preoperative, perioperative and postoperative viral infections in liver transplant recipients - diagnosis and management

1. Viral infections in liver transplant
recipients
By : Dr. Rohit Saini
Moderator : Dr. Udit

2. Introduction
• LTx is the only curative therapy for ESLD
• Viral infection can be : ‘de novo’ or ‘recurrence’
• de novo infection: new onset viral illness in the absence of
previous exposure (environmental or donor derived)
• Recurrence: disease reactivation (latent infection)
• Optimal immunosuppression is essential to maintain balance
between rejection and infection in post Tx period.

4. Hepatitis C
• Recurrent Hepatitis C (rHCV) infection of liver allograft is
universal in untreated Tx patients.
• Allograft colonisation by viral particles occurs at the time of
reperfusion followed by a rapid increase in RNA level inducing
liver damage as early as 72 hours post-LT.
• Post Tx immunosuppression accelerates rHCV related liver
damage with progression of fibrosis, cirrhosis and graft loss.
• Over all patients transplanted for HCV have a lower 3 and 5
year survival of 73% and 67%, respectively
Berenguer M, et al. Hepatology 2000

5. Risk factors for rHCV
• Recipient, donor and viral factors :
1. Age,
2. DM,
3. severe liver disease (Child Pugh >10),
4. IL-28B polymorphism,
5. high HCV RNA > 107 IU/ml,
6. CMV,
7. donor age >65 years,
8. CIT over 8 h and WIT over 90 min,
9. marginal graft, DCD donor,
10. higher immunosuppression: high dose CS for acute cellular
rejection, use of ATG.s

6. Sustained virologic response (SVR)
• SVR: undetectable HCV RNA at 24 weeks following antiviral
therapy, but recently reduced to 12 weeks (SVR12).
• Similar to chronic HCV in pre Tx patients, achieving SVR in
post-transplant patients results in stability of disease or even
regression of fibrosis in 75%
• Whereas failure to achieve SVR leads to worsening of fibrosis
• 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
Berenguer M, et al. J Hepatol 2012
Gitto S, et al. World J Gastroenterol 2015

7. Diagnosis of rHCV
• Abnormal LFT.s
• HCV – RNA level
• Fibroscan using transient elastography
• Liver histology is definitive in the diagnosis and management
 variable severities of portal tract lymphocytic infiltration,
interface hepatitis, ductular reaction, lobular activity with
mononuclear inflammatory infiltrate, necro inflammatory foci
and apoptotic bodies

8. Treatment
• Decade ago, Rx of HCV in decompensated CLD was
impossible.
• Peg-IFN and ribavirin achieved 50-70% SVR in compensated
disease.
• C/I in decompensated CLD: anemia and sepsis
• Subsequent introduction of 1st gen. DAA (PI): telaprevir and
boceprevir achieved SVR around 70% with Peg-IFN and
ribavirin.
• However, PI were effective only against HCV genotype 1 and
C/I in advanced liver disease.
• Both these drugs were discontinued in 2015

9. Treatment
• Sofosbuvir (2nd gen. DAA) changed Rx of decompensated
HCV- CLD with high efficacy, shorter Rx course, better safety
profile and IFN free regime
• Sofosbuvir with ribavirin for up to 48 weeks in 61 HCV HCC
patients awaiting LTx, showed an undetectable HCV RNA at
the time of LT was a/w 70% SVR12 in the post-transplant
period.

10. • Conducted in HCV related decompensated cirrhosis
• Ledipasvir – NS5A inhibitor
• Treatment for 12 and 24 weeks in CTP- B and C patients
• SVR for CTP-B: 87% and 89%
• SVR for CTP-C: 86% and 87%
• Adverse events occurred in 23% of patients but only 4%
discontinued treatment

11. Post LT rHCV management
• IFN and Ribavirin Rx a/w side effects including graft rejection
• Telaprevir and Boceprevir: poorly tolerated and inhibition of
cyt. P450-3A4 enzyme (increased CNI trough levels).
• Second gen. DAA: completely changed outlook of post Tx
rHCV infection
• Multiple studies clearly demonstrated high SVR 12 rate of 2nd
gen. DAA combination with ribavirin with no significant drug
interaction with CNI.
Charlton M, et al. SOLAR-1. Gastroenterology 2015
Patel N, et al. World J Gastroenterol 2016
Manns M, et al. SOLAR2. Lancet Infect Dis 2016

12. Hepatitis C positive donors
• Utilized to curb cadaver organ demand

13. • In a recent innovative approach, HCV-uninfected organ
recipients without pre-existing liver disease were treated with
ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-
pibrentasvir (300 mg/120 mg) before and after
transplantation from HCV infected donors.
• showed 100% viral clearance at week 12.
• can prevent the establishment of chronic HCV infection in the
recipient.

