  vast number of HCV-infected patients awaiting LT, this may not be feasible for  many programs.

Steatosis
Steatosis has been shown to accelerate the progression of HCV disease in immuno-competent patients; moreover, a strong association exists between the presence of donor steatosis and the development of primary nonfunction after LT[59].

Literature
regarding the potential impact of steatosis  on post-LT outcome in HCV recipients is scarce and no standard grading of  steatosis is used; thus, no comparison is possible. Two recent studies have  addressed this question and
found that steatotic grafts do not have a negative  impact on the progression of HCV recurrence and on patient survival in HCV  positive recipients[60,61]. Different results were reported by Briceño  and coworkers who evidenced that HCV recurrence was earlier and more frequent in  recipients with moderate-severe steatosis. 

Therefore, the authors suggest that  grafts with a steatosis > 30% should be avoided in HCV positive  recipients[62]. Considering the conflicting results, no recommendation  can be drawn in this context.

Ischemia time
Prolonged cold and warm ischemia times have also been identified as risk factors for more severe post-LT HCV infection[63].

Donors after cardiac death
The use of livers from DCD is a recovery technique based on  cardiopulmonary rather than neurological criteria for death, and the warm ischemic time is typically prolonged. It is associated with a significantly higher risk of graft failure and development of biliary complications[64-67], although more recent studies have reported  good clinical outcomes[68,69].

Two recent studies evaluated the impact of DCD livers on survival in HCV positive recipients. Yagci and coworkers evidenced a reduced 1 year and 5  year graft survival in the DCD group compared to the donation after brain death  group (55% and 46% versus 85% and 78%, respectively; P < 0.0003)[70]; Tao and coworkers showed a reduced 1 and 5 year graft  survival in the DCD group, although the  difference is not significant (70% and  61% vs 82% and 74%, respectively, P = 0.24). However, the  rates of severe HCV recurrence (re-transplantation or death due to recurrent  hepatitis C and/or the development of stage 4/6 fibrosis or more within 2 years)  were similar in the  two groups[71]. The evidence is not sufficiently complete to advise against the use of DCD liver in this setting; additional studies with a large number of patients are required to fully determine how HCV positive patients can  truly benefit from the use of DCD livers. According to experts, a donor graft  biopsy is highly
recommended when a DCD liver is used in an HCV positive recipient[72].

LIVING DONOR LIVER  TRANSPLANTATION

Living donor LT (LDLT) is a further important strategy to increase  the pool of organs available for patients awaiting LT. There are several  theoretical advantages over deceased donor LT (DDLT), including reduced cold  ischemia time, generally younger donor age, lack of steatosis and the ability to  perform the transplant electively. Theoretically, these factors may
positively  affect graft outcome. However, controversy remains as to whether HCV recurs with  greater severity in LDLT and whether this negatively affects graft and patient  survival.

Early reports suggested that HCV infection recurred with greater severity in recipients of LDLT compared with recipients of DDLT[73-75]. A more severe HCV recurrence in LDLT could be explained by: (1)  human leukocyte antigen homology between donor and recipient[76]; (2) HCV  replication in proliferating hepatocytes; (3) a greater relative  immunosuppression[77] in particular; and (4) more biliary and vascular  complications, thus enhancing fibrosis progression[78].
In 2007, the Adult-to-Adult Living Donor Liver Transplantation  Cohort Study (A2ALL), involving different liver transplant centers in the USA and including 275 HCV patients, showed that graft survival rates for LDLT and  DDLT were similar, once centers have sufficient experience with LDLT[79]. Moreover,  the authors found no differences in terms of histological features or time to progression to Ishak stage 3 or more, at 1 year after transplant between the two  groups. However, only 28% of the HCV positive population in this study received  a liver biopsy at 1 year after transplantation. These findings were confirmed in  other studies[80-82].

