Ebook Comprehensive textbook of hepatitis B: Part 2

Hepatitis B in Pregnancy

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Hepatitis B
in Pregnancy
Desmond Wai, Kai-Chah Tan

INTRODUCTION
Chronic hepatitis B is a major cause of morbidity and mortality in many parts of
Asia, as prevalence of hepatitis B ranged from 4 to 20% in various parts of Asia.
It is not uncommon for physicians to encounter pregnant hepatitis B patients in
their clinical practice. Besides, maternal-fetal transmission is considered the major
source of transmission of hepatitis B in Asia. Hence, it is important for physicians
to be aware of hepatitis B management before, during, and after pregnancy.
PREPREGNANCY MANAGEMENT
Physicians must be aware that none of the antivirals against hepatitis B are classified
as FDA pregnancy category A. In patients with chronic hepatitis B requiring
antiviral therapy, injectables such as interferon, pegylated interferon α-2a and 2b are generally given over a 6–12 months period, while oral antivirals such as
nucleoside or nucleotide analogs are often given over prolonged period of up to
a few years in duration.
Therefore, before treating female hepatitis B patients in the reproductive age
group, physicians must discuss the potential benefits of antivirals, the possible
need for prolonged administration of antivirals, and the insufficient safety data of
antivirals during pregnancy with both the patient and the spouse. In patients having
mild liver disease, it may be better to wait till the patient has completed her family
before administering oral antivirals. Alternatively, physicians can consider using
pegylated interferons as the first line treatment for young female hepatitis B patients
as they are given over a defined period of time. In patients with severe liver disease

and oral antivirals are being administered, it is prudent to ask patients to consider
using contraceptives while they are on antiviral treatment.
WHEN A HEPATITIS B INFECTED PATIENT BECOMES PREGNANT
The Advisory Committee on Immunization Practices (AICP), which advises the
Center for Disease Control and Prevention (DCD) on the control of vaccinepreventable diseases, recommends that all pregnant women be tested for HBsAg
during an early prenatal visit in each pregnancy, irregardless of whether they have


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been vaccinated or tested previously. Many previously undiagnosed hepatitis B
cases are discovered by this screening exercise.
Several case studies from Hong Kong and USA have shown that both maternal
and neonatal outcomes in mother with chronic hepatitis B were comparable to
non-hepatitis B mothers.
Among all antivirals against hepatitis B, telbivudine and tenofovir are classified
as FDA pregnancy category B drug. However, safety data of both of them among
pregnant hepatitis B carriers are lacking. Lamivudine, though classified as category
C, has the longest safety record among pregnant women, and should be used as
first-line antiviral agent during pregnancy. After delivery, lamivudine can be
switched to more potent drugs such as entecavir or tenofovir. In a study of 1633
infants who had been exposed to lamivudine in utero during the first trimester of
pregnancy, the rate of congenital defects was 2.7%, a rate comparable to that in
unexposed pregnant females.
While some patients may be worried about the lack of safety data of antivirals,
the thought of stopping antivirals must be balanced with the risk of withdrawal
flares when antivirals are stopped prematurely.
Other hepatitis B patients whom are not on antiviral treatment should be

monitored as per normal, with liver panel and ultrasound scan being tested every
6 months. During pregnancy, alkaline phosphatase level may be mildly elevated,
and albumin may be slightly depressed, even in the absence of significant liver
disease.
RISKS OF MATERNAL CHILD TRANSMISSION
Prior to the introduction of neonatal hepatitis B vaccination, 10% of neonates
born to HBsAg+ve/HBeAg-ve mother, and 90% of neonates born to HBsAg+ve/
HBeAg+ve, became hepatitis B carriers. Since the introduction of active
(intramuscular administration of 3 doses of recombinant hepatitis B vaccine
0.5 microgram within 12 hours of birth, then at 1 and 6 months of age) and passive
vaccination (intramuscular administration of hepatitis B immunoglobulin, HBIG,
0.5 ml within 12 hours of birth), the risk of vertical transmission has dropped to
<10%.
Failure of 100% prevention is thought to be due to transplacental leakage of
hepatitis B virus, also known as “intrauterine transmission”. Intrauterine
transmission occurred before or during the delivery and hence, cannot be prevented
by postnatal measures. Risk of intrauterine transmission is related to level of
maternal viremia, with hepatitis B mother being HBeAg+ve and high serum HBV
DNA level being at highest risk.
Several measures have been proposed to reduce such risk. Maternal
administration of HBIG 200 IU at weeks 28th, 32nd, and 36th, together with
standard practice of neonatal active-passive immunoprophylaxis, was shown to
be effective in several studies from China in reducing risk of vertical transmission


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to <5%. Administration of lamivudine after week 34th has been showed in several

studies as equally effective in reducing risk of intrauterine transmission.
It has to be emphasized that all of these studies involve small number of subjects
so their conclusion may not be applicable to the general public. Besides, both
HBIG and lamivudine are of FDA pregnancy category C and their use in pregnant
patients should be considered experimental and be given only as part of a clinical
study.
MODE OF DELIVERY: ELECTIVE CESAREAN SECTION VS
VAGINAL DELIVERY
During labor, mother-to-child transmission could potentially occur through
microtransfusion of maternal blood into the baby, neonatal swallowing of
circulation tear of placenta, amniotic fluid, or vaginal secretions while passing
through birth canal. It has been postulated that risk of transmission during labor
could be reduced by cesarean section. However, the efficacy of elective cesarean
section in preventing maternal transmission of hepatitis has not been proven
conclusively in clinical studies. With the highly effective active-passive
immunoprophylaxis given to newborns from birth, it is unknown if elective cesarean
section can provide any further benefits. Weighing against the risk of increased
maternal and neonatal morbidity and mortality, we do not recommend elective
cesarean section as the mode of delivery in hepatitis B mothers purely for the
reason of reducing maternal-fetal transmission rate.
POSTPARTUM HEPATITIS B FLARES
There is a tendency for HBV DNA titer to increase during pregnancy, and drop
after delivery. Liver transaminases also tend to drop during pregnancy, but then
increase after delivery. This is thought to be due to immunosuppressive effects of
pregnancy. Postpartum flares, i.e. acute rise of HBV DNA and ALT, have been
described, and was thought to be due to reconstitution of the immune system.
Decompensation can occur in severe flares so mothers with chronic hepatitis B
ought to be closely followed-up after their delivery.
BREASTFEEDING
Hepatitis B virus can be found in breast milk in some mothers with hepatitis B.

