key: cord-284693-mgpxnnk0
authors: Jothimani, Dinesh; Venugopal, Radhika; Vij, Mukul; Rela, Mohamed
title: Post Liver transplant recurrent and de novo viral infections
date: 2020-09-26
journal: Best Pract Res Clin Gastroenterol
DOI: 10.1016/j.bpg.2020.101689
sha: 
doc_id: 284693
cord_uid: mgpxnnk0

Survival following liver transplantation has changed dramatically owing to improvement in surgical techniques, peri-operative care and optimal immunosuppressive therapy. Post-Liver transplant (LT) de novo or recurrent viral infection continues to cause major allograft dysfunction, leading to poor graft and patient survival in untreated patients. Availability of highly effective antiviral drugs has significantly improved post-LT survival. Patients transplanted for chronic hepatitis B infection should receive life-long nucleos(t)ide analogues, with or without HBIg for effective viral control. Patients with chronic hepatitis C should be commenced on directly acting antiviral (DAA) drugs prior to transplantation. DAA therapy for post-LT recurrent hepatitis C infection is associated with close to 100% sustained virological response (SVR), irrespective of genotype. De novo chronic Hepatitis E infection is an increasingly recognised cause of allograft dysfunction in LT recipients. Untreated chronic HEV infection of the graft may lead to liver fibrosis and allograft failure. Similarly, CMV and EBV can reactivate leading to systemic illness following liver transplantation. With COVID-19 pandemic, post-transplant patients are at risk of SARS-Co-V2 infection. Majority of the LT recipients require hospitalisation, and the mortality in this population is around 20%. Early recognition of allograft dysfunction and identification of viral aetiology is essential in the management of post-LT de novo or recurrent infections. Optimising immunosuppression is an important step in reducing the severity of allograft damage in the treatment of post-transplant viral infections. Viral clearance or control can be achieved by early initiation of high potency antiviral therapy.

Liver transplantation (LT) is the only curative therapy for patients with decompensated cirrhosis, with an one year and 5-year survival of around 90% and 70%, respectively 1 Survival following OLT has improved over the years from a 1 and 5 year survival of 70% and 50% to 90% and 70%, respectively. Significant improvement in surgical techniques, peri-operative care and immunosuppression therapy has translated in to improved survival. However, In this review, we focus on the prevalence, natural history and clinical outcomes of hepatitis C (rHCV), hepatitis B (rHBV), HEV and other viral infections such as CMV, HSV and EBV in LT recipients. In addition, given the current COVID-19 pandemic, we discuss impact of SARS-CoV-2 in the liver allograft and their outcomes.

Recurrent Hepatitis C (rHCV) infection of the liver allograft is universal in untreated patients transplanted for this indication. Allograft colonisation by viral particles occurs at the time of portal reperfusion inducing liver damage as early as 72 hours post-liver transplantation. A study on HCV viral kinetics demonstrated an initial sharp decline in the RNA levels within 24 hours of reperfusion followed by a rapid increase to nearly 20 fold higher than the pretransplant values during the first week 6 . Untreated rHCV may progress with necroinflammation, leading to allograft injury and fibrosis. In a study to evaluate the natural course of 183 HCV liver transplanted patients using protocol liver biopsies, fibrosis score progressed from 1.2 to 2.2 over 10 year period. In addition, patients with severe fibrosis at 1 J o u r n a l P r e -p r o o f year due to rHCV was associated with poor survival. Furthermore, donor age >33 years and HCV genotype 1 or 4 developed rapid fibrosis 7 .

Post-transplant immunosuppression accelerates rHCV related liver damage with fibrosis progression at the rate of 0.3%-0.8% per year leading to cirrhosis and graft loss in 20-40% of patients within 5 years 8, 9 . Up to 40% patients with rHCV develop hepatic decompensation within a year of cirrhosis 10 . These patients follow an accelerated course with a three year survival of only 10% following hepatic decompensation unlike 60% in those with native cirrhotic liver. Over all patients transplanted for HCV have a lower 3 and 5 year survival of 73% and 67%, respectively 11 . Rarely (<10%), rHCV can present in a severe form, Fibrosing cholestatic hepatitis (FCH), characterized by bilirubin >6 mg/dl, ALP and GGT >5x upper limit normal, high HCV RNA typically occurring in the first 6 months post liver transplantation. Liver histology characterised by severe cholestasis, hepatocyte ballooning spotty necrosis and Kupffer cell hypertrophy. Progressive FCH is associated with severe allograft dysfunction leading to graft failure leading to death within 12 months. In summary, HCV LT recipients had worst long term survival until 5 years ago.

