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Rananaware SR, Vesco EK, Shoemaker GM, Anekar SS, Sandoval LSW, Meister KS, Macaluso NC, Nguyen LT, Jain PK. Programmable RNA detection with CRISPR-Cas12a. Nat Commun 2023; 14:5409. [PMID: 37669948 PMCID: PMC10480431 DOI: 10.1038/s41467-023-41006-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 08/21/2023] [Indexed: 09/07/2023] Open
Abstract
Cas12a, a CRISPR-associated protein complex, has an inherent ability to cleave DNA substrates and is utilized in diagnostic tools to identify DNA molecules. We demonstrate that multiple orthologs of Cas12a activate trans-cleavage in the presence of split activators. Specifically, the PAM-distal region of the crRNA recognizes RNA targets provided that the PAM-proximal seed region has a DNA target. Our method, Split Activator for Highly Accessible RNA Analysis (SAHARA), detects picomolar concentrations of RNA without sample amplification, reverse-transcription, or strand-displacement by simply supplying a short DNA sequence complementary to the seed region. Beyond RNA detection, SAHARA outperforms wild-type CRISPR-Cas12a in specificity towards point-mutations and can detect multiple RNA and DNA targets in pooled crRNA/Cas12a arrays via distinct PAM-proximal seed DNAs. In conclusion, SAHARA is a simple, yet powerful nucleic acid detection platform based on Cas12a that can be applied in a multiplexed fashion and potentially be expanded to other CRISPR-Cas enzymes.
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Affiliation(s)
| | - Emma K Vesco
- Department of Chemical Engineering, University of Florida, Gainesville, FL, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Grace M Shoemaker
- Department of Chemical Engineering, University of Florida, Gainesville, FL, USA
| | - Swapnil S Anekar
- Department of Chemical Engineering, University of Florida, Gainesville, FL, USA
| | | | - Katelyn S Meister
- Department of Chemical Engineering, University of Florida, Gainesville, FL, USA
| | - Nicolas C Macaluso
- Department of Chemical Engineering, University of Florida, Gainesville, FL, USA
| | - Long T Nguyen
- Department of Chemical Engineering, University of Florida, Gainesville, FL, USA
| | - Piyush K Jain
- Department of Chemical Engineering, University of Florida, Gainesville, FL, USA.
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
- UF Health Cancer Center, University of Florida, Gainesville, FL, USA.
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2
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Rananaware SR, Vesco EK, Shoemaker GM, Anekar SS, Sandoval LSW, Meister KS, Macaluso NC, Nguyen LT, Jain PK. Programmable RNA detection with CRISPR-Cas12a. RESEARCH SQUARE 2023:rs.3.rs-2549171. [PMID: 36824842 PMCID: PMC9949221 DOI: 10.21203/rs.3.rs-2549171/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
CRISPR is a prominent bioengineering tool and the type V CRISPR-associated protein complex, Cas12a, is widely used in diagnostic platforms due to its innate ability to cleave DNA substrates. Here we demonstrate that Cas12a can also be programmed to directly detect RNA substrates without the need for reverse transcription or strand displacement. We discovered that while the PAM-proximal "seed" region of the crRNA exclusively recognizes DNA for initiating trans-cleavage, the PAM-distal region or 3'-end of the crRNA can tolerate both RNA and DNA substrates. Utilizing this property, we developed a method named Split Activators for Highly Accessible RNA Analysis or 'SAHARA' to detect RNA sequences at the PAM-distal region of the crRNA by merely supplying a short ssDNA or a PAM containing dsDNA to the seed region. Notably, SAHARA is Mg2+ concentration- and pH-dependent, and it was observed to work robustly at room temperature with multiple orthologs of Cas12a. SAHARA also displayed a significant improvement in the specificity for target recognition as compared to the wild-type CRISPR-Cas12a, at certain positions along the crRNA. By employing SAHARA we achieved amplification-free detection of picomolar concentrations of miRNA-155 and hepatitis C virus RNA. Finally, SAHARA can use a PAM-proximal DNA as a switch to control the trans-cleavage activity of Cas12a for the detection of both DNA and RNA targets. With this, multicomplex arrays can be made to detect distinct DNA and RNA targets with pooled crRNA/Cas12a complexes. In conclusion, SAHARA is a simple, yet powerful nucleic acid detection platform based on Cas12a that can be applied in a multiplexed fashion and potentially be expanded to other CRISPR-Cas enzymes.