But risk of transmission from mother to child through breast milk has not been
shown in large scale clinical studies. In fact, in several case control studies, no
difference in infection rates between breastfed and bottlefed infants of hepatitis
B mothers was found. It is postulated that newborns of hepatitis B mother are
already protected under active and passive immunoprophylaxis administered at
birth so risk of transmission via breast milk is minimized. Weighing against the
vast benefits of breastfeeding to both the mother and the newborn, the American


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Academy of Pediatrics recommended that maternal hepatitis B being not a
contraindication to breastfeeding.
LIVER CANCER IN PREGNANCY
Hepatocellular carcinoma (HCC) is a complication of chronic hepatitis B, and
can occasionally occurr in pregnant women. Prognosis for HCC was particularly
poor with 1 year survival being <20%, which was thought to be due to tumorpromoting effects of estrogen. Ultrasonography is the initial investigation in
pregnant patients suspecting of having HCC. CT scan is contraindicated, so noncontrast MRI is the next investigation of choice. Physicians must also be aware
that alpha-fetoprotein (AFP) level can be elevated for obstetric causes, such as
miscarriage and fetal neural tube defects so a mildly elevated AFP does not equate
presence of liver cancer. Treatment of choice is termination of pregnancy followed
by resection, if applicable.
CONCLUSION
Pregnancy is an emotional event and physicians must be prepared to provide ample
information to reassure anxious patients and their husbands. From our experience,
most hepatitis B mothers have uneventful pregnancy and good pregnancy
outcomes.
FURTHER READING

1. Gambarin-Gelwan M. Hepatitis B in pregnancy. Clin Liver Dis 2007;11(4):945-63.
2. Gartner LM, Morton J, Lawrence RA, Naylor AJ, O’Hare D, Schanler RJ, et al.
American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the
use of human milk. Pediatrics 2005;115(2):496-506.
3. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B:
summary of a clinical research workshop. Hepatology 2007;45:1056-75.
4. Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al. Asian-Pacific
consensus update working party on chronic hepatitis B. Asian-Pacific consensus
statement on the management of chronic hepatitis B: a 2005 update. Liver Int
2005;25:472-89.
5. Mast EE, Margolis HS, Fiore AE, Brink EW, Goldstein ST, Wang SA, et al. Advisory
Committee on Immunization Practices (ACIP). A comprehensive immunization
strategy to eliminate transmission of hepatitis B virus infection in the United States:
recommendations of the Advisory Committee on Immunization Practices (ACIP)
part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep
2005;54(RR-16):1-31.
6. Ranger-Rogez S, Denis F. Hepatitis B mother-to-child transmission. Expert Rev
Anti Infect Ther 2004;2(1):133-45.


HBV and HCV Coinfection

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HBV and HCV
Coinfection
Hasan Ozkan, Gokhan Kabacam

EPIDEMIOLOGY
Hepatitis B virus infection with Hepatitis C virus coinfection is mostly seen in
Southeast Asia and Mediterranean countries. In East Europe, healthy population
has the Hepatitis B virus infection with Hepatitis C virus coinfection at the ratio
of 0.68%. The study of Soriano, on 350 HBV infected and 175 HCV infected
patients revealed that, HBV and HCV coinfection rate is 1%. Chen and his friends
found 14.9% HCV positivity among 712 HBV patients. Generally, the studies
show the HCV prevalence rate is between 9–30% on Hepatitis B infected patients.
However, the HBV prevalence identified among chronic HCV patients is between
2–10%. In another study performed among HCV positive patients, the reported
HBV positivity rate is 14%.
Among the 1036 viral hepatitis B and C infected patients that was followed by
a single experienced hepatologist at our clinic, 42 of them (around 4%) have the
HBV and HCV coinfection. On the other hand, a study made in Mongolia shows
the HCV and HBV coinfection rate around 7.7%. Hepatitis B with Hepatitis C virus
coinfection are most frequently found in HIV positive patients (66%), IV drug addicts
(42.5%), thalassemics (10%), organ transplanted patients (8%), and hemodialysis
patients (3.7%) patients. The multicenter study from Italy showed that the independent
risk factors for HBV and HCV coinfection are being at or above the age of 42, IV
drug addiction, blood transfusion and living in the southern parts of the country.
VIRUS INTERACTION
The two viruses are able to inhibit each other mutually at the same time. Generally
one plays a dominant role over the other. In addition the two viruses are able to
induce each others’ seroconversion. Generally, HBV dominates HCV. Because of
the interaction of two viruses, both HCV and HBV replication rate are low on
coinfected patients.
Mostly, HCV strongly suppresses HBV replication on HCV coinfected patients.
Also, HBV may suppress HCV. The core protein of HCV has been shown to
suppress the HBV replication. As a result HBV DNA decreases HBV DNA
polymerase activity diminishes and HBcAg and HBsAg expression in liver tissue

decreases. If the patient with chronic HBV has the HCV superinfection, then


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Table 17.1: Subgroups of HBV and HCV coinfection
HBV DNA

HBsAg

HBeAg

Anti-HBc Anti-HCV
IgG

HCV
RNA

Active HBV+
Active HCV

+, >20,000
IU/ml

+

+/–

+

+

+

Active HCV +
Inactive HBV

+, >2000
IU/ml

+

–

+

+

+

Active HBV+
Inactive HCV

+, >20,000
IU/ml

+

+/–

+

+

–

Active HCV +
Occult HBV

+,<200 IU/ml –

–

+/–

+

+

Inactive HBV+
Inactive HCV

+,>2000
IU/ml

–

+

+

–

+

HBeAg seroconversion and anti-HBsAg formation will be realized. Annual HBsAg
seroconversion ratio is 2.08% in coinfected patients and 0.43% in HBV monoinfected patients.
PATTERNS OF HBV AND HCV COINFECTION
The subgroups of coinfection are seen on Table 17.1.
Acute HBV and HCV Coinfection
Mimms and colleagues studied on 5 incidents that have acute HBV and HCV
coinfection. Their study show that ALT levels are low, determination duration is
slow on HBsAg serum and HBs antigen time is short. 4 of these 5 patients have
advanced chronic HCV. The studies made by Alberti and his friends on 30 acute
hepatitis patients show that the 30 patients have active HBV+HCV. The observed
ALT level is high on these patients but inveteracy of HBV and HCV is varied. In
the acute period, biphasic fluctuations in ALT are observed. Feray C and friends
studied on 40 patients with diagnose of fulminant hepatitis. The observation shows
that 12.5% (5 patients) have acute HBV and HCV coinfection and 7.5% (3 patients)
have HCV superinfection.
HCV and Occult HBV Infection
Patients having HCV and occult HBV infections have also serious liver diseases.
In these patients’ conditions, the inflammation is too much, histological activity
is high and ALT level is at higher levels. A study made on 200 HCV (+) patients
show that 33 of them have HBV DNA (+).
CLINICAL COURSE IN HBV AND HCV COINFECTION
Patients with dual active HBV and HCV coinfection (HBV DNA + and HCV
RNA +) progress to cirrhosis and patients decompensed rapidly. It is observed