In 2008, Selzner and coauthors evidenced a slower fibrosis progression in LDLT recipients than in DDLT recipients (DDLT: 0.19 fibrosis stage/year vs LDLT: 0.11 fibrosis stage/year; P < 0.05), showing for the first time a possible beneficial impact of LDLT on HCV recurrence; the authors explained that this finding was likely due to younger donor age in LDLT recipients[83].
A strategy to improve the outcome of LDLT in HCV positive disease would be to treat HCV infection before LT, planning the optimal timing to initiate antiviral therapy; this is easier compared to DDLT since LDLT is a scheduled surgical procedure.
It is well known that the incidence of biliary complications (or vascular complications leading to biliary leaks or stenosis) can be reduced in experienced hands after the learning curve[84].

Some authors also suggest that an LDLT program should be preferentially started in individuals with alcoholic cirrhosis, cholestatic diseases or hepatitis B virus-related cirrhosis, in whom the graft will not unequivocally suffer cumulative injuries[85]. This  latter point, however, has not been validated.

CYTOMEGALOVIRUS INFECTION

Cytomegalovirus (CMV) infection has been associated with an increased risk for severity of HCV recurrence. It is not clear whether this is correlated to the inherent immunosuppressive properties of the CMV itself or  if CMV infection is only a surrogate marker for over-immunosuppression[10]. While CMV  prophylaxis is largely used when needed in the transplant protocols, its impact on HCV recurrence is difficult to assess.

TREATMENT

Current approaches to the management of HCV recurrence after LTare  represented by pre-transplant antiviral therapy, with the goal of preventing  re-infection of the graft and post-transplant antiviral therapy,with the goal  of eradicating recurrent infection, thus preventing recurrent disease and graft  loss.

Hepatitis C therapy before LT
The primary goal of pre-transplant antiviral therapy is the achievement of an undetectable HCV RNA level prior to transplantation  eliminating the risk of re-infection of the graft[86].

 Antiviral treatment with a standard regimen of Pegylated-Interferon  (Peg-IFN) and Ribavirin (RBV) for patients with
compensated cirrhosis (Child  Pugh Class A) is widely accepted and recommended by international practice  guidelines[87,88]. On the other hand, antiviral treatment of  patients with decompensated cirrhosis (Child class B or C) represents a far more  problematic approach.

Everson and co-workers analyzed the largest cohort (n =124) of HCV-candidates for LT (mean CPT score = 7.4; mean MELD score = 11)  undergoing antiviral treatment with interferon (peginterferon and nonpegylated  forms) and RBV with a low-accelerating dose regimen, reporting an on-treatment virological response rate of 46% and a SVR rate of 24% (50% in genotype 2 or 3 and 13% in genotype 1). Seventy-one percent failed to achieve full doses and 13%  discontinued early. Recurrent HCV infection was prevented in all patients achieving SVR[86]. Similar rates were reported in another experience with  a smaller population[89]. The achievement of “on-treatment virological response” represents a  secondary goal in pre-transplant treatment, as it has been shown to significantly reduce the risk of graft reinfection[90]. Forns and  co-workers treated 30 patients (50% Child-Pugh class A), starting the treatment  when the expected time to LT was around 4 mo; the rationale was that most  virological responders achieve HCV-RNA undetectability by week 12 and this could  be sufficient to
prevent infection after removing the main source of virus. 9  (30%) of 30 patients achieved on-treatment virological response, which persisted  in 6 (20%)  after transplantation.

 Pre-transplant treatment should be limited to patients with mild liver decompensation as those with advanced decompensation (Child-Class B to C or MELD >18) have a high risk for severe complications[10,91].

Close monitoring during treatment is suggested and the therapy should be administered in liver clinics affiliated with liver transplant programs. In order to manage severe cases of liver decompensation, patients should ideally already be on the list for transplantation before initiation of antiviral therapy[87].

Good candidates for pre-transplant therapy would be naïve patients  or prior relapsers of standard IFN and RBV treatment, as the chances for an  on-treatment virological response before transplant are relevant in these  groups. Furthermore, good candidates may be patients with living donors, with a  predictable timing of transplantation, patients with compensated
cirrhosis and  those with hepatocellular carcinoma, who typically have lower MELD scores.

Recent data suggest that thrombopoietin receptor agonists, such as eltrombopag, may be a useful tool for improving pretreatment platelet counts in HCV cirrhotic patients who would otherwise be ineligible for therapy[92].

