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Next Article 
Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1127-1136
REVIEW ARTICLE
Hepatitis Viruses and Hematopoietic Cell Transplantation: A Guide to
Patient and Donor Management
By
Simone I. Strasser and
George B. McDonald
From the Gastroenterology/Hepatology Section, Fred Hutchinson Cancer
Research Center and the University of Washington School of Medicine,
Seattle, WA.
 |
INTRODUCTION |
HEMATOPOIETIC CELL transplantation (HCT)
is performed annually in over 30,000 patients worldwide for a range of
underlying disorders including hematologic malignancy, severe aplastic
anemia, solid tumors, and genetic diseases.1 While the risk
of acquiring hepatitis virus infection from transfusion of blood
products is now extremely low, it is not uncommon for patients to come
to transplantation already infected with hepatitis viruses from past exposure. Particularly in endemic areas, potential hematopoietic cell
donors may also have evidence of hepatitis virus infection. Furthermore, there is a large group of long-term HCT survivors with
chronic hepatitis B and/or hepatitis C infection, many of whom
are unaware they are infected.
Clinical manifestation of hepatitis B and C infection are determined by
host-virus interactions. In both infections, hepatocellular damage
appears to be mediated primarily by host cellular immune responses.
Inflammatory and fibrogenic cytokines, released by infiltrating T
cells, potentiate inflammation, hepatocyte damage, and progression to
fibrosis. The marked immunosuppression and subsequent immune
reconstitution associated with HCT have the potential to significantly
impact the pathobiology of hepatitis virus infection. So that
appropriate management decisions can be made, it is important to
understand the impact of recipient and donor hepatitis virus infection,
on the short-term and long-term outcome of HCT.
| |
HEPATITIS B VIRUS |
Transplant candidates with hepatitis B infection.
Patients may come to HCT already infected with hepatitis B virus (HBV)
(see Table 1). These patients potentially
are at risk for venocclusive disease (VOD) and/or recurrent HBV
infection after transplantation. While transplantation is frequently
avoided or delayed in candidates with abnormal serum aminotransferases, a finding of positive hepatitis B surface antigen (HBsAg) alone is not
considered a contraindication and does not confer an increased risk for
VOD.2 However, preexisting cirrhosis or marked hepatic fibrosis does increase the risk of severe VOD and multiorgan failure and should be considered a contraindication to high-dose cytoablative therapy and HCT3 (G.B.M., unpublished observations).
Even in patients with very low levels of viral replication before
transplantation and relatively normal liver function and histology, the
impaired cellular immunity seen in the first 3 to 6 months after
transplantation can result in HBV reactivation, often with progressive
elevations in HBV levels in serum and liver. Reconstitution of cellular
immunity posttransplant often leads to a biochemical
hepatitis,4 however some patients rapidly develop acute
hepatitis and fulminant hepatic failure.5-8
The risk of fatal HBV liver disease among patients who are persistently
HBsAg-positive after transplantation is approximately 12%.5-12 Risk factors for an adverse outcome have not been
identified; however, fatal cases may be related to infection with a
precore mutant form of HBV.11,13,14 This variant HBV with
one or more nucleotide substitutions in the precore region of the
genome fails to produce hepatitis B e antigen (HBeAg); patients lack
HBeAg, are anti-HBe positive, but have circulating HBV
DNA.15 In hematopoietic cell transplant recipients who are
anti-HBc ± anti-HBs-positive, but HBsAg-negative, reactivation of
latent infection can occur and may lead to fulminant hepatic
failure.6,8,16-18
Thus, the following recommendations can be made when a patient is found
to be HBsAg positive before transplantation (Table 1). First, the
replication status of the virus should be determined. Patients should
be tested for HBeAg, anti-HBe and HBV DNA and have the level of HBV DNA
quantitated if positive. Patients with replicating, wild-type HBV will
usually be HBsAg, HBeAg, and HBV DNA positive. The presence of a
precore mutant form of HBV is suggested by the finding of a positive
HBsAg, HBV DNA and anti-HBe, and a negative HBeAg, and can be confirmed
by polymerase chain reaction (PCR)-based mutation
analysis19 or by direct sequencing. Pretransplant liver
biopsy to assess for the presence of fibrosis or cirrhosis is
recommended in patients with abnormal liver-associated enzymes or
clinical stigmata of chronic liver disease. Patients with active viral
replication, regardless of whether they have evidence of the precore
mutant form of HBV, should receive prophylactic antiviral therapy as
discussed below.
