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Hepatology Highlights
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Hepatology, January 2003, Volume 37, Number 1
Harvey J. Alter, Viral Hepatitis Editor
--HBV and Genotypes: disease progression, sustained response to therapy
--Spontaneous Anti-Hbs After Liver Transplantation: a New Adoption Clinic
--HBV Superinfection in Chronic Hepatitis C
--Extrahepatic Manifestations of HCV
--Steatosis (fat in the liver) With HCV Genotype 3
--Funding available for HCV research from the NIH
--HCV vaccine research
--spontaneous viral clearance in patients with acute HCV can be predicted by
viral load
HBV and Genotypes: sustained response to therapy, disease progression
HBV can now be sequenced into 7 major genotypes designated A to G. Two recent
studies among Chinese and Japanese subjects indicate that genotype B disease
has a slower progression and a better treatment response than the more common
genotype in these populations, genotype C. Sumi et al. found that among 254
patients with biopsy-proven chronic liver disease, genotype B patients were
significantly less likely to be HBeAg+ (43% vs. 71%) or to have stage 3 or 4
fibrosis (13% vs. 33%) compared with genotype C patients. Similarly, the
cumulative rate of anti-HBe seroconversion was significantly greater for
genotype B cases (53% vs. 26% at 2 years). Stepwise multivariate analysis
showed that HBV genotype was an independent predictor of HBe seroconversion.
Of note, the beneficial effect of genotype B was observed only in patients
<45, and patients who had advanced disease related to genotype B were
significantly older than those of genotype C. This suggests that although
patients with genotype B have earlier HBe seroconversion and slower
progression to advanced fibrosis or HCC, the life-long risk of these
deleterious outcomes may not differ among genotypes. This implies that
disease progresses, albeit more slowly, even after HBe seroconversion and
that the clinical advantage of genotype B may be overcome with increased
duration of infection.
Wai et al. provide evidence for a different advantage of genotype B, namely
an improved sustained response to IFN. In a retrospective analysis of a
previously reported clinical trial, it was shown that the IFN response rate
(loss of HBV DNA by hybridization assay or loss of HBeAg at 6 months) was 39%
for HBV genotype B patients and 17% for genotype C patients (P = .03); among
patients with elevated pretreatment ALT, the relative response rates by
genotype were 57% vs. 21% (P = .019). Importantly, multivariate analysis
showed HBV genotype B to be an independent predictor of treatment response
similar to that of pretreatment ALT elevation and low pretreatment HBV DNA
level. It is recommended by the authors that stratification for HBV genotypes
should be considered in future clinical trials of antiviral therapy and this
seems very reasonable. Both of these studies show that precore mutations
(A1896) are more common in genotype B patients, and although this adds
complexity to the interpretation of HBeAg loss, I am taking the message from
these two studies that it is better to be B than not to be B when it comes to
HBV. (HEPATOLOGY 2003;37:19-26 and 2002;36:1425-1430.)
Spontaneous Anti-Hbs After Liver Transplantation: a New Adoption Clinic liver
The spontaneous appearance of anti-HBs in patients transplanted for end-stage
hepatitis B has not been previously reported and would not be expected since
most patients receive passively administered HBIG or have recurrent HBsAg
that would complex and mask any surface antibody produced. Lo et al. now
report on 50 patients who received lamivudine monotherapy before and after
transplantation, thus suppressing HBV DNA/HBsAg without adding passive
antibody. In this transplant setting, 21 of 50 (42%) recipients had evidence
of active anti-HBs production that increased in titer over time and that
lasted for a median of >200 days and >12 months in 4 of 10 who were followed
long-term (>34 months in 1). The fascinating part of this study is that in
every instance of spontaneous anti-HBs production, the transplant donor was
anti-HBs positive and by logistic regression analysis, donor anti-HBs status
was the only predictor of recipient antibody response. The logical
explanation therefore is that transplanted donor lymphocytes at least
temporarily engrafted resulting in a chimeric state with beneficial
consequences. Thus, individuals who have recovered from HBV infection are not
only acceptable liver transplant donors, but they are particularly
advantageous donors in the setting of nucleoside monotherapy. It is
intriguing to speculate that the chimeric state might be prolonged or
intensified by boosting anti-HBs production in the donor by predonation HBV
vaccination. Additionally, with lamivudine-induced viral suppression, the
recipient may regain HBV immunocompetence and respond to posttransplantation
HBV vaccine, adding adaptive immunity to the transplanted adoptive immunity.
