Vitamin D in Standard HCV Regimen (PEG-Interferon Plus Ribavirin), Its Effect on the Early Virologic Response Rate: A Clinical Trial

Authors

1 Department of Gastroenterology and Hepatology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

2 1Department of Gastroenterology and Hepatology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

3 Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

4 Department of Community Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

5 Rheumatic Diseases Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

6 Department of Radiology, School of Medicine, Mashhad Branch, Islamic Azad University, Mashhad, IR Iran

7 Department of Pathology, Research and Education Department, Razavi Hospital, Mashhad, IR Iran

10.30483/rijm.2016.118399

Abstract

Background: Patients chronically infected with the hepatitis C virus (HCV) are more likely to have vitamin D deficiency Recent studies revealed that vitamin D has immunomodulator and antiviral properties and can enhance the effect of interferon on the HCV virus.
Objectives: We aimed to assess the influence of vitamin D supplementation on viral response to PegINF/RBV therapy.
Patients and Methods: In a randomized-controlled trial 66 patients with HCV (30 with genotype 1or 4 and 36 with genotype 2 or 3) were randomly divided into two groups in gastroenterology clinic: the study group (n = 34) received oral vitamin D supplementation (1600 IU/day) to maintain serum levels > 30 ng/mL besides the routine treatment of 180 g PegINF- 2a plus oral ribavirin. The control group (n = 32) received the same treatment without vitamin D supplementation. The primary outcome was undetectable HCV-RNA at week 12 of treatment, referred to as complete early viral response (cEVR). Real-time polymerase chain reaction (sensitivity: 10 IU/mL) was used to assess HCV RNA. Serum Vitamin D levels were measured at baseline and weeks 4, 8, 12 and 24 of treatment.
Spearman’s correlation showed that baseline vitamin D correlated with the stage of liver fibrosis in both study and control group (P = 0.04, r = 0.57).
Results: There were no significant differences in baseline characteristics between two groups except serum AST level. Complete EVR rate at week 12 in the vitamin D group was significantly higher than the controls (100% vs 84.4%; P = 0.023) whereas this figure was not significant when genotypes 1 and 4 or 2 and 3 in the test group were compared to those of the control (100% vs 86.7%; P = 0.19 and 100% vs 82.4%; P = 0.22). Serum vitamin D levels were lowest at baseline (2215 ng/mL), but increased after 12 weeks of vitamin D therapy to a mean level of 5238 ng/mL (P = 0.02) in study group.
Conclusions: The addition of vitamin D to conventional PegIFN/RBV therapy in HCV patients may significantly improve the viral response.

Keywords


  1. 1.Neal KR, Trent Hepatitis CG, Ramsay S, Thomson BJ, Irving WL. Excess mortality rates in a cohort of patients infected with the hepatitis C virus: a prospective study. Gut. 2007;56(8):1098–104. doi: 10.1136/gut.2006.113217. [PubMed: 17344277].