Donors with hepatitis B infection.
The most suitable stem cell donor for an HCT recipient may be infected
with HBV. The risks of using such a donor depend on the virological and
serological HBV markers present in both the donor and recipient (see
Table 1). Unfortunately precise risks are difficult to determine, as
the HBeAg, anti-HBe, and HBV DNA status of HBsAg-positive donors are
not always reported in the literature. These incomplete data, in part,
explain the apparent low frequency of transmission from HBsAg-positive
donors to recipients who have no serological markers of HBV infection.
Of 22 such cases, nine remained uninfected, three were only transiently
HBsAg positive, and 10 developed chronic HBV infection after
transplantation.7,20,21 The lack of HBV transmission from
many HBsAg-positive donors suggests either that the donors had no
active viral replication (or circulating virus) or that their
hematopoietic cells, a recognized site of HBV persistence, were not
infected by the virus.22,23
If a recipient has had prior exposure to hepatitis B and has cleared
the infection (ie, HBsAg-negative and anti-HBs-positive), there is an
even lower chance of acquiring HBV infection from a HBsAg-positive
donor. In series involving 14 such recipients, only one patient
developed transient HBsAg, and one became a chronic carrier.7,20,24 There are, however, reports of rapid
progression to cirrhosis and hepatic failure in anti-HBs-positive
recipients transplanted from HBsAg-positive donors.21,25
To summarize, there is clear evidence that HBV can be transmitted from
HBsAg-positive donors to either naive or anti-HBs-positive recipients.
The subsequent infection is more likely to have severe consequences if
the recipient has no serological markers of prior HBV infection. There
is a small risk of HBV transmission from a donor whose only serum
marker is a positive anti-HBc. Such donors may harbor latent HBV in
their liver,26 but are unlikely to be viremic or transmit
HBV through hematopoietic cell infusions, however, they should undergo
testing for HBV DNA (by PCR) to exclude the remote possibility of
viremia.27 The finding of negative HBV DNA by PCR in such a
donor's serum and hematopoietic cells should virtually eliminate the
risk of transmission of HBV. There is a negligible risk of transmission
from a donor who is anti-HBs and anti-HBc-positive.
These data suggest that a hepatitis B-infected individual can be used
as a hematopoietic cell donor, if no alternative donor is available.
Various strategies have been attempted to further reduce the risk of
viral transmission. Attempts to protect the recipient by either
prophylactic infusions of HB immune globulin7 or by active
immunization of the recipient28 have been unsuccessful, probably because of prolonged absence of T-cell-dependent B-cell responses after myeloablative therapy. Several antiviral agents have
been shown to be extremely effective in suppressing HBV replication. Treatment with interferon-alfa or nucleoside analogs such as lamivudine or famciclovir dramatically reduces circulating HBV DNA in most patients with chronic HBV infection.29-31 For instance,
lamivudine at 100 mg or 300 mg per day results in total suppression of
HBV DNA in 77% to 100% of patients by 3 to 6 months, with maximum suppression occurring within 2 weeks of starting
therapy.32,33 Consideration should be given to treating
HBsAg/HBV DNA-positive donors with antiviral therapy before
hematopoietic cell collection, although there are currently no data to
support this approach. Both lamivudine and famciclovir are
well-tolerated and do not cause significant myelosuppression, a
potential concern with the use of interferon.
Donors with immunity to hepatitis B.