HCV viral clearance described as sustained virological response (SVR) defined as undetectable HCV RNA at 24 weeks following antiviral therapy, but recently reduced to 12 weeks (SVR12). SVR has a major implication in disease progression in rHCV. Similar to chronic hepatitis C in pre-transplant patients, achieving SVR in post-transplant patients results in stability of the disease or even regression of fibrosis in 75% of patients 12 . Whereas, failure to achieve SVR results in worsening of fibrosis. Unlike, in patients with chronic liver disease, fibrosis in rHCV progresses at faster pace. In patients untreated rHCV, fibrosis score ≥2 progress rapidly to cirrhosis and graft failure than patients with absent or mild fibrosis 13 .

In a 10 year follow up Italian study of 358 LT patients for HCV, patients who did not achieve SVR had the worst 10-year survival 39.8% compared to 84.7% in those with SVR 14 .

A number of studies evaluated recipient, donor and virus related risk factors associated with rHCV. Advanced recipient age, diabetes mellitus, severe liver disease (Child Pugh >10), IL-28B polymorphism, high HCV RNA >10 7 IU/ml, ischemic/reperfusion injury, CMV, donor age >65 years, cold ischaemic time over 8 hours and warm ischemia over 90 minutes, marginal graft, DCD donor, higher immunosuppression in particular high dose corticosteroids for acute cellular rejection, use of anti-thymocyte globulin were significantly associated with rHCV in the liver allograft 15, 16 .

Calcineurin inhibitors (CNI) such as tacrolimus and cyclosporine are the most commonly used immunosuppressive drugs in LT recipients. Ideal immunosuppressive regimen in HCV LT recipients to avoid rejection and at the same time to reduce the risk of rHCV is not established. Corticosteroid was considered to be the main drug associated with increased risk of rHCV. In particular, use of steroid boluses and rapid tapering has been shown to reactivate hepatitis C in the graft 17 . Various immunosuppressive modifications were adopted in the past to reduce rHCV of the allograft. Low dose slow steroid tapering has shown to reduce rHCV in the graft. A study by Berenguer et al., showed 29% rHCV in patients with CNI and tapering steroids over 9-12 months compared to 48% in the historical controls 18 .

Studies attempted to eliminate corticosteroids using IL-2receptor antagonist induction regimens to reduce rHCV. In a prospective randomised multi-centre trial evaluation dacluzimab induction followed by tacrolimus and MMF (n=153) vs standard treatment rHCV occurred in 33% vs 40% (P not significant) 19 

With increasing demand for cadaveric organs, DCD organ harvest has been increasingly utilized. Studies showed increased rHCV in patients undergoing LT from a DCD compared to Donation after brain death (DBD) liver, probably related to ischaemic reperfusion injury 22 .

Interestingly, a large case control study on HCV patients who received DCD liver showed no significant differences in the HCV RNA titres (P=0.7), severe rHCV with fibrosis 8% vs 15%, P=0.38) and graft loss (5% vs 9%, P=0.6) between the two groups at 12 months posttransplant 23 .

Previously, interpretation of abnormal LFTs in patients transplanted for HCV infection was difficult to distinguish between a rejection episode and rHCV infection, in the absence of liver biopsy. Therefore, management of graft dysfunction in HCV transplant recipients was a challenge. This led to the development of non-invasive markers of liver fibrosis. Fibroscan using transient elastography technique plays a major role in the assessment of disease severity in these patients 24 .

Liver histology is definitive in the diagnosis and management of rHCV. Acute hepatitis C in the liver allograft shows mild lobular activity with mononuclear inflammatory infiltrate, necroinflammatory foci and apoptotic bodies. Nodular lymphoid aggregates may also be present. FCH is characterised histologically by irregular portal expansion, portal fibrosis with immature pericellular/sinusoidal fibrous bands, extensive hepatocyte ballooning and degeneration, bile ductular reaction, marked canalicular and intracellular bilirubinostasis, J o u r n a l P r e -p r o o f and mild to moderate mononuclear inflammation. Confluent or bridging necrosis may be present.