14. Hepatitis B
• Initially was absolute C/I
• Subsequent evolution of antiviral drugs and HBIg in 1980s in
postop. period has improved clinical outcomes.
• Factors a/w rHBV: pre Tx HBeAg status and high HBV DNA
levels (>20,000 IU/ ml)
• Diagnosis: high HBV DNA with or without abnormal LFTs
• Liver histology: lymphoplasmacytic portal inflammation,
portal fibrosis, interface activity, bile ductular reaction, lobular
disarray, lobular spotty or confluent necrosis and Kupffer cell
hyperplasia

15. HBV - Treatment
• Aim to reducing HBV DNA viral load in post Tx period
• In addition, HBIg provides an adequate cover to minimize viral
transmission in the peri operative period
• In previous era: Lamivudine monotherapy
• Subsequently Adefovir : particularly in lamivudine resistance
• In 2012, introduction of nucleos(t)ide analogue drugs
(Entecavir and Tenofovir) due to high genetic barrier to
resistance and showed better viral suppression.

16. HBV - Treatment
• Combination of HBIg and nucleos(t)ide analogue is the most
commonly used regimen to minimize rHBV
• Initial high dose HBIg is usually administered at the anhepatic
phase, and subsequent daily maintenance dose for a week
followed by once in a month or depends on the antiHBs
antibody titres.
• Later studies found that, HBIg can be discontinued after 12
months with similar outcomes.
Gane EJ, et al. Gastroenterology 2007
Fernandez I, et al. Transpl Infect Dis 2015
Cholongitas E, et al. Transpl Infect Dis 2012

18. HBcAb positive donors
• HBsAg -, HBcAb+ organs utilize to expand organ pool
• long term anti-viral prophylaxis is necessary in post Tx period
to prevent de novo HBV infection
• de novo allograft HBV infection: showed similar rates
irrespective of lamivudine monotherapy or lamivudine with
HBIg combination (3.6% vs 2.7%) indicating that oral antiviral
therapy alone sufficient to prevent de novo HBV infection
• Currently, most centres use entecavir or tenofovir long term.
Saab S, Liver Transplant 2010
Yu AS, et al. Liver Transplant 2001

20. HEV
• HEV is a single stranded RNA virus, four genotypes
• Genotype 1 and 2: faeco-oral contamination, self-limiting
illness
• Genotype 3 and 4: zoonotic infection by consumption of
undercooked meat and milk
• Post-LT HEV infection: chronic allograft dysfunction
predominantly genotype 3 and 4
• over all seroprevalence is low in Tx recipients compared to
general population, but given the immunosuppressive state
the rates of chronic infection remains high (50-65%), leading
to significant graft fibrosis and failure

21. HEV
• Diagnosis: HEV-RNA quantification, HEV IgM or IgG
• Treatment: no treatment has been firmly established
1. Lowering immunosuppression as in other post Tx viral
infections may lower HEV RNA level
2. Ribavirin has been found useful in post-LT chronic HEV
infection, with a clearance rate of 78%
3. Patients on MMF but not mTOR inhibitor showed higher viral
suppression
Kamar N, et al. N Engl J Med 2014

22. Cytomegalovirus (CMV)
• CMV is a ubiquitous large DNA herpes virus (Beta herpes)
• latent infection in hematopoietic cells esp. in myeloid lineage
• MC infection in post Tx setting with highest risk first 3 months
correlate with higher levels of immunosuppression
• either as a de novo primary infection or as a reactivation
• Clinical manifestations:

23. Cytomegalovirus (CMV)
• CMV (D+/R-): highest risk (44-65%) of de novo CMV infection
• CMV (D+/R+) and CMV (D-/R+): moderate risk (8-19%)
• CMV (D-/R-): lower risk
• Diagnosis: CMV serology, CMV-DNA PCR, pp65 antigenemia,
culture and histopathology.
• In immunosuppressed state, serology is not an useful test
• CMV-DNA: more sensitive and allows early detection and level
also determines the risk and severity of the disease
Gane E, et al. Lancet 1997
Singh N, et al. Liver Transplant 2005
Humar A, et al. Am J Transplant 2004

