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104^th AARC meeting

Dr. Keith Leung

Dr. Ruveena

Universiti Malaya Medical Centre

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Patient details

Ms T
72-year-old lady
Single
Works as administrative officer in a law firm

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Index Presentation (9^th Feb 2021)

Unwell since 5^th Feb 2021

Jaundice, unwell, poor appetite
Slight abdominal distention and constipation – 1 day.
? fever

No abd pain, dyspnoea, cough, UTI sx
Denies alcohol consumption/taking any TCM/OTC meds/recent travel to areas endemic to Hep A, E infection

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Background medical history

DLBCL (Diffuse large B cell lymphoma)

Diagnosed in 9/2020
Commenced R-CHOP on 21/9/2020
Completed 6^th cycle on 16/1/2021

CHB (eAg +ve)

TDF since 28/11/2020
Reported to be compliant

MASLD/Hypertension/Dyslipidaemia

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Clinically

Alert, orientated to T/P/P
Jaundiced, Pink
Vital signs – unremarkable
No Hepatic flap
Abdomen: No hepatomegaly or mass, shifting dullness present
Otherwise, other examination was normal

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Vital signs

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U/S Abd: liver cirrhotic, no lesion, moderate ascites, no PVT/HVT

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Assessment & Diagnosis on presentation

ACLF secondary to reactivation of HBV

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Management

ACLF secondary to reactivation of HBV

i/v N-acetylcysteine (NAC)
Cont Tenofovir 300mg OD
T. Entecavir 1mg daily
i/v Tazosin 4.5g tds
i/v Human Albumin 20% 40g daily
Sy. Lactulose 15mls tds

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D2-D3

BO daily at least 2-3 times per day
Jaundice
No overt HE
Vital sign were stable, BP not supported

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D4-D7

Slow in response
Able to orientated
Not in respiratory distress
Abdomen, minimal shifting dullness

In view of ammonia level increasing – lactulose increase to 20mls QiD and rifaximin 550mg bid

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Hep A IgM: NR

Hep C Ab: NR

eAg+ve

VL: 3,200,000 IU/mL

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	8/2/2021	9/2/2021
Na, mmol/L (136-145)	128	128
K. mmol/L (3.6-5.2)	4.5	4.8
Urea, mmol/L (3.2-8.2)	8.6	6
Creat, umol/L (44-71)	73	52
eGFR	70	>90
Albumin, g/L (32-48)	28	27
TB, umol/L (<17)	267	274
ALP, U/L (45-129)	171	164
ALT, U/L (10-49)	4817	3650
AST, U/L (<34)	4650	3548
Lactate, mmol/L (<2.2)
INR		4.5

Day 1 NAC

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	8/2/2021	9/2/2021
Hb, g/L (12.0-15.0)	121	118
Platelet, 10^9/L (150-400)	74	79

CRP, mg/L (<5.0)		13.49
Procalcitonin, ng/ml (<0.1)		0.93
Blood culture		Pending
HBV DNA, iu/ml	3,200,000

Ultrasound abdomen		No cirrhosis, no focal liver lesion
Echocardiography		Normal

Day 1 NAC

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	10/2/2021	11/2/2021
Na, mmol/L (136-145)	134	132
K. mmol/L (3.6-5.2)	3.8	3.8
Urea, mmol/L (3.2-8.2)	5.5	4.6
Creat, umol/L (44-71)	66	57
eGFR	80	89
Albumin, g/L (32-48)	28	27
TB, umol/L (<17)	262	247
ALP, U/L (45-129)	135	92
ALT, U/L (10-49)	2495	1537
AST, U/L (<34)	2285	1253
Lactate, mmol/L (<2.2)	>12.2	2.2
INR	5.2	4.9
Ammonia, umol/L (11.2-35.4)		39.1