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Affiliation(s)
- Santosh R. Rananaware
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Emma K. Vesco
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Grace M. Shoemaker
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Swapnil S. Anekar
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | | | - Katelyn S. Meister
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Nicolas C. Macaluso
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Long T. Nguyen
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Piyush K. Jain
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA
- UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
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3
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Rananaware SR, Vesco EK, Shoemaker GM, Anekar SS, Sandoval LSW, Meister KS, Macaluso NC, Nguyen LT, Jain PK. Programmable RNA detection with CRISPR-Cas12a. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.29.525716. [PMID: 36778248 PMCID: PMC9915489 DOI: 10.1101/2023.01.29.525716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
CRISPR is a prominent bioengineering tool and the type V CRISPR-associated protein complex, Cas12a, is widely used in diagnostic platforms due to its innate ability to cleave DNA substrates. Here we demonstrate that Cas12a can also be programmed to directly detect RNA substrates without the need for reverse transcription or strand displacement. We discovered that while the PAM-proximal "seed" region of the crRNA exclusively recognizes DNA for initiating trans- cleavage, the PAM-distal region or 3'-end of the crRNA can tolerate both RNA and DNA substrates. Utilizing this property, we developed a method named Split Activators for Highly Accessible RNA Analysis or 'SAHARA' to detect RNA sequences at the PAM-distal region of the crRNA by merely supplying a short ssDNA or a PAM containing dsDNA to the seed region. Notably, SAHARA is Mg 2+ concentration- and pH-dependent, and it was observed to work robustly at room temperature with multiple orthologs of Cas12a. SAHARA also displayed a significant improvement in the specificity for target recognition as compared to the wild-type CRISPR-Cas12a, at certain positions along the crRNA. By employing SAHARA we achieved amplification-free detection of picomolar concentrations of miRNA-155 and hepatitis C virus RNA. Finally, SAHARA can use a PAM-proximal DNA as a switch to control the trans-cleavage activity of Cas12a for the detection of both DNA and RNA targets. With this, multicomplex arrays can be made to detect distinct DNA and RNA targets with pooled crRNA/Cas12a complexes. In conclusion, SAHARA is a simple, yet powerful nucleic acid detection platform based on Cas12a that can be applied in a multiplexed fashion and potentially be expanded to other CRISPR-Cas enzymes. Abstract Figure
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Affiliation(s)
- Santosh R. Rananaware
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Emma K. Vesco
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Grace M. Shoemaker
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Swapnil S. Anekar
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | | | - Katelyn S. Meister
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Nicolas C. Macaluso
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Long T. Nguyen
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
| | - Piyush K. Jain
- Department of Chemical Engineering, University of Florida, Gainesville, Florida, USA
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA
- UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
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Elbadry M, Moussa AM, Eltabbakh M, Al Balakosy A, Abdalgaber M, Abdeen N, El Sheemy RY, Afify S, El-Kassas M. The art of managing hepatitis C virus in special population groups: a paradigm shift. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00226-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
AbstractThe first direct-acting antiviral (DAA) medications were approved for the treatment of chronic hepatitis C virus (HCV) in 2011. Later, the appearance of novel DAAs had revolutionized the landscape of HCV treatment whose early treatment options were limited to interferon (IFN) either alone or in combinations. This review discusses the paradigm shift in legibility for treating different groups of patients with HCV after the introduction of DAAs, along with the consequent changes in treatment guidelines. IFN-based therapy was the firstly used for treating chronic HCV. Unfortunately, it exhibited many pitfalls, such as low efficacy in some patients and unsuitability for usage in lots of patients with some specific conditions, which could be comorbidities such as autoimmune thyroiditis, or liver related as in decompensated cirrhosis. Furthermore, IFN failed to treat all the extrahepatic manifestations of HCV. Nowadays, the breakthroughs brought by DAAs have benefited the patients and enabled the treatment of those who could not be treated or did not usually respond well to IFN. DAAs achieve a high success rate of HCV eradication in addition to avoiding unfavorable harms and, sometimes, adverse effects related to the previously used PEGylated IFN regimens.