Pre-LT HCV RNA level strongly predicts post-transplant rHCV severity. Therefore, treatment should be aimed at making the patient virus free prior to liver transplantation.. SVR has consistently shown to improve several aspects of HCV related complications. Achieving SVR in patients awaiting liver transplantation has shown to decrease the rate of disease progression, symptomatic improvement, improvement in MELD score and importantly improves post-transplant survival 25, 26 Treatment of HCV in the previous era:

A decade ago, the treatment of HCV in patients with decompensated cirrhosis was nearly impossible. In the absence of advanced liver disease, the use of Peg IFN and ribavirin achieved 50-70% SVR depending on the genotype. Unfortunately, both these drugs are contraindicated in patients with decompensated cirrhosis due to higher adverse events, like anaemia and sepsis. Subsequent introduction of first generation directly acting antiviral (DAA) therapy, protease inhibitors telaprevir and boceprevir achieved SVR around 70% given with Peg IFN and ribavirin. However, protease inhibitors were effective only against HCV genotype 1 and similarly these were contraindicated in advanced liver disease. Both these drugs were discontinued in 2015.

Treatment of HCV in patients with decompensated cirrhosis changed significantly following the introduction of Sofosbuvir, the second generation DAA with high efficacy, shorter treatment course, better safety profile and importantly interferon free regime.

Sofosbuvir with ribavirin for up to 48 weeks in 61 HCV HCC patients awaiting liver transplantation, showed an undetectable HCV RNA at the time of LT was associated with J o u r n a l P r e -p r o o f 70% SVR12 in the post-transplant period. Moreover, patients with undetectable HCV RNA at least 4 weeks prior to LT never developed rHCV. Adverse events leading to drug discontinuation was noted in 2 patients (sepsis and kidney injury) which was unrelated to Sofosbuvir 27 . The success of this therapy changed the perspective of HCV management in patients undergoing liver transplantation.

Subsequent studies were conducted in HCV patients with decompensated cirrhosis with second generation DAA. SOLAR-1 was a phase 2 open label multi-centre study on 12 or 24 weeks of ledipasvir (NS5A polymerase inhibitor), sofosbuvir and ribavirin in patients with advanced cirrhosis (Child Pugh B or C, n=108). SVR12 for Child Pugh B was 87% and 89%, and for Child Pugh C was 86% and 87%, with 12 and 24 weeks treatment irrespective of previous therapy. Adverse events occurred in 23% of patients but only 4% discontinued treatment 28 . Similarly, SOLAR-2 study was conducted across European and New Zealand sites on HCV Child Pugh B (n=56) and Child Pugh C (n=51) with SVR12 of 87% and 96%, and 85% and 78% for 12 and 24 weeks, respectively. Adverse events occurred in 11-50% of patients, predominantly in Child Pugh C, including 3 (12%) patients death. These two studies clearly demonstrated high SVR rates in patients with 12 weeks of this combination therapy with effective HCV clearance in patients with decompensated cirrhosis. With the higher viral eradication rates, MELD score improved in these patients over a period of time; however, in many of the study centres patients have undergone liver transplantation in view of shorter waiting times in different parts of the study sites 29 .Data from our liver unit showed a weeks daclatasvir 60 mg daily in combination with sofosbuvir 400 mg twice a day and weight based ribavirin in patients with decompensated cirrhosis (n=60) with an SVR12 of 83% 30 . Patients with Child Pugh A and B had a higher SVR12 than C, 94%, 94% and 56%, respectively. Likewise, genotype 1b had a better SVR12 than genotype 1a (100% vs 76%). In patients with decompensated cirrhosis, MELD score improved by -0. Higher rates of SVR with DAA has shown to reduce HCV related death by 74% 31 . Achieving SVR has shown to reduce the chance of liver disease progression with improvement in portal pressure 32 . In several cases there were significant improvement in MELD score leading to delisting of patients waitlisted for LT. In a study involving 409 patients with Child B and C cirrhosis, the mean MELD declined by 0.85 within 6 months compared to untreated patients (P<0.0001) and they encountered reduced episodes of hepatic decompensation (3.7% vs 10%, P=0.009) in patients with SVR 33 . Importantly, a cohort study from SRTR database showed 32% reduction in the HCV LT waitlist after they cleared HCV with DAA therapy 34 .