Immunity to HBV can be transferred from anti-HBs-positive donors to HCT
recipients. Prolonged expression of anti-HBs has been documented in
recipients after transplantation from donors whose immunity followed
either natural infection or vaccination.34 In addition, the
posttransplant infusion of peripheral blood lymphocytes obtained from
donors who received hepatitis B vaccination after marrow donation has
resulted in prolonged expression of anti-HBs in the recipient, which
may be further boosted by subsequent immunization.35 There
are a number of reports of clearance of HBV infection after marrow
transplantation from anti-HBs-positive donors to HBsAg-positive recipients.9,36-38 Factors associated with sustained
clearance of HBsAg include having a donor who is anti-HBs-positive
after natural infection and negative pretransplant serum HBeAg and HBV DNA (by dot blot hybridization) in the recipient.38 In
these cases, loss of HBsAg is seen between 3 and 10 months
posttransplant; adoptive transfer of HBsAg-specific cytotoxic T
lymphocytes is probably responsible for seroconversion in the
recipients. Hepatitis B vaccination of a HBV-naive donor is probably
insufficient to effect viral clearance in a HBV-infected
recipient.39,40
The course of hepatitis B in the posttransplant period.
Posttransplant HBV infection may arise in a number of ways. Patients
may have active HBV infection before transplant or may reactivate
latent HBV infection. Infection may occur during the transplantation
process, either from an infected hematopoietic cell donor, or rarely
from infected blood products, a risk currently estimated in the United
States to be 1 in 63,000 units.41 In 1993 through 1994, three HCT recipients developed acute hepatitis B after receiving marrow
or peripheral blood stem cells infected by storage in a contaminated
cryopreservation tank.42
After cytoreductive therapy and before the return of cellular immunity,
there is usually no clinical or biochemical evidence of viral
hepatitis, although HBV DNA titers may increase to very high levels,
particularly in patients receiving corticosteroids, cyclosporine (CyA),
or other immunosuppressive drugs. This is in part because of
suppression of immune mechanisms that normally serve to control viral
replication, but in patients receiving corticosteroids, direct
transcriptional regulation of the HBV genome is also likely to be
important in increasing the level of viremia.43 At the time
of immune reconstitution or during tapering of immunosuppressive drugs,
a clinical flare of hepatitis may occur. In most cases, this flare is
manifest by a transient increase in serum aspartate aminotransferase
(AST) and alanine aminotransferase (ALT). Severe hepatitis with marked
elevations of AST and ALT may culminate in fulminant hepatic failure
and death in approximately 12% of HBV-infected transplant
recipients.5,18 Patients at particular risk for fulminant
hepatic failure are those harboring precore mutant
HBV.13,14 These patients remain HBeAg-negative despite high
levels of viral replication, reinforcing the necessity to monitor
HBsAg-positive patients with HBV DNA levels.
Progressive elevations of AST, ALT, and bilirubin at the time
immunosuppressive drugs are being tapered in a hepatitis B-infected allograft recipient may be due to hepatic graft-versus-host disease (GVHD), HBV, a herpesvirus infection, or drug-induced liver
injury.44 In this situation, liver biopsy should be
performed to determine the dominant pathologic process. Even in the
setting of marked thrombocytopenia, liver biopsy can be performed
safely by a transvenous approach, using either a forceps-style biopsy
instrument via the femoral vein or a needle via the jugular
vein.45,46 If the biopsy shows characteristic changes of
GVHD, then immunosuppression should be targeted to this disease, which
has the effect of also suppressing the immune response to HBV
infection. However, in the absence of antiviral therapy, this approach
will usually lead to increasing levels of viral replication, putting
the patient at further risk of a serious flare when the
immunosuppression is finally reduced.
