occult HBV

1. Occult Hepatitis B Virus in Haemodialysis Patients
Mostafa Abdel_Salam Mohamed, MD
MUH

2. Requirements for admission to dialysis unit
• HBsAg, HBc antibody, and HBsAb, HCV and
HIV status
Monthly monitoring
• ALT, AST
• HBsAg (in patients not immune to hepatitis B)
Annual monitoring
• HBsAb
• HCV

3. WHAT IS A VIRUS?
• Viruses may be defined as acellular organisms
whose genomes consist of nucleic acid, and
which obligately replicate inside host cells
using host metabolic machinery to different
extents, to form a pool of components which
assemble into particles called virions

4. These naming conventions can lead to confusion later, e.g.,
viral hepatitis is caused by at least 6 different viruses
D
“Infectious”
“Serum”
Viral
hepatitis
A
NANB
B
Enterically
transmitted
Parenterally
transmitted
E
C
F, G,
? Other *

5. Recognition of viruses
F How long viruses have been within our midst?
1500 BC: Leg deformities indicative of poliomyelitis, pock marks indicative of smallpox.
"Virus" is from the
Greek meaning for
"poison" and was
initially described by
Edward Jenner in 1798.

6. • During the 1800's, all infectious agents were considered to
be viruses until Koch developed pure culture techniques
which allowed the separation and growth of bacteria. In the
late 1800's: Bacteria were purified and established as disease
causing agents. It then became possible to distinguish them
from the "filterable agents", those able to pass through special
filters designed to prevent the passage of bacteria. The first
viruses described were foot and mouth disease (a
picornavirus), 1898, Yellow fever (a flavivirus), 1900, Rous
sarcoma virus (an oncogenic retrovirus), 1906.

7. European Association for the Study of
the Liver (EASL)
more than 2 billion people are infected with HBV
globally, of whom 350 million are chronically
infected; 15%-25% of the chronically infected
persons die from chronic liver diseases
McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis 2005; 25: S3-S9.

8. Distribution of Chronic HBV Infection
1. WHO. Hepatitis B. 2002.
2. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl): p. 158.
3. WHO/WPRO data.
> 8 % High
< 2 % Low
2 - 8 % Intermediate

9. Chronic Hepatitis B is a Silent Threat
• Half of all people with chronic hepatitis B show
no symptoms1
• People who have the hepatitis B virus may infect
others without knowing it
• People often find out they have the hepatitis B
virus after they get really sick, when it’s usually
too late or difficult to treat the infection
• There is no cure, but there are effective
treatments available
1 Centers for Disease Control and Prevention. Hepatitis B. Available at: http://www.cdc.gov/communication/tips/hep-b.htm. Accessed May 21,
2004.

10. • Chronic hepatitis B is one of the top 10 causes
of death worldwide1
• The hepatitis B virus is 100 times more
infectious than HIV2
1 Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures.J Viral
Hepatitis. 2004;11:97-107.2
2 Hepatitis B Foundation. Hep B Statistics. Available at: http://www.hepb.org/hepb/statistics.htm. Accessed December 29, 2009.
Hepatitis B is Serious – Global Impact

11. Source: CDC and Prevention. MMWR 2009;58(SS03):1-27.
Patients with Acute Hepatitis B who Report Selected Epidemiologic
Characteristics, by age group, U.S. 2007
HEPATITIS B : EPIDEMIOLOGY
*The percentage of cases for which a specific risk factor was reported was calculated on the basis of the total number of cases for
which any information for that exposure was reported.

12. How Hepatitis B is NOT Spread
• It is NOT spread from hugging, holding hands,
sharing food, breastfeeding, kissing, or living
with an infected person

13. Immunologic Markers of HBV Infection
HBsAg HBeAg HBVDNA Anti HBc
IgM
Anti HBc
IgG
Anti
HBe
Anti
HBs
ALAT
Acute Virus B
Hepatitis
+ + + + Ø Ø Ø
Chronic HBeAg
pos. Hepatitis
+ + + Ø + Ø Ø
Chronic HBeAg
neg. Hepatitis
+ Ø + Ø + + Ø
Chronic HBeAg
neg. HBV
Infection (Carrier)
+ Ø Low or
negative
Ø + + Ø normal
Occult Virus B
Hepatitis
Ø Ø + Ø + + + normal
Hepatitis
Recovery
Ø Ø Ø Ø + + + normal
Vaccination Ø Ø Ø Ø Ø Ø + normal

14. Clinical Outcome of Chronic HBV Infection
Acute
Hepatitis B
____________
Acute liver
infection is
subclinical in
about 70%
Liver Cirrhosis
____________
5-year rate of
progression from
chronic Hepatitis
to cirrhosis is 10-
20%
Chronic
Hepatitis B
____________
Development of
chronic liver
disease in 5 –
95%
Liver Cancer
HCC
____________
Increasing risk for
HCC in patients
with cirrhosis and
with high
HBVDNA levels

15. Who Should Be Tested for Hepatitis B?
Patients with abnormal ALT
Patients engaged in high-risk sexual behaviors
Injection drug users
Immigrants, refugees, or adoptees from areas of high endemicity
Immunocompromised patients
Dialysis patients
Recipients of organ/tissue transplants or blood transfusion
Household members or sexual partners of known HBV carriers
Occupational exposure (healthcare workers, police, EMTs)
residents in institutions for the developmentally disabled
Pregnant women
Individuals infected with HCV or HIV
Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed, 2005.
Lok ASF, et al. Hepatology. 2001;34:1225.