In the previous decade, management of post-transplant rHCV has been posed several difficulties. Introduction of Peg-IFN and ribavirin in the treatment of rHCV slightly improved clinical outcome. Unfortunately, these drugs were associated with significant side effects including graft rejection. Therefore, treatment was recommended only in patients with moderate and severe rHCV. Fatigue, diarrhoea and anaemia occurred in 30%, 28% and 20% of patients 37 .

Initial studies with sofosbuvir and ribavirin combination therapy for post-transplant rHCV showed poor drug tolerance, however, the main adverse event was anaemia related to ribavirin in 62% of patients, and subsequent hepatic decompensation related to the low haemoglobin 38 . SOLAR 1 and SOLAR 2 also evaluated the efficacy of the combination of sofosbuvir and Ledipasvir also included post liver transplantation rHCV patients.

SOLAR-1 study involving 12 or 24 weeks of ledipasvir, sofosbuvir and ribavirin in post-LT rHCV (n=229), the SVR12 was 96%, 96%, 86%, 60%, 100% in patients with no cirrhosis, Child A, Child B, Child C and FCH patients with 12 weeks and, 98%, 96%, 88%, 75% and 100% for 24 weeks therapy. Adverse events such as mild hyperbilirubinemia and anaemia however, mostly managed by reducing median dose of ribavirin to 600 mg daily 37 .

SOLAR-2 trial evaluated 226 post-transplant rHCV patients with ledipasvir sofosbuvir combination however, with Child Pugh score above 13 were excluded. SVR12 was 93%, 100% and 95% in patients with no cirrhosis, Child A and Child B cirrhosis with 12 weeks J o u r n a l P r e -p r o o f therapy and 100%, 96%, 100% with 24 weeks therapy. These drugs were well tolerated with 5% adverse events, 2% discontinuation rates, and 2% viral relapse rates 39 .The success of SOLAR trial with all oral DAA in this challenging population opened the avenue for patients post LT rHCV.

These two studies clearly demonstrated high SVR rates in patients with 12 weeks of this combination therapy with effective HCV clearance post-transplant rHCV, than the previous generation drugs.

ALLY-1 study also recruited patients with post-transplant rHCV infection (n=53) to assess the efficacy of 12 weeks daclatasvir 60 mg daily in combination with sofosbuvir 400 mg twice a day and weight based ribavirin. SVR12 was 94% in LT recipients. Viral relapsed in 3 posttransplant patients and were subsequently treated with 24 weeks of daclatasvir, sofosbuvir and ribavirin. There was no significant drug interactions with CNI requiring dose adjustments 30 . Interestingly, a real world analysis of daclatasvir and sofosbuvir showed 87-100% SVR12 in patients with Child B and C cirrhosis, and 58% of decompensated cirrhotic patients showed improvement in MELD score 40 .

A large multicentre study on daclatasvir in combination with sofosbuvir or simeprevir with or without ribavirin for 24 weeks was carried out on 97 LT recipients with severe rHCV including 37% patients with FCH and 31% with cirrhosis. SVR12 with DAC + SOF was 91% and DAC + SMV was 72%. There was a significant improvement in Child Pugh score from 6.8 to5.7 (P<0.001) and MELD score from 12.1 to 9.7 (P<0.001) following SVR. However, these scores worsened in 13% patients despite antiviral therapy 41.

Introduction of pangenotypic Velpatasvir-sofosbuvir combination further simplified HCV therapy with maximal efficacy. A phase 3 study on 624 patients with HCV increased SVR to 99% including in cirrhotic patients 42 .

Higher ALT was shown to accelerate disease progression and cirrhosis. ALT>100 U/L was shown to predict cirrhosis at 5 years due to rHCV (35% vs 6%). Similarly, serum bilirubin >3.5 mg/dl was strongly associated with development of cirrhosis following rHCV (Prieto 1999 Hepatology, Rosen 1999 Transplantation) 43, 44 . Practice of protocol liver biopsies at regular intervals post transplantation were carried out in the past. Presence of moderate to severe lobular inflammation was associated with disease progression (30% vs 0.10%) compared to no or minimal inflammation over 5 years post transplantation.

HCV RNA titres has a direct correlation with the severity of post-transplant rHCV infection.

