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HEPATOLOGY, August 2014

types, such as regulatory T cells,6 also may alter the course of liver injury progression in CD732/2 mice. In summary, resistance to MDB formation in CD732/2 mice likely is related to a number of hepatocyte-intrinsic and -extrinsic mechanisms. Generation of mice with targeted deletion of CD73 from specific cell types should help resolve many outstanding questions pertaining to the functions of this enzyme in the liver.

2.

3. 4.

NATASHA T. SNIDER, PH.D. M. BISHR OMARY, M.D., PH.D. Department of Molecular & Integrative Physiology University of Michigan Medical School Ann Arbor, MI

References 1. Snider NT, Griggs NW, Singla A, Moons DS, Weerasinghe SV, Lok AS, et al. CD73 (ecto-5’-nucleotidase) hepatocyte levels differ across mouse

5. 6.

strains and contribute to Mallory-Denk body formation. HEPATOLOGY 2013;58:1790-1800. Resta R, Hooker SW, Hansen KR, Laurent AB, Park JL, Blackburn MR, et al. Murine ecto-5’-nucleotidase (CD73): cDNA cloning and tissue distribution. Gene 1993;133:171-177. Zimmermann H, Zebisch M, Strater N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 2012;8:437-502. Antonioli L, Pacher P, Vizi ES, Hasko G. CD39 and CD73 in immunity and inflammation. Trends Mol Med 2013;19:355-367. Junger WG. Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol 2011;11:201-212. Ernst PB, Garrison JC, Thompson LF. Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol 2010;185:1993-1998. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26952 Potential conflict of interest: Nothing to report.

Vitamin D Levels in Patients With Chronic Hepatitis B 1

Department of Gastroenterology Hacettepe University Ankara, Turkey 2 Department of Gastroenterology Numune Research and Education Hospital Ankara, Turkey

To the Editor: We read with interest the article by Farnik et al.1 regarding the low vitamin D levels in patients with chronic hepatitis B virus (HBV). A remarkable finding was the inverse relationship between serum vitamin D levels and HBV viral load. A previous study in patients with chronic hepatitis C had also shown that necroinflammatory activity as well fibrosis scores were independently linked to low vitamin D levels.2 Because of small cohort size, the researchers could not show an association between serum vitamin D levels and fibrosis scores. However, considering that necroinflammatory activity was not included in statistical analysis in this study; we would like to point out that high necroinflammatory activity may also explain the low vitamin D levels in patients with HBV. Before drawing a definitive conclusion, more details ought to be presented about this important issue. CUMALI EFE, M.D.1 TUGRUL PURNAK, M.D.1 ERSAN OZASLAN, M.D.2

References 1. Farnik H, Bojunga J, Berger A, Allwinn R, Waidmann O, Kronenberger B, et al. Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. HEPATOLOGY 2013;58:1270-1276. 2. 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;51:1158-1167. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26962 Potential conflict of interest: Nothing to report.

Trends in Hepatitis C Treatment Uptake in the United States To the Editor: In May 2011, the United States Food and Drug Administration (FDA) approved the direct-acting antiviral (DAA) drugs boceprevir (BOC) and teleprevir (TVR) to be used in combination with peginterferon and ribavirin (PEG/RBV) for genotype 1 (G1) chronic hepatitis C (HCV). These drugs offered improvements in efficacy and reduced duration for some patients, benefits somewhat compromised by increased adverse events and pill burden. Major increases in treatment uptake rates are required to impact the growing burden of disease from HCV complications including cirrhosis and hepatocellular carcinoma.1 However, it is not clear whether HCV treatment uptake increased since the availability of BOC and TVR. We surveyed prescription activity in the USA after

the FDA approval of BOC and TVR, using proprietary databases (see online methods). The impact of these medications on the total number of HCV patients treated was small (Table 1). Over 80,000 patients were

Table 1. Prescription Rates for Hepatitis C Therapy 2008-2012 Year

2008 2009 2010 2011 2012

PEGalfa-2A

PEGalfa-2B

Telaprevir

Boceprevir

57,544 53,066 53,610 64,466 52,656

26,081 17,340 13,311 12,790 11,596

N/A N/A N/A 26,177 36,801

N/A N/A N/A 7,932 14,787

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75% only gains an additional 1% improvement in liver-related mortality. In contrast, increasing rates of diagnosis and subsequently increasing the number of patients treated by 1.5-fold yields an additional 9% improvement in liver-related mortality. This suggests that the true rate-limiting step for addressing the HCV-associated cirrhosis epidemic lies not solely in more efficacious agents, but in getting more patients diagnosed and treated. Birth cohort-based HCV screening in baby-boomers offers one such attempt to address this need. As newer and better drugs are becoming available to clinicians, parallel public health efforts are needed to improve rates of diagnosis, referral, and treatment, to ensure that the full potential of new HCV therapies can be realized. Fig. 1. Number of prescriptions for Victrelis (boceprevir) and Incivek (telaprevir) May 2011 to December 2012. treated in 2008 prior to BOC/TVR introduction, slipping to just over 66,000 in 2010. After initially brisk uptake of the agents after FDA approval of TVR and BOC, utilization plateaued and then declined (Fig. 1). Over 77,000 patients started HCV treatment in 2011, and of these 34,000 were also begun on TVR or BOC (i.e., after May 2011). By 2012, while a greater proportion of patients were on DAAs, the total number of patients treated had dropped to just over 64,000 (Table 1). Thus, ironically, within the period the total annual number of patients treated for HCV declined since DAA introduction. These data suggest limited uptake of newer therapies, and raise concern about the public health impact of future treatments. Using a previously developed Markov model,1 we sought to determine the potential impacts of treatment patterns on HCVrelated morbidity and mortality. We assumed a sustained virological response (SVR) rate of 65% with BOC or TVR, accepting lower real-world SVR rates than those observed in clinical trials. These results project that should rates of treatment with current antiviral therapy continue, liver-related mortality from HCV in the U.S. will only reduce by 21% over the next 20 years. The evolution of HCV therapy is a source of much optimism in addressing the increasing burden of complicated liver disease, yet barriers exist to realizing the potential. 2 In our model, major benefits come not from the increase in SVR but improving treatment rates. An increase in SVR from 65% to

PAUL J. CLARK, M.D. ALEXANDER J. THOMPSON, M.D. KEYUR PATEL, M.D. ANDREW J. MUIR, M.D. MICHAEL L. VOLK, M.D. Duke Clinical Research Institute Duke University Medical Center Durham, NC

References 1. Volk ML, Tocco R, Saini S, Lok ASF. Public health impact of antiviral therapy for hepatitis C in the United States. HEPATOLOGY 2009;50:1750-1755. 2. Clark PJ, Muir AJ. Overcoming barriers to care for hepatitis C. N Engl J Med 2012;366:2436-2438. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27213 Potential conflict of interest: Dr. Patel consults for and advises Gilead. Dr. Thompson consults for, advises, and received grants from Merck, Janssen, and Roche. Dr. Muir consults for and received grants from AbbVie, Achillion, Bristol-Myers Squibb, Gilead, Dr. Falk, and Vertex. He received grants from Roche.

Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s website.

Trends in hepatitis C treatment uptake in the United States.

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