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Jiang XW, Ye JZ, Li YT, Li LJ. Hepatitis B reactivation in patients receiving direct-acting antiviral therapy or interferon-based therapy for hepatitis C: A systematic review and meta-analysis. World J Gastroenterol 2018; 24:3181-3191. [PMID: 30065564 PMCID: PMC6064961 DOI: 10.3748/wjg.v24.i28.3181] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/02/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the incidence of hepatitis B virus (HBV) reactivation in patients receiving direct-acting antiviral agent (DAA)-based therapy or interferon (IFN)-based therapy for hepatitis C and the effectiveness of preemptive anti-HBV therapy for preventing HBV reactivation. METHODS The PubMed, MEDLINE and EMBASE databases were searched, and 39 studies that reported HBV reactivation in HBV/hepatitis C virus coinfected patients receiving DAA-based therapy or IFN-based therapy were included. The primary outcome was the rate of HBV reactivation. The secondary outcomes included HBV reactivation-related hepatitis and the effectiveness of preemptive anti-HBV treatment with nucleos(t)ide analogues. The pooled effects were assessed using a random effects model. RESULTS The rate of HBV reactivation was 21.1% in hepatitis B surface antigen (HBsAg)-positive patients receiving DAA-based therapy and 11.9% in those receiving IFN-based therapy. The incidence of hepatitis was lower in HBsAg-positive patients with undetectable HBV DNA compared to patients with detectable HBV DNA receiving DAA therapy (RR = 0.20, 95%CI: 0.06-0.64, P = 0.007). The pooled HBV reactivation rate in patients with previous HBV infection was 0.6% for those receiving DAA-based therapy and 0 for those receiving IFN-based therapy, and none of the patients experienced a hepatitis flare related to HBV reactivation. Preemptive anti-HBV treatment significantly reduced the potential risk of HBV reactivation in HBsAg-positive patients undergoing DAA-based therapy (RR = 0.31, 95%CI: 0.1-0.96, P = 0.042). CONCLUSION The rate of HBV reactivation and hepatitis flare occurrence is higher in HBsAg-positive patients receiving DAA-based therapy than in those receiving IFN-based therapy, but these events occur less frequently in patients with previous HBV infection. Preemptive anti-HBV treatment is effective in preventing HBV reactivation.
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Affiliation(s)
- Xian-Wan Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Zhong Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Ya-Ting Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
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Chen G, Wang C, Chen J, Ji D, Wang Y, Wu V, Karlberg J, Lau G. Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: A systematic review and meta-analysis. Hepatology 2017; 66:13-26. [PMID: 28195337 DOI: 10.1002/hep.29109] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 01/27/2017] [Accepted: 02/06/2017] [Indexed: 12/12/2022]
Abstract
UNLABELLED There is an increased awareness of hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients coinfected with HBV treated with pan-oral direct-acting antiviral agents (DAAs). We performed a systematic review and meta-analysis to compare the rate of HBV reactivation in CHC patients coinfected with overt HBV (hepatitis B surface antigen [HBsAg] positive) and occult HBV (HBsAg negative with positive HBV DNA) infection separately, treated with interferon (IFN)-based therapy to those with pan-oral DAAs. The primary outcome was HBV reactivation, and the secondary outcomes included hepatitis due to HBV reactivation, sustained virologic response (SVR) for CHC, loss of HBV DNA and HBsAg seroclearance. Although the pooled incidence rate of HBV reactivation, among CHC patients with overt HBV (n = 779), was similar among those treated with IFN-based therapy (14.5%, P < 0.001) and DAAs (12.2%, P = 0.03; P = 0.91 for heterogeneity between subgroups), it was reported to occur much earlier in those treated with DAAs (4-12 weeks during treatment) than in those treated with IFN-based therapies (most at the end of treatment and some during follow-up). Also, studies with DAA-based therapies were more likely to report incidence of hepatitis due to HBV reactivation (12.2% in DAAs vs. 0% in IFN; P = 0.009 for heterogeneity between subgroups). HBV reactivation and hepatitis due to HBV reactivation also occurred, though less frequently in CHC patients with occult HBV infection. CHC SVR was not affected by HBV reactivation (P = 0.27). CONCLUSION HBV reactivation occurs earlier and is clinically more significant in CHC patients coinfected with overt and occult HBV who are treated with pan-oral DAAs compared with IFN-based therapy. It is therefore important to have all patients screened for evidence of overt or occult HBV infection and managed during pan-oral DAAs therapy. (Hepatology 2017;66:13-26).
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Affiliation(s)
- Guofeng Chen
- Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, China.,Second Liver Cirrhosis Diagnosis and Treatment Center, 302 Hospital, Beijing, China
| | - Cheng Wang
- Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, China.,Humanity and Health Research Centre, Hong Kong SAR, China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Chen
- Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, China.,Humanity and Health Research Centre, Hong Kong SAR, China
| | - Dong Ji
- Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, China.,Second Liver Cirrhosis Diagnosis and Treatment Center, 302 Hospital, Beijing, China
| | - Yudong Wang
- Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, China.,Humanity and Health Research Centre, Hong Kong SAR, China
| | - Vanessa Wu
- Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, China.,Humanity and Health Research Centre, Hong Kong SAR, China
| | - Johan Karlberg
- Humanity and Health Research Centre, Hong Kong SAR, China
| | - George Lau
- Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Center, Beijing, China.,Humanity and Health Research Centre, Hong Kong SAR, China.,Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong SAR, China.,Institute of Translational Hepatology, 302 Hospital, Beijing, China
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The influence of anti-HBc status on the sustained virological response rate in HCV-infected patients treated with pegylated interferon alfa 2 and ribavirin. Clin Exp Hepatol 2016; 2:155-160. [PMID: 28856281 PMCID: PMC5497428 DOI: 10.5114/ceh.2016.63873] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 10/16/2016] [Indexed: 12/19/2022] Open
Abstract
Aim of the study To determine the influence of HBsAg and HBeAg negative but anti-HBc positive status on the sustained virological response (SVR) rate in HCV-infected patients treated with pegylated interferon alfa 2 (Peg-IFNα-2) and ribavirin (RBV). Material and methods The study was based on the retrospective analysis of medical records of HCV-infected patients who started Peg-IFNα and RBV treatment between 1 January 2011 and 31 December 2013 at the 1st and 2nd Department of Infectious Diseases of the Regional Hospital in Wrocław, Poland. Results Among 240 patients included in the analysis 99 were anti-HBc positive and 141 anti-HBc negative. In the genotype 1, anti-HBc positive group the SVR rate was 47% and in the anti-HBc negative group it was 42.7% (p = 0.591). In the genotype 3, anti-HBc positive group the SVR rate was 60% and in anti-HBc negative patients it was 63.2% (p = 0.79). Differences in SVR rates between anti-HBc positive and negative groups were not statistically significant. None of the anti-HBc positive patients developed reactivation of HBV infection during or in the 24 weeks following the end of treatment. Conclusions Anti-HBc determination does not seem to be useful in predicting treatment outcome of conventional Peg-IFNα/RBV therapy in patients infected with HCV genotypes 1 and 3.