Day 2 NAC

ETV+ TDF

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	12/2/2021	13/2/2021	14/2/2021	15/2/2021
Na, mmol/L (136-145)	134	134	136	137
K. mmol/L (3.6-5.2)	3.3	3.6	3	3
Urea, mmol/L (3.2-8.2)	3.8	4.1	3.3	3.2
Creat, umol/L (44-71)	42	42	46	45
eGFR	>90	>90	>90	>90

TB, umol/L (<17)	282	328	345	364
ALP, U/L (45-129)	122	112	97	85
ALT, U/L (10-49)	1445	1108	817	636
AST, U/L (<34)	988	664	422	277
Lactate, mmol/L (<2.2)	1.3	1.8	1.7	2.0
INR	5.6	6.3	6.6	>8.0

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	12/2/2021	13/2/2021	14/2/2021	15/2/2021
Hb, g/L (12.0-15.0)	96	96	90
Platelet, 10^9/L (150-400)	71	71	56

Ammonia, umol/L (11.2-35.4)	55.6	101.4	196.2	105.4

D-dimer, ng/ml		Positive

CRP, mg/L (<5.0)				6.97
Procalcitonin, ng/ml (<0.1)				0.23

NAC on going, increase lactulose 20ml QID & rifaximin

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Day 8

BO regularly
No asterixis
Orientated
Not in respiratory distress
BP not supported

NAC stopped ( a week duration, bloods parameters static)

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D9-11

Grade 2 hepatic encephalopathy
Oxygen support with Nasal prong

Planned for PLEX – however, family member not agreed

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	16/2/2021	17/2/2021	18/2/2021	19/2/2021
Na, mmol/L (136-145)	137	136	135	130
K. mmol/L (3.6-5.2)	3.5	3.7	3.9	4.1
Urea, mmol/L (3.2-8.2)	3.6	4.2	4.4	5.7
Creat, umol/L (44-71)	44	46	53	63
eGFR	>90	>90	>90	85

TB, umol/L (<17)	378	433	443	490
ALP, U/L (45-129)	73	76	75	75
ALT, U/L (10-49)	504	398	312	273
AST, U/L (<34)	197	144	124	113
Lactate, mmol/L (<2.2)	2.3	1.8	4.3	5.3
INR	>8.0	>8.0	>8.0	>8.0

NAC stopped

PLEX was planend but family members not keen

Day 8

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	16/2/2021	17/2/2021	18/2/2021	19/2/2021
Hb, g/L (12.0-15.0)	88	86	84	86
Platelet, 10^9/L (150-400)	48	46	38	25

Ammonia, umol/L (11.2-35.4)	42	34.6	63	46.2

D-dimer, ng/ml

CRP, mg/L (<5.0)			8.26
Procalcitonin, ng/ml (<0.1)

NAC stopped

PLEX was planend but family members not keen

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D12-14

Clinically more ill
Conscious level reducing Grade 3 HE
Oxygen support increases – Face mask

AARC ACLF score 12 (grade 3)

Survival 39% at week 3 of onset

MELD Na score 40

Mortality 71.3%

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	20/2/2021	22/2/2021
Na, mmol/L (136-145)	130	128
K. mmol/L (3.6-5.2)	3.5	4
Urea, mmol/L (3.2-8.2)	6.5	8.6
Creat, umol/L (44-71)	92	135
eGFR	54	34

TB, umol/L (<17)	548	625
ALP, U/L (45-129)	71	72
ALT, U/L (10-49)	231	195
AST, U/L (<34)	95	103
Lactate, mmol/L (<2.2)	2.8	6
INR	>8.0	>8.0

Day 12

	20/2/2021	22/2/2021
Hb, g/L (12.0-15.0)	85	92
Platelet, 10^9/L (150-400)	Fibrin clot	Clumping

Ammonia, umol/L (11.2-35.4)	114.4	74.9

D-dimer, ng/ml

CRP, mg/L (<5.0)		8.51
Procalcitonin, ng/ml (<0.1)		0.35

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Family discussion – palliative care

Patient was succumbed at day 13 of admision

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CHRONIC HEPATITIS B

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Epidemiology – WHO

In 2010, ~ 2.3 billion have been living with viral hepatitis B. [1]