16. Occult HBV infection
• HBV DNA detection in serum or in the liver by
sensitive diagnostic tests in HBsAg-negative
patients with or without serologic markers of
previous viral exposure.
• Biswas R, Tabor E, Hsia CC, Wright DJ, Laycock ME, et al. (2003) Comparative sensitivity of HBV NATs and
HBsAg assays for detection of acute HBV infection. Transfusion 43: 788-798.
• Scheiblauer H, Soboll H, Nick S (2006) Evaluation of 17 CEmarked HBsAg assays with respect to
clinical sensitivity, analytical sensitivity, and hepatitis B virus mutant detection. J Med Virol 78 Suppl 1:
S66-70.

17. Studies of donors who transmit posttransfusion hepatitis.
Tabor E, Hoofnagle JH, Smallwood LA, Drucker JA,
PinedaTamondong GC, et al. (1979)

18. OBI prevalence seems to be
higher among subjects at
high risk for HBV infection
and with liver disease

19. OBI is the major cause of post
transfusion hepatitis B in western
countries and in countries like
India and Taiwan, with higher risk
of transmission than for HCV or
HIV
F. A. M. Regan, P. Hewitt, J. A. J. Barbara, and M. Contreras, “Prospective investigation of transfusion transmitted infection in recipients of over 20,000 units of blood,” British
Medical Journal, vol. 320, no. 7232, pp. 403–406, 2000

20. Hepatocyte is a reservoir of HBV
Hepatitis B after OLT with OBI in donor
is a well-known cause of de novo
hepatitis in the HBV-negative recipient
Very low rates of occurrence in cases of
kidney, heart, and bone marrow
transplantation

21. HBs antigen –ve
Seropositive Seronegative
HBV DNA as the only marker of the
infection.
HBV DNA in the serum (<200 IU/mL)

22. • OHB patients on hemodialysis has ranged from 0
to 20%

23. S-escape mutants infection
HBV strains with key mutations
in pre-S region which is not
recognized by commercially
available kits, even when the
most sensitive ones are used

24. False OBI has been
reported in up to 40%
of patients with OBI.

25. Complications
Reactivation of the infection
Development of the HBV- related liver disease
Transmission of the “occult” virus mainly through
blood transfusion and organs transplantation (OLT)

26. Treatment
All patients receiving chemo- and immunotherapy
anti-HBc antibodies
ALT elevations.
HBV reactivation.

30. • Of 289 patients enrolled in this study, 18
subjects (6.2%, 95% confidence interval (CI),
3.5%–8.9%) had isolated anti-HBc. HBVDNA
was detectable in 9 of 18 patients.

32. • 96 patients
• one hundred sixty seven healthy blood
donors were included in the study.
• HBV DNA was detected in 18(18.8%)
compared to blood donors (2.4%)
• Hepatitis core IgG was positive in 19
patients (19.8%)
• control group (2.4%).

34. The patients on haemodialysis are at
increased risk of acquiring HBV infection
as compared to the general population.
Edey M, Barraclough K, Johnson DW. Hepatitis B and dialysis. Nephrology (Carlton) 2010; 15: 137-45.

35. HBV
The hepatitis B surface antigen
(HBsAg) positivity rate in dialysis
patients varies among different
localities and correlates with the
endemicity in the general
population of the region.

36. HBsAg positivity rates among
dialysis patients are reported to
be 0.9% in the USA, 1.6% in
Japan, 10.0% in Brazil, 10.0% in
Hong Kong, 11.8% in Saudi Arabia
and 16.8% in Taiwan
Tokars JI, Finelli L, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in
the United States, 2001. Semin. Dial.2004; 17: 310–19.
Oguchi H, Miyasaka M, Tokunaga S et al.Hepatitis virus infection (HBV and HCV) in eleven
Japanese hemodialysis units. Clin. Nephrol.1992; 38: 36–43

37. Why are Dialysis Patients at Risk for Infection?
• Frequent use of catheters
or insertion of needles to
access the bloodstream
• Weakened immune
systems
• Frequent hospital stays
and surgery
Risk factors
Tokars JI, Finelli L, alter MJ, Arduino MJ. National surveillance of dialysisassociated diseases in
the United States, 2001. Semin Dial 2004; 17: 310-9.