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Jang JY, Park EJ. [Occult hepatitis B virus infection in chronic hepatitis C]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2014; 62:154-9. [PMID: 24077625 DOI: 10.4166/kjg.2013.62.3.154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Occult HBV infection is defined as the presence of HBV DNA in the liver (with or without detectable or undetectable HBV DNA in the serum) of individuals testing negative for HBsAg. Studies on occult HBV infection in hepatitis C patients have reported highly variable prevalence, because the prevalence of occult HBV infection varies depending on the hepatitis B risk factors and methodological approaches. The most reliable diagnostic approach for detecting occult HBV detection is through examination of liver DNA extracts. HCV has been suspected to strongly suppress HBV replication up to the point where it may be directly responsible for occult HBV infection development. However, more data are needed to arrive at a definitive conclusion regarding the role of HCV in inducing occult HBV infection. Occult HBV infection in chronic hepatitis C patients is a complex biological entity with possible relevant clinical implications. Influence of occult HBV infection on the clinical outcomes of chronic hepatitis C may be considered negative. However, recent studies have shown that occult HBV infection could be associated with the development of hepatocellular carcinoma and contribute to the worsening of the course of chronic liver disease over time in chronic hepatitis C patients. Nevertheless, the possible role of occult HBV infection in chronic hepatitis C is still unresolved and no firm conclusion has been made up until now. It still remains unclear how occult HBV infection affects the treatment of chronic hepatitis C. Therefore, in order to resolve current controversies and understand the pathogenic role and clinical impacts of occult HBV infection in chronic hepatitis C patients, well-designed clinical studies are needed.
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Affiliation(s)
- Jae Young Jang
- Institution for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
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Melchiorre D, Morfini M, Linari S, Zignego AL, Innocenti M, Matucci Cerinic M. Anti-TNF- therapy prevents the recurrence of joint bleeding in haemophilia and arthritis. Rheumatology (Oxford) 2013; 53:576-8. [DOI: 10.1093/rheumatology/ket280] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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The influence of hepatitis B virus on antiviral treatment with interferon and ribavirin in Asian patients with hepatitis C virus/hepatitis B virus coinfection: a meta-analysis. Virol J 2012; 9:186. [PMID: 22950520 PMCID: PMC3511228 DOI: 10.1186/1743-422x-9-186] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2011] [Accepted: 08/29/2012] [Indexed: 12/21/2022] Open
Abstract
Background Clinical and laboratory studies have indicated that coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) can suppress one another, eliciting a dominant disease phenotype. To assess whether HBV can influence the antiviral effect of treatment on HCV, we performed a meta-analysis to comparatively analyze the response to interferon plus ribavirin treatment in patients with HBV/HCV coinfection and HCV mono-infection. Methods Published studies in the English-language medical literature that involved cohorts of HBV/HCV coinfection and HCV mono-infection were obtained by searching Medline, Cochrane and Embase databases. Studies that compared the efficacy of treatment with interferon plus ribavirin in HBV/HCV coinfection and HCV mono-infection were assessed. End-of-treatment virological response (ETVR), sustained virological response (SVR), HCV relapse rate, and alanine aminotransferase (ALT) normalization rate were compared between HBV/HCV coinfection and HCV mono-infection patients. Results Five trials involving 705 patients were analyzed. At the end of follow-up serum ALT normalization rates in patients with HCV mono-infection were significantly higher than in patients with HBV/HCV coinfection (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.40–0.80, P = 0.001). The ETVR and SVR achieved in HBV/HCV coinfection patients were comparable to those in HCV mono-infection patients (OR = 1.03, 95% CI: 0.37–2.82, P = 0.96 and OR = 0.87, 95% CI: 0.62–1.21, P = 0.38, respectively). The rate of relapse for HCV or HCV genotype 1 was not significantly different between HBV/HCV coinfection patients and HCV mono-infection patients (OR = 1.55, 95% CI: 0.98–2.47, P = 0.06; HCV genotype 1: OR = 2.4, 95% CI: 1.17–4.91, P = 0.19). Conclusions Treatment with interferon and ribavirin achieves similar ETVR and SVR in HBV/HCV coinfection and HCV mono-infection. HBV/HCV coinfection patients had distinctively lower end of follow-up serum ALT normalization.
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Emara MH, El-Gammal NE, Mohamed LA, Bahgat MM. Occult hepatitis B infection in egyptian chronic hepatitis C patients: prevalence, impact on pegylated interferon/ribavirin therapy. Virol J 2010; 7:324. [PMID: 21083926 PMCID: PMC2998483 DOI: 10.1186/1743-422x-7-324] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Accepted: 11/17/2010] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chronic HCV infection combined with occult hepatitis B infection has been associated with liver enzymes flare, advanced hepatic fibrosis and cirrhosis, poor response to standard interferon-α, and increased risk of HCC. This study aimed to elucidate the prevalence of occult hepatitis B infection in Egyptian chronic HCV patients, and to clarify its role in non-response of those patients to pegylated interferon/ribavirin therapy. This study enrolled 155 consecutive chronic HCV patients under pegylated interferon/ribavirin therapy. All patients were exposed to clinical assessment, biochemical, histological and virological examinations. HBV parameters (HBV DNA, anti-HBc, anti-HBs) and patients' response status to the combination therapy were determined. RESULTS In this study, occult hepatitis B infection occurs in 3.9% of Egyptian chronic HCV patients; tends to affect younger age patients, associated with higher base line HCV viral load, less hepatic fibrosis than monoinfected patients. This occult hepatitis B infection is not a statistically significant cause of non-response to pegylated interferon/ribavirin therapy. Anti-HBs was not associated with any biochemical, histological or virological abnormalities in those patients, contrary to low response rate to therapy and higher HCV viral load that was observed with anti-HBc. CONCLUSIONS Detection of HBV DNA in HBsAg negative chronic HCV patients plays a non significant role in non-response of Egyptian patients to pegylated interferon/ribavirin therapy.