24. CMV – preventive strategies

26. CMV - Treatment
• Foscarnet, Cidofovir (off label) use in ganciclovir resistance (UL97).
• Leflunomide: immunosuppressive in RA has tried in gancyclovir
resistant cases with mixed results.
• Letermovir (AIC246): novel nonnucleoside CMV inhibitor that
targets viral terminase complex (UL54) with good efficacy in
resistant cases and has received orphan designation and fast track
designation from FDA.
Eid AJ, Razonable RR. Drugs 2010
Verghese PS, Drugs Future 2013
Antiviral Rx should be continued till two samples are negative
for CMV DNA one week apart

27. CMV & immunosuppression
• Immunosuppression increases risk of CMV reactivation
• Studies show MMF increases risk and severity of CMV
infection
• Interestingly, everolimus, a mTOR inhibitor has been found to
have a virostatic effects on CMV
• Therefore, it is better to avoid MMF and maintain low
tacrolimus trough level.
Sarmiento JM, et al. Clin Transplant 2000
Malvezzi P, et al. Clin Transplant 2016

28. Epstein Barr virus (EBV)
• EBV is a DNA virus belonging to herpes virus family (HHV4)
• MC acquired in childhood with 90% seropositivity in adults
• The virus remains latent in B cells for life
• Reactivation occurs due to reduced activity of cytotoxic T-cells
• Post-LT, immunosuppression supresses memory T cell
function causing proliferation of EBV mediated B cells

29. Epstein Barr virus (EBV)
• Clinical manifestations:
o Asymptomatic - MC
o nonspecific viral syndrome
o may involve any organ (including allograft): pharyngitis, lung
masses, LAP, hepatosplenomegaly, CNS and GI disease with
bleeding or perforation
o PTLD (spectrum of disease ranging from lymphoid
proliferation to overt lymphomas)
 EBV-related PTLD has bimodal onset; most cases within 1st
year post Tx, though late cases (5–7 years) have been
reported in the aging SOT population

30. Epstein Barr virus (EBV)
• Diagnosis: only in pre Tx period
• EBV DNA viral load monitoring is required in the post-LT
period.
• High EBV viral load is a/w severity of PTLD and therefore serial
monitoring of EBV DNA level is recommended.
Tsai DE, et al. Am J Transplant 2008

31. EBV - management

32. Herpes simplex virus (HSV)
• HSV type 1 and 2 belong to alpha herpes virus subfamily
• Humans are the only known reservoir
• With high prevalence in general population, most adults are
seropositive by 5th decade
• Post Tx occurs primarily as a reactivation of latent infection
and in few as a de novo including donor derived infection
• Clinical features: majority has mucocutaneous lesions in post
Tx period (85% are orolabial followed by anogenital lesions)
• Pneumonitis and encephalitis by HSV in LT recipients l/t
significant mortality and morbidity

33. HSV - treatment
• Antiviral prophylaxis during first month post Tx may reduce
incidence of infection/reactivation.
• DOC - Acyclovir
• Alternate Rx: Valacyclovir and ganciclovir can also be used
 Mucocutaneous infection usually need treatment for 7-14
days whereas, visceral infections need a prolonged course of
antivirals.
Wilck MB, et al. Am J Transplant 2013

34. Varicella Zoster virus (VZV)
• causes chicken pox and remains latent in dorsal root ganglia
• reactivate following immunosuppression causes Herpes
zoster, characterized by painful vesicular rash along the
dermatomal distribution, usually restricted to one side
• The1-year incidence is 3% whereas the 5-and10-year
incidences are 14%and 18% respectively
• Study: 209 consecutive LT recipients 12% (25) developed
zoster infection in a median time of about 23 months.
Hamaguchi Y, et al. Transpl Infect Dis 2015
Herrero JI, et al. Liver Transplant 2004

35. VZV - treatment
• Reduction of immunosuppression is the first step esp.
temporarily withholding anti-metabolites like azathioprine
and MMF.
• Antivirals: valacyclovir, acyclovir and ganciclovir
 Antivirals should be given for at least 2 weeks along with pain
killers like gabapentin

36. HIV
• In cuurent era, reductions in AIDS-related deaths and near-
normal life is expected who achieve a normal CD4+ cell count
and viral load suppression on ART
• Organ Tx of HIV-infected individuals has been steadily gaining
traction since the late 1990s
• acceptable short-term survival and no increased risk of HIV-
related complications in kidney and nonhepatitis C virus LT
recipients
Haidar G, et al. Liver Transpl 2017
Stock PG, et al. N Engl J Med 2010
Cooper C, et al. AIDS 2011

37. HIV
• The advent of integrase strand transfer inhibitors (which
donot interact with the CYP3A4 system) has made dosing post
Tx immunosuppression much less cumbersome.
• Although HIV-infected Tx recipients have 3-fold increased risk
of acute rejection compared to HIV-uninfected, but graft and
patient-survival rates are generally comparable