(HEPATOLOGY 2003;37:36-43.)
HBV Superinfection in Chronic Hepatitis C
This study in Italy enrolled 44 consecutive patients who were hospitalized
with acute hepatitis B. The patients were predominantly drug addicts, and 21
were known to have been previously infected with HCV (anti-HCV+ >1 year). The
serologic and virologic course of hepatitis B was the same in patients who
were infected with HBV alone or had HBV superimposed on HCV, except for more
rapid seroconversion to anti-HBe in the latter. In contrast, the virologic
course of chronic hepatitis C was markedly influenced by superimposed HBV
infection. HCV RNA was, or soon became, undetectable in all 21 coinfected
patients, whereas it was present in 86% of those infected with HCV alone.
Thus, HBV infection severely repressed HCV replication and strikingly, the
repression continued even after HBV clearance such that of 13 coinfected
patients, 6 remained HCV RNA negative >6 months after HBsAg clearance. In 3
patients acutely infected with both agents, again HBV ran its typical course,
but the onset of HCV viremia was delayed until HBV was cleared. Lastly, the
acute hepatitis was considerably more severe when HBV was superimposed on
HCV; a severe clinical presentation (portosystemic encephalopathy or ascites
or PT <25%) occurred in 29% of B and C coinfected patients and none of those
acutely infected with B alone. The potential severity of superimposed HBV
infection provides rationale for vaccinating all HCV carriers if possible,
but particularly those who continue high-risk behaviors or reside in HBV
endemic areas. (HEPATOLOGY 2002;36:1285-1291.)
Extrahepatic manifestations of HCV
Extrahepatic manifestations of HCV have been well documented, but rarely have
they been studied in as comprehensive, long-term and unselected manner as in
the VA hospital-based case-control study reported by El-Serag et al. These
investigators analyzed the ICD-9 codes of 34,204 HCV-infected patients
admitted to 172 VA hospitals between 1992 and 1999, as well as 136,816
controls without HCV matched on year of admission. Although the study is
limited by the accuracy of ICD-9 coding and its limitation to hospitalized
patients, the numbers assessed are astounding and the data very relevant. In
a multivariate logistic regression analysis, the extrahepatic diseases
strongly associated with HCV were membranoproliferative GN (OR 4.5) but not
membranous GN, lichen planus (OR 2.3), porphyria cutanea tarda (OR 9.3), and
cryoglobulinemia (OR 14.7). There was a very weak association with
non-Hodgkin's lymphoma. What this study does best is not just solidify these
relationships that are already known, but put them in the perspective of
their frequency in HCV infection. Thus, membranoproliferative GN was seen in
only 0.33% of HCV-infected patients, lichen planus in 0.3%, PCT in 0.77%, and
cryoglobulinemia in 0.57%. Hence, in composite, these four major extrahepatic
manifestations of HCV infection were seen in no more than 2% of patients.
Milder, undiagnosed forms of these entities may exist in a larger proportion
of patients, but may not be clinically relevant. (HEPATOLOGY
2002;36:1439-1445.
Editorial note from Jules Levin: just because there may be an association
between having HCV and patients experiencing conditions outside the liver,
thisdoes not necessarily mean HCV is present in these other parts of the
body. It is uncertain whether HCV is present in these other parts of the body
or if these extrahepatic manifestations of HCV are due to immune dysfunction
caused by HCV which in turn affects other parts of the body causing specific
conditions. Some studies have been conducted finding HCV outside the liver
suggesting that HCV can be outside the liver in other areas of the body but
the methodology used in the studies have been questioned and the study
authors themselves often say these results need confirmation. Further study
of this question is ongoing.
