Focus

Abstract

It is a great pleasure to join my colleague and friend, Professor Daniel Shouval in contributing to the Focus feature in this journal. The opportunity to share with the readership some of the great advances in our specialty, while injecting a little perspective and occasional humor is tremendously satisfying. I will do my best to match Dani’s wonderful qualities of wisdom, breadth, and balance, and appreciate the vote of confidence in me by the leadership of the Journal of Hepatology and EASL. In this, my first article, I would like to highlight some ups and downs within this month’s issue. By now most readers appreciate the importance of the discovery that genetic polymorphisms in the IL28B gene influence the likelihood of spontaneous clearance and response to interferon/ribavirin therapy in HCV infection [[14]Thomas D.L. Thio C.L. Martin M.P. Qi Y. Ge D. O’Huigin C. et al.Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.Nature. 2009; 461: 798-801Crossref PubMed Scopus (1809) Google Scholar]. These findings not only heralded a breakthrough for management of HCV, but also vaulted hepatology into the lead as a specialty whose clinical decision-making is being driven by the impact of genetic variation. Moreover, the finding has led to new insights about the vulnerabilities of HCV and has accelerated the emergence of new therapies. In the meantime, given the high response rate to conventional interferon/ribavirin in genotype 3, it is reasonable to ask whether we can use the IL28 genotype to ratchet up the sustained virologic response rate (SVR) even further, or refine therapy in these patients. We already have indications that patients with low BMI who lack severe fibrosis may achieve SVR in as little as 12 weeks if they are young and have a rapid virologic response (RVR) [7Lagging M. Langeland N. Pedersen C. Farkkila M. Buhl M.R. Morch K. et al.Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection.Hepatology. 2008; 47: 1837-1845Crossref PubMed Scopus (155) Google Scholar, 8Mangia A. Thompson A.J. Santoro R. Piazzolla V. Tillmann H.L. Patel K. et al.An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response.Gastroenterology. 2010; 139 ([827, e821]): 821-827Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar], so it makes sense to keep pushing the envelope on shortening duration of therapy in this genotype. In this issue, Scherzer and colleagues from Vienna have explored the impact of IL28 polymorphisms on the response to interferon/ribavirin in 69 patients with HCV genotype 3. The study follows reports emphasizing that even in this ‘permissive’ C/C genotype, an RVR is still a strong predictor of SVR, and since favorable IL28B genotypes increase RVR rates, the authors asked whether these genotypes might increase the RVR and thereby achieve a higher SVR. The answers are “yes” and “no”. That is, RVR was more likely in patients with the permissive C/C genotype than in those with the T allele, but this did not translate into a higher SVR. Almost all patients (97%) had undetectable virus at the end of treatment yet SVR dropped to 74%, independent of genotype and ribavirin dose. While the authors have not addressed whether the lack of difference could reflect a type II error due to a small sample size [[5]Freiman J.A. Chalmers T.C. Smith Jr., H. Kuebler R.R. The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. Survey of 71 “negative” trials.N Engl J Med. 1978; 299: 690-694Crossref PubMed Scopus (1261) Google Scholar], the findings reinforce the notion that the IL28B genotype exerts its primary effect during treatment in accelerating the viral decline, not in sustaining an aviremic state. Developing an RVR remains the key to successful shortening of therapy duration. However, we may have gone as far as we can in achieving SVR in genotype 3 patients using current therapy, and the next frontier will be determining the impact of direct-acting antivirals in this population. We are currently faced with a challenging public health paradox in viral liver disease. The introduction of effective antiviral therapies and widespread vaccination programs for hepatitis B are generating declines in morbidity and the need for liver transplantation, while the aging of the chronically infected hepatitis C cohort presages an impending spike in end-stage liver disease and hepatocellular carcinoma in the coming years [[3]Davis G.L. Alter M.J. El-Serag H. Poynard T. Jennings L.W. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression.Gastroenterology. 2010; 138 (521, e511–e516): 513-521Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar]. In the United States, at least, the response to the viral hepatitis threat has been woefully inadequate, underscored by a Report from the Institute of Medicine of the National Academy of Sciences last year that decried a lack of knowledge and awareness about viral hepatitis, inadequate surveillance, and insufficient resources, among several deficiencies [[9]Mitchell A.E. Colvin H.M. Palmer Beasley R. Institute of medicine recommendations for the prevention and control of hepatitis B and C.Hepatology. 