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Hepatology Highlights
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.)
Treating Hard To Treat Patients
Reported by Jules Levin
Some groups of individuals with chronic hepatitis C do not respond to
therapy with interferon plus ribavirin as others and these include: previous
non-responders to combination therapy of interferon plus ribavirin,
African-Americans, and patients with genotype 1. Here are studies that
explored experimental ways to perhaps improve treatment responses using
interferon in a non-traditional way.
There were several studies presented at AASLD and the Viral Hepatitis
Workshop meeting just prior to AASLD suggesting ways to improve response
rates in non-responders and hard to treat patients, but these were pilot
studies and the approaches are relatively experimental. The RENEW study gave
patients double the dose of PegIntron and found better preliminary viral
responses but we don't have data yet following patients after stopping
therapy, see data below. Another experimental approach was suggested by a
study presented at the Viral Hepatitis Workshop and the data is on the
website in the Conference Reports section, see data below. They found better
responses by using interferon for a day and then starting peginterferon on
the second day. The theory is to achieve better viral response in first day
by using standard interferon. They used Consensus Interferon in this study.
There are no other studies I know of on this subject so it has not really
been explored yet. Perhaps some combination of daily interferon up front
plus peginterferon might increase response rates in hard to treat patients
including non-responders.
RENEW Study: treating previous nonresponders to IFN + RBV
In the RENEW study reported on here previous nonresponders to interferon
plus ribavirin were randomized to 1 year of retreatment with PegIntron 0.5 ,
1.5, or 3.0 mcg/kg/week each with ribavirin 12-15 mg/kg/day. Treatment doses
are reduced by 33% if necessary. 800 patients are being enrolled but after
week among 195 that have been enrolled HCV RNA was undetectable in 235 of
patients receiving 0.5 PegIntron, 39% receiving 1.5 dose, and 53% receiving
3.0 PegIntron dose. These are preliminary data but so far The rate of
response appears to be related to dose and high dose of PegIntron 3.0
mcg/kg/week is yielding better responses. Dose reduction occurred in 22/132
in the 0.5 dose group, 24/213 in the 1.5 group, and 33/213 in the 3.0 group
showing not much difference. Discontinuation rates were also similar.
Regarding discontinuation just for adverse event 5 in the 1.5 and 9 in the
3.0 group discontinued. We need to wait for more data but raising
peginterferon dose presents another possible option for dealing with
nonresponders and other hard to treat patients.
Interferon Plus Pegylated Interferon
There was an interesting pilot study presented here by a Brazil research
group (abstract 36) that raises a question I feel is worthy. They used
Consensus Interferon (CIFN) in this study but I think that any interferon
could be used. The notion is that starting therapy with interferon for a day
or more and then using pegylated interferon may yield better results for
hard to treat patients such as genotype 1, previous non-responders, and
HIV-infected patients. This approach is experimental and needs further study
and refinement. For example, do you use one or two days of a daily dose of
interferon and how much do you use? Do you then use pegylated interferon on
the following day or do you start both together? Although this concept makes
sense I'd like to see studies showing it improves the sustaimed response. An
initial loading dose of interferon may improve the initial reduction in
viral load but studies need to explore if the sustained response rates are
improved.
The purpose of this study was to analyze early HCV viral load decrease
after CIFN on the first day followed by 180 ug of peg-IFN/weekly + 1000 mg
of ribavirin per day. HCV RNA was determined by qualitative and/or
quantitative PCR (Amplicor Roche Monitor) pre-treatment, 24 hour and at
weeks 2, 4, and 12. 5 patients, a small study, were treated with 24-30 ug of
CIFN on the first day followed by peginterferon. The researchers reported
that the median HCV viral loads at pretreatment were 6.3 log and 4.2 log
after 24 hours (after the initial CIFN dose). At week two the median HCV RNA
viral load was 2.1 log and it was 2.5 log at week 4. At weeks 2 and 4, 2/5
and 2/5 patients had negative viral load, respectively. The researchers
concluded that the use of a "fast acting" interferon (CIFN) at the first day
of treatment resulted in a profound viral load decrease in 24 hours. All
patients showed an absolute count less than 5 log, including a decrease of
more than 1.7 log (mean drop 2.1 log) in all but one patient. In the opening
session in a talk on viral load kinetics after starting HCV therapy, Avidan
Neumann (a noted HCV viral kinetics researcher), also suggested that for
some hard to treat patients such as non-responders or genotype 1 using a
brief loading dose approach with daily interferon may help improve
responses.
New Drugs
At AASLD the first study in the first HCV protease inhibitor was
presented. Boerhinger Ingleheim reported that patients with chronic HCV
achieved potent 2-3 log drops after 48 hours of receiving this drug as
monotherapy. This was a phase I study and followup studies are planned to
begin in early 2003. Several companies are trying to develop polymerase
inhibitors for HCV. Phase I study of 1 polymerase inhibitors has started.
The availability of these drugs are several years away if they are able to
pass through the difficulties of drug development. Safety issues do
sometimes occur and drugs need to be proven effective. Some researchers feel
peginterferon will have to be used in combination with these new drugs but
research has not yet gotten that far with the new drugs.
Maintenance Therapy
Many studies show interferon has the ability to slow or stop liver
inflammation and fibrosis for some patients. For patients unable to achieve
sustained viral responses and who have advanced liver disease interferon
maintenance therapy utilized usually a half dose is an important option to
consider until new drugs become available. Two large studies are ongoing,
Copilot and HALT-C, two prove more firmly the effectiveness of maintenance
therapy.
Source: www.natap.org
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