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Affiliation(s)
- Mohamed H Emara
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nahla E El-Gammal
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Lamiaa A Mohamed
- Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Maged M Bahgat
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN, Wu SS, Liao LY, Chen CL, Kuo HT, Chao YC, Tung SY, Yang SS, Kao JH, Liu CH, Su WW, Lin CL, Jeng YM, Chen PJ, Chen DS. Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology 2009; 136:496-504.e3. [PMID: 19084016 DOI: 10.1053/j.gastro.2008.10.049] [Citation(s) in RCA: 163] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Revised: 10/20/2008] [Accepted: 10/23/2008] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Dual chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is common in areas endemic for either virus. Combination therapy with ribavirin and pegylated interferon (peginterferon) is the standard of care for patients with HCV monoinfection. We investigated the effects of combination therapy in patients infected with both HBV and HCV (genotypes 1, 2, or 3). METHODS The study included 321 Taiwanese patients with active HCV infection; 161 also tested positive for hepatitis B surface antigen (HBsAg) and 160 were HBsAg-negative (controls). Patients with HCV genotype 1 infection received peginterferon alfa-2a (180 mug) weekly for 48 weeks and ribavirin (1000-1200 mg) daily. Patients with HCV genotypes 2 or 3 received peginterferon alfa-2a weekly for 24 weeks and ribavirin (800 mg) daily. At 24 weeks posttreatment, patient samples were examined for a sustained virologic response (SVR) against HCV (serum HCV levels decreased to <25 IU/mL). RESULTS In patients with HCV genotype 1 infection, the SVR was 72.2% in dually infected patients vs 77.3% in monoinfected patients after treatment. For patients with HCV genotype 2/3 infections, the SVR values were 82.8% and 84.0%, respectively, after treatment. Serum HBV DNA eventually appeared in 36.3% of 77 dual-infected patients with undetectable pretreatment levels of HBV DNA; this was not accompanied by significant hepatitis. Posttreatment HBsAg clearance was observed in 11.2% of 161 dual-infected patients. CONCLUSIONS Combination therapy with peginterferon alfa-2a and ribavirin is equally effective in patients with HCV monoinfection and in those with dual chronic HCV/HBV infection.
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Affiliation(s)
- Chun-Jen Liu
- National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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Piroth L, Carrat F, Larrat S, Goderel I, Martha B, Payan C, Lunel-Fabiani F, Bani-Sadr F, Perronne C, Cacoub P, Pol S, Morand P. Prevalence and impact of GBV-C, SEN-V and HBV occult infections in HIV-HCV co-infected patients on HCV therapy. J Hepatol 2008; 49:892-8. [PMID: 18752863 DOI: 10.1016/j.jhep.2008.06.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Revised: 06/10/2008] [Accepted: 06/10/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS It has been suggested that, in HIV-HCV co-infected patients, co-infections with other viruses may affect the response to HCV therapy. We aimed to assess the prevalence of GBV-C, SEN-V and occult HBV infections, their impact on HCV and HIV infections and on the response to HCV therapy in HIV-HCV co-infected patients. METHODS Three-hundred and sixty eight patients were tested before starting interferon-ribavirin for the presence of occult hepatitis B DNA, GBV-C RNA and SEN-V DNA by using real time PCR. Clinical, immunological, virological, histological characteristics and response to HCV therapy were compared according to the presence or not of each viral co-infection. RESULTS HBV DNA, GBV-C RNA and SEN-V DNA were found in 5 (1.4%, CI95%: 0.2-2.4%), 104 (29.9%, CI95%: 25.1-34.7%) and 209 patients (57.9%, CI95%: 52.8-63.0%), respectively. GBV-C positive patients had significantly higher CD4 count at baseline, during and after HCV therapy, even after stratification on antiretroviral treatment. No other significant difference was observed according to the presence or not of GBV-C or SEN-V co-infection, in particular regarding virological responses to HCV combination therapy. CONCLUSIONS There is no reason to withhold HCV therapy in HIV infected patients who have access to HAART, because of occult HBV, GBV-C or SEN-V co-infections.
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Affiliation(s)
- Lionel Piroth
- Service des Maladies Infectieuses, CHU Dijon, 10, Boulevard du Maréchal de Lattre de Tassigny, 21079 DIJON Cedex, France.
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Carreño V, Bartolomé J, Castillo I, Quiroga JA. Occult hepatitis B virus and hepatitis C virus infections. Rev Med Virol 2008; 18:139-57. [PMID: 18265423 DOI: 10.1002/rmv.569] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Occult HBV infection is a well-recognised clinical entity characterised by the detection of HBV-DNA in serum and/or in liver in the absence of detectable hepatitis B surface antigen (HBsAg). Occult HBV infection has been described not only in patients who have resolved an acute or chronic HBV infection but also in patients without any serological markers of a past HBV infection. Occult HBV infection in patients with chronic HCV infection may induce more severe liver disease and lower response rate to interferon treatment. The existence of occult HCV infections has been also reported more recently. Occult HCV infection is characterised by the presence of HCV-RNA in liver and peripheral blood mononuclear cells in the absence of detectable serum HCV-RNA. Occult HCV infection may occur under two different clinical situations: in hepatitis C antibody-(anti-HCV) negative and serum HCV-RNA-negative patients with abnormal liver function tests and in anti-HCV-positive patients who have no detectable serum HCV-RNA and who have normal liver enzymes. The clinical relevance of occult HCV infections is still under investigation.
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Affiliation(s)
- Vicente Carreño
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain.