38. Molecular biological study
Hemodialysis
units
Patient-to-
patient
transmission
Carrilho FJ, Moraes CR, Pinho JR et al.Hepatitis B virus infection in Haemodialysis Centres from
Santa Catarina State, Southern Brazil. Predictive risk factors for infection and molecular
epidemiology. BMC Public Health2004; 4: 13–23

39. remain viable for at least 7
days on environmental
surfaces at room temperature.
Burdick RA, Bragg-Gresham JL, Woods JD et al.Patterns of hepatitis B prevalence and
seroconversion in hemodialysis units from three continents: the DOPPS. Kidney Int. 2003; 63:
2222–9.

40. HBsAg
environmental
surfaces
clamps, scissors,
doorknobs

41. patients on peritoneal
dialysis are reported to
have a lower prevalence of
HBV infection compared
with hemodialysis patients

42. reduced response to
vaccination because of
the general immune
suppression associated
with uremia
decreased cellular
responses
disturbances in humoral
innate immunity e.g. low
complement IV factor,
decreased cytokine
response after stimulation

43. Once infected, 50 to 60% of HD patients are
likely to become chronic carriers of HBV

44. haemodialysis
and chronic
HBsAg carriage
rarely develop
symptoms of
hepatitis
silent
hepatocellular
injury.
Fabrizi F, Lunghi G, Martin P. Hepatitis B virus infection in hemodialysis: recent discoveries.
J Nephrol 2002; 15: 463-8.
Elghannam DM, Aly RM, Goda EF, Eltoraby EE, Farag RE. Clinical significance of antibody
to hepatitis B core antigen in multitransfused hemodialysis patients. Asian J Transfus Sci
2009; 3: 14-7.

45. The transaminase levels
depressed in
haemodialysis patients
'normal' values of these
enzymes may be
indicative of a
pathological state.
Lopes EP, Sette LH, Sette JB, Luna CF, Andrade AM, Moraes M, et al. Serum alanine
aminotransferase levels, hematocrit rate and body weight correlations before and after
hemodialysis session. Clinics (Sao Paulo) 2009; 64: 941-5.

46. Tseng GY, Lin HJ, Fang CT, Cheng YT, Huang CH, Tseng GC, et al. Hemodialysis reduces the
viral load in uremic patients with chronic hepatitis B infection. Ren Fail 2008; 30: 1000-5.
Elghannam DM, Aly RM, Goda EF, Eltoraby EE, Farag RE. Clinical significance of antibody
to hepatitis B core antigen in multitransfused hemodialysis patients. Asian J Transfus Sci
2009; 3: 14-7.

47. Although many patients with end-stage renal
disease (ESRD) do not live long enough to
develop HBV-related complications,
increased risk of hepatocellular carcinoma
and mortality associated with HBV is
reported in the ESRD population
Jha R, Kher BA, Naik S, Elhence R, Gupta A, Sharma RK. Hepatitis B associated liver
disease in dialysis patients: Role of vaccination. J Nephrol 1993; 6: 98-103.

48. Liver Biopsy
The only definitive and reliable
means to establish the activity of
liver disease in dialysis patients
Highly recommended before starting
antiviral therapy and undergoing
kidney transplantation

49. Treatment of Chronic Hepatitis B
 Pegylated Interferon is given by injection once a week for 48 weeks.
The drug can cause side effects such as flu-like symptoms and depression.
 Lamivudine (adjusted) with few side effects, but drug resistance
 Adefovir Dipivoxil (Hepsera) (nephrotoxic agent) with few side effects, but low
antiviral activity
 Entecavir (Baraclude) with few side effects, high antiviral activity (it is often
recommended as a first-line oral therapy in patients with kidney disease)

50. Treatment of Chronic Hepatitis B
 Telbivudine (Tyzeka, Sebivo) with few side effects, but development of drug
resistance (dose adjustment is recommended in patients with creatinine
clearance of less than 50 mL/min, including dialysis patients).
 Tenofovir (Viread) (However, nephrotoxicity and acute kidney injury have
been reported in some patients treated with tenofovir )

51. The response rate to
HBV vaccine in
haemodialysis
patients is low,
ranging from 50%
to 80
Girndt M, Sester M, Sester U, Kaul H, Kohler, H. Defective expression of B7-2 (CD68)
on monocytes of dialysis patients correlates to the uremia associated immune defect.
Kid Int 2001; 59:1382-1389.