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Liu M, Du L, Cheng X, Yuan M, Shang J, Shi Y, Yang H, Tang H. CpG Island Methylation of Suppressor of Cytokine Signaling-1 Gene Induced by HCV Is Associated With HCV-Related Hepatocellular Carcinoma. Front Microbiol 2022; 13:679593. [PMID: 35733955 PMCID: PMC9207397 DOI: 10.3389/fmicb.2022.679593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
Suppressor of cytokine signaling 1 (SOCS-1) is implicated in both virus infection and carcinogenesis. This study investigated the role of HCV infection on SOCS-1 in normal and HCV-infected tissues and revealed a possible mechanism underlying HCV-induced hepatocellular carcinoma (HCC) genesis. In total, 10 HCV-HCC tissues, seven adjacent tissues, seven distal tissues, and 16 normal liver tissues were collected. SOCS-1 expression in tissue sections was detected by immunohistochemistry. After viral load was quantified, the correlation between SOCS-1 expression and viral load was analyzed in different tissues. Then, HCV replicon model was used to detect a relationship between HCV and SOCS-1. Subsequently, methylation-specific PCR (MSP) was applied to show the methylation status of SOCS-1 genes in normal tissues and HCV-replicating cell lines. A correlation between gene methylation, SOCS-1 expression, and HCV was analyzed. The lowest expression of SOCS-1 was observed in HCV-HCC tissues. Tissues with a higher HCV viral load showed lower SOCS-1 expression (p = 0.0282). Consistently, SOCS-1 mRNA and protein were lower in HCV-replicating cell lines than in uninfected ones. Furthermore, gene methylation was found in all examined tissues but higher in HCC tissues, and it is positively correlated with HCV viral load (r2 = 0.7309, p < 0.0001). HCV infection would upregulate methylation of the SOCS-1 gene in HCV-replicating cell lines. The downregulation of SOCS-1 in normal and HCV-replicating cell lines may result from HCV infection through epigenetic regulation, in which gene methylation in the CpG island of SOCS-1 promoters upon HCV infection suppresses its expression.
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Affiliation(s)
- Miao Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Xing Cheng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Man Yuan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Jin Shang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ying Shi
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hailing Yang
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, United States
- Graduate Program in Cellular and Molecular Physiology, School of Graduate Biomedical Sciences, Tufts University, Boston, MA, United States
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Hong Tang,
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6
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:819-837.e6. [DOI: 10.1016/b978-0-323-67293-1.00075-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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7
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MacBrayne CE, Marks KM, Fierer DS, Naggie S, Chung RT, Hughes MD, Kim AY, Peters MG, Brainard DM, Seifert SM, Castillo-Mancilla JR, Bushman LR, Anderson PL, Kiser JJ. Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate. J Antimicrob Chemother 2019; 73:2112-2119. [PMID: 29746648 DOI: 10.1093/jac/dky146] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/21/2018] [Indexed: 12/12/2022] Open
Abstract
Background The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions. Objectives To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate. Methods HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS. Results Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment. Conclusions These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.
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Affiliation(s)
- Christine E MacBrayne
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | | | | | | | | | | | | | | | | | - Sharon M Seifert
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | | | - Lane R Bushman
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Peter L Anderson
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Jennifer J Kiser
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
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Naggie S, Fierer DS, Hughes MD, Kim AY, Luetkemeyer A, Vu V, Roa J, Rwema S, Brainard DM, McHutchison JG, Peters MG, Kiser JJ, Marks KM, Chung RT. Ledipasvir/Sofosbuvir for 8 Weeks to Treat Acute Hepatitis C Virus Infections in Men With Human Immunodeficiency Virus Infections: Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals. Clin Infect Dis 2019; 69:514-522. [PMID: 31220220 PMCID: PMC6637278 DOI: 10.1093/cid/ciy913] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/12/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Current guidelines for the management of hepatitis C virus (HCV) infections provide varying recommendations for the optimal treatment of acute HCV infections. There are limited data from small cohort studies to provide guidance on the best approach to treatment of this important patient population. METHODS Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals is an open-label, 2-cohort, Phase 1 clinical trial in which the second cohort assessed the safety and efficacy of 8 weeks of ledipasvir/sofosbuvir for the treatment of acute HCV infections in participants with chronic human immunodeficiency virus (HIV)-1 infections. This final analysis of the second cohort had a planned accrual of 27 participants, based on non-inferiority criteria, compared to the study-defined, historical, sustained virologic response (SVR) of 60% with pegylated-interferon/ribavirin. RESULTS We enrolled 27 men (9 Hispanic; 11 White, non-Hispanic; 5 Black, non-Hispanic; 2 Asian or Pacific Islander; median age 46 years). Most (96%) had HCV genotype-1 infection and 59% had the favorable interleukin 28B CC genotype. The median baseline HCV RNA load was 6.17 log10 IU/mL (interquartile range 4.51 - 6.55). All participants (100%) achieved the primary outcome of a sustained virologic response 12 weeks after the date of the last dose of study treatment (90% confidence interval 90-100%), achieving non-inferiority versus the 60% historic benchmark. No treatment discontinuations occurred. CONCLUSIONS This multicenter clinical trial, investigating 8 weeks of ledipasvir/sofosbuvir for acute HCV infections in men with HIV infections, reports a 100% SVR. This study provides the rationale for larger studies of shortened courses of direct-acting antiviral therapies in persons with HIV infections, including those with high baseline HCV RNA loads. CLINICAL TRIALS REGISTRATION NCT02128217.