Treatment of established hepatitis C  recurrence
The most widely used strategy involves initiating antiviral therapy  once the consequences of the recurrence of HCV infection are detected on liver  biopsy. The goal of therapy is to achieve viral eradication and this is  associated with a survival benefit[93-95].

Treatment duration after transplantation is generally 12 mo,  regardless of HCV genotype. The SVR rate is far less than that reported for immunocompetent HCV-infected patients. The mean overall SVR rate in the studies considering the efficacy of Pegylated-IFN and RBV was 30.2%, with a range of 8%-50%, 28.7% for genotype 1, with a range of 12.5%-40% and 71%-100% in patients  with genotype 2 (Table 2). Secondary end-points of the treatment to be considered are the  biochemical response (around 60% of cases) and histological improvement, in  terms of reduction of inflammation, although this seems to be confined only to  patients achieving a SVR.

Table  2
Results of studies on  treatment  with Pegylated interferon and Ribavirin of recurrent hepatitis C after liver  transplant

Results of studies on treatment with Pegylated interferon and Ribavirin of recurrent hepatitis C after liver transplant
Ref.YrType of StudyTime since LT (mo)nGenotype (%)Antiviral TherapySVR (%)Discontinuation (%)
Rodriguez-Luna et al[88]2004Prospective, uncontrolled4.21963Peg-IFN 0.5-1.5 μg/kg/wk + RBV 400-1000 mg daily x 48 wk after neg. RNA2649
Neff et al[89]2004Retrospective, uncontrolled23.55798Peg-IFN 1.5 μg/kg/wk + RBV 400-600 mg daily x 48 wk1432
Dumortier et al[97]2004Prospective, uncontrolled282080Peg-IFN 0.5-1.0 μg/kg/wk + RBV 400-1200 mg daily x 48 wk4520
Castells et al[107]2005Prospective, controlled3.824100Peg-IFN 1.5 μg/kg/wk + RBV 400-800 mg daily x 48 wk3513
Berenguer et al[102]2006Retrospective, uncontrolled16.63689IFN and RBV/Peg-IFN and RBV1840
Oton et al[103]2006Prospective, uncontrolled63.35591Peg-IFN 180 μg/1.5 μg/kg/wk + RBV 11 mg/kg/d x 48 wk247
Mukherjee et al[104]2006Retrospective, uncontrolled163275Peg-IFN 180 μg + RBV 1000-1200 mg daily x 48 wk3415
Mukherjee et al[104]2006Prospective, uncontrolled203979Peg-IFN 1.5 μg/kg/wk + RBV 800 mg daily x 6-12 mo3343
Fernandez et al[105]2006Prospective, uncontrolled324793Peg-IFN 1.5 μg/kg/wk + RBV 800-1000 mg daily x 48 wk2321
Neumann et al[106]2006Prospective, uncontrolled382580Peg-IFN 1.0 μg/kg/wk + RBV 600 mg daily x 48 wk364
Picciotto et al[94]2007Prospective, uncontrolled256187Peg-IFN 1 μg/kg/wk RBV 600-800 mg daily x 6-12 mo2815
Angelico et al[108]2007Prospective, controlled482181Peg-IFN 180 μg + RBV 200-800 mg daily x 48 wk3355
Carriòn et al[140]2007Prospective, controlled14.55492Peg-IFN 1.5 μg/kg/wk + 400-1200 mg daily x 48 wk3339
Sharma et al[141]2007Retrospective, uncontrolled163577Peg-IFN 90-180 μg/0.5-1.5 μg/kg/wk + RBV 800 mg daily x 48 wk3774
Zimmermann et al[107]2007Prospective, uncontrolled9.4268890 μg/wk for 4 wk then 135-180 μg/wk + 600 mg for 5 wk, then 800–1200 mg x 48 wk1911
LT: Liver transplant; IFN: Interferon; Peg: Pegylated; RBV: Ribavirin; SVR: Sustained virological response.

World J Gastrointest Pharmacol Ther. 2012 August 6; 3(4): 36–48.
Published online 2012 August 6. doi: 10.4292/wjgpt.v3.i4.36.


