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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.)
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