Clinical Case Conference
Ravi Maddipati
September 29, 2010
History
• CC: Bilateral Lower Extremity Edema
• HPI: 61M h/o Stage IVa Follicular lymphoma, HTN, DM, CAD
s/p CABG, EtOH cirrhosis, p/w BLE
• Edema was consistent with prior venous stasis for which he
was taking lasix
• On arrival to the floor patients edema was improved but a
new supraclavicular node was found.
• Reports h/o Stage IVa follicular lymphoma w/ mediastinal,
peritoneal, axillary LN, and BM metastases. Diagnosed in May
but had not initiated chemo 2/2 questionable HBV status
• Patient was seen by Heme-Onc who wanted to initiate RCHOP ASAP but due to black box warning about rituximab
and HBV they needed clarification of patients HBV status and
possible management options while on chemo.
History
•
PMH:
– Stage IVa follicular lymphoma.
Diagnosed in 5/2010 with
mediastinal, peritoneal, axillary, and
Bone marrow metastases.
– CAD s/p CABG
– EtOH cirrhosis but improved with
alcohol abstinence. No Biopsy
performed
– Persistently elevated anti-HBc IgG
since 2007 with rest of panel
negative
– HTN, HL, DM2, PTSD
•
SH:
– EtoH: Stopped 2mo ago but used to
drink 1pt Jack Q2 days
– Drug: Stopped crack cocaine 2
months ago. No IVDU
•
FH:
– Sister with diabetes
•
•
•
ROS: increasing neck swelling,
occasional chills, weight loss
NKDA
Meds:
–
–
–
–
–
–
–
Isordil
Sertraline
Prazosin
Insulin
Metoprolol
Glipizide
Lasix
Physical
• Gen: Lying comfortably in bed, NAD, A&O X 3
• HEENT: PERL, sclera anicteric, EOMI
• Neck: JVP at 10cm, 1cm fixed L supraclavicular
LN, no thyroid enlargement
• Chest: CTAB, 3cm fixed R axillary LN
• Card: RRR, III/VI SEM loudest at RUSB
• Abd: Soft, NT/ND, normal bowel sounds, liver
edge 2cm below costal margin
• Extr: 2+ BLE edema w/ mild erythema
• Neuro: non-focal
Labs
• CBC: 2.5/12.6/41
• CMP: 140/3.5/105/27 BUN/Cr: 6/0.65 Glc: 138
• ALT/AST: 121/65 Aphos: 350 TB/DB: 2.3/1.4
Alb: 3.6
• PTT/INR: 42/1.24
• Hepatitis Panel: HAV immune, HCV negative
– HBV: cAb+(IgG+, IgM-), sAg-, sAb-, eAg-, eAb-, DNA-
Discussion
• What is the HBV status of this patient?
• What is the best HBV management strategy
while patient is on Rituximab?
Hepatitis B
• Leading cause of Cirrhosis and HCC in the world
• Nearly 400million people are HBV carriers worldwide
• 75% of those are from Asia and Pacific Islands
– Lifetime risk of HBV is 60-80% in highly endemic regions
– Majority of transmission is vertical, especially in HBeAg +mothers
• US HBV rates declining due to vaccination, sex education, blood
product screening
– 78,000 new cases/year, mainly in 20-29y.o.
– 40% heterosexual contact, 20% IVDU, 12% MSM
– Chronic HBV in 0.2-0.3% of US population
• HBV is highly infectious, even more so than HCV and HIV
– HbeAg + indicates higher risk of transmission
• Blood transfusions rare cause of HBV now due to effective screening
methods
– Isolated anti-HBc + blood also excluded due to low levels of HBV DNA.
HBV Genotypes
Geographic Distributions
A: Northwestern Europe, North America, Central Africa
B: Southeast Asia, including China, Japan, and Taiwan (prevalence is increasing in North America)
C: Southeast Asia (prevalence is increasing in North America)
D: Southern Europe, Middle East, India
E: West Africa
F: Central and South America, United States (Native Americans), Polynesia
G: United States, France
H: Central and South America
Proposed Clinical Associations
Time to HBeAg seroconversion and probability of HBsAg loss: B < C
Response to treatment with interferon-α: A > B ≥ C > D
Precore/core promoter mutant frequency: precore mutation not selected with A and F
Liver disease activity and risk of progression: B < C
Evolution to chronic liver disease: A < D
Hepatocellular carcinoma risk: B > C in younger age group in Taiwan but B < C in older age group in Japan
Mechanism of liver injury
• HBV is generally not a cytopathic virus, and severity of
liver disease is related to intensity of host immune
response
• Initial response involves both innate and adaptive
immune system to help clear the virus
• CD8+ T-cells are activated by presentation of virus in
lymphoid organs and are mainly responsible for clearing
the virus in acute infection.