52. In a study from Egypt, the
response rate was 84.2% in
patients below 40 years of
age which decreased to
33.3% at 60 years or above
Shatat HZ, Kotkat AM, Farghaly AG. Immune respon se to hepatitis B vaccine in
haemodialysis patients. J Egypt Public Health Assoc 2000; 75(3-4): 257-75

53. it is recommended that for uremic
patients, a four-dose schedule (40
mg/dose given at 0, 1, 2 and 6
months)
intradermal route is more
effective
Charest AF, McDougall J, Goldstein MB. A randomized comparison of intradermal and
intramuscular vaccination against hepatitis B virus in incident chronic hemodialysis
patients. Am J Kidney Dis 2000; 36:976-982.

54. clinical Practice Guidelines for
Prevention of Blood Borne Virus
Infection in the Renal Unit
UK Renal Association 5th Edition Draft Version
2 nd Feb 09
Guidlines Prevention and Control of
Infections in Dialysis Settings
Version 3 – May 2013

55. Guideline 1.1 - BBV Infection : Prevention of spread to patients and
staff in the renal unit (Universal precautions)
• Infection-control procedures that effectively
prevent the transfer of blood or fluids
contaminated with blood between patients
(often referred to as “universal precautions”).
(1A) (KDIGO Hepatitis C Guideline 3.2)

56. Guideline 1.2 - BBV Infection : Prevention of spread to
patients and staff in the renal unit
• We recommend that multi-dose vials of
medicines should either not be used or be
discarded after single use. (1B)

57. Guideline 2.1 - BBV Infection : Dialysis equipment
• We recommend that separate machines
should be used for patients known to be
infected with HBV (or at high risk of new HBV
infection). (1A)

58. Guideline 4.3 - BBV Infection : Segregation of patients
infected with BBV or at high risk
• for new BBV infection We recommend that
healthcare workers performing dialysis on
patients infected with BBV should not dialyse
patients with no BBV infection or a different
BBV infection at the same time. (1C)

59. Guideline 3.1 - BBV Infection : BBV surveillance in
dialysis patients
• We recommend that all patients starting
haemodialysis should be known to be plasma
HBV surface antigen (HbsAg) and HCV
antibody negative before having dialysis on
the main dialysis unit. (1A) KDIGO 1.1.2, 1.2.1

60. Guideline 5.1 - BBV Infection : Immunisation of patients
against hepatitis B
• We recommend that patients who require
renal replacement therapy (RRT) or likely to
require RRT for CKD should be immunised
against HBV. (1A)

61. Guideline 6.1, 6.2 - BBV Infection : Immunisation of
staff against hepatitis B
• We recommend that staff who have clinical
contact with patients should be immunised
against HBV and demonstrate that they are
immune to, or not HBV infective. (1A)
• We suggest that staff who are not immune to
HBV and are not HBV infective should ideally
not dialyse patients who are HBV infective.
(2B)

62. Guideline 5.3 - BBV Infection : Immunisation of patients
against hepatitis B
• We suggest that patients who are at high risk
for previous HBV infection should be known to
have undetectable anti HB core antibody (anti
HBc) before administering an immunisation
schedule. (2B)

63. Guideline 5.6 - BBV Infection : Immunisation of patients
against hepatitis B
• We recommend that patients should be
regarded as a ‘responder’ if anti HBs antibody
titre is >10mIU/mL 8 weeks after completing
immunisation. (1C)

64. Guideline 3.3 - BBV Infection : BBV surveillance in
dialysis patients
• We recommend that patients on regular
hospital haemodialysis who have responded
to hepatitis B immunisation (annual anti HBs
antibody titre >10mIU/ml, only need to be
tested for HBsAg once a year. Non-responders
should be tested at least every 3 months. (1C)

65. Guideline 5.7 - BBV Infection : Immunisation of patients
against hepatitis B
• We recommend that responders to HBV
immunisation should receive a further booster
dose if the annual anti HBs titre is
<10mIU/mL. (1B)

66. Guideline 5.8 - BBV Infection : Immunisation of patients
against hepatitis B
• We recommend that non-responders to HBV
as described in 5.6 should receive no further
immunisation with currently available
preparations. (1C)

67. Guideline 3.2 - BBV Infection : BBV surveillance in
dialysis patients
• We recommend that patients who require
haemodialysis before the result of the HBsAg
test is known should be dialysed in an area
that is segregated from the main dialysis unit
and the machine should not be used for
another patient until the result is known to be
negative. (1A)

68. Guideline 3.10 - BBV Infection : BBV surveillance in
dialysis patients
• We recommend that testing for HBV DNA
and HCV RNA should be performed in
haemodialysis patients with unexplained
abnormal serum aminotransferase levels.
(1B)(KDIGO Hepatitis C guideline 1.2.3)

69. Guideline 3.11 - BBV Infection : BBV surveillance in
dialysis patients
• We recommend that if a new BBV infection in
a haemodialysis unit is suspected to be
nosocomial, testing for viral RNA or DNA
should be performed in all patients who may
have been exposed (1B) (KDIGO Hepatitis C
guideline 1.2.4)