Consideration should be given to the use of antiviral therapy as a
means of preventing progression to high levels of viremia and the risk
of a clinical flare of hepatitis when immunity is restored after HCT. A
number of nucleoside analogues have efficacy against HBV. These include
ganciclovir, famciclovir (and its active component, penciclovir), and
lamivudine. Ganciclovir has been used to manage hepatitis B in liver
transplant47 and renal transplant48 recipients,
however, it is not universally effective in suppressing HBV replication
and is myelosuppressive. In one reported HCT recipient, ganciclovir,
given for treatment of cytomegalovirus (CMV) disease, completely suppressed HBV DNA levels, although after ganciclovir was
discontinued, an abrupt increase in HBV DNA levels led to acute
hepatitis and liver failure.49 Both famciclovir and
lamivudine have been used in clinical trials of immunocompetent
patients with chronic HBV infection30,33 and for
prophylaxis and treatment of HBV infection in liver
transplant50,51 and renal transplant recipients.52 Both agents are very effective at suppressing HBV replication, however, their use has been associated with the emergence of drug-resistant variant viruses, which have mutations in
the HBV polymerase gene.53-56 The clinical impact of these
mutations remains to be determined, however, in one study of patients
treated with lamivudine after liver transplantation, breakthrough
hepatitis associated with a lamivudine-resistant mutant resulted in
only mild elevations of ALT levels.57 In the future, higher
doses of antiviral drugs or therapy with combinations of antiviral
drugs may well reduce the rate of emergence of variant
viruses.56
There is little experience in the use of antiviral therapy to control
HBV after HCT. Lau et al58 reported their experience with
the use of oral famciclovir, starting at least 1 week before marrow
transplantation and continuing for 24 weeks after transplantation. This
strategy reduced the incidence of posttransplant hepatitis due to HBV
compared with historical controls.58 An alternative approach is to carefully monitor posttransplant HBV levels in patients
at risk for HBV infection. Increasing levels of HBV DNA can usually be
detected as early as 1 to 2 weeks after transplantation and antiviral
therapy with famciclovir or lamivudine could be introduced at that
time. It is important not to wait until a clinical flare of hepatitis
has developed, before instituting antiviral therapy. This preemptive
approach appears to be effective in preventing HBV liver disease after
orthotopic liver transplantation,59 but has not been
reported in the HCT setting. The aim should be to completely suppress
viral replication to minimize the risk of viral mutation. The most
appropriate antiviral stategy (monotherapy v combination
therapy), drug dosage, and treatment duration are unknown at this time.
Based on the liver transplantation experience, anti-HBV therapy may
need to be continued long-term.
Chronic hepatitis B in long-term survivors.
The prevalence of chronic HBV infection among transplant survivors
varies widely around the world. Most of the series examining the
long-term effects of HBV infection are from Asia and southern Europe,
where the seroprevalence of hepatitis B in the general population is
high. The serologic patterns of HBV infection may be atypical in
transplant survivors, probably as a consequence of immunosuppression.
Clearance of antigenemia is commonly observed and is particularly
likely if the hematopoietic cell donor was anti-HBs-positive.6,9 Once they are stable and off all
immunosuppression, long-term survivors who remain HBsAg-positive
generally exhibit only mild liver disease.10 However, in
the presence of chronic GVHD and added requirements for
immunosuppressive drugs, patients with chronic HBV infection remain at
risk for acute flares of hepatitis whenever immunosuppression is
tapered or ceased.17 Such flares in activity may result in
hepatic failure and death. Cirrhosis due to chronic hepatitis B has not
emerged as a major problem in long-term survivors, although this may be
due to an inadequate period of follow-up.
| |
HEPATITIS C |
Transplant candidates with hepatitis C.
Before the introduction of routine blood donor screening for hepatitis
C, many patients with disorders such as hematologic malignancy,
aplastic anemia, or thalassemia, came to transplant already infected
with hepatitis C virus (HCV). For example, during 1987 to 1988, 32% of
patients presenting in Seattle for marrow transplantation for acute
myeloid leukemia had elevations of serum aminotransferases and
hepatitis C viremia.60,61 HCT centers continue to see
patients who acquired HCV infection either from a transfusion before
1991, or from other parenteral exposure, such as injecting drug use.
Serological testing for hepatitis C antibodies is inadequate for
exclusion of HCV infection among immunocompromised patients, such as
those with hematologic malignancy,62 therefore, at-risk
individuals should be assessed for the presence of viremia by PCR.
Transplant candidates who received blood products before 1991, who have
a history of injecting drug use or intranasal cocaine use, who have had
multiple sexual partners, who are spouses or close household contacts
of hepatitis C patients, or who have an elevated serum AST or ALT
levels should be tested for hepatitis C, with a PCR test for HCV RNA
performed in a reputable laboratory.