• Neutralizing antibody production limits intra-hepatic
spread of virus and prevents re-infection
• In chronic HBV majority of response is mediated in a
non-antigen specific manner.
HBV mutations
• HBV virus replication is highly replicative with low fidelity leading to many
mutations
• Surface antigen: mutations in antibody-binding domain but clinical
significance is controversial
• Pre-core, Basal Core promoter, and Core genes: mutations result in
decrease of HBeAg
– Pre-core mutations result in abolishing HBeAg synthesis while core promoter
mutations decrease production by 70%
– Associated with cases of fulminant hepatitis, blocking recognition of HBV by
CTL’s thus decreasing viral clearance, and poor response to IFN therapy
• Polymerase: mutations are often associated with nucleos(t)ide analog
resistance
– YMDD mutants have marked resistance to Lamivudine.
– Lamivudine resistance is 20% at 1 year and 70% at five years. Adefovir is 3% at
two years and 29% at five years. Entecavir is only 1% at five years
– Cross resistance exists among Lamivudine, Telbivudine, and Entecavir but
entecavir requires additional mutations so resistance is less.
Natural History
Infection with HBV
Chronic HBV
Acute HBV
Immunotolerant
Clearance of
virus
Fulminant
hepatic failure
Immunoactive
Inactive Carrier
Resolution
Clinical features of Acute HBV
• Age at which someone is infected is the principal determinant
of clinical outcome
– Infected Neonates: 95% will develop Chronic HBV
– In adults only 1-5% will develop Chronic HBV. Most clear the
infection
• Less than 1% of infected adults will go on to develop fulminant
hepatic failure.
– If liver failure ensues there is only a 20% survival rate without
transplant and 50-60% with transplant.
– Patients >40 years of age are more susceptible
• Usually clinical symptoms include:
– Serum sickness like prodrome (fever, arthralgia, and rash) due to
immune complex activation of complement.
– ALT/AST in the 1000-2000 range. Jaundice occurs in 30% of patients.
– Symptoms are self-limited and resolve with clearance of infection
Chronic HBV
Chronic HBV
Check eAg, eAb, DNA, ALT
eAg+, eAb-
eAg-, eAb+
Immunetolerant or Active
ALT >2xULN
DNA>20K
Y
Inactive Carrier or eAg- Hepatitis
ALT >2xULN
DNA>20K
Immunoactive
Y
N
Immunotolerant
eAg- Hepatitis
N
ALT nml
DNA<2K
N
ALT 1-2xULN
DNA 2K to 20K
Inactive
Carrier
Q3 ALT x3
then Q6-12
Monitor ALT & DNA q36mo and eAg q6-12mo
Q3mo ALT
& DNA
Treat
Y
DNA >20K
ALT normal
ALT 1-2XULN &DNA>20K
or
Age >40 and DNA >20k
Liver Biopsy Inflam
Persistent
elevation
Marker for response to treatment
Virologic response
Decrease in serum HBV DNA level to <105
copies/mL or <20,000 IU/mL in HBeAg-positive
cases and <104 copies/mL or <2000 IU/mL in
HBeAg-negative cases
Loss of HBeAg with or without seroconversion to
anti-HBe
Biochemical response
Normalization of serum ALT levels
On-treatment response
Initial response
Suppression of HBV DNA levels to <104-5 copies/mL
with or without loss of HBeAg, in addition to
normalization of serum ALT levels
Maintained response
Requiring continuation of therapy
Off-treatment response
Sustained response
Virologic and biochemical response observed for
6-12 months after treatment is discontinued
Durable response
Indefinite virologic and biochemical response after
treatment is discontinued
Treatments
•
•
•
•
•
•
•
•
•
•
Peg-IFN
Lamuvidine
Adefovir
Entecavir
Tenofivir
Telbuvidine
Emtricitabine
Celvudine
Truvada
IFN+LAM
Isolated anti-HBc positivity
• Window period of acute hepatitis B, when anti-HBc is
predominantly of the IgM class
• Many years after recovery from acute hepatitis B, when
anti-HBs has fallen to undetectable levels
• False-positive serologic test result
• Years after chronic HBV infection, when the HBsAg titer
has fallen below the level of detection
• HBV-infected persons who are co-infected with HCV
• Rarely as a result of varying sensitivity of HBsAg assays.
Rituximab and HBV
• “Reactivation of Hepatitis B virus after Rituximab-containing Treatment in
Patients with CD20-Positive B-Cell Lymphoma”. Matsue K, Kimura S, Takanashi
Y, Iwama K, Fujiwara H, Yamakura M, Takeuchi M. Cancer. July 1, 2010
– Determine the rates of reactivation of HBV in patients treated with Rituximab
– Retrospective investigation of HBV reactivation after rituximab-containing
chemotherapy in 252 B-cell lymphoma patients admitted to a Japanese hospital
over a period of five years
• Methods:
– 252 consecutive patients between April 2004 and April 2009 who were receiving
rituximab contacting chemo were enrolled and follow-up occurred for at least 2mo
post treatment
– All patients were screened at time of admission with HBsAg, anti-HBc, and antiHBs.