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that 23 coinfected patients with HBV DNA replication inhibits HCV RNA
replication and histological activity increased. In a study of 44 acute HBV
superinfection case follow-ups, 13 of the patients recovered. A comparison made
between coinfected and HBV monoinfected patients against progress to cirrhosis
and it is found that 24 of the 44 coinfected patients decompensed; 6 of the 24
chronic hepatitis B patients decompensed. Another study made to compare between
coinfected and HCV monoinfected patients against decompensed ratio of cirrhosis.
It is found that the decompensed ratio is 90% for coinfected patients while it is
48% for HCV monoinfected patients.
Coinfected patients have the high risk of progressing HCC. Findings of
Benvegu and colleagues made on cirrhosis patients showed that 10 years of
cumulative HCC progress risk found on coinfected patients is 45%; the 10 years
of cumulative HCC progress risk found on patients with cirrhosis related to HCV
monoinfection is 28% and the 10 years of cumulative HCC progress risk found
on cirrhosis related to HBV is 16%. Depending on these results, the USG and
AFP follow-ups of HBV and HCV coinfected patients must be in 6 months time
interval or less.
TREATMENT IN HBV AND HCV COINFECTION
The treatment criteria of HBV and HCV coinfection is similar to treatment of
monoinfected patients. Before starting to treatment, it is crucial to identify which
virus is dominant. The suggested treatments for the active HBV + active HCV
infection with HBV DNA (+) and HCV RNA (+) patients are peg interferon +
ribavirin or peg interferon + ribavirin + nucleoside/nucleotide analog. The
suggested treatments for active HCV + inactive HBV infection with HBV DNA
(–) and HCV RNA (+) patients are peg interferon + ribavirin. The suggested

treatments for active HBV + inactive HCV infection with HBV DNA (+) and
HCV RNA (–) patients are peg interferon, peg interferon + nucleoside / nucleotide
analog or only nucleoside/nucleotide analog.
In a study, 16 HBV DNA (+) patients were given IFN 6 MU and ribavirin
1200 mg treatment for 6 months. 5 patients responded to treatment as 31.3%
permanent HBV (excluded genotype lb) virological responses; 1 patient have HBV
and HCV clearance; 5 patients have developed HBsAg seroconversion. After
treatment; the observed HBV DNA positivity ratio is high on IFN responded HCV
cases than IFN non-responders HCV patients. The studies show that loss of HCV
RNA with interferon is 16.7 to 43.8%. On the other hand HCV RNA negativity
ratio found is 66.7 to 88%.
Lu and colleagues found the permanent response ratio of interferon + ribavirin
treatment of HBV and HCV coinfected patients is 43%; the permanent response
ratio found by Hung and his friends is 69% and the permanent response ratio
found by Chuang and his friends is 69%.
Above all, the factors effecting HCV clearance in HCV infected patients are
genotype-non 1-b and considered as low viral load before treatment. However, in


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dual infection, there are no meaningful factors to contemplate the HCV clearance.
In dual infection, combined treatment provides more HCV clearance. A study
indicated that HBV and HCV dual infected patients and solely HCV patients
responded similarly to combined treatment. Two separate studies made with
standard IFN-α and ribavirin show that there is no sustainable virological response
difference on solely HCV infected patients compared to HBV+HCV coinfected
patients. Nonetheless; after first fall, it is seen that HBV DNA serum levels

rebounds, also HBV replication reoccurs on patients having ambiguously low HBV
DNA levels.
CONCLUSION
There is still little information and knowledge on HBV and HCV coinfection
treatments. At present, there is no clear HBV and HCV coinfection treatment
suggestion. Series of broad case groups with longer follow-ups are needed.
FURTHER READING
1. Atanasova MV, Haydouchka IA, Zlatev SP, Stoilova YD, Iliev YT, Mateva NG.
Prevalence of antibodies against hepatitis C virus and hepatitis B coinfection in
healthy population in Bulgaria. A seroepidemiological study. Minerva Gastroenterol
Dietol 2004;50:89-96.
2. Chuang WL, Dai CY, Chang WY, Lee LP, Lin ZY, Chen SC, et al. Viral interaction
and responses in chronic hepatitis C and B coinfected patients with interferon-alpha
plus ribavirin combination therapy. Antivir Ther 2005;10(1):125-33.
3. Claudia da Silva, Neiva Sellan Lopes Gonçales, Josiane Silveira Felix Pereira, Cecília
Amélia Fazio Escanhoela, Maria Helena Postal Pavan, Fernando Lopes Gonçales
Junior. The influence of occult infection with hepatitis B virus on liver histology
and response to interferon treatment in chronic hepatitis C patients. Braz J Infect
Dis 2004;8(6):10.1590/S1413.
4. Liu JY, Chen PJ, Lai MY, et al. Ribavirin and interferon is effective for for hepatitis
C virus clearence in hepatitis B and C dually infected patients. Hepatology
2003;37:568-76.
5. Liu Z, Hou J. Hepatitis B virus and hepatitis C virus dual infection.Int J Med Sci
2006;3:57-62.
6. Sagnelli E, Pasquale G, Coppola N, Scaran F. Influence of chronic coinfection with
hepatitis B and C virus on liver histology. Hepatology 2002;36:1285-91.
7. Seth D Crockett, Emmet B Keeffe. Natural history and treatment of hepatitis B
virus and hepatitis C virus coinfection. Annals of Clinical Microbiology and
Antimicrobials 2005;4:13doi:10.1186/1476-0711-4-13.
8. Soriano V, Barreiro P, Nuñez M. Management of chronic hepatitis B and C in HIVcoinfected patients. J Antimicrob Chemother 2006;57(5):815-8.

9. Villa E, Grottola A, Buttafoco P, et al. High doses of alpha_interferon are required
in chronic hepatitis duo to coinfection with hepatitis b virus and hepatitis C virus
long term results of a prospective randomised trial. Am J Gastroenterol 2001;
96:2973-7.


Hepatitis B and Delta Virus Coinfection and Superinfection

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Hepatitis B and Delta
Virus Coinfection and
Superinfection
Khalid Mumtaz, Saeed S Hamid

HISTORY
In 1977 a new virus was discovered accidentally by an Italian scientist, named
Mario Rizzeto, while studying the liver biopsy from patients with hepatitis B surface
antigen (HBsAg) positive. The virus was then named as hepatitis delta agent, which
evolves into hepatitis delta virus (HDV).
Hepatitis ‘D’ is a defective virus. HDV infection is closely associated with
hepatitis ‘B’ virus (HBV) infection; simultaneous presence of HBV is required
for complete virion assembly and secretion. As a result individuals with hepatitis
D are always dually infected with HDV and HBV.
VIRION STRUCTURE
Hepatitis B virus belongs to the family of hepadnaviruses, which include duck
hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus.
The complete virion or Dane particle is 42 nm in diameter. HBV also produces

22 nm subviral particles in the form of filaments and spheres that are composed
of envelope proteins only.
The HD virion is composed of an outer lipoprotein envelope made of the
surface antigen of the HBV (HBsAg) and an inner ribonucleo-protein structure in
which the HDV genome resides. The HDV genome consists of a single stranded
RNA which is folded as a rod-like structure (Fig. 18.1) through internal basepairing is complexed with the only HDV-encoded antigen, the HDAg.
HBV Genome
The genome of HBV is a relaxed circular, partially double stranded DNA of
approximately 3200 base pairs in length. There are four partially overlapping open
reading frames (ORFs) encoding the envelope (pre-S/S), core (precore/core),
polymerase, and X proteins. HBV has been classified into eight genotypes (A to
H) based upon an intergroup divergence of 8% or more in the complete nucleotide
sequence. The clinical significance of the genotypes is still being determined.