In a study by Shakel et al., 45 .peak HCV RNA in the first year of untreated patients was associated with poor patient survival. A level of less than 10 7 , 10 7 -10 8 and >10 8 49 .In a recent innovative approach non-liver recipients of HCV positive donors were prescribed a short 7 day course of newer DAA Glecaprevir/pibrentasvir along with ezetimibe (HCV entry inhibitor) showed 100% viral clearance at week 12 50 .

In summary, long term survival of HCV LT recipients has improved dramatically following second generation DAA. With current SVR close 100%, excellent safety profile DAA therapy are increasingly used in decompensated cirrhosis and for post-transplant rHCV treatment.

Most centres treat HCV decompensated cirrhosis because it is associated with significant improvement in MELD and may help reducing transplant waitlist. There was a debate J o u r n a l P r e -p r o o f whether to treat these patients while waiting for transplant or to treat in the posttransplant period, because some studies observed an increased risk of HCC following SVR.

In the management of rHCV, the timing of antiviral therapy is not well established. Most experts recommend starting DAA after first 3 months with stable immunosuppression onboard. A study by Pellicelli et al., showed significant adverse events including hepatic decompensation and 25% mortality in those with advanced disease following treatment with daclatasvir and sofosbuvir for post-transplant rHCV 51 . Similarly, Forns et al, provided compassionate access sofosbuvir and ribavirin to 104 patients with severe rHCV with life expectancy less than 12 months. SVR was 59% and much higher (73%) in patients with severe rHCV. However, severe adverse event occurred in 47% of patients including 13% mortality 52 . Therefore, it is advisible to commence antiviral therapy prior to hepatic decompensation. Post-transplant rHCV management previously included allograft biopsy to assess the severity of rHCV before commencing anti-viral therapy. However, the necessity of biopsy may be arguable with the currently available DAA. Abnormal liver enzymes in the presence of high HCV RNA level may suffice to commence DAA.

Retransplantation for graft failure secondary to rHCV had much worse outcomes.

Retransplantation for rHCV related graft failure is associated with prolonged hospitalization, increased cost and reduced survival. However, outcome and patients selection differed amongst various studies. In a multi-centred study from the US showed 1 and 3 year survival of HCV retransplantation was 69% and 49% with no difference in survival compared to other indications 53 .However, the currently available DAA, the need for retransplantation likely to have reduced.

Hepatitis B is the major cause of chronic liver disease across the world affecting 350 million population, with higher prevalence in Asian and African countries despite universal vaccination. Hepatitis B was a considered an absolute contraindication in the initial years of liver transplantation due to early graft reinfection and poor survival benefit (less than 50%, J o u r n a l P r e -p r o o f Therefore, most liver transplant centres adopted lifelong entecavir or tenofovir to reduce viral relapse following liver transplantation, particularly in low risk patients such as those with decompensated cirrhosis and low viral load (<100 copies/ml), ALF presentation. Low dose and short course HBIg with antivirals may be useful in patients with high HBV DNA, HBeAg positive patients.

Tenofovir alafenamide (TAF) is the most recently introduced formulation of tenofovir, to overcome renal and bone related adverse events related to tenofovir disoproxil fumarate.

The efficacy is similar to its prodrug tenofovir disoproxil fumarate with a good safety profile.

It is recommended in patients with chronic kidney disease and osteoporosis. Data in posttransplant patients with TAF is scarce. Small case series found switching from TDF to TAF 

Hepatic involvement occurs in 14-53% of patients with COVID-19, particularly in severe cases 73 . ACE2 receptor is highly expressed in cholangiocytes (59.7%), vascular endothelial cells. Interestingly, only 2% hepatocytes express ACE2 and no expression observed in sinusoidal endothelial cells 72 .

In a recent multicentre study on COVID-19 patients with underlying cirrhosis (n=50), 97% required hospitalization and 71% required respiratory support. The number of patients with MELD>15 increased from 13% to 26% (p=0.037) and ACLF occurred in 28% of patients. In that study the 30-day mortality was 34% 74 . SARS-CoV-2 in decompensation in patients is associated with higher mortality 75 . Analysis of APASL COVID-19 Liver injury spectrum study (APCOLIS) on 228 patients (43 cirrhotics), hepatic decompensation occurred in 9% and ACLF in 11.6% of patients. Child Pugh score >9 predicted higher mortality (ROC 0.94, HR 19.2). In patients with decompensated cirrhosis, mortality was 33% compared to 16.3% in compensated cirrhosis 76 

to the non-transplant setting, however, chronic presentation defined as detectable HEV RNA or HEV IgM in the serum for 6 months, is exclusively observed in the post-transplant patients 86 .