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Lo Re V, Frank I, Gross R, Dockter J, Linnen JM, Giachetti C, Tebas P, Stern J, Synnestvedt M, Localio AR, Kostman JR, Strom BL. Prevalence, risk factors, and outcomes for occult hepatitis B virus infection among HIV-infected patients. J Acquir Immune Defic Syndr 2007; 44:315-20. [PMID: 17159655 DOI: 10.1097/qai.0b013e31802ea499] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Occult hepatitis B virus (HBV) is defined by the presence of HBV DNA in individuals with HBV core antibodies (anti-HBc) but without HBV surface antigen (HBsAg). The prevalence of occult HBV in HIV-infected patients remains controversial, and the risk factors and clinical significance are unknown. OBJECTIVES To determine the prevalence, risk factors, and clinical significance of occult HBV among HIV-infected patients. Hypothesized risk factors include chronic hepatitis C virus (HCV), CD4 count < 200 cells/mm, HIV RNA level >1000 copies/mL, and lack of use of anti-HBV antiretrovirals. METHODS We examined randomly selected HBsAg/anti-HBc HIV-infected patients in the Penn Center for AIDS Research Adult/Adolescent Database and Specimen Repository. HBV DNA was qualitatively detected using a transcription-mediated amplification assay. Risk factors and transaminases were ascertained at the time sera were collected. RESULTS A total of 699 HBsAg/anti-HBc HIV-infected patients were identified. Of 179 randomly selected subjects, 17 (10%; 95% confidence interval [CI]: 5% to 14%) had occult HBV. Differences in the prevalence of HBV surface antibody (anti-HBs) between those with (7 [41%]) and without (94 [58%]) occult HBV were not statistically significant (P = 0.3). An HIV RNA level >1000 copies/mL (adjusted odds ratio [OR] = 4.88, 95% CI: 1.01 to 30.26) and the absence of chronic HCV (adjusted OR = 0.26, 95% CI: 0.05 to 0.95) were associated with occult HBV. Occult HBV did not increase the risk of transaminitis (adjusted OR = 0.42, 95% CI: 0.12 to 1.45). CONCLUSIONS Occult HBV occurred in a sizable proportion of HIV-infected patients and was associated with detectable HIV and the absence of chronic HCV. It did not increase the risk of transaminitis. The presence of anti-HBs does not rule out occult HBV. Future studies should examine the long-term clinical implications of occult HBV in HIV-infected patients.
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Affiliation(s)
- Vincent Lo Re
- Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, 423 Guardian Drive, Philadelphia, PA 19104, USA.
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Hui CK, Lau E, Monto A, Kim M, Luk JM, Poon RTP, Leung N, Lo CM, Fan ST, Lau GKK, Wright TL. Natural history of patients with recurrent chronic hepatitis C virus and occult hepatitis B co-infection after liver transplantation. Am J Transplant 2006; 6:1600-8. [PMID: 16827860 DOI: 10.1111/j.1600-6143.2006.01370.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
It is uncertain whether occult hepatitis B virus co-infection will hasten progressive liver disease in chronic hepatitis C patients after liver transplantation. This study evaluated fibrosis progression and severe fibrosis in 118 consecutive hepatitis B surface antigen-negative patients with virological and histological evidence of recurrent chronic hepatitis C infection co-infected with occult hepatitis B virus after liver transplantation. HBV DNA was detected from serum at the time of recurrent chronic hepatitis C infection by polymerase chain reaction. Each subject underwent a repeat liver biopsy 5 years post-liver transplantation. Occult hepatitis B virus co-infection was present in 41 of the 118 (34.7%) patients. At 5 years post-liver transplantation, 13 of the 41 occult hepatitis B virus co-infected patients compared with 16 of the 77 patients without occult hepatitis B virus co-infection developed fibrosis progression (31.7% vs. 20.8%, respectively, p = 0.39). Eight of 41 the occult hepatitis B virus co-infected patients compared with 13 of the 77 patients without occult hepatitis B virus co-infection had severe fibrosis (19.5% vs. 16.9%, respectively, p = 0.97). In conclusion, occult hepatitis B virus co-infection in patients with recurrent chronic hepatitis C infection was not associated with accelerated fibrosis progression or severe fibrosis after liver transplantation.
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Affiliation(s)
- C-K Hui
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
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Goral V, Ozkul H, Tekes S, Sit D, Kadiroglu AK. Prevalence of occult HBV infection in haemodialysis patients with chronic HCV. World J Gastroenterol 2006; 12:3420-4. [PMID: 16733862 PMCID: PMC4087876 DOI: 10.3748/wjg.v12.i21.3420] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the prevalence and clinical effects of occult HBV infection in haemodialysis patients with chronic HCV.
METHODS: Fifty chronic hemodialysis patients with negative HbsAg, and positive anti-HCV were included in the study. These patients were divided into two groups: HCV-RNA positive and HCV-RNA negative, based on the results of HCV-RNA PCR. HBV-DNA was studied using the PCR method in both groups.
RESULTS: None of the 22 HCV-RNA positive patients and 28 HCV-RNA negative patients revealed HBV-DNA in serum by PCR method. The average age was 47.2 ± 17.0 in the HCV-RNA positive group and 39.6 ± 15.6 in the HCV-RNA negative group.
CONCLUSION: The prevalence of occult HBV infection is not high in haemodialysis patients with chronic HCV in our region. This result of our study has to be evaluated in consideration of the interaction between HBsAg positivity (8%-10%) and frequency of HBV mutants in our region.
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Affiliation(s)
- Vedat Goral
- Department of Gastroenterology, Dicle University School of Medicine, Diyarbakir, Turkey.
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Abstract
Coinfection of hepatitis C virus (HCV), hepatitis B virus (HBV), and HIV is common due to shared modes of transmission. These coinfections accelerate the course of chronic liver disease and facilitate progression to cirrhosis and hepatocellular carcinoma. The viral interactions between these viruses are complex, and their treatment may be challenging for clinicians.