    1. Jabbari H, Bayatian A, Sharifi AH, Zaer-Rezaee H, Fakharzadeh E, Asadi R, et al. Safety and efficacy of locally manufactured pegylated interferon in hepatitis C patients. Arch Iran Med. 2010;13(4):306–12. [PubMed: 20597564].
    2. Khodabandehloo M, Roshani D. Prevalence of hepatitis C virus genotypes in Iranian patients: a systematic review and meta-analysis. Hepat Mon. 2014;14(12):ee22915. doi: 10.5812/hepatmon.22915. [PubMed: 25685164].
    3. Merat S, Rezvan H, Nouraie M, Jafari E, Abolghasemi H, Radmard AR, et al. Seroprevalence of hepatitis C virus: the first populationbased study from Iran. Int J Infect Dis. 2010;14 Suppl 3:e113–6. doi: 10.1016/j.ijid.2009.11.032. [PubMed: 20362479].
    4. Kermani FR, Sharifi Z, Ferdowsian F, Paz Z, Zamanian M. Distribution of hepatitis c virus genotypes among chronic infected injecting drug users in Tehran, Iran. Jundishapur J Microbiol. 2013;6(3):265–8.
    5. Kheirandish P, SeyedAlinaghi S, Jahani M, Shirzad H, Seyed Ahmadian M, Majidi A, et al. Prevalence and correlates of hepatitis C infection among male injection drug users in detention, Tehran, Iran. J Urban Health. 2009;86(6):902–8. doi: 10.1007/s11524-009-9393-0. [PubMed: 19844670].
    6. Manns M, Marcellin P, Poordad F, de Araujo ES, Buti M, Horsmans Y, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2014;384(9941):414–26. doi: 10.1016/S0140-6736(14)60538-9. [PubMed: 24907224].
    7. Namazee N, Sali S, Asadi S, Shafiei M, Behnava B, Alavian SM. Real response to therapy in chronic hepatitis C virus patients: a study from iran. Hepat Mon. 2012;12(9):ee6151. doi: 10.5812/hepatmon.6151. [PubMed: 23087759].
    8. Yu JW, Wang GQ, Sun LJ, Li XG, Li SC. Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon alpha-2a and ribavirin. J Gastroenterol Hepatol. 2007;22(6):832–6. doi: 10.1111/j.1440-1746.2007.04904.x. [PubMed: 17565637].
    9. Chopp S, Vanderwall R, Hult A, Klepser M. Simeprevir and sofosbuvir for treatment of hepatitis C infection. Am J Health Syst Pharm. 2015;72(17):1445–55. doi: 10.2146/ajhp140290. [PubMed: 26294237].
    10. Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naive patients. World J Gastroenterol. 2012;18(8):800–5. doi: 10.3748/wjg.v18.i8.800. [PubMed: 22371640].
    11. Watkins RR, Lemonovich TL, Salata RA. An update on the association of vitamin D deficiency with common infectious diseases. Can J Physiol Pharmacol. 2015;93(5):363–8. doi: 10.1139/cjpp-2014-0352. [PubMed: 25741906].
    12. Iruzubieta P, Teran A, Crespo J, Fabrega E. Vitamin D deficiency in chronic liver disease. World J Hepatol. 2014;6(12):901–15. doi: 10.4254/wjh.v6.i12.901. [PubMed: 25544877].
    13. Van Belle TL, Gysemans C, Mathieu C. Vitamin D in autoimmune, infectious and allergic diseases: a vital player?. Best Pract Res Clin Endocrinol Metab. 2011;25(4):617–32. doi: 10.1016/j.beem.2011.04.009. [PubMed: 21872803].
    14. Yano M, Ikeda M, Abe K, Dansako H, Ohkoshi S, Aoyagi Y, et al. Comprehensive analysis of the effects of ordinary nutrients on hepatitis C virus RNA replication in cell culture. Antimicrob Agents Chemother. 2007;51(6):2016–27. doi: 10.1128/AAC.01426-06. [PubMed: 17420205].
    15. Matsumura T, Kato T, Sugiyama N, Tasaka-Fujita M, Murayama A, Masaki T, et al. 25-Hydroxyvitamin D3 suppresses hepatitis C virus production. Hepatology. 2012;56(4):1231–9. doi: 10.1002/hep.25763. [PubMed: 22487892].
    16. Petta S, Ferraro D, Camma C, Cabibi D, Di Cristina A, Di Marco V, et al. Vitamin D levels and IL28B polymorphisms are related to rapid virological response to standard of care in genotype 1 chronic hepatitis C. Antivir Ther. 2012;17(5):823–31. doi: 10.3851/IMP2100. [PubMed: 22505587].
    17. Luo YQ, Wu XX, Ling ZX, Cheng YW, Yuan L, Xiang C. Association between serum vitamin D and severity of liver fibrosis in chronic hepatitis C patients: a systematic meta-analysis. J Zhejiang Univ Sci B. 2014;15(10):900–6. doi: 10.1631/jzus.B1400073. [PubMed: 25294379].
    18. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients. World J Gastroenterol. 2011;17(47):5184–90. doi: 10.3748/wjg.v17.i47.5184. [PubMed: 22215943].
    19. Yokoyama S, Takahashi S, Kawakami Y, Hayes CN, Kohno H, Kohno H, et al. Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b: a randomized controlled trial. J Viral Hepat. 2014;21(5):348–56. doi: 10.1111/jvh.12146. [PubMed: 24716637].
    20. Esmat G, El Raziky M, Elsharkawy A, Sabry D, Hassany M, Ahmed A, et al. Impact of vitamin D supplementation on sustained virological response in chronic hepatitis C genotype 4 patients treated by pegylated interferon/ribavirin. J Interferon Cytokine Res. 2015;35(1):49–54. doi: 10.1089/jir.2014.0060. [PubMed: 25061714].
    21. Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010;55(9):2624–8. doi: 10.1007/s10620-009- 1069-9. [PubMed: 19960254].
    22. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010;85(8):752–7. doi: 10.4065/mcp.2010.0138. [PubMed: 20675513] quiz 757-8. Razavi Int J Med. 2016; 4(2):e36632. 7 Vosoghinia H et al.