Tolerance is worse compared with nontransplant patients with  chronic hepatitis, with a percentage rate of dose reduction and discontinuation of 68 and 25, respectively. Usually, RBV is initiated at a dose of 400-600 mg daily and then increased slowly according to patient tolerability. The use of growth factors is common due to the high prevalence of hematological side effects[94,96-108].

The same SVR on treatment predictor used in the non-transplant setting, such as early virological response (EVR), treatment adherence, baseline  viremia and HCV genotype, seem to also be reliable after LT.Recently, Berenguer et al[50], in a retrospective analysis of 107  recipients treated with Peg-IFN and RBV, evidenced a strong relationship between  donor age and outcome of antiviral therapy, as treatment failure was significantly more frequent in recipients of grafts from older donors. Authors recommend that antiviral therapy should be started in the early stages of disease in recipients of grafts from old donors, in whom the risk of progressive  recurrent disease is higher and the chances of antiviral success are  lower.
IFN-therapy after transplant is historically associated with a potential risk of acute cellular rejection (ACR), due to the immunomodulatory properties of IFN. The reported incidence of ACR ranges from 0 to 25%, with a mean incidence of 12%. The frequency and severity of ACR is typically not greater than that reported in patients with recurrence of HCV infection who are  not receiving antiviral therapy[109].

A higher risk of developing alloimmune hepatitis is reported, typically after HCV RNA clearance (approximately 5% of cases)[110].

Preemptive antiviral therapy and early therapy
In the preemptive strategy, the treatment is started within the first few weeks post-transplantation, when HCV-RNA values are low, before peaking at 3 mo to 4 mo post-transplantation. Candidates for preemptive therapy  are patients without significant post-transplant complications, such as  cytopenias, renal dysfunction and infections.

There are only two RCTs reporting the safety and efficacy of peginterferon alfa-2a in the early postoperative period[110] but the  sample size is small. In the “prophylaxis trial”, the treatment was initiated  within 3 wk after LT and achieved a SVR of 8% (n = 2). In the “treatment trial”, where the treatment was started 6 mo post-LT, the SVR was 12%  (n = 5). The rate  of discontinuation of therapy was 31%.

Non-randomized preemptive trials reported rates of SVR ranging from  5% to 33% in genotype 1 patients and from 14% to 100% in genotype 2/3 patients.  The reported rate of treatment discontinuation ranged from 0% to 57% and dose  reductions (ranging from 28% to 85%) were required more frequently for RBV  rather than for interferon[111-114]. Interestingly, Kuo et al[115], analyzing a cohort of recipients  receiving preemptive therapy, evidenced a long-term histological benefit in  those receiving preemptive therapy, even if non-responders; fibrosis score ≥ 2  at 48 mo post-LT was reported in 22% patients undergoing preemptive therapy versus 49% of those that did not receive preemptive therapy (P =  0.08). Another strategy consists of starting the antiviral therapy at the  first clinical manifestation of “acute” recurrent HCV, usually occurring
within  the first 6 mo after transplantation (“early therapy”). SVR rates range from 13%  to 35% in genotypes 1 and the tolerability seems to be improved (discontinuation  0%-13%). However, early preemptive therapy is not suitable for
all transplant  recipients[107,116,117]. Considering its low tolerability profile and the dismal  results in terms of SVR, preemptive and early antiviral therapies are not  largely recommended for the treatment of HCV recurrence, except in patients at  high risk for progressive disease.

Adoptive immunotherapy
The immunosuppressive regimen currently used after LT reduces the adaptive immune components but effectively maintains the innate components of cellular immunity[118-120]. The enhancement of the natural killer  cellular response that plays a pivotal role in innate immunity may be a  promising immunotherapeutic approach, also in the prevention of HCV recurrence  post-LT[121]. Ohira et al[122] report an interesting immunotherapeutic approach for  preventing post-transplant HCV
recurrence, based on adoptive transfer of  interleukin 2 (IL-2)/anti-CD3 monoclonal antibody (OKT3)-treated liver  allograft-derived lymphocyte pools enriched in natural killer and natural killer  T cells. This was a phase 1 clinical trial in which 14 patients were  treated  with liver allograft-derived lymphocytes. During the first months after LT, HCV  RNA levels were significantly lower on average in the treated recipients than in  the controls. HCV RNA became undetectable after
immunotherapy in two treated  patients 4 wk after LT but in none of the controls. In one of the treated  patients, HCV RNA was still undetectable 20 mo after LT, whereas HCV infection  recurred 2 mo after transplantation in the second one.
Although the results were incomplete or transient, this  study provides a new approach to the problem and opens new perspectives in the  prevention of HCV infection after LT.