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Affiliation(s)
- James S Park
- Division of Liver Diseases, Department of Medicine, Mount Sinai Medical Center, 5 East 98th Street, 11th Floor, New York, NY 10029, USA
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15
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Fabrizi F, Messa PG, Lunghi G, Aucella F, Bisegna S, Mangano S, Villa M, Barbisoni F, Rusconi E, Martin P. Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther 2005; 21:1341-7. [PMID: 15932364 DOI: 10.1111/j.1365-2036.2005.02501.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The epidemiology and clinical significance of occult hepatitis B virus infection (serum hepatitis B surface antigen-negative patients with detectable hepatitis B virus viraemia in serum) remains controversial with only limited information about its prevalence in patients on long-term dialysis. AIM To address the epidemiology of occult HBV infection in a large cohort of dialysis patients. METHODS We screened a large cohort (n = 585) of Italian chronic dialysis patients; from this population, a group of hepatitis B virus surface antigen seronegative patients (n = 213) was tested by Amplicor hepatitis B virus Monitor Test to detect hepatitis B virus viraemia (hepatitis B virus-DNA) in serum. RESULTS Occult hepatitis B virus infection was absent (zero of 213 = 0%). Persistent hepatitis B virus surface antigen carriage was less frequent than anti-hepatitis B virus core antibody (anti-hepatitis B core antigen) seropositive status in this study group [1.88% (11 of 585) vs. 36% (216 of 585), P = 0.0001]. No dialysis patients seropositive for anti-hepatitis B core antibody in serum (zero of 123 = 0%) had detectable hepatitis B virus-DNA by polymerase chain reaction technology. No significant association between abnormal biochemical liver tests and serum anti-hepatitis B core antibody was noted in our population. Nominal logistic regression analysis demonstrated an independent and significant relationship between anti-HCV antibody and anti-hepatitis B virus core antibody in serum (Wald chi-square 16.06, P = 0.0001). The rate of seropositive patients for anti-hepatitis B virus core antibody was higher among study patients than controls with normal renal function [36.9% (216 of 585) vs. 21.4% (59 of 275), P = 0.0001]; this difference partially persisted after correction for demographic parameters, and viral markers. CONCLUSION In conclusion, occult hepatitis B virus was absent in our study group. Anti-hepatitis B core antibody was significantly related to presence of anti-HCV antibody supporting shared modes of transmission. Clinical studies based on molecular biology techniques provided with higher sensitivity are planned.
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Affiliation(s)
- F Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milano, Italy.
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16
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17
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Gish RG, Afdhal NH, Dieterich DT, Reddy KR. Management of hepatitis C virus in special populations: patient and treatment considerations. Clin Gastroenterol Hepatol 2005; 3:311-8. [PMID: 15822034 DOI: 10.1016/s1542-3565(04)00666-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The most common chronic blood-borne infection in the United States is caused by hepatitis C virus. An estimated 3.9 million people (1.8%) in the United States have been infected with the hepatitis C virus, excluding certain subpopulations who are at high risk for hepatitis C virus infection. Among these subpopulations are an estimated 255,000 (15%) of prison inmates and 175,000 (22%) of homeless people. Prevalence of hepatitis C virus infection is also high among veterans (6.6% overall and even higher among homeless veterans). The single most important risk factor for hepatitis C virus infection is injection drug use; up to 90% of illicit injection drug users are infected with hepatitis C virus. This review describes the prevalence of hepatitis C virus in special populations and discusses the treatment options for patients with severe disease, transplant recipients, and patients at high risk for infection. Close monitoring and management of therapeutic side effects are required to assist these patients in adhering to therapy.
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Affiliation(s)
- Robert G Gish
- Liver Transplant Program and Division of Hepatology and Complex GI, California Pacific Medical Center, 2340 Clay Street #232, San Francisco, CA 94115, USA.
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18
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Sagir A, Adams O, Kirschberg O, Erhardt A, Heintges T, Haussinger D. SEN virus does not affect treatment response in hepatitis C virus coinfected patients but SEN virus response depends on SEN virus DNA concentration. World J Gastroenterol 2004; 10:1893-7. [PMID: 15222031 PMCID: PMC4572225 DOI: 10.3748/wjg.v10.i13.1893] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To clarify the effect of SEN virus (SENV) infection on a combination therapy including interferon alfa (IFN-α) or pegylated-IFN with ribavirin in patients with chronic hepatitis and the effect of a combination therapy on SENV.
METHODS: SENV DNA was determined by polymerase chain reaction in serum samples from 95 patients with chronic hepatitis C. Quantitative analysis was done for SENV H DNA.
RESULTS: Twenty-one (22%) of 95 patients were positive for SENV DNA. There was no difference in clinical and biochemical parameters between patients with HCV infection alone and coinfected patients. The sustained response rate for HCV clearance after combination therapy did not differ between patients with SENV (52%) and without SENV (50%, n.s.). SENV DNA was undetectable in 76% of the initially SENV positive patients at the end of follow-up. SENV H response to combination therapy was significantly correlated with SENV DNA level (P = 0.05).
CONCLUSION: SENV infection had no influence on the HCV sustained response rate to the combination therapy. Response rate of SENV to the combination therapy depends on SENV DNA level.
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Affiliation(s)
- Abdurrahman Sagir
- Klinik fur Gastroenterologie, Hepatologie und Infektiologie, Universitatsklinikum Dusseldorf, Moorenstrasse 5, 40225 Dusseldorf, Germany.
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19
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Fabris P, Brown D, Tositti G, Bozzola L, Giordani MT, Bevilacqua P, de Lalla F, Webster GJM, Dusheiko G. Occult hepatitis B virus infection does not affect liver histology or response to therapy with interferon alpha and ribavirin in intravenous drug users with chronic hepatitis C. J Clin Virol 2004; 29:160-6. [PMID: 14962784 DOI: 10.1016/s1386-6532(03)00117-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2002] [Revised: 03/03/2003] [Accepted: 04/15/2003] [Indexed: 12/20/2022]
Abstract
BACKGROUND the frequency and the impact of occult HBV infection in patients with chronic hepatitis C infection is still a matter of some controversy. OBJECTIVES our aim was to evaluate the prevalence of occult HBV infection and assess its impact on liver biochemistry, HCV viral titre, liver histology and on outcome of therapy in patients with chronic hepatitis C. STUDY DESIGN paired liver biopsies and serum samples were collected from 51 patients (84% IVDUS) with HBsAg negative chronic hepatitis C, and tested for HBV-DNA with nested PCR. Liver biopsies were further studied histologically, with morphometric analyses and immunostaining techniques. Twenty-five were treated with alpha Interferon and ribavirin and followed for at least 18 months. RESULTS HBV DNA was detected in 29.4% of liver tissue specimens and in only one (1.9%) serum sample. Three liver specimens were positive for surface gene, nine for core gene, three for both and none for the X gene. No significant difference in mean transaminase values, HCV viral titre, HCV genotype, or grading and staging and morphometric analysis was observed in patients with or without HBV DNA. Moreover, all 51 liver specimens were negative for both HBsAg and HBcAg. Sustained response to combination therapy was achieved in 40% of patients with and in 53% of patients without HBV DNA in the liver specimens (P=NS). CONCLUSIONS HBV DNA is frequently found in the liver of patients with chronic hepatitis C. However, the lack of any significant impact on HCV viral titre, liver enzymes, histological parameters and response to therapy, suggests that in most cases HBV DNA detected in the liver by PCR may be either an integrated or low level replicative form.