Chronic HEV following in transplant recipients was first recognised by Kamar et al, including in LT patients. These patients continued to have allograft dysfunction following an acute infection and persistent positive HEV RNA in serum or stool for 10 to 24 months 87 . Exact prevalence of HEV seroprevalence in LT recipients is unknown. Tests based on HEV RNA or HEV IgG level, a retrospective analysis of frozen sera showed 1% to 16% seroprevalence of HEV in LT recipients 88 . In a French study, HEV seroprevalence (HEV IgG) was observed in 12.9% of patients during pre-LT evaluation, interestingly one third of these patients became HEV negative in the post-transplant period 89 Late onset CMV disease occurs after completion of prophylaxis. Especially in (R-/D+) recipients and its incidence is 25% which when compared to 8.3% in preemptive treatment 3-6 months reduces the advantage of universal prophylaxis. Some studies report mitigation of this by extending the prophylaxis to 200 days, but data are insufficient 118 

Varicella Zoster, that causes chicken pox remains latent in the dorsal root ganglion. This can reactivate following immunosuppression leading to Herpes zoster, characterized by painful vesicular rash along the nerve distribution, usually restricted to one side. The 1-year incidence is 3% whereas the 5-and 10-year incidences are 14% and 18% respectively 146 

Human Herpes Virus 6 (HHV-6) belongs to beta herpesviridae subfamily under Roseolovirus genus. This is a common name for 2 similar viruses HHV-6A and HHV-6B, the latter accounting in most cases 149 . Asymptomatic exposure to HHV-6 occur in childhood such that 90-95% adult population are seropositive 150 . The circular DNA of the virus integrates with the host genome and may remain latent for several years in the mononuclear cells 151, 152 .

HHV-6 infection occurs as a result of reactivation in the post-transplant state. Occasionally, donor derived infections or rarely through blood products have been reported 153 .

Incidence of HHV6 varies between 14% to 82% 154 , commonly occurring in the first 2-8 weeks after liver transplantation. Sporadic cases were reported as early as 10 days and rarely after 5 years following liver transplantation 155 . In a prospective study of 51 LT patients, 11 (21.5%) developed HHV-6B reactivation, of which 4 had fever and abdominal pain 156 . Reactivation rates are less when patients are covered up for CMV prophylaxis with Ganciclovir.

Most HHV-6 reactivation are asymptomatic with low viral load 156 and they usually do not require treatment. Clinically, HHV-6 reactivation presents with fever, and skin rash and raised liver enzymes 158, 159 .

Histologically, HHV-6 hepatitis may mimic acute cellular rejection with elevated liver enzymes and portal lymphocytic infiltration and confluent periportal necrosis on liver 153, 158 .

In 170 LT patients with graft hepatitis, high levels of intra-hepatic HHV-6 DNA and HHVantigenemia was significantly associated with decreased graft survival 160 . HHV-6 J o u r n a l P r e -p r o o f encephalitis though rare in LT recipients occurs usually within 4-6 weeks of transplantation.

HHV-6A is neurotrophic and is detected in plasma as well as CSF. Brain imaging shows characteristic signal intensity in medial temporal lobes involving amygdala and hippocampi.

HHV-6 infection may also present as post-transplant colitis in some 161 . It can also occur as co infection with CMV where HHV-6 antigenemia precedes CMV antigenemia 162 To summarise, HHV-6 infection after Liver transplantation is rare, but its reactivation is associate with significant increase in graft failure, mortality, hepatitis C progression and CMV disease 169 . HHV infections in LT patients can be treated successfully with CMV antivirals ganciclovir, Cidofovir and foscarnet.

Post LT viral infections can cause significant allograft dysfunction. Early recognition, diagnosis and systematic approach can ameliorate the infective process and preserve allograft function. Newly evolving less familiar viral infections such as COVID-19 should also be considered in the differential diagnosis of post-transplant viral infections. Management J o u r n a l P r e -p r o o f of post-transplant viral infection has improved over the last decade due to significant changes in immunosuppression protocols with optimal usage, and introduction of effective anti-viral drugs with high genetic barrier for resistance. These high potency anti-viral drugs have translated in to better long-term allograft and patient survival.