63% of cases increment of mortality due to viral hepatitis (1990-2013). [2]

World Health Organization. Sixty Third World Health Assembly - Viral Hepatitis (WHA63.18) Available from: http://apps.who.int/gb/ebwha/pdf_files/WHA63-REC1/WHA63_REC1-en.pdf.
Stanaway J.D. et al, The global burden of viral hepatitis from 1990 to 2013: Findings from the global burden of disease study 2013. Lancet. 2016;388(10049):1081–1088. doi: 10.1016/S0140-6736(16)30579-7.

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Hepatitis B

Geographic prevalence of chronic hepatitis B

Increasing prevalence in some European countries:^5,6

Migration from high endemic countries

HBsAg prevalence, adults (19−49 years), 2005³

<2%

2−4%

5−7%

≥8%

Not applicable

Decreasing prevalence in some endemic countries, e.g. Taiwan⁷

Possible reasons:

Improved socioeconomic status
Vaccination
Effective treatments

�5. Coppola N, et al. Euro Surveill 2015;20:30009; 6. Hampel A, et al. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2016;59:578–83; �7. Chen C-L, et al. J Hepatol 2015;63:354–63.

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Hepatitis in Malaysia

Raihan R. Hepatitis in Malaysia: Past, Present, and Future. Euroasian J Hepatogastroenterol. 2016 Jan-Jun;6(1):52-55. doi: 10.5005/jp-journals-10018-1167. Epub 2016 Jul 9. PMID: 29201726; PMCID: PMC5578560.

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Treatment Indications for patients with cirrhosis

HBV DNA	ALT	Treatment	Remarks
>2000	Regardless	Treat	Compensation
Any detectable	Regardless	Treat	Decompensation

Sarin SK et al. Asian-Pacific CPG HBV:2015 update. Hepatol Int. 2016 Jan;10(1):1-98.

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Treatment indication without cirrhosis

	HBV DNA	ALT	Treatment	Remarks
e Ag positive	>= 20,000 IU/ml	>2x ULN	Treat	Treat if mod-severe inflammation or significant fibrosis.
e Ag negative	>= 2,000 IU/ml	>2x ULN	Treat	Treat if mod-severe inflammation or significant fibrosis.

Sarin SK et al. Asian-Pacific CPG HBV:2015 update. Hepatol Int. 2016 Jan;10(1):1-98.

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Treatment guideline (WHO) – All adult (pregnant lady)

1. Evidence of significant fibrosis (≥F2 ) based on an APRI score of >0.5 or transient elastography value of >7 kPa or evidence of cirrhosis (F4) based on clinical criteria (or an APRI score of >1 or transient elastography value of >12.5 kPa ), regardless of HBV DNA or ALT levels

2. HBV DNA >2000 IU/mL and an ALT level above the upper limit of normal (ULN)

3. Presence of coinfections (such as HIV, hepatitis D or hepatitis C)

family history of liver cancer or cirrhosis; immune suppression (such as long-term steroid use, solid organ or stem cell transplant)

comorbidities (such as diabetes or metabolic dysfunction–associated steatotic liver disease)

or extrahepatic manifestations (such as glomerulonephritis or vasculitis), regardless of the APRI score or HBV DNA or ALT levels.

4. Persistently abnormal ALT levels alone (defined as two ALT values above the ULN at unspecified intervals during a 6- to 12-month period)

Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection: Published by the World Health Organization in 2024.

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Risk of HBV reactivation

Reverse seroconversion (seroreversion) from HBsAg negative to HBsAg positive for

HBsAg-negative, anti-HBc–positive patients.

AASLD 2018

Marked increase in HBV replication (>2 log increase from baseline levels or a new appearance of HBV DNA to a level of >100 IU/ml) in a person with previously stable or undetectable levels.

APASL 2016

Detection of HBV DNA, with levels >20,000 IU/ml in a person with no baseline HBV DNA.