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Affiliation(s)
- Paolo Fabris
- Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, Viale Rodolfi, Vicenza 36100, Italy.
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20
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Shukla NB, Poles MA. Hepatitis B virus infection: co-infection with hepatitis C virus, hepatitis D virus, and human immunodeficiency virus. Clin Liver Dis 2004; 8:445-60, viii. [PMID: 15481349 DOI: 10.1016/j.cld.2004.02.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) shares routes of transmission, namely exchange of infected body fluids, sharing of contaminated needles, and blood transfusion, with other hepatotropic viruses, such as hepatitis C virus (HCV) and hepatitis D virus (HDV) and with systemic retroviral infections, such as the human immunodeficiency virus (HIV). Thus, many HBV infected patients are co-infected with other viral pathogens. Co-infection appears to increase the risk of progression of liver disease and may have important ramifications on choice of antiviral medication and treatment regimen. This article reviews the current knowledge of co-infection of HBV with HCV, HDV, and HIV.
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Affiliation(s)
- Nilesh B Shukla
- Division of Gastroenterology, New York University School of Medicine, 650 1st Avenue, 3rd floor, New York, NY 10016, USA
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21
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Park SG, Lee SM, Jung G. Antisense oligodeoxynucleotides targeted against molecular chaperonin Hsp60 block human hepatitis B virus replication. J Biol Chem 2003; 278:39851-7. [PMID: 12869561 DOI: 10.1074/jbc.m301618200] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The major role of hepatitis B virus polymerase (HBV pol) is polymerization of nucleotides, but it also participates in protein priming and the packaging of its own genome into capsids. Therefore, HBV pol may require many assistance factors for its roles. Previous reports have shown that Hsp60, a molecular chaperone, activates HBV pol both in vitro and ex vivo, such as inside insect cells. Moreover, HBV pol binds to Hsp60 in the HepG2 host cell line. In this report, we show that Hsp60 plays a role in the in vivo replication of HBV. Antisense oligodeoxynucleotides (A-ODNs) specifically directed against Hsp60 induced its down-regulation, severely reducing the level of replication-competent HBV without influencing cell proliferation and capsid assembly under these conditions. Furthermore, we found that Hsp60 did not encapsidate into nucleocapsids. Our results indicate that Hsp60 is important for HBV replication in vivo, presumably through activation of HBV pol before encapsidation of HBV pol into HBV core particle. In addition, A-ODNs specific for Hsp60 also inhibit replication of a mutant HBV strain that is resistant to the nucleoside analogue 3TC, which is the main drug used for HBV treatment, and we suggest that A-ODNs directed against Hsp60 are possible reagents as anti-HBV drugs. Conclusively, this report shows that the host factor, Hsp60, is essential for in vivo HBV replication and that mechanism of Hsp60 is probably through an activation of HBV pol by Hsp60.
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Affiliation(s)
- Sung Gyoo Park
- School of Biological Sciences, Seoul National University, Seoul, 151-742, Korea
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22
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Liu CJ, Chen PJ, Shau WY, Kao JH, Lai MY, Chen DS. Clinical aspects and outcomes of volunteer blood donors testing positive for hepatitis-C virus infection in Taiwan: a prospective study. Liver Int 2003; 23:148-55. [PMID: 12955877 DOI: 10.1034/j.1600-0676.2003.00820.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIM The natural history of hepatitis-C virus (HCV) infection has been explored in volunteer blood donors, but not yet in hepatitis-B endemic areas. Whether previous or concurrent hepatitis-B virus (HBV) infection influences the natural history of HCV infection remains unknown. Thus, we followed the anti-HCV-positive blood donors who had past or concurrent HBV infection in Taiwan. METHODS From 1992 to 1993, 1588 anti-HCV reactive volunteer blood donors were referred to us from the Taipei Blood Center and 879 (55%) repeatedly reactive for anti-HCV were enrolled. Two hundred and forty-three donors (HCV RNA seropositive rate 49% by polymerase chain reaction (PCR)) received regular follow-ups (mean period: 4.9 years) with their liver disease status determined mainly by clinical and biochemical parameters, serum alpha-fetoprotein level and imaging studies. Hepatitis-C virus genotype and occult HBV infection were determined by PCR-based assays. RESULTS Of the initial 879 subjects, 250 (28%) had chronic hepatitis, nine (1%) had liver cirrhosis (LC) and two (0.2%) had hepatocellular carcinoma (HCC) already. In the 243 regularly followed donors, 30% had repeatedly normal serum alanine aminotransferase (ALT) and 70% had more than once elevated ALT. Cirrhosis developed in four (1.6%; follow-up period range: 2-6 years) and HCC in two (0.8%; follow-up period: 3 and 4 years, respectively). Distribution of HCV genotype and hepatitis-B surface antigen (HBsAg) did not differ between those with and those without elevation of ALT. Of the 15 donors with LC and/or HCC, only 1(7%) was positive for both HBsAg and HBV DNA and the other 14 were negative for both HBsAg and serum HBV DNA. CONCLUSIONS Incidentally detected hepatitis-C was progressive in a small proportion of anti-HCV-positive volunteer blood donors in Taiwan. Occult HBV infection played a minimal role in the development of LC in this donor population.