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Fig. 18.1: HDV Virion: Schematic representation of the hepatitis D virus virion. The HD
virion comprises an RNA genome, a single HDV encoded antigen, and a lipoprotein envelope
provided by HBV

HDV Genome
The HDV genome is a small RNA molecule (1676 to 1683 nucleotides in size)
bearing some structural analogies with plant viroids and virusoids. HDV RNA is
a single-stranded circle, with a high degree of self-complementarity and G+ C
content causing the circle to collapse as a rod-like structure. Significant sequence
heterogeneity (as high as 39 percent) exists among the different HDV isolates that
have been sequenced, and is basis of its classification into three HDV genotypes.

Hepatitis D Antigen
The only antigen associated with HDV, the hepatitis D antigen (HDAg), is a
structural component of the virion. It consists of a phosphoprotein encoded by an
open reading frame (ORF) present on the RNA strand complementary to the RNA
genome (antigenomic strand). Approximately 70 molecules of HDAg are
complexed with each molecule of HDV RNA to form a ribonucleic core-like
structure.
HBV LIFE CYCLE
The replication cycle of HBV begins with attachment of the virion to the hepatocyte
membrane. The exact mechanisms of virus attachment are not clear but are thought
to be mediated through the pre-S1 region of the virion envelope. The virion is
uncoated in the hepatocyte cytoplasm and the viral genome enters the hepatocyte
nucleus. Inside the hepatocyte nucleus, synthesis of the plus strand HBV DNA is
completed and the viral genome is converted into a covalently closed circular


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DNA (cccDNA). The HBV genome replicates by reverse transcription via an RNA
intermediate, the pregenomic RNA. The cccDNA appears to have a long half-life
and is very resistant to antiviral therapy, accounting for the difficulty in achieving
virus clearance during treatment of chronic hepatitis B.
HDV LIFE CYCLE
HDV replicates at very high levels in hepatocytes. The receptor of HDV is
unknown. The steps in HDV replication cycle can be summarized as follows:
• Once inside the hepatocyte, HDV RNA is found within the nucleus, where it
is transcribed into its complementary RNA (antigenomic HDV RNA). The
synthesis of the full length genomic and antigenomic RNAs involves distinct

cellular enzymes, but the respective mechanisms have not been elucidated.
• HDV RNA replication is activated by the small HDAg through direct binding
of the HDAg to the HDV RNA.
• Completion of the HD virion assembly and release is dependent on the
simultaneous presence of HBV which provides the envelope. In the absence
of HBV, HDV infection is abortive, unless rescued by HBV at a later time.
HBV AND HDV-INFECTION
The hepatitis D virus is a defective pathogen that requires the presence of the
hepatitis B virus (HBV) for infection. HDV is complexed with the only HDVencoded antigen, the HDAg.
HDAg can elicit a specific immune response in the infected host, consisting
of antibodies of the IgM and IgG class (anti-HDV). Due to its dependence upon
HBV, HDV infection always occurs in association with HBV infection. The clinical
and laboratory findings vary with the type of infection (Table 18.1). In HDV
infected individuals, the timing of appearance and level of HDV RNA, HDAg,
and anti-HDV in serum allow the three HDV-related clinical entities to be
discriminated:
Acute HBV/HDV coinfection.
Acute HDV superinfection of a chronic HBV carrier.
Chronic HDV infection
COINFECTION
Coinfection of HBV and HDV in an individual susceptible to HBV infection
results in acute hepatitis B + D. This entity is clinically indistinguishable from
classical acute hepatitis B and is usually transient and self-limited. The rate of
progression to chronic infection is not different from that observed after classical
acute hepatitis B, since persistence of HDV infection is dependent upon
persistence of HBV-infection.


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Table 18.1: Diagnosis of hepatitis D virus infection in different clinical settings
Diagnostic markers Acute HBV/HDV
coinfection

Acute HDV
superinfection

Chronic HDV
infection

HBsAg

Positive

Positive
Negative

Positive

Anti-HBc, IgM

Positive

Negative

Serum HDAg
(by EIA/RIA)

Early and shortlived, frequently
missed

Early and transient, Not detectable
and frequently
missed

Serum HDV RNA
(by hybridization)

Early, transient but
last longer than
HDAg

Early and
persistent

Usually positive

Anti-HDV, total

Late, low titer

Rapidly increasing
titers

High titers

Anti-HDV, IgM

Transient, may be
the only marker

Rapidly increasing
titers

Variable titers,
usually high

Liver HDAg

Not indicated

Positive

Usually positive,
may be negative in
late stages

Along with the HBsAg the additional presence of IgM antibody to hepatitis
B core antigen (IgM anti-HBc) is necessary for the diagnosis of acute HBV/HDV
coinfection (Table 18.1).
SUPERINFECTION
HDV superinfection of a chronic HBsAg carrier may present as usually severe
acute hepatitis in a previously unrecognized HBV carrier, or as an exacerbation
of preexisting chronic hepatitis B. Progression to chronic HDV-infection occurs
in almost all patients. However, HBV replication is usually suppressed by HDV.
PATHOGENESIS OF HDV-INDUCED HEPATITIS
The detailed mechanisms by which HDV induces liver damage are unknown.
However, the pathogenesis of hepatitis D-related liver disease appears to depend

on the interplay of three major factors:
• HDV-associated factors, such as genotype and the expression of specific HDAg
species.
• Host-associated factors, such as the immune response.
• Helper virus-associated factors, such as the HBV genotype and the level of
HBV replication.
HDV is believed to cause directly cytopathic damage during acute infection,
whereas immune-mediated damage predominates during chronic infection.
In a study the genotypes and viremia of hepatitis D virus (HDV) and hepatitis
B virus (HBV) were studied to be associated with outcomes. Viremia and viral
genotypes were analyzed in 194 consecutive chronic hepatitis B patients with


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HDV superinfection and correlated with outcomes. Patients infected with genotype
I HDV had a lower remission rate and more adverse outcomes (cirrhosis,
hepatocellular carcinoma, or mortality) than those with genotype II HDV. Similarly,
patients infected with HBV genotype C had a lower remission rate and more
adverse outcomes than those with HBV genotype B. Age, HBV genotype C, and
HDV genotype I were independent factors associated with adverse outcomes.
HDV GENOTYPES
HDV is currently classified into 3 genotypes based on sequence comparison.
Genotype I
More prevalent in the western world and has an increased risk of a fulminant
course. Genotype I is widely distributed in Europe, North America, North Africa,
the Middle East, and East Asia. Recently, HDV genotype I is reported from Pakistan
and it is seen in younger patients and seems to be causing cirrhosis at early age

as is reported in other studies.
Genotype II
Genotype II has only been isolated from Japan and Taiwan. There is less frequent
association between FHF and acute HDV-infection and between rapidly progressive
liver disease and chronic HDV-infection.
Study showed that genotype I is relatively more pathogenic than genotype II.
Genotype III
Genotype III appears to be localized in northern South America. Reported among
Indians of Venezuela, Colombia, Brazil, Amazon basin, Kashmir region and Central
African Republic. Viral factors have been postulated to be related to fulminant
course in outbreaks in these areas.
Recently, 4 additional new genotypes have been classified by Radjef and
colleagues; genotype IV (genotype IIb by old nomenclature), distributed in Taiwan
and Okinawa islands, and genotypes V–VII, found in west and central Africa.
IMPACT OF HDV ON HBV
Numerous clinical studies have reported that patients with chronic HDV-infection
often show severe chronic hepatitis or cirrhosis on initial liver biopsy. Crosssectional studies have indicated that patients with hepatitis B surface antigen
(HBsAg) positive chronic hepatitis and HDV infection have more severe liver
disease than those with HBV infection alone.
Moreover, longitudinal studies have reported that HDV-infection in patients
with chronic hepatitis B is associated with a more rapid progression to cirrhosis
than in HBsAg carriers with chronic hepatitis and no evidence of HDV-infection.