Prophylactic therapy
There is evidence suggesting a possible role for hepatitis C immune globulin in the prevention of recurrent HCV infection after LT. The prevalence of HCV recurrence after LT was lower in those who received HBIg that  presumably contained anti-HCV antibodies (Ab) (prior to 1990, when plasma donors  were not screened for the HCV Ab)[123]. Phase I trials with chimpanzees
have  demonstrated the ability of hepatitis C Ig (human) to decrease hepatic inflammation and to neutralize the HCV antibody, but this effect was not sustained over time[124,125]. Phase I/II human studies have currently  been unable to replicate the animal studies[126,127]. Therefore, at present, there is no  established role for HCV antibody therapy in the management of liver transplant  recipients with HCV.

IMPACT OF GENOMIC MEDICINE ON HCV RECURRENCE

From 2009, single nucleotide polymorphisms (SNPs) near the  IL28B gene were identified by genome-wide association studies and were  associated with SVR or non-response to treatment with PEG-IFN-α and RBV alone or  in combination with protease-inhibitors[128-133]. It was estimated that the genotype of  these SNPs accounts for approximately 15% of the
inter-individual differences in  SVR rates after standard treatment in HCV genotype 1 patients[134].

Most recently, a number of studies have analyzed the role of genetic variants of IL-28b in the severity of HCV recurrence and on antiviral  treatment response.
Eurich et al[135] evaluated only the role of the recipient genotype and  reported that IL-28b polymorphism seems
to influence the degree of graft  inflammation at the biochemical and histological levels. The G-allele has been  proposed as a marker for graft inflammation and a predictor for unfavorable  antiviral therapy outcome in HCV-infected LT-population.
Lange et al[136], who also investigated the donor genotype, evidenced  that response to antiviral therapy was strongly associated with the donor IL28B major genotype (T/T) but only weakly with the recipient’s IL28B genotype[136].
In contrast, other studies have reported that both recipient and  donor genotypes seemed to influence the response to Peg-IFN + RBV[137-139].
 
Furthermore, it has been shown that an unfavorable IL28B  genotype was associated with more rapid fibrosis, but not with decreased  survival[139].
These findings may open new interesting scenarios in the  field of recurrence of HCV disease after LT, such as changes in the graft allocation system by determining the IL28B genotype of potential  donors; this may identify the optimal graft/recipient matching in order to improve the sensitivity to antiviral therapy for HCV infection  post-transplantation and therefore improve outcomes.

CONCLUSION

Management of recurrent HCV disease is one of the most  challenging  problems in the transplant hepatology. Overall excess
immunosuppression seems to  have an impact on HCV disease progression, although no beneficial  immunosuppressive drug has been identified so far. Optimizing the donor  selection, with donor age limitations, the exclusion of moderately to
severely  steatotic livers and the reduction of ischemic times, could be a potential  strategy to minimize the severity of HCV recurrence and improve the outcome of  HCV positive recipients. Pre-transplant antiviral therapy is limited by low  tolerability, low SVR and is indicated in a limited population of  transplant  candidates.

Post-transplant combination antiviral therapy in those with evidence of recurrent disease is the mainstay of management and has a beneficial  effect on virological, biochemical and histological responses in patients with  HCV infection post-LT.
In the long term, specifically targeted antiviral therapies that block the replication of HCV, such as HCV protease and polymerase inhibitors, associated with Peg-IFN and RBV, may achieve higher rates of SVR becoming the standard of care.
Future research focusing on the role of prophylactic therapy and immunotherapy are needed in this important patient  population.

References
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