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Affiliation(s)
- Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University College of Medicine, National Taiwan University Hospital, 1 Chang-Te Street, Taipei 100, Taiwan
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23
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Myers RP, Thibault V, Poynard T. The impact of prior hepatitis B virus infection on liver histology and the response to interferon therapy in chronic hepatitis C. J Viral Hepat 2003; 10:103-10. [PMID: 12614466 DOI: 10.1046/j.1365-2893.2003.00407.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Patients with chronic hepatitis C frequently have antibodies to the hepatitis B core antigen (anti-HBc), indicative of prior hepatitis B virus (HBV) infection. In these patients, persistence of HBV may exacerbate liver injury and diminish the response to treatment. The aim of this study was to evaluate the relationship between previous HBV infection and liver histology and the sustained virologic response (SVR) to interferon (IFN)-based therapy in patients with chronic hepatitis C. A total of 132 HBsAg-negative, treatment-naive patients were evaluated. Using multiple logistic regression analysis, the impact of anti-HBc-positivity on the rate of SVR was determined. Progression to bridging fibrosis or cirrhosis was assessed using Cox proportional hazards regression and Kaplan-Meier survival analysis. The median age of the patients was 47 years (IQR, 37-60), 57% were male, and 73% had genotypes 1, 4, 5, or 6. Fifty-one patients (39%) were anti-HBc-positive. The prevalence of moderate to severe necroinflammatory activity (P = 0.36) and progression to bridging fibrosis or cirrhosis (log-rank P = 0.83) was similar between anti-HBc-positive and -negative patients. After a median of 48 weeks (IQR, 26-52) of therapy (IFN, n = 116; IFN and ribavirin, n = 16), 23 patients (17%) achieved a SVR; the rate of response was similar in anti-HBc-positive and -negative patients (18%vs 17%, P = 1.00). After controlling for age, gender, genotype, fibrosis, and treatment regimen, anti-HBc status did not independently affect the rate of SVR (anti-HBc-positive vs negative: odds ratio, 1.36; 95% confidence interval, 0.45 to 4.06; P = 0.58). In conclusion, previous HBV infection does not affect liver histology or the response to IFN-based therapy in patients with chronic hepatitis C.
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Affiliation(s)
- R P Myers
- Department of Hepatology and Gastroenterology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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24
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Abstract
Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 104 copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV-DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV-DNA sequence; (ii) integration of HBV-DNA into host's chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV-containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well-designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.
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Affiliation(s)
- Ke-Qin Hu
- Transplantation Institute and Division of Gastroenterology, Loma Linda University Medical Center and Jerry L. Pettis Memorial VA Medical Center, Loma Linda, California 92354, USA.
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25
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Das K, Xiong X, Yang H, Westland CE, Gibbs CS, Sarafianos SG, Arnold E. Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC). J Virol 2001; 75:4771-9. [PMID: 11312349 PMCID: PMC114232 DOI: 10.1128/jvi.75.10.4771-4779.2001] [Citation(s) in RCA: 226] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Success in treating hepatitis B virus (HBV) infection with nucleoside analog drugs like lamivudine is limited by the emergence of drug-resistant viral strains upon prolonged therapy. The predominant lamivudine resistance mutations in HBV-infected patients are Met552IIe and Met552Val (Met552Ile/Val), frequently in association with a second mutation, Leu528Met. The effects of Leu528Met, Met552Ile, and Met552Val mutations on the binding of HBV polymerase inhibitors and the natural substrate dCTP were evaluated using an in vitro HBV polymerase assay. Susceptibility to lamivudine triphosphate (3TCTP), emtricitabine triphosphate (FTCTP), adefovir diphosphate, penciclovir triphosphate, and lobucavir triphosphate was assessed by determination of inhibition constants (K(i)). Recognition of the natural substrate, dCTP, was assessed by determination of Km values. The results from the in vitro studies were as follows: (i) dCTP substrate binding was largely unaffected by the mutations, with Km changing moderately, only in a range of 0.6 to 2.6-fold; (ii) K(i)s for 3TCTP and FTCTP against Met552Ile/Val mutant HBV polymerases were increased 8- to 30-fold; and (iii) the Leu528Met mutation had a modest effect on direct binding of these beta-L-oxathiolane ring-containing nucleotide analogs. A three-dimensional homology model of the catalytic core of HBV polymerase was constructed via extrapolation from retroviral reverse transcriptase structures. Molecular modeling studies using the HBV polymerase homology model suggested that steric hindrance between the mutant amino acid side chain and lamivudine or emtricitabine could account for the resistance phenotype. Specifically, steric conflict between the Cgamma2-methyl group of Ile or Val at position 552 in HBV polymerase and the sulfur atom in the oxathiolane ring (common to both beta-L-nucleoside analogs lamivudine and emtricitabine) is proposed to account for the resistance observed upon Met552Ile/Val mutation. The effects of the Leu528Met mutation, which also occurs near the HBV polymerase active site, appeared to be less direct, potentially involving rearrangement of the deoxynucleoside triphosphate-binding pocket residues. These modeling results suggest that nucleotide analogs that are beta-D-enantiomers, that have the sulfur replaced by a smaller atom, or that have modified or acyclic ring systems may retain activity against lamivudine-resistant mutants, consistent with the observed susceptibility of these mutants to adefovir, lobucavir, and penciclovir in vitro and adefovir in vivo.
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Affiliation(s)
- K Das
- Center for Advanced Biotechnology and Medicine, Department of Chemistry, Rutgers University, Piscataway, New Jersey 088854, USA
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26
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De Maria N, Colantoni A, Friedlander L, Leandro G, Idilman R, Harig J, Van Thiel DH. The impact of previous HBV infection on the course of chronic hepatitis C. Am J Gastroenterol 2000; 95:3529-36. [PMID: 11151889 DOI: 10.1111/j.1572-0241.2000.03371.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Individuals with chronic hepatitis C who are anti-HBc positive may carry an occult hepatitis B virus (HBV) infection that can affect their response to antiviral therapy. METHODS In this study the prevalence of anti-HBc and HBV-DNA positivity was assessed in the serum and liver of 285 HCV-RNA-positive subjects treated with interferon-alpha at 5 mU/day for 12 months. The response to interferon (normal ALT and undetectable serum HCV-RNA) was evaluated at three different endpoints: 1) after 6 months; 2) at the end of treatment; and 3) 6 months after interferon discontinuation. RESULTS Ninety individuals were anti-HBc positive (32%), 2 of these were HBV-DNA positive in serum and 7 in liver (8%). None of the anti-HBc-negative individuals was HBV-DNA positive in serum or liver. The prevalence of cirrhosis was greater in the anti-HBc-positive group than in the anti-HBc-negative group (p < 0.05), whereas HCV-RNA levels were lower. Anti-HBc-positive individuals had a lower response rate to interferon at 6 months and at the end of treatment as compared to anti-HBc-negative subjects (respectively 42% vs 66%, p < 0.01; and 32% vs 57%, p < 0.01). No difference between the two groups in terms of sustained response was detected 6 months after interferon discontinuation. CONCLUSIONS The prevalence of anti-HBc is high among HCV-positive individuals. HCV-positive individuals who are anti-HBc positive have: 1) a higher prevalence of cirrhosis; 2) lower HCV-RNA levels; and 3) an impaired ability to respond to interferon treatment.