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Overall, these data indicate that HDV-infection tends to influence unfavorably
the clinical outcome of chronic hepatitis B.

DIAGNOSIS OF HDV-INFECTION WITH HBV
Due to dependence of HDV on HBV, the presence of HBsAg is necessary for the
diagnosis of HDV infection (Fig. 18.2). The additional presence of IgM antibody
to hepatitis B core antigen (IgM anti-HBc) is necessary for the diagnosis of acute
HBV/HDV coinfection (Table 18.1).
Following serological tests are available for the diagnosis and follow-up of a
patient with HDV infection:
• HDV Ab (IgM)
• HDV Ab (IgG)
• HDV Ab (Total)
[most frequently available assay]
• HDV Ag
• HDV RNA
[most informative investigation]
HDV Ab and HDV RNA are the two tests which have definite value in
diagnosing and assessing the response to treatment respectively.

Fig. 18.2: Schematic representation of the typical serologic response to acute HBV/HDV
infection. Patients should be positive for HBsAg and have high titer IgM anti-HBc; serum
HDAg and/or HDV RNA are usually positive at presentation


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Serum HDV RNA
It can be detected either by molecular hybridization or reverse transcriptasepolymerase chain reaction (RT-PCR) based assays. HDV RNA is an early and
sensitive marker of HDV replication in acute hepatitis D. In chronic HDV-infection,
HDV RNA is detectable in the serum of 70 to 80% of patients who had positive

staining for HDV Ag in liver tissue.
Hybridization assays using riboprobe have a detection limit of about 104 to
6
10 genomes per ml and are relatively easy to perform.
RT-PCR assays have a detection limit of less than 10 genomes per ml but it
is difficult to choose suitable primers for the amplification of HDV RNA since
only a few conserved region exist in the HDV genome. RT-PCR assays for HDV
RNA is useful in assessing the response to treatment.
Anti-HDV Antibody
•
•

Total (IgM and IgG ) anti- HDV antibodies can be detected by EIAs or RIAs
(Table 18.1).
High titer anti- HDV of the IgG class is present in chronic HDV-infection. It
correlates well with ongoing HDV replication and may help in differentiating
current from past HDV-infection.

CLINICAL PRESENTATIONS OF HDV-INFECTION
The diagnosis of HDV-infection should be considered in the following clinical
presentations:
Acute Hepatitis ‘B’ Virus Infection
In patients with acute HBV infection, testing for HDV coinfection should be
considered in those who have risk factors (intravenous drug users and patients
from endemic countries) or who present with unusually severe or protracted
hepatitis. Patients should be positive for HBsAg and have high titer of IgM antiHBc. Serum HDV Ag and/or HDV RNA are usually positive, if these are not
available, repeated testing for anti-HDV (total or IgM) should be performed to
document anti- HDV seroconversion.
Acute Hepatitis of Undetermined Origin in a Chronic HBV Carrier
Tests for HDV should be considered to rule out acute HDV superinfection in this

setting. Since HDV superinfection may occur in previously unrecognized chronic
HBV carriers, distinguishing between this condition and acute HBV/HDV coinfection can be difficult. This distinction is important because of the difference
in the prognosis.
• HBsAg is present in both situations, but IgM anti-HBc should be negative in
acute HDV superinfection.


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Diagnosis is made more difficult since HDV superinfection may cause
transient suppression of HBV replication, resulting in very low and, rarely,
undetectable levels of HBsAg.
In contrast to acute coinfection, acute HDV superinfection is characterized by
persistent detection of HDV RNA in serum and rapidly increasing titers of
anti- HDV (total and IgM).

HBsAg Positive Chronic Liver Disease
Tests for HDV should be considered in such patients to rule out coexistent chronic
HDV infection by screening for total anti- HDV antibody.
TREATMENT OF HBV AND HDV-INFECTION
In most cases of HDV infection, HBV replication is suppressed to very low levels
by HDV. Liver damage in these patients is essentially due to HDV only.
Occasionally, HBV and HDV replicate simultaneously, each virus is contributing
to liver damage, thereby resulting in more severe liver disease.
Clinical Course of HDV-Infection

The clinical course and treatment outcome is dependent on the viremia and
genotypes of HDV and HBV. The genotype-I which is predominant in western
world and Pakistan result in severe and progressive disease; While HDV genotype
II which is prevalent in Far East cause less progressive disease.
Aims of Treatment
The treatment of hepatitis D is aimed at eradicating both HDV and HBV.
• The primary end point of treatment is the suppression of HDV replication,
which is accompanied by normalization of serum ALT levels and amelioration
of necro-inflammatory activity on liver biopsy. Suppression of HDV replication
is documented by undetectable HDV RNA in serum.
• A secondary endpoint is the eradication of HBV-infection, with HBsAg to
anti-HBs seroconversion. There is little information to support that current
treatment is effective in achieving this goal.
• Patients who clear HDV but who remains HBsAg-positive are still at risk of
re-infection with HDV.
TREATMENT OF ACUTE HDV SUPERINFECTION
Interferon and Foscarnet has been used in limited number of patients with acute
HDV infection with very disappointing results. Trisodium phosphonoformate
(Foscarnet) was used to treat three patients with fulminant HBV/HDV hepatitis;
surprisingly it was observed that all three recovered. Paradoxically in vitro studies
showed that Foscarnet enhances rather than inhibits HDV replication; so it is