    23. Terrier B, Lapidus N, Pol S, Serfaty L, Ratziu V, Asselah T, et al. Vitamin D in addition to peg-interferon-alpha/ribavirin in chronic hepatitis C virus infection: ANRS-HC25-VITAVIC study. World J Gastroenterol. 2015;21(18):5647–53. doi: 10.3748/wjg.v21.i18.5647. [PubMed: 25987791].
    24. Kitson MT, Sarrazin C, Toniutto P, Eslick GD, Roberts SK. Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and metaanalysis. J Hepatol. 2014;61(6):1247–52. doi: 10.1016/j.jhep.2014.08.004. [PubMed: 25135863].
    25. Berak H, Laskus T, Kolakowska-Rzadzka A, Wasilewski M, Stanczak JJ, Bardadin K, et al. Peginterferon alfa-2a and peginterferon alfa2b combined with ribavirin in patients with genotype 1 chronic hepatitis C: results of a prospective single-centre study. Adv Med Sci. 2014;59(2):261–5. doi: 10.1016/j.advms.2014.01.005. [PubMed: 25117425].
    26. Alavian SM, Ahmadzad M, Keshvari M. Efficacy and safety of interferon-alpha (PDferon B) and ribavirin combination therapy in patients with chronic hepatitis C in Iran. Hepat Mon. 2006;6:11–8. 28. Chen EQ, Shi Y, Tang H. New insight of vitamin D in chronic liver diseases. Hepatobiliary Pancreat Dis Int. 2014;13(6):580–5. [PubMed: 25475859].
    27. Jimenez-Sousa MA, Rallon N, Berenguer J, Pineda-Tenor D, Lopez JC, Soriano V, et al. TLR3 polymorphisms are associated with virologic response to hepatitis C virus (HCV) treatment in HIV/HCV coinfected patients. J Clin Virol. 2015;65:62–7. doi: 10.1016/j.jcv.2015.02.004. [PubMed: 25766991].
    28. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80(6 Suppl):1689S–96S. [PubMed: 15585789].
    29. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005;289(1):F8–28. doi: 10.1152/ajprenal.00336.2004. [PubMed: 15951480].
    30. Muller K, Bendtzen K. 1,25-Dihydroxyvitamin D3 as a natural regulator of human immune functions. J Investig Dermatol Symp Proc. 1996;1(1):68–71. [PubMed: 9627696].
    31. Hewison M. Vitamin D and the intracrinology of innate immunity. Mol Cell Endocrinol. 2010;321(2):103–11. doi: 10.1016/j.mce.2010.02.013. [PubMed: 20156523].
    32. Trochoutsou AI, Kloukina V, Samitas K, Xanthou G. Vitamin-D in the Immune System: Genomic and Non-Genomic Actions. Mini Rev Med Chem. 2015;15(11):953–63. [PubMed: 25985946].
    33. Sabry D, Al-Ghussein MA, Hamdy G, Abul-Fotouh A, Motawi T, El Kazaz AY, et al. Effect of vitamin D therapy on interleukin-6, visfatin, and hyaluronic acid levels in chronic hepatitis C Egyptian patients. Ther Clin Risk Manag. 2015;11:279–88. doi: 10.2147/TCRM.S66763. [PubMed: 25737638]. 36. Bitetto D, Fattovich G, Fabris C, Ceriani E, Falleti E, Fornasiere E, et al. Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology. 2011;53(4):1118–26. doi: 10.1002/hep.24201. [PubMed: 21480318].
    34. 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(4):1158–67. doi: 10.1002/hep.23489. [PubMed: 20162613].
    35. Lange CM, Gouttenoire J, Duong FH, Morikawa K, Heim MH, Moradpour D. Vitamin D receptor and Jak-STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-alpha. J Immunol. 2014;192(12):6037–44. doi: 10.4049/jimmunol.1302296. [PubMed: 24821973].
    36. Duan X, Guan Y, Li Y, Chen S, Li S, Chen L. Vitamin D Potentiates the Inhibitory Effect of MicroRNA-130a in Hepatitis C Virus Replication Independent of Type I Interferon Signaling Pathway. Mediators Inflamm. 2015;2015:508989. doi: 10.1155/2015/508989. [PubMed: 26060358].
    37. Alipour S, Saberi A, Seifollahi A, Shirzad N, Hosseini L. Risk factors and prevalence of vitamin d deficiency among Iranian women attending two university hospitals. Iran Red Crescent Med J. 2014;16(10):eee15461. doi: 10.5812/ircmj.15461. [PubMed: 25763193].
    38. Heshmat R, Mohammad K, Majdzadeh SR, Forouzanfar MH, Bahrami A, Omrani GHR. Vitamin D deficiency in Iran: A multi-center study among different urban areas. Iran J Public Health. 2008;37(suppl).
    39. Pinzone MR, Di Rosa M, Malaguarnera M, Madeddu G, Foca E, Ceccarelli G, et al. Vitamin D deficiency in HIV infection: an underestimated and undertreated epidemic. Eur Rev Med Pharmacol Sci. 2013;17(9):1218–32. [PubMed: 23690192].
    40. Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, et al. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology. 2012;56(1):49–56. doi: 10.1002/hep.25631. [PubMed: 22318926].
    41. Lambert AA, Drummond MB, Mehta SH, Brown TT, Lucas GM, Kirk GD, et al. Risk factors for vitamin D deficiency among HIV-infected and uninfected injection drug users. PLoS One. 2014;9(4):eee95802. doi: 10.1371/journal.pone.0095802. [PubMed: 24756000].
    42. Grammatikos G, Lange C, Susser S, Schwendy S, Dikopoulos N, Buggisch P, et al. Vitamin D levels vary during antiviral treatment but are unable to predict treatment outcome in HCV genotype 1 infected patients. PLoS One. 2014;9(2):ee87974. doi: 10.1371/journal.pone.0087974. [PubMed: 24516573].