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Affiliation(s)
- N De Maria
- Department of Internal Medicine, Loyola University at Chicago, Maywood, Illinois 60153, USA
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27
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Raimondo G, Balsano C, Craxì A, Farinati F, Levrero M, Mondelli M, Pollicino T, Squadrito G, Tiribelli C. Occult hepatitis B virus infection. Dig Liver Dis 2000; 32:822-826. [PMID: 11215565 DOI: 10.1016/s1590-8658(00)80362-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Many studies have shown that hepatitis B virus infection may also occur in hepatitis B surface antigen-negative patients. This occult infection has been identified both in patients with cryptogenic liver disease and in patients with hepatitis C virus-related chronic hepatitis, and much evidence suggests that it may be a risk factor of hepatocellular carcinoma development. However several aspects of this occult infection remain unclear such as its prevalence and the factor(s) involved in the lack of circulating hepatitis B surface antigen. Moreover, it is uncertain whether the occult hepatitis B virus infection may contribute to chronic liver damage, considering that it is usually associated with a suppressed viral replication. Evidence and hypotheses concerning this fascinating field of bio-medical research are reviewed.
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Affiliation(s)
- G Raimondo
- Department of Internal Medicine, University of Messina, Italy.
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28
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Abstract
Hepatitis C shares common routes of infection with hepatitis B (HBV) and the human immunodeficiency virus (HIV). It is, therefore, not surprising to find that some patients with HCV are co-infected with either HIV and/or HBV. Until recently, the effects of HIV on HCV infection have not been investigated--sadly patients with HIV died long before their liver disease became problematic. However, the development of successful therapies for HIV have led to dramatic improvements in life expectancy for patients infected with this virus and in these patients, with well controlled HIV, it is becoming clear that hepatitis C may lead to the early onset of advanced liver disease. The optimal treatment for these patients is unknown but it seems likely that combination antiviral therapy will be required. The effects of HBV on HCV are also beginning to be investigated and, again, it is clear that co-infection leads to more aggressive liver disease with the two viruses interacting in poorly defined ways to increase the rate of hepatic fibrosis. Management of combined HCV/HBV infection is still under investigation and will probably involve combination therapy.
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Affiliation(s)
- I Cropley
- Department of Medicine, Imperial College School of Medicine at St Mary's Hospital, London, UK
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29
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Guptan RC, Thakur V, Raina V, Sarin SK. Alpha-interferon therapy in chronic hepatitis due to active dual infection with hepatitis B and C viruses. J Gastroenterol Hepatol 1999; 14:893-8. [PMID: 10535471 DOI: 10.1046/j.1440-1746.1999.01952.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Nearly 14% of non-alcoholic chronic liver disease in India is related to hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection. There are no clear data available from the literature on the therapeutic management of these patients who often suffer an unfavourable course. METHODS Fourteen consecutive cases of biopsy-proven chronic liver disease fulfilling the following criteria were included: Child's A or B liver disease, hepatitis B surface antigen positive, HBV-DNA positive, antibody to HCV positive and HCV-RNA positive. Seven patients had chronic liver disease (group I), while the remaining seven patients (group II) had additional disorders (non-Hodgkin's lymphoma (two), acute leukaemia (two), thalassaemia (two), chronic renal failure (one). Interferon alpha-2b (IFN) was given in a dose of 6 MIU thrice weekly for 6 months. Complete response was defined as loss of HBV-DNA and HCV-RNA at 6 months and sustained response (SR) as the sustained loss of HBV-DNA and HCV-RNA for more than 6 months during the follow-up period. RESULTS At the end of 6 months, alanine aminotransferase (ALT) levels remained unchanged (120 +/- 40 vs 136 +/- 64 IU/L), but six of the seven (86%) patients in group I lost HBV-DNA. All three hepatitis Be antigen (HBeAg)-positive patients lost HBeAg with an early flare of ALT (at 45 +/- 12 therapy days). Two of these patients (29%) lost HCV-RNA. Thus, SR was seen in 29%, while HBV-DNA loss was found in 100% during the follow-up period. In group II patients, there was a significant decrease in ALT (308 +/- 14 vs 65 +/- 25 IU/L, P < 0.001), but only three (43%) patients lost HBV-DNA and two (29%) lost HCV-RNA. One patient with acute leukaemia and another with renal failure had a complete response to IFN, but none of the lymphoma patients showed any antiviral response. CONCLUSIONS In chronic hepatitis due to dual infection with HBV and HCV, interferon therapy is: (i) safe; (ii) effective (more so in clearing HBV); (iii) often associated with early ALT flare; and (iv) may be less effective if non-Hodgkin's lymphoma is present.
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MESH Headings
- Adult
- Alanine Transaminase/blood
- Antiviral Agents/therapeutic use
- Asian People
- Biomarkers/blood
- Biopsy
- DNA, Viral/analysis
- Follow-Up Studies
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/ethnology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/ethnology
- Humans
- India
- Interferon alpha-2
- Interferon-alpha/therapeutic use
- Prospective Studies
- Recombinant Proteins
- Reverse Transcriptase Polymerase Chain Reaction
- Serologic Tests
- Statistics, Nonparametric
- Treatment Outcome
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Affiliation(s)
- R C Guptan
- Department of Gastroenterology, GB Pant Hospital, New Delhi, India
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