APASL 2016

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Causes of reactivation of HBV

Spontaneous reactivation of hepatitis B virus replication
Due to immunosuppressive medications: cancer chemotherapy, anti-rejection drugs, corticosteroids
Cessation of anti-viral agents
Emergence of drug resistance
Due to antiviral therapy: interferon, corticosteroid withdrawal
Due to superimposed infections with other hepatotropic viruses: hepatitis A/E virus, hepatitis C virus, hepatitis delta virus
Caused by interaction with HIV infection: reactivated hepatitis, effect of immune reconstitution therapy
Other hepatotropic insults: drugs, alcohol

Sarin SK et al. Asian-Pacific CPG HBV:2015 update. Hepatol Int. 2016 Jan;10(1):1-98.

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Nucleos(t)ide analogs should be started immediately without delay or waiting for the HBV DNA result.

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Lau G, et al.APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int. 2021.

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Lau G, et al.APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int. 2021.

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Cessation of prophylaxis differs

Different duration proposed by major guidelines
American Society of Clinical Oncology ; update 2020 – at least 12 mths after cessation of IST
EASL 2017 – at least 12 mths after cessation of IST (18 mths for high-risk)

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Risk stratification of HBV reactivation: High

Risk level	HBsAg( +)	HBsAg(-)/anti-HBc( +)
High risk >10%	Anti-CD20 monoclonal antibodies: Rituximab, Ofatumumab, Obinutuzumab Steroid (high dose) ≥ 20 mg/day for ≥ 4 weeks Anti-TNF agents with higher potency: Adalimumab, Infliximab, Golimumab, Certolizumab Anthracyclines Hematopoietic stem cell transplantation (both allogeneic and autologous) DAA for HBV/HCV coinfection, except non-cirrhotics with HBsAg < 10 IU/ml Immune Checkpoint inhibitors (moderate to high risk): Anti-PD-1: nivolumab, pembrolizumab Anti-PD-L1: atezolizumab Anti-CTLA-4: ipilimumab Tyrosine kinase inhibitors (moderate-to-high): Imatinib, Nilotinib, Dasatinib, Erlotinib, Gefitinib, Osimertinib, Afatinib	Anti-CD20 monoclonal antibodies: Rituximab, Ofatumumab, Obinutuzumab Allogeneic hematopoietic stem cell transplantation

Lau G, et al.APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int. 2021.

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Risk stratification of HBV reactivation: Moderate

Risk level	HBsAg( +)	HBsAg(-)/anti-HBc( +)
Moderate (1–10%)	Cytotoxic chemotherapy (except anthracyclines) Anti-TNF agents with lower potency: Etanercept Steroid (median dose): 10–20 mg/day for ≥ 4 weeks Proteasome inhibitor: Bortezomib Ustekinumab	Anthracyclines Autologous hematopoietic stem cell transplantation Anti-TNF agents with higher potency: Adalimumab, Infliximab, Golimumab, Certolizumab Proteasome inhibitor: Bortezomib Ustekinumab

Lau G, et al.APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int. 2021.

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Risk stratification of HBV reactivation: Low and uncertain

Risk level	HBsAg( +)	HBsAg(-)/anti-HBc( +)
Low <1%	Methotrexate Azathioprine Steroid (low dose < 10 mg/day) DAA for HBV/HCV coinfection for non-cirrhotic patients with HBsAg < 10 IU/ml	Cytotoxic chemotherapy (except anthracyclines) Steroid (high dose) ≥ 20 mg/day Anti-TNF agents with lower potency: Etanercept Tyrosine kinase inhibitors Imatinib, Nilotinib, Dasatinib DAA for HCV
Uncertain	Abatacept Tocilizumab Ibrutinib Alemtuzumab Natalizumab Ocrelizumab Ibritumomab	Immune Checkpoint inhibitors Anti-PD-1: nivolumab, pembrolizumab Anti-PD-L1: atezolizumab Anti-CTLA-4: ipilimumab

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Thank you for your attention