It is important to identify HCV-infected patients before
transplantation so that the severity of underlying liver disease can be
assessed and posttransplant abnormalities of liver function can be
interpreted. Assessment of disease severity should include physical
examination to identify signs of chronic liver disease, hepatosplenomegaly or portal hypertension, and review of laboratory values, particularly serum aminotransferase levels, serum albumin, and
prothrombin time. Liver biopsy should be considered in (1) patients in
whom there is a clinical suspicion of cirrhosis, (2) patients who are
likely to have had hepatitis C infection for more than 15 years and
have elevated serum aminotransferase levels, and (3) patients with
hepatitis C who have a history of excessive alcohol
intake.63,64 Patients with established cirrhosis or marked
hepatic fibrosis should not proceed to high-dose cytoablative therapy
and HCT because of the high risk of severe VOD, multiorgan failure, and
death3 (G.B.M., unpublished observations). Even in the
absence of cirrhosis, HCV infection may increase the risk of severe
VOD.65 The inclusion of pretransplant HCV RNA status in the
previously published multivariable analysis of risk factors for severe
VOD,61 identified hepatitis C infection associated with AST
elevation in the pretransplant period as a major risk factor for severe
VOD, with a relative risk of 9.6.66 Other investigators
have not found an association between HCV infection and an increased
incidence of severe VOD.67-69
The presence of chronic hepatitis C without cirrhosis is not considered
a contraindication to HCT,70 as the risk of severe VOD in
individual patients is difficult to predict, and in general, the
posttransplant course of hepatitis C is benign. Currently, there is no
effective way to treat HCV infection before transplant or in the
immediate posttransplant period. Interferon- is usually contraindicated at these times because of its myelosuppressive effects
and the possibility of inducing or exacerbating GVHD. Ribavirin has
been reported to result in clearance of HCV RNA in three marrow
transplant patients,71 a finding that is not supported in
studies of the use of ribavirin as a single antiviral agent in other
patients with chronic hepatitis C.72,73
Donors with hepatitis C infection.
Hepatitis C is universally transmitted from HCV RNA-positive allogeneic
or syngeneic donors to their recipients74 (see Table 1).
Recipients become viremic within days of hematopoietic stem cell
infusion, however they do not immediately develop clinical or
biochemical hepatitis, probably because of lack of cellular immunity
after myeloablation and transplantation.75 It is the general policy in Seattle to use hepatitis C-infected donors in preference to less well HLA-matched donors who are not HCV-infected, as
the risks of acute and chronic GVHD far outweigh those of HCV infection, at least in the 5- to 10-year period after
HCT.76 Transmission of HCV from an infected hematopoietic
cell donor to a recipient may be preventable by pretreatment of the
donor with interferon-alfa, so that serum HCV RNA is not detectable at
the time of harvest.77 It is our recommendation that if
time permits, HCV RNA-positive donors should be treated with
interferon- before marrow or peripheral blood stem cell harvest. The
dose and duration of interferon therapy that would be optimal in this setting is not known. The administration of 3 million units, 3 times a
week results in irradication of viremia at 6 months of treatment in
29% of patients with chronic HCV,78 with almost all
responding patients having undetectable viremia by 3 months.79 Suppression of HCV replication is
dose-dependent,80 so higher and daily dosing may be more
effective. The addition of ribavirin to interferon may increase the
chance of eliminating viremia. The presence or absence of viremia can
be monitored by PCR. Interferon should be stopped at least 1 week
before marrow harvest to avoid engraftment problems in the recipient.
However, complete irradication of hepatitis C infection in the donor
requires 6 to 12 months of antiviral therapy; therefore interferon ± ribavirin of the donor should be recommenced after hematopoietic
cell harvest.
The course of hepatitis C in the posttransplant period.
Regardless of whether patients come to HCT with preexisting HCV
infection20,81 or acquire infection around the time of transplant,74,82 clinical or biochemical evidence of
hepatitis is not seen in the immediate posttransplant period.