• If + for anti-HBc then IgM class was checked
• If HBsAg was positive during treatment course, HBV-DNA was checked
– HBV hepatitis was defined as 2 consecutive ALT >3xULN measured >5 days apart
– HBV reactivation defined as seroconversion from sAg neg to sAg pos +/- Rise in
DNA
Conclusions
• HBV reactivation dose occur in the setting of
treatment with Rituximab
• Isolated Anti-HBc positivity seems to confer
the greatest risk to eventual reactivation
• Treatment with Entecavir is effective and safe
to administer once HBV reactivation is
detected
• No incidences of Fulminant Hepatic failure
were found.
• “Prospective Analysis of Heaptitis B virus Reactivation in Patients with Diffuse
Large B-Cell Lymphoma after Rituximab Combination Chemotherapy”. Nitsu N,
Hagiwara Y, Tanae K, Khori M, Takahashi N. J. of Clin. Oncology. 2010 Sept 13
– 314 patients negative for HBsAg treated fro DLBCL with Rituximab
– 16% were found to be HBV carriers and reactivation occurred in 12% with 50% of
those being solely anti-HBc+.
– Entecavir was initiated when HBV DNA became positive. DNA returned neg. in 13wks.
– Risk factors for HBV reactivation were being male and having low anti-HBs titer
• “Management of Hepatitis B Virus Reactivation in Patients with Hematological
Malignancies Treated with Chemotherapy”. Francisci D, Falcinelli F, Schiaroli E,
Capponi M, Belfiori B, Flenghi L, Baldelli F. Infection 2010; 38: 58-61
– 318 consecutive patients undergoing chemo were screened for HBV
– HBsAg+ ( 20%), Anti-HBc+/sAb- (19%), Anti-HBc+/sAb+ (61%)
– Those with sAg+ were prophylaxed 1wk before chemo and 6mo after chemo with
either adefovir, Lamivudine, or combo of the two. DNA became negative after 6
months of treatment in 9/12 patients.
– Of those with anti-HBc+ only, were monitored Q1-3mo with serologies. 3/13
became DNA+ and sAg+. Treatment with Adefovir was begun at this time and all
achieved virologic and biochemical.
Guidelines for HBV carriers who are
initiating immunosuppressive therapy
• HBV testing should be performed in those at high risk for
HBV prior to initiating chemotherapy/immunosuppressive
treatment
• Prophylaxis is recommended at the initiation of
chemotherapy
• For VL<2000 anti-viral should be continued for 6mo post
chemo
• For VL>2000 anti-viral should be continued until they reach
same endpoints as in immunocompetent’s
• Lamuvidine or Telbuvidine can be used for courses lasting
<12mo but for longer courses Entecavir or Tenofovir are
preferred
• IFN should be avoided
Patient Follow-up
• Likely recovery from acute hepatitis B(many years
ago) vs. Chronic HBV with waning titers of sAb
• Patients HBV status should not delay initiation of
urgent Chemo
• Considering underlying cirrhosis and need for
long term treatment he should be started on
Entecavir 0.5mg QD and continue 6-12mo after
Chemo is completed
• Monitor LFT’s and HBV serology's closely
References
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“Slesienger and Fordtran’s Gastrointestinal And Liver Disease: Pathophysiology,
Diagnosis, Management”. Feldman M, Friedman LS, Brandt LJ. 9th Edition.
“Chronic Hepatitis B”. Lok ASF, McMahon BJ. AASLD guidelines 2009
“Reactivation of Hepatitis B virus after Rituximab-containing Treatment in Patients
with CD20-Positive B-Cell Lymphoma”. Matsue K, Kimura S, Takanashi Y, Iwama K,
Fujiwara H, Yamakura M, Takeuchi M. Cancer. July 1, 2010
“Prospective Analysis of Hepatitis B virus Reactivation in Patients with Diffuse
Large B-Cell Lymphoma after Rituximab Combination Chemotherapy”. Nitsu N,
Hagiwara Y, Tanae K, Khori M, Takahashi N. J. of Clin. Oncology. 2010 Sept 13
“Management of Hepatitis B Virus Reactivation in Patients with Hematological
Malignancies Treated with Chemotherapy”. Francisci D, Falcinelli F, Schiaroli E,
Capponi M, Belfiori B, Flenghi L, Baldelli F. Infection 2010; 38: 58-61
“Indications for Therapy in Hepatitis B”. Lok ASF, Degertekin B. Hepatology. May
2009
“The Natural History of Chronic Hepatitis B Virus Infection”. McMachon BJ.
Hepatology. May 2009
“Reactivation of Hepatitis B”. Hoofnagle, JH. Hepatology. May 2009