• Patients with decompensated cirrhosis due to chronic Hepatitis B or hepatitis C infection should be commenced on high efficacy antiviral therapy 

• Pathogenesis of COVID-19 in post-liver transplant patients requires larger studies.

• Ideal immunosuppressive regimen to reduce the chance of recurrent or de novo viral infection needs to be studied.

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Human cytomegalovirus detection by real-time PCR and pp65-antigen test in hematopoietic stem cell transplant recipients: a challenge in low and middle-income countries. Pathog Glob Health

The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solidorgan Transplantation

Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors: A Randomized Clinical Trial

Evaluation of clinical outcomes of prophylactic versus preemptive cytomegalovirus strategy in liver transplant recipients

Cytomegalovirus Infection in Liver Transplant Recipients: Current Approach to Diagnosis and

The Use of Antibiotics: A Clinical Review of

Three Volume Set

New developments in the management of cytomegalovirus infection after solid organ transplantation. Drugs

The human cytomegalovirus terminase complex as an antiviral target: a close-up view

The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients

Impact of a preemptive strategy after 3 months of valganciclovir cytomegalovirus prophylaxis in kidney transplant recipients. Transplantation

Mycophenolate mofetil increases cytomegalovirus invasive organ disease in renal transplant patients

Selection and use of immunosuppressive therapies after liver transplantation: current German practice

Use of Everolimus-based Immunosuppression to Decrease Cytomegalovirus Infection After Kidney Transplant

Antiviral drug resistance of human cytomegalovirus

Epstein-Barr virus infections: biology, pathogenesis, and management

Lymphoproliferative disorders and de novo malignancies in intestinal and multivisceral recipients

Posttransplant lymphoproliferative disease following liver transplantation

Occurrence of post-transplant lymphoproliferative disorders among over thousand adult recipients: any role for hepatitis C infection?

Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States

Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients -BCSH and BTS Guidelines

PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial

World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues

Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome

Posttransplantation lymphoproliferative disorder--the great mimic in liver transplantation: appraisal of the clinicopathologic spectrum and the role of Epstein-Barr virus

virus and posttransplant lymphoproliferative disorder in solid organ transplantation

Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial

Therapeutic options in post-transplant lymphoproliferative disorders

Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review

Herpes Simplex Virus

Principles and Practice of Infectious Diseases

Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: transmission by donated organ and the effect of OKT3 antibodies

Herpes Simplex Virus and Varicella-Zoster Virus Infections in

Hematopoietic Stem Cell or Solid Organ Transplantation

Transplant Infections

Infections after liver transplantation

Infections in solid-organ transplant recipients

Oral acyclovir therapy for mucocutaneous herpes simplex virus infections in immunocompromised marrow transplant recipients

Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans

Herpes simplex virus in solid organ transplantation

Incidence and risk factors for herpes zoster in patients undergoing liver transplantation

Herpes zoster after liver transplantation: incidence, risk factors, and complications

Varicella zoster virus in solid organ transplantation

Classification of HHV-6A and HHV-6B as distinct viruses

Update on human herpesvirus 6 biology, clinical features, and therapy

Latent human herpesvirus 6 infection of human monocytes/macrophages

The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors

et pediatric liver transplant patients

HHV-6A, 6B, and 7: persistence in the population, epidemiology and transmission

Human herpesvirus-6 infection after liver transplantation

Clinical impact of human herpesvirus 6 infection after liver transplantation

in syncytial giant-cell hepatitis

Detection of HHV-6 in over a thousand samples: new types of infection revealed by an analysis of

antigenemia related to CMV infection after liver transplantation

Co-infection and clinical impact of human herpesvirus 5 and 6 in liver transplantation

Human herpesvirus-6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome

and cytomegalovirus DNA in liver donor biopsies and their correlation with HLA matches and acute cellular rejection

Acute hepatitis with periportal confluent necrosis associated with human herpesvirus 6 infection in liver transplant patients

Encephalitis caused by human herpesvirus-6 in a liver transplant recipient

Treating HHV-6 Infections

Diagnosis and Clinical Management

HHV-6 in liver transplantation: A literature review