38. HIV infected donors
• Can expand donor pool
• HIV-to-HIV kidney and to a lesser extend LT have already been
performed in South Africa, Switzerland and UK
• 1, 3, and 5 year graft and patient survival rates were similar
and there were no cases of AIDS-defining opportunistic
infections despite use of thymoglobulin induction.
• Currently, HIV-to-HIV kidney and LT are being performed in
the US, but under clinical trial protocols only.
Muller E, et al. N Engl J Med 2015
Calmy A, et al. Am J Transplant 2016
Hathorn E, et al. N Engl J Med 2016

39. COVID 19
• Current pandemic COVID-19 is caused by a new strain of
corona virus named as SARS-CoV-2
• single positive stranded RNA virus (beta coronavirus genus)
• SARS-CoV-2 uses ACE2 receptors for cell entry
• ACE2 is abundantly expressed in alveolar type II cells and less
commonly in bronchial epithelial cells of lungs.
• ACE2 is also expressed in stratified epithelial cells of oral and
esophageal mucosa, enterocytes of small intestine and colon,
liver, myocardial cells, vascular endothelium and smooth
muscle cells
Zhou C. medRxiv; 2020

40. COVID 19 - manifestations
varies from mild to severe or even death
 Asymptomatic
 Viral flu like illness
 mild respiratory or gastrointestinal symptoms
 interstitial pneumonia
 acute respiratory distress syndrome (ARDS)
 diffuse thromboembolic events
 multiorgan failure
 death

41. Liver & SARS-CoV-2
• Hepatic involvement: 14-53% particularly in severe cases
• ACE2 receptors highly expressed in cholangiocytes (59.7%),
vascular endothelial cells, only 2% in hepatocytes and not in
sinusoidal endothelial cells
• Liver involvement in COVID-19 is probably to the direct viral
cytopathic effect or due to increased cytokine storm in severe
disease
Jothimani D, et al. J Hepatol 2020
Chai X, et al. BioRxiv Feb 2020

42. • COVID-19 with underlying cirrhosis (n = 50)
• 97% required hospitalization and 71% required resp. support
• number of patients with MELD>15 increased from 13% to 26%
(P = 0.037) and ACLF occurred in 28% of patients
• 30 day mortality rate was 34%
• Conclusion: COVID-19 is a/w liver function deterioration and
elevated mortality in patients with cirrhosis
 Another study: SARS-CoV-2 in patients with decompensated
cirrhosis is a/w higher mortality
Rela M, et al. Hepatology International 2020

43. • N=228 (185 CLD without cirrhosis and 43 cirrhotics)
• 43% of CLD w/o cirrhosis presented as acute liver injury
• 20% cirrhotics presented with either acute decompensation
(9%) or ACLF (11.6%)
• In patients with decompensated cirrhosis, mortality was 33%
compared to 16.3% in compensated cirrhosis
• Conclusion: SARS-Cov-2 infection causes signifcant liver injury
in CLD patients, decompensating one fifth of cirrhosis and
worsening the clinical status of already decompensated.
Sarin SK, et al. Hepatol Int 2020

44. Post-LT de novo COVID-19
• LT recipients are more susceptible for SARS-CoV-2 infection,
owing to their immunosuppressive state and associated
comorbidities.
• Incidence of COVID-19 in post-LT patients was 0.34% (0.1-
4.8%), with a crude death rate of 15%
• Similar to non Tx COVID-19 patients, majority of LT recipients
have fever (79%), cough (55%) and GI symptoms (33%).
• Risk factors: HTN (56%) and DM (37%) were observed
• ARDS developed in 19% with a case fatality rate of 12-17%
Polak WG, et al. Transpl Int 2020
Becchetti C, et al. Gut 2020

45. Post LT – COVID management
• Based on expert opinions, international bodies recommends
against stopping or reducing immunosuppressives.
• MMF is an independent predictor of severe COVID-19
• MMF dose to be reduced or stopped in COVID-19 illness,
particularly in severe lymphopenia, superadded bacterial or
fungal infection
• Drugs used in COVID-19 treatment can cause liver injury and
drug interactions (e.g. Remdesevir, lopinovir)
• Unfortunately, 10-13% of patients developed DILI and causes
allograft dysfunction.

47. Other viral infections
• HHV 6 (roseola virus genus)
• HHV 8 (kaposi sarcoma herpes virus)
• RNA respiratory viruses: Influenza, parainfluenza, RSV,
rhinovirus
• Adenovirus
• Norovirus
• Polyoma viruses: BK and JC virus