Steatosis (fat in the liver) and Genotype 3
Although steatosis has long been known to be a concomitant of non-A,
non-B/HCV infection, only recently has a specific association with HCV
genotype 3 been recognized. Kumar et al. hypothesized that if the steatosis
was a direct effect of the genotype 3 virus, it should disappear after
treatment-induced viral clearance of genotype 3, but not genotype 1. They
identified patients of genotype 1 and 3 who had equal amounts of hepatic fat
pretreatment as determined by conventional semiquantitative biopsy scoring
and computer-assisted morphometric image analysis. Patients with nonviral
causes of steatosis were reasonably excluded. The findings supported their
initial hypothesis in that a sustained viral response in type 1 infection had
no effect on steatosis, whereas a sustained response in type 3 infection was
accompanied by a significant reduction in steatosis. Convincingly, type 3
patients who did not have a virologic response had no change in steatosis
level. In a comprehensive logistic regression model, the only independent
predictor of steatosis reversal was a sustained virologic response in type 3
infection (OR 36, P = .007). The genotypic/phenotypic configuration of the
type 3 HCV genome that accounts for this steatotic effect is unknown, but
should be amenable to study. This year's Postgraduate Course at AASLD
included brilliant lectures on the mechanisms of steatosis in NASH and
alcoholic liver disease with emphasis on intracellular cascades that result
in excessive lipid peroxidation, the generation of ROS, and perturbations in
both the production and export of intrahepatic lipid. Perhaps HCV genotype 3
taps into these mechanisms in unique ways distinct from other HCV genotypes.
(HEPATOLOGY 2002;36:1266-1272.)
Funding Available for HCV Research
Hepatitis C is now the most common cause of chronic liver disease, cirrhosis,
and hepatocellular carcinoma in the United States and most of the Western
world. Since the identification of the hepatitis C virus (HCV) 13 years ago,
there has been an explosion of knowledge about this virus and the disease
that it causes. Important discoveries and developments in the field include
the sequencing and characterization of the RNA genome, isolation and
definition of function of the major polypeptides of HCV, the definition of
the regulatory nontranslated regions of the genome, the development and
application of a cell-culture replicon system for HCV, the description of
several small animal models of infection, the development of sensitive and
specific diagnostic tests for viral RNA as well as antigen and antibody for
clinical use, the delineation of immune responses to HCV antigens and their
correlation with clinical outcomes, insights into the natural history of
acute and chronic hepatitis C and its major complications including fibrosis
and carcinogenesis, and development of therapies for chronic hepatitis C that
are effective in at least half of treated patients. Many of these advances
were presented at the recent National Institutes of Health (NIH) Consensus
Development Conference entitled "Management of Hepatitis C: 2002" which was
held June 10-12, 2002 and the proceedings of which were published in a
November 2002 Supplement to HEPATOLOGY.
Although there have been many advances in hepatitis C research, there are
just as many gaps in our knowledge about this virus and disease. The needs
for future research in hepatitis C were defined at the recent Consensus
Conference and are delineated in detail in the panel statement, as well as at
the end of each of the 28 articles in the proceedings. In response to these
needs, the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) has published a "Request for Applications" (RFA: 03-DK-011) for
investigator-initiated research grant applications in the area of hepatitis
C. Importantly, this RFA was cosponsored by several other institutes and
centers at the NIH, including the National Cancer Institute (NCI); National
Institute of Allergy and Infectious Diseases (NIAID); National Institute on
Alcoholism and Alcohol Abuse (NIAAA); National Institute on Drug Abuse
(NIDA); National Heart, Lung, and Blood Institute (NHLBI); and the Office of
AIDS Research (OAR). A similar RFA on hepatitis C was published after the
1997 NIH Consensus Development Conference, which led to the funding of 29 new
research project grants at a total cost of over $8.5 million yearly. The
current RFA is likely to provide a similar increase in amount of funding,
although the absence of a final budget for the NIH at the time of publication
did not allow for the commitment of specific amounts of funding. Both typical
research project grants (R01s for up to $250,000 direct costs per year for 5
years) and innovative and exploratory research grants (R21s for no more than
$100,000 direct costs each year for 2 years) are requested. Areas of
importance given in the text of the RFA include basic virology, cell culture,
animal models, vaccine development, immunology, pathogenesis, epidemiology,
natural history, and therapy. The full text of the RFA will be available on
the Web at http://www.niddk.nih.gov/fund/crfo/rfas.htm#1. The receipt date
for applications is March 17, 2003, and grants will be awarded in September
2003.