2010; 51: 729-733Crossref PubMed Scopus (154) Google Scholar]. It’s instructive, therefore, to turn to population studies, both to project better the burden of disease going forward, and to learn what interventions, if any, have bent the curve of rising mortality and health care costs due to viral hepatitis. With that in mind, the study in this issue by Walter and colleagues from Australia, offers some important findings to inform efforts addressing the public health impact of chronic viral liver disease. The investigative team, led by Gregory Dore, examined trends in mortality following the diagnosis of HBV or HCV over a 14 year interval from 1992 to 2006 based on a public health registry in New South Wales, the most populous state in Australia, where notification of HBV, HCV, and HIV is mandatory. Focusing on a study from Australasia has unique resonance, since this region has an especially enlightened approach to understanding and treating viral liver disease, as evidenced by the biennial Australasian Viral Hepatitis Conference, which combines programming in equal proportions from Community and Social Research, Epidemiology and Public Health, Clinical Medicine, and Basic Science (http://www.hepatitis.org.au/default.asp?active_page_id=1). The Walters paper is a follow-up to an earlier study that had reported increased mortality from both HBV and HCV; whereas deaths from HBV were largely resulting from liver disease, HCV deaths were more likely due to drug use and related illnesses, than specifically from liver disease [[1]Amin J. Law M.G. Bartlett M. Kaldor J.M. Dore G.J. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study.Lancet. 2006; 368: 938-945Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar]. This difference between HBV and HCV underscored the more complex social milieu surrounding acquisition of HCV, which may involve high-risk behaviors and poor social support [[12]Roy E. Nonn E. Haley N. Cox J. Hepatitis C meanings and preventive strategies among street-involved young injection drug users in Montreal.Int J Drug Policy. 2007; 18: 397-405Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. The current Walter study tracked ∼42,000 individuals with HBV mono-infection, ∼82,000 with HCV mono-infection, 3200 with HBV and HCV co-infection, and 889 with HIV co-infection with either HBV or HCV. There was a moderate decline in non-HCC liver disease mortality in HBV infected individuals, but a persistently large fraction of deaths from HCC. Most likely, this improvement in non-HCC liver disease due to HBV reflects improving therapies, although only a small percentage of the overall HBV cases were treated, so this issue requires further scrutiny. As before, HCV deaths were primarily related to drug use rather than liver disease, but the mortality from liver disease occupied an enlarging fraction of the total, possibly owing to the increasing prevalence of end-stage liver disease over time, but also to a markedly decreased mortality from drug-related causes beginning in 1999. The authors attribute this heartening decrease to needle and syringe programs and harm-reduction efforts, and the findings reinforce the need to develop more comprehensive approaches to HCV disease mitigation, as underscored in the IOM report. As the number of new HCV cases becomes increasingly confined to those with high-risk behaviors, it will also be important to document the incidence of acute HCV infections, something not discernible from the New South Wales database. While one might think that short-term mortality is not likely to eventuate from cases of acute HCV infection, an emerging syndrome of rapid fibrosis in patients with HIV who acquire HCV [4Fierer D.S. Uriel A.J. Carriero D.C. Klepper A. Dieterich D.T. Mullen M.P. et al.Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study.J Infect Dis. 2008; 198: 683-686Crossref PubMed Scopus (98) Google Scholar, 10Osinusi A. Kleiner D. Wood B. Polis M. Masur H. Kottilil S. Rapid development of advanced liver fibrosis after acquisition of hepatitis C infection during primary HIV infection.AIDS Patient Care STDS. 2009; 23: 403-406Crossref PubMed Scopus (7) Google Scholar] raises the possibility that the natural history of disease may be radically altered in some patients in the coming years. Overall, the study by Walters provides some hopeful signs that: (1) HBV therapy is really having an impact (albeit not yet sparing patients from HCC), and; (2) thoughtful, comprehensive efforts to address the social conditions that confer risk of HCV may be paying off. There’s been a flurry of news about Vitamin D lately in both the public and in the scientific communities. While Vitamin D levels have always been of concern for patients with cholestatic liver diseases, more recently they have become relevant for treatment of HCV infection as well. Vitamin D could have a beneficial role in interferon-mediated HCV treatment since it has strong anti-inflammatory properties and may have salutary effects on insulin sensitivity, mood and innate, and adaptive immunity [[6]Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10286) Google Scholar]. Moreover, low Vitamin D levels diminish responsiveness to HCV therapy [[11]Petta S. Camma C. Scazzone C. Tripodo C. Di Marco V. Bono A. et al.Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.Hepatology. 2010; 51: 1158-1167Crossref PubMed Scopus (348) Google Scholar]. As a result, trials are ongoing to assess the impact of Vitamin D levels and supplementation on responsiveness to HCV therapies. These efforts have converged with studies to identify genetic determinants of Vitamin D metabolism and their association with the risk of several diseases, including diabetes and heart failure, among others. There are single nucleotide polymorphisms within the gene encoding cytochrome P450 27B1 (CYP27B1), also known as 25-hydroxyvitamin D3 1-alpha-hydroxylase, which regulates hydroxylation of Vitamin D. The enzyme generates the active form of Vitamin D, 1,25-dihydroxyvitamin D, which binds to the Vitamin D receptor, and a polymorphism in the promoter region at −1260 bp reduces the enzyme activity through an unknown mechanism, potentially diminishing the level of activated Vitamin D. Much like the IL28B story, these polymorphisms may affect the response to HCV therapy by altering the levels of active Vitamin D. The study by Lange and colleagues in this issue directly assesses whether the −1260 bp polymorphism of CYP27B1 is associated with levels of activated Vitamin D in serum in patients of 110 patients with HCV, and in turn whether these levels affect the response to PEG-interferon/ribavirin therapy. As expected, the polymorphism was associated with significantly reduced levels of active Vitamin D in serum, which correlated with reduced likelihood of SVR in all patients, and in the subset of patients with genotype 1 HCV. While the study was retrospective and raises several unanswered questions, it nonetheless introduces another host determinant of HCV responsiveness, and raises the question already under study elsewhere – whether Vitamin D supplementation can increase SVR rates. Just because the levels of Vitamin D are low, it does not necessarily follow that supplementation will overcome the problem. In a similar example, whereas elevated homocysteine levels were correlated with heart disease risk, efforts to reduce the risk by lowering homocysteine were unsuccessful [[2]Bonaa K.H. Njolstad I. Ueland P.M. Schirmer H. Tverdal A. Steigen T. et al.Homocysteine lowering and cardiovascular events after acute myocardial infarction.N Engl J Med. 2006; 354: 1578-1588Crossref PubMed Scopus (1244) Google Scholar]. It’s also surprising that the CYP27B1 polymorphism did not emerge from the earlier large-scale studies that uncovered the IL28B polymorphism [[14]Thomas D.L. Thio C.L. Martin M.P. Qi Y. Ge D. O’Huigin C. et al.Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.Nature. 2009; 461: 798-801Crossref PubMed Scopus (1809) Google Scholar], but presumably its genetic impact is much smaller – still, it’s worth re-interrogating these databases. The final issue is whether liver disease in general, or HCV in particular, lower 25(OH)D levels and/or activity. In a subgroup of the Lange cohort, those who had an SVR displayed a trend toward a lower incidence of severe Vitamin D deficiency thereafter, but the increase in 25(OH)D levels was very small, just 2 ng/ml, and well within the range caused by seasonal variation [[13]Snellman G. Melhus H. Gedeborg R. Olofsson S. Wolk A. Pedersen N.L. et al.Seasonal genetic influence on serum 25-hydroxyvitamin D levels: a twin study.PLoS One. 2009; 4: e7747Crossref PubMed Scopus (85) Google Scholar]. Fortunately, vitamin D supplements can raise 25(OH)D levels into an optimal range for good health even in patients with advanced liver disease, indicating that the nutrient can be absorbed, and metabolized by the injured liver. More rigorous studies are needed to determine the potential benefits of vitamin D supplements for patients with liver disease and to investigate the impact of mutations within genes controlling vitamin D metabolism. In conclusion, these three studies explore both genetic and societal influences on the outcomes of chronic viral hepatitis. Together, they illustrate the interwoven matrix of investigations that are contributing to steady progress. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.