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173

conceivable that remission of fulminant hepatitis occurred by chance and hence
drug has not been used further.
In one trial, recombinant interferon-α was administered to nine patients with

fulminant HDV hepatitis. Eight died and in the survivor treatment for 3 months
did not prevent the development of chronic delta infection and liver cirrhosis.
Author has concluded that interferon-alpha has no therapeutic value in fulminant
HDV hepatitis.
Based on limited trials it is recommended that patients with acute delta hepatitis
require monitoring of the clinical and biochemical parameters of liver function to
allow the early detection of progression to fulminant hepatitis.
Until now, there is no treatment effective for acute HDV-infection. If fulminant
hepatitis occurs due to HDV, orthotopic liver transplantation is the only treatment.
TREATMENT OF CHRONIC HDV AND COINFECTION
Different drugs are used for the treatment of chronic HDV infection, but none is
proven effective in achieving the desired success. The main hindrance in clearing
HDV-infection is concomitant RNA (HDV) and DNA (HBV) virus infection as
compared to treating chronic hepatitis B alone. As with hepatitis B, poor results
were obtained in the treatment of HDV with immunosuppressive and immunostimulant drugs.
Interferon Alfa
The only drug approved at present for treatment of chronic hepatitis D is interferon
alfa (IFN-α). In the mid-1980s, pilot clinical trials suggested that interferon-α
(IFN) could inhibit HDV replication.
The mechanism of action of IFN in chronic hepatitis D is poorly understood.
In vitro experiments showed a reduction in HDV viremia and ALT levels,
suggesting a direct antiviral effect of the cytokine on HDV. Moreover, efficacy of
IFN-α in patients with chronic HDV may be dependent on its antiviral effects on
the HBV or its immunomodulatory effects.
Trials of Therapy
Until 2003, the total number of reported patients with chronic hepatitis D who
have been treated with IFN-α was small (Table 18.2). As a result, it is difficult to
draw firm conclusions on the efficacy, optimal dose regimen, and factors predictive
of response to IFN-α therapy.
The response, assessed on the normalization of serum ALT levels and the

clearance of serum HDV RNA, varied widely and occurred at different times from
the beginning of treatment, sometimes after discontinuation of IFN.
In the largest multicenter trial, 61 Italian patients with chronic hepatitis D
were randomized to receive IFN-α in doses of 5 MU TIW for four months,
followed by 3 MU TIW for an additional eight months, or placebo. They were
then followed for another 12 months. The following results were noted:


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Table 18.2: Controlled trials of treatment of hepatitis delta
virus infection with interferon alfa

Reference

Rosina et al

No of
IFN schedule
patients

31

30
Farci et al

14

14

14
Gaudin et al

11

11
Madejon
et al

12

14

Borgheso
et al

05

04

•

•

Alpha 2b recombinant
TIW
05 MU x 4 months.
03 MU x 8 months.
untreated

Alpha 2a recombinant
TIW
9 MU x 12 months
Alpha 2a recombinant
TIW
3 MU x 12 months
untreated

End of treatment

End of follow-up

HDV
RNA
Negative

HDV
ALT
RNA
Normal
Negative

ALT
Normal

14 (45%) 8(25%)

14(45%) 1(3%)

8 (27%)

10(33%) 0(0%)

0 (0%)

10 (71%) 10 (71%) 0 (0%)

0 (0%)

5 (36%)

4 (28%)

0 (0%)

5 (30%)

1 (7%)

1 (7%)

0 (0%)

0 (0%)

7 (66%)

7 (66%)

1 (9%)

1 (9%)

4 (36%)

2 (18%)

NA

NA

Alpha 2a recombinant
TIW
18 MU x 6 months
9 MU x 1 month
6 MU x 1 month
3 MU x 4 months
Alpha 2a recombinant
daily
3 MU x 12 months

6 (50%)

4 (37%)

0 (0%)

0 (0%)

3 (19%)

1 (7%)

0 (0%)

0 (0%)

Lymphoblatoid TIW
10 MU up to normal
ALT plus 12 months
Lymphoblatoid daily
5 MU up to normal
ALT plus 12 month

NA

0 (0%)

NA

NA

NA

2 (50%)

NA

NA

Alpha 2b recombinant
TIW
05 MU/M 2 x 4 months.
03 MU/M 2 x 8 months.
untreated

Eight (25%) of 31 treated patients had normal serum ALT levels versus none
of the 30 controls at end of 12 months treatment period. However, all but one
of responder had biochemical relapse after discontinuation of therapy. Only
one patient had a normal ALT at end of the follow-up period.
Fourteen (45%) treated patients were HDV RNA–negative at the end of
treatment; however, similar proportion (27%) of control also became HDV
RNA negative, suggesting that spontaneous fluctuation in HDV viremia may
occur.


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•

Author concluded that IFN-α therapy did not produce any appreciable benefit
in patients with chronic hepatitis D.
In another smaller Italian study, 42 patients with chronic hepatitis D were
randomly assigned to receive two different doses (9 versus 3 MU TIW) of
IFN-α for 48 weeks or placebo. Normal serum ALT levels at the end of treatment
occurred more frequently in the patients receiving 9 MU doses of IFN-α than in
the other two groups (70, 29, and 8%, respectively). Complete response (normal
ALT level and undetectable serum HDV RNA at the end of treatment) was also

more frequent with 9 MU dosing (50, 21, and 0%, respectively). Treatment with
9 MU doses of IFN-α was also associated with a marked improvement in liver
histology. Five of the 10 responders in the 9 MU dose group had normal ALT
levels that lasted for up to four years. However, none of the patients had sustained
clearance of HDV RNA. Furthermore, virological and biochemical evidence of
relapse was common when IFN was reduced to 3 MU/m2 after a 4-months course
with 5 MU/m2.
In trial concomitant sustained biochemical and virological responses were
usually accompanied by the clearance of serum HBsAg and seroconversion to
anti-HBs. Histological examination revealed a significant decrease in hepatic injury
and in hepatitis D antigen (HDAg) staining in patients responding to IFN.
Gunsar and colleagues examined the ideal duration and dose of interferon
that would produce long-term beneficial outcome, and whether simultaneous
administration of ribavirin would improve the outcome of the patient with chronic
HDV. They found improvement in about 20% of subjects after a two-year course
of interferon. Subjects with liver disease before starting therapy did not respond,
and ribavirin use did not seem to help the outcome.
Pegylated Interferon
The way pegylated interferon has shown promise in the treatment of hepatitis C,
it is expected that it may also be beneficial for HBV and HDV-infection.
The published experience with pegylated interferon in the treatment of chronic
hepatitis D is growing up gradually. One published study included 38 patients
who were treated with pegylated IFN-α-2b (1.5 MU/kg per weak) alone or in
combination with ribavirin for 48 weeks. Most patients had previously failed
treatment with standard IFN. All patients were maintained on pegylated interferon
for an additional 24 weeks, and then followed off therapy for 24 weeks. At the
end of follow-up, HDV DNA was undetectable in eight patients (21%). The
response rate was similar in the monotherapy and combination therapy groups
suggesting that ribavirin had no effect on the viral clearance rate. The response
rate was somewhat higher in a subset of patients who had not previously received

interferon-based therapy (three of eight patients).
A higher virologic response rate (43%) was found in another study involving
14 patients treated with 12 months of pegylated interferon.