Asymptomatic elevation of serum aminotransferases in recipients of
allogeneic marrow does not occur until around days 60 to 120, coinciding with the return of cellular immunity and the tapering of
immunosuppressive drugs used for GVHD
prophylaxis.69,74,76,83-85 It might be expected that
clinical hepatitis may occur earlier in recipients of peripheral blood
stem cell transplants because of faster leukocyte
engraftment.86 As flares of GVHD can also be seen during
this time, it may be difficult to decide whether a flare of hepatitis C
or GVHD is responsible for the elevations of AST and ALT. The
differentiation of these two disorders is crucial, as GVHD of the liver
usually requires increased immunosuppression, while acute exacerbations of hepatitis C are self-limited and do not normally require specific therapy. The presence of hepatitis C viremia, even in high titer, is
insufficient to make the distinction between these two disorders. The
absence of hepatitis C viremia, however, means that HCV is not a cause
of AST/ALT elevations. Unless there is evidence of active GVHD in other
organs, a liver biopsy may be required before a therapeutic decision is
made. Pathologic distinction between hepatitis C and GVHD may be
difficult, as both processes may be associated with portal lymphoid
infiltration and bile duct injury, however, marked bile duct injury
with epithelial cell drop-out and loss of interlobular bile ducts is
more typical of GVHD.87-89 A flare of hepatitis C and
hepatic GVHD may occur simultaneously. If, on the basis of liver
biopsy, it is felt likely that both processes are present, patients
should receive immunosuppressive therapy for GVHD of the liver, as
ongoing lymphocytic attack leading to loss of interlobular bile ducts
may result in severe and progressive cholestasis.90
Fulminant immune-rebound hepatitis C has been reported only rarely
after HCT83 and chemotherapy withdrawal.91
Patients with known hepatitis virus infection who develop a rapid,
marked increase in serum aminotransferases at any time posttransplant, must also be fully evaluated for hepatic infection with viruses other
than hepatitis viruses. In particular, hepatitis associated with herpes
simplex virus, varicella zoster virus, or adenovirus, can result in
rapidly progressive liver failure if not recognized and treated
appropriately.44 Acute hepatitis can also be a
manifestation of chronic GVHD, particularly after immunosuppressive
therapy has been withdrawn.92 A rapid increase in
aminotransferase levels due to hepatitis C may occur uncommonly, but
usually does not progress to liver failure.76,93 In this
situation, reinstitution of CyA may lead to a reduction in serum AST
and ALT and may lessen the hepatocellular damage related to
infiltration with cytotoxic T cells. The role of antiviral agents, such
as ribavirin and interferon-alfa, has not been defined in this circumstance.
After the initial hepatitic flare with immune reconstitution, the AST
and ALT may again normalize, but often settle into a pattern of chronic
hepatitis seen in other patients with HCV
infection.68,76,94,95 Therapy directed at chronic HCV
infection should be considered once the patient has ceased all
immunosuppressive drugs and has no evidence of active GVHD.
Chronic hepatitis C in long-term survivors.
The prevalence of chronic hepatitis C in long-term HCT survivors ranges
from 5% to 70%, depending on the endemic
seroprevalence.76,94,96,97 Because of the high prevalence
of HCV infection in most countries, screening for hepatitis C infection
in all patients treated for hematologic malignancy before 1991 has been
advocated.96
Long-term survivors with HCV infection commonly have fluctuating levels
of AST and ALT; however, little impact on morbidity or mortality has
been observed in the first decade of follow-up.76 The
Seattle group has recently reported that patients in their second and
third decade of follow-up are starting to present with cirrhosis and
its complications.98 It is anticipated that with longer
duration of follow-up, cirrhosis may emerge as an important late
complication of marrow transplantation. Perhaps because of specific
transplant-related factors such as myeloablation, immunosuppression, and iron overload, the rate of progression to cirrhosis after marrow
tranplantation seems to be accelerated in comparison to immunocompetent
patients with posttransfusion hepatitis C.64 The rate of
progression is comparable to that seen in HIV-infected individuals with
fluctuating immunity, but slower than seen in hypoglobulinemic patients
or some liver transplant recipients.99-103
To prevent progression to cirrhosis, antiviral therapy should be
considered in any long-term HCT survivor with chronic hepatitis C
infection. Interferon-alfa can be safely administered to patients who
have been off all immunosuppressive agents for at least 6 months and
have no evidence of GVHD or myelosuppression.76,104,105 While experience is limited, response rates to interferon-alfa appear
no different from those seen in nontransplant patients with hepatitis
C. A recent meta-analysis of all available randomized clinical trials
of interferon alfa-2b in patients with chronic hepatitis C demonstrated
an overall biochemical response that was sustained for at least 6 months after completing therapy in 23% of treated patients and a
sustained virologic response in only 8%.78 When
interferon-alfa is given in combination with oral ribavirin, sustained
virologic response rates of 40% to 50% have been
observed.106-108 Use of combination therapy has not been reported in HCT survivors with chronic hepatitis C, although patients with genotype 1 and with a higher viral load (both features commonly present in long-term survivors of HCT) are more likely to achieve a
sustained response with combination therapy than with interferon alone.108 In May 1998, the US Food and Drug Administration
(FDA) approved a combination of interferon-alfa 2b plus ribavirin for patients with chronic hepatitis C who have relapsed after receiving interferon monotherapy. Recent controlled clinical trials also support
the use of combination therapy in previously untreated patients. It
should be noted that ribavirin therapy is commonly associated with the
development of hemolytic anemia, therefore patients with preexisting
anemia or underlying coronary artery disease should not be treated.