HCV vaccine research
We have previously described the generation of hepatitis C virus-like
particles (HCV-LPs) in insect cells and shown that immunization with HCV-LPs
elicited both humoral and cellular immune responses in mice. To further
characterize the HCV-LPs as a vaccine candidate, we evaluated the effects of
adjuvant AS01B (monophosphoryl lipid A [MPL] and QS21), CpG 10105, and the
combination of the 2 adjuvants on the immunogenicity of HCV-LPs in AAD mice
(transgenic for HLA-A2.1). All HCV-LP-immunized mice (with or without
adjuvant) developed high titers of anti-HCV E1/E2 antibodies after 4
injections intramuscularly. However, antibody titers in mice immunized with
HCV-LP plus AS01B, plus CpG 10105, or plus the combination of AS01B and CpG
10105 were 4, 3, and 10 times higher, respectively, than that of HCV-LP
alone. Isotype analysis of the induced anti-envelope antibodies showed that
HCV-LP alone induced a predominant immunoglobulin (Ig) G1 response. In
contrast, when the 2 adjuvants AS01B and CpG 10105 were combined, the
response became predominantly IgG2a whereas HCV-LP plus AS01B or CpG 10105
gave a mixed IgG1 and IgG2a response, indicating that AS01B and CpG 10105
promote a more T-helper type 1 (Th1) response and that combining the 2
adjuvants results in an additive or synergistic interaction. These
observations were further confirmed by the results of CD4+ enzyme-linked
immunospot assay for interferon (IFN)- and interleukin (IL)-4 and
intracellular cytokine staining of IFN- producing CD8+ cells. In conclusion,
HCV-LP is a promising vaccine candidate against HCV infection and the
adjuvants used are potent immune enhancers for this approach. (HEPATOLOGY
2003;37:52-59.)
Spontaneous viral clearance in patients with acute hepatitis C can be
predicted by repeated measurements of serum viral load
Early interferon (IFN) therapy prevents viral persistence in acute hepatitis
C, but in view of the resulting costs and morbidity patients who really need
therapy have to be identified. Twelve consecutive patients with acute
hepatitis C (9 women, 3 men, mean age: 39.5 ± 18.8 y, genotype 1: 7, genotype
3a: 3, 2 could not be genotyped) were studied. The sources of infection were
medical procedures in 6, sexual transmission in 3, and intravenous drug abuse
in 3 patients. Viral load was measured by Cobas Amplicor HCV Monitor v2.0
(Roche Diagnostic Systems, Branchburg, NY). The time from infection to
clinical symptoms was 43.3 ± 8.6 (mean ± SD) days. Eight patients cleared
hepatitis C virus (HCV) spontaneously and remained HCV-RNA negative with a
follow-up of 9.0 ± 3.9 months. In these patients viral load declined fast and
continuously. The time from exposure to HCV-RNA negativity was 77.4 ± 25.3
and from the first symptoms was 34.7 ± 22.1 days. In 4 patients HCV-RNA
levels remained high or even increased. Two of them became sustained
responders to treatment initiated after a 6-week observation period. The 2
remaining patients were not treated (one because of contraindications for
IFN, the other declined therapy) and are still HCV-RNA positive. In
conclusion, patients with acute icteric hepatitis C have a high rate of
spontaneous viral clearance within the first month after the onset of
symptoms. IFN therapy appears only needed in patients who fail to clear the
virus within 35 days after onset of symptoms. By this approach, IFN therapy
was not necessary in two thirds of patients with acute hepatitis C.
(HEPATOLOGY 2003;37:60-64.)
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