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In a recent study, 12 patients with chronic HDV were prospectively treated
with 1.5 mg/kg pegylated IFN-α2b for 48 weeks and followed for 24 weeks;
Sustained viral response (SVR) was achieved in 2/12 patients (17%). The negative
predictive value of <3 log HDV RNA decrease at month 6 was 100%. The positive
predictive value of >3 log HDV RNA decrease at month 6 was 67%. Ishak
histological score was comparable at baseline and significantly improved in
responders compared with non-responders at the end of follow-up (13.5 vs 8.0;
P < 0.02).
These two studies indicate that pegylated IFN-α2b is a promising treatment
option in chronic hepatitis D. Non-responders could be identified by <3 log
decrease of HDV RNA at 6 months of treatment.
Few studies have evaluated combination of pegylated interferon plus adefovir
dipivoxil therapy for HDV using nucleoside analogs. One of the largest controlled
trials included 90 patients with compensated chronic HDV-infection who were
randomly assigned to pegylated interferon alone or in combination with adefovir,
or adefovir monotherapy. After 48 weeks, both pegylated interferon groups
demonstrated significant suppression of HBV DNA (25% becoming undetectable).
Combination therapy appeared to offer no advantage while adefovir monotherapy
had no effect on HDV replication. Patients receiving combination therapy had a
significant decline in HBsAg levels while two cleared HBsAg.
Other Treatment Options

Antiviral drugs, including Suramin, Acyclovir, Ribavirin, Lamivudine, and
synthetic analogs of Thymosin have all been used.
Suramin in vitro blocks entry of HDV virions into hepatocytes. It is also known
to act on hepadna-viruses and retroviruses, but the drug is too toxic for long-term
use in humans.
Acyclovir, used previously and unsuccessfully as an adjuvant therapy in IFNtreated patients, seems to enhance rather than inhibit HDV replication in vitro.
Ribavirin, a nucleotide analog, inhibits HDV replication in cell culture. It was
given at 15 mg/kg/day orally for 16 weeks to nine patients but had to be suspended
in two after 2 weeks, in one for hemolytic anemia and in the other for intractable
itching. There was no significant virological or biochemical results were seen.
Thymosin-a, a synthetic thymus derived octapeptide possessing a wide range
of immunomodulatory effects, has been effective in chronic infection by HBV.
The drug was used in 11 patients with chronic HDV disease without any
consistent virological or biochemical effect.
Although HBV is not involved in the replicative cycle of HDV, the HBsAg
represents the envelope of HDV without which HDV cannot be secreted out the
hepatocyte. Repression of HBsAg production could lead to eradication of HDVinfection by preventing the spread of infectious virions to contiguous hepatocytes.


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This reasoning has provided the rationale for testing the therapeutic potential of
deoxynucleotide analogs in hepatitis D (e.g. famciclovir, lamivudine etc).
There are multiple small trials of LAM in HDV infection. An extensive study
has compared 12 months vs 24 months-course of LAM 100 mg/day. A total of 31
patients were randomized to treatment, 11 patients received placebo and 20 LAM
for 12 months; thereafter all were given LAM on an open-label basis for 12 months
and followed-up for further 16 weeks. At end of treatment, HDV-RNA was negative

and ALT normal in 3 patients; only 2 patients remained virus-free at the end of
follow-up. In this study, no significant differences in necro-inflammation and
fibrosis scores were observed in the two groups; one patient exhibited a complete
response and became HBsAg-negative (normal ALT, negative HDV-RNA,
histological improvement). Author has concluded that 12 or 24 months LAM did
not significantly affect biochemical, virological or histological parameters of
chronic HDV.
A study was designed to evaluate the effect of the combination of Lamivudine
with high-dose IFN-α therapy, 8 patients with chronic HDV were treated with
LAM for 24 weeks. Lamivudine was then combined with a high dose of IFN-α
followed by a regular dose (9 MU TIW), the patients were follow-up for 12 weeks
posttherapy. The results showed that HBsAg-concentration in serum decreased in
2 patients. The drop of HDV RNA from baseline during treatment was not
significant. In 4 patients ALT decreased at end of treatment, but showed a rebound
after withdrawal of therapy. The HAI score did not improved significantly.
Therefore, available evidence does not support the use of deoxynucleotide
analogues with IFN for the treatment of chronic HDV.
CURRENT RECOMMENDATIONS FOR TREATMENT
•

•
•
•

•

Until now, there is no effective treatment for acute HDV superinfection; these
patients require monitoring of clinical and biochemical parameters for
progression to acute liver failure.
It is generally accepted that patients with chronic hepatitis D and active liver

disease, should be treated and treated early, although the rate of success is low.
Asymptomatic HDV carriers with normal ALT levels don’t require therapy
but should be monitored for signs and symptoms.
Pegylated interferon is a new and viable option. Due to pegylation of interferon
the dose delivered is effective and tolerable as compared to high dose of
standard interferon.
Patients with decompensated HDV liver disease should be considered for liver
transplantation.

FUTURE PERSPECTIVES FOR TREATMENT
Interest in the therapy of chronic hepatitis D by pharmaceutical companies has
much reduced in recent years. The dramatic reduction of HDV-infection in western


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countries accounts for the absence of interest on new options for the treatment
of chronic delta hepatitis.
Antisense oligonucleotides hold considerable promise as therapeutic agents
against several classes of viral infections. Recently, an analysis has begun of the
effects of antisense oligonucleotides on HDV RNA replication in transfected cells
in culture. Oligonucleotides directed against the self-cleavage domain were highly
effective at reducing the level of replicating genomic HDV RNA (>90%).
The essential role of prenylation in HDV assembly suggests a basis for a novel
anti-HDV strategy. Mice were treated with prenylation inhibitors FTI-277 and
FTI-2153; both agents were effective at clearing HDV viremia dependent on the
duration-of-treatment.
PREVENTION OF HDV-INFECTION

The mainstay of prevention of HDV infection is vaccination against its helper
virus, the HBV. Anti-HBs-positive chimpanzees are protected against experimental
HDV-infection. There is no vaccine for HDV, but there is an effective vaccine for
HBV. In order to prevent HDV-HBV coinfection, the HBV vaccine or post exposure
prophylaxis (Hepatitis B Immune Globulin) can be used to prevent infection. The
only way to prevent HBV-HDV superinfection is to educate chronic HBV carriers
about transmission and risky behaviors. Prevention of HDV by vaccinating against
HBV is successful as demonstrated in Italian study model.
REFERENCES
1. Bordier BB, Marion PL, Ohashi K, Kay MA, Greenberg HB, Casey JL, et al. A
prenylation inhibitor prevents production of infectious hepatitis delta virus particles.
J Virol 2002;76(20):10465-72.
2. Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al. In vivo antiviral
efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003;
112:407-14.
3. Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, Boyer N,
et al. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: Relevance of
quantitative RT-PCR for follow-up. Hepatology 2006;44(3):728-35.
4. Chien-Wei Su, Yi–Hsiang Huang, Teh-Ia Huo, Hsuan Hui Shih, Jane Sheen, SuWen Chen, et al. Genotypes and Viremia of Hepatitis B and D Viruses Are Associated
With Outcomes of Chronic Hepatitis D Patients. Gastroenterology 2006;130:162535.
5. Erhardt A, Gerlich W, Starke C, Wend U, Donner A, Sagir A, Heintges T, et al.
Treatment of chronic hepatitis delta with pegylated interferon-a2b. Liver International
2006;26(7):805-10.
6. Gunsar F, Akarca US, Ersoz G, Kobak AC, Karasu Z, Yuce G, et al. Two-year
interferon therapy with or without ribavirin in chronic delta hepatitis. Antiviral
Therapy 2005;10(6):721-6.
7. Moatter T, Abbas Z, Shabir S, Jafri W. Clinical presentation and genotype of hepatitis
delta in Karachi. World J Gastroenterol 2007;13(18):2604-7.