Ribavirin is a teratogen in animals, and female patients should not
become pregnant while taking ribavirin, or for at least 6 months after
discontinuing therapy. Nonribavirin containing alternative strategies
associated with higher response rates than standard interferon
monotherapy include higher or daily doses of
interferon-alfa,78 or the use of consensus interferon (interferon alfacon-1), which was licensed by the FDA in
1997.109,110
In patients with concomitant iron overload, phlebotomy or chelation
therapy to reduce hepatic iron stores should be considered before
interferon therapy; mobilization of liver iron may increase the chance
of response.111 Hepatitis A vaccination should be offered
to all long-term survivors of HCT with chronic viral hepatitis, because
of an increased risk of fulminant hepatitis should they develop acute
hepatitis A.112,113 Hepatitis A vaccination is safe and
illicits an immune response in at least 94% of patients with chronic
liver disease.114
| |
HEPATITIS G VIRUS |
Hepatitis G virus (HGV), also referred to as GB virus-C or hepatitis
virus GB-C, is a recently identified member of the flaviviridae family
of viruses and shares significant homology with HCV. HGV RNA is found
in 1.5% to 4% of routine blood donors115-117 and is readily transmitted by blood product transfusion.118 HGV
RNA has been identified in serum of 31% to 65% of hematopoietic cell transplant recipients,119-121 most likely related to
transfusion of contaminated blood products. However, accumulated
evidence suggests this virus is not hepatotropic122 and has
no role in either acute or chronic liver disease,123-127
including after HCT.120,121 Some extrahepatic disease
processes, including aplastic anemia, may be associated with HGV
infection,128 although this association remains
controversial.129
| |
CONCLUSIONS |
Much is now known of the impact of hepatitis B and hepatitis C on the
process of HCT. Compared with HCV, hepatitis B is more likely to result
in severe clinical hepatitis and death from posttransplant liver
disease, although these outcomes occur only in the minority of
HBV-infected patients. Hepatitis C infection is a risk factor for VOD
of the liver, but otherwise, has little short-term impact on outcome
after HCT. In the long-term, however, HCV infection may prove to be a
significant cause of morbidity and mortality, as some infected patients
gradually progress to cirrhosis and liver failure. It is, therefore,
important to screen all transplant candidates and donors for HBV and
HCV infection so that appropriate counselling and management can be
undertaken. Liver biopsy may be required before transplantation in
potential HCT recipients found to have HCV or HBV infection, so that
the severity of underlying liver disease can be considered when making
decisions about transplantation regimens to be used. Appropriate
guidelines for the use of antiviral therapies in the setting of HCT
have not been established, however, with the availability of potent
HBV-suppressive agents, the potential exists to significantly alter the
natural history of HBV infection during the periods of profound
immunosuppression and immune recovery. Antiviral treatment should be
considered for all HBV- and HCV-infected survivors of HCT unless
specific contraindications are present.
| |
ACKNOWLEDGMENT |
The authors are grateful to Drs Larry Corey and Robert Carithers for
their critical review of this manuscript.
| |
FOOTNOTES |
Submitted July 14, 1998; accepted September 30, 1998.
Supported by Grants No. CA15704 and CA18029 from the National
Institutes of Health.
Address correspondence to George B. McDonald, MD,
Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research
Center, 1100 Fairview Ave N (D2-190), PO Box 19024, Seattle WA
98109-1024.
| |
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