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8. Modahl LE, Lai MM. The large delta antigen of hepatitis delta virus potently
inhibits genomic but not antigenomic RNA synthesis: a mechanism enabling
initiation of viral replication. J Virol 2000;74(16):7375-80.
9. Mumtaz K, Hamid SS, Adil S, Afaq A, Islam M, Abid S, et al. Epidemiology and
clinical pattern of hepatitis delta virus infection in Pakistan. J Gastroenterol Hepatol
2005;20(10):1503-7.
10. Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A, et al. Pegylated
interferon alpha-2b as monotherapy or in combination with ribavirin in chronic
hepatitis delta. Hepatology 2006;44(3):713-20.
11. Niro GA, Ciancio A, Tillman HL, Lagget M, Olivero A, Perri F, et al. Lamivudine
therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study.
Aliment Pharmacol Ther 2005;22(3):227-32.
12. Radjef N, Gordien E, Ivaniushina V, Gault E, Anais P, Drugan T, et al. Molecular
phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta
virus, suggesting a deltavirus genus of at least seven major clades. J Virol 2004;78:
2537-44.
13. Rosina F, Conoscitore P, Smedile A, Mangia A, Borghesio E, Martinotti R, et al.
Treatment of chronic hepatitis D with thymus-derived polipeptide thymic humoral
factor-gamma 2: a pilot study. Digest Liver Dis 2002;34:285-9.
14. Wolters LM, van Nunen AB, Honkoop P, Vossen AC, Niesters HG, Zondervan PE,
et al. Lamivudine high dose interferon combination therapy for chronic hepatitis B
patients co-infected with the hepatitis D virus. J Viral Hepat 2000;7(6):428-34.
15. Yamaguchi Y, Filipovska J, Yano K, Furuya A, Inukai N, Narita T, et al. Stimulation
of RNA polymerase II elongation by hepatitis delta antigen. Science 2001;293(5527):
124-7.
16. Yurdaydin C, Wedemeyer H, Dalekos G. A multicenter randomised study comparing

the efficacy of pegylated intereron alfa-2A plus adefovir dipivoxil vs. pegylated
intereron alfa-2A plus placebo vs. adefovir dipovoxil for the treatment of chronic
delta hepatitis: the intervention trial (HID-IT) (abstract). Hepatology 2006;41(Suppl
1):230A.


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19

Hepatitis B and
HIV Coinfection
Anil Arora, Naresh Bansal

INTRODUCTION
Hepatitis B Virus (HBV) and HIV-infection commonly occur together due to shared
modes of viral transmission. HBV/HIV coinfection is a major global health problem
as it carries high morbidity and mortality. Liver disease has emerged as a leading
cause of mortality amongst patients with HIV-infection following the introduction
of highly active anti retroviral therapy (HAART). Therefore, screening for
underlying HBV coinfection and appropriate management of liver disease is of
vital importance. With the introduction of new agents for the treatment of hepatitis
B and availability of drugs with dual activity against HIV and HBV, a substantial
amount of data has been published in the area of HBV/HIV coinfection in recent
years and a number of treatment guidelines have been published by various
associations or by key opinion leaders. However, there are potential shortcomings
in treatment strategies against HBV/HIV coinfection. This review will discuss
important issues in diagnosis and management of HBV/HIV coinfection.

EPIDEMIOLOGY
HBV coinfection is seen in 6-14% in HIV patients. Since the rate of clearance of
HBV varies according to the age of acquisition, the risk of coinfection depends
on patient’s age at the time of exposure to both viruses. Moreover, the rate of
spontaneous clearance of HBV in HIV patients is less than in immunocompetent
persons of similar age. The prevalence is higher among homosexual men and
intravenous drug users. In Asian countries the prevalence of HBV infection amongst
HIV-infected persons is higher (20–30%) than in western counterparts because
vertical and perinatal transmission of HBV is more common.
NATURAL HISTORY
Various studies have shown that HBV/HIV coinfected patients are at higher risk
for liver disease compared with those infected with either virus alone. Overall
mortality is also higher in coinfected patients as compared to those with HIV or
HBV alone. HBV DNA levels are higher in coinfection whereas alanine
aminotransferase (ALT) levels may not be elevated. Higher serum HBV DNA


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181

levels are associated with more rapid hepatic fibrosis progression and increased
risk of hepatocellular carcinoma (HCC). There is also increased incidence of
hepatotoxicity associated with anti retroviral drugs in patients with HBV/HIV
coinfection. The risk of liver disease related mortality is inversely related to the
CD4 cell count. The increase in liver related mortality may be the result of either
more severe liver disease or decrease in mortality from opportunistic infections
with introduction of HAART, which allows longer survival and the opportunity
for liver disease to progress.
PREVENTION OF HBV

Patients with HIV-infection if not immune, should be vaccinated against both
hepatitis A virus (HAV) and hepatitis B virus (HBV). Unfortunately, HIV patients
may have an impaired response to the HBV vaccine, especially in presence of
low CD4 count. Currently three doses of HBV vaccine at 0, 1 and 6 months or
two doses of combination HBV/HAV vaccine at 0 and 1 month are recommended.
Anti-HBs titer should be evaluated one month after the vaccination series has
been completed. In these patients, antibody titers are lower and less durable, and
fewer patients develop protective levels of antibodies against HBV. The rates of
response to HAV and HBV vaccines decrease with lower CD4 counts and higher
levels of HIV RNA. In a study, primary non-response to HBV vaccine in HIVinfected individuals was 30% as compared to 2.5% in healthy individuals. If the
primary series of vaccination fails to achieve protective anti-HBs levels, increased
number of doses or higher doses should be considered. The anti-HBs titer
(protective level >10 mIU/ml) should be confirmed yearly and a booster dose
should be given as and when required.
DIAGNOSIS
All patients with HIV-infection should be screened for HBV-infection. The optimal
screening strategy has not yet been defined but is usually based on the determination
of hepatitis B surface antigen (HBsAg) and anti-HBs. Testing for HBsAg and
anti-HBs, however, will not identify patients with occult HBV-infection who are
typically serologically positive for anti-HBc only. In this situation anti-HBc and
serum HBV DNA should be determined. A variable fraction (10–45%) of HIV
positive patients with an isolated positive test for anti-HBc have detectable levels
of HBV DNA, known as occult HBV infection. Such findings have lead to the
recommendations that all patients with HIV-infection should undergo testing for
HBsAg, anti-HBs and anti-HBc. If the test for HBsAg, anti-HBc or both are
positive, these patients should be tested for HBV DNA. Patients with positive
anti-HBc and negative HBV DNA should be vaccinated against HBV which may
have primary or anamnestic response similar to HIV-negative patients. Liver
enzymes such as ALT and aspartate aminotransferase (AST) may be deceptively
low or normal in coinfected patients. Hepatitis B e-antigen (HBeAg) is a marker