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Affiliation(s)
| | | | | | | | | | - Vincent Vu
- Harvard T.H. Chan School of Public Health, Boston
| | - Jhoanna Roa
- Harvard T.H. Chan School of Public Health, Boston
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Takamizawa S, Yamada T, Kitamura K, Hiraoka E. Difficulty of acute hepatitis C diagnosis in a hospitalised patient. BMJ Case Rep 2018; 11:11/1/e226907. [PMID: 30567115 DOI: 10.1136/bcr-2018-226907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The hepatitis C virus (HCV) causes acute hepatitis C and is commonly detected via HCV antibody testing. However, delayed seroconversion of HCV antibodies and non-specific symptoms may hinder the diagnosis of this disease. A 71-year-old woman developed acute hepatitis while hospitalised for back pain. An HCV antibody test was negative, and she had no risk factors for hepatitis C. She was referred to our hospital for further evaluation. The HCV antibody test was repeated 16 days after the initial test; owing to a positive result, she was diagnosed with acute hepatitis C. Several months thereafter, the HCV spontaneously cleared. When diagnosing an HCV infection, the time at which the testing is performed needs to coincide with the time at which HCV antibody seroconversion occurs. Timely diagnosis of an HCV infection allows appropriate treatment during the acute phase which may prevent disease progression to the chronic phase.
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Affiliation(s)
- Shigemasa Takamizawa
- Department of Internal Medicine, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
| | - Toru Yamada
- Department of Internal Medicine, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
| | - Koichi Kitamura
- Department of Nephrology, Endocrinology, and Diabetes, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
| | - Eiji Hiraoka
- Department of Internal Medicine, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
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10
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Martinello M, Hajarizadeh B, Grebely J, Dore GJ, Matthews GV. Management of acute HCV infection in the era of direct-acting antiviral therapy. Nat Rev Gastroenterol Hepatol 2018; 15:412-424. [PMID: 29773899 DOI: 10.1038/s41575-018-0026-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The management of acute HCV infection has not been standardized following the availability of direct-acting antiviral agents (DAAs) for chronic HCV infection, and substantial uncertainty exists regarding the optimal treatment regimen and duration. Despite the lack of direct evidence, the 2016 American Association for the Study of Liver Diseases (AASLD)-Infectious Diseases Society of America (IDSA) guidelines supported "the same regimens for acute HCV as recommended for chronic HCV infection … owing to high efficacy and safety", whereas the 2016 European Association for the Study of the Liver (EASL) guidelines recommended sofosbuvir-ledipasvir, sofosbuvir-velpatasvir or sofosbuvir plus daclatasvir for 8 weeks in acute HCV infection, with a longer duration of 12 weeks recommended for those infected with HIV and/or baseline HCV RNA levels >1,000,000 IU/ml. This Review outlines the epidemiology, natural history and diagnosis of acute HCV infection and provides contemporary information on DAAs for acute and recent HCV infection. The Review also discusses the 2016 AASLD-IDSA and EASL recommendations for acute HCV infection management in light of available evidence and highlights key differences in study populations and design that influence interpretation. We focus on populations at high risk of HCV transmission and acquisition, including people who inject drugs and HIV-positive men who have sex with men, and highlight the potential effects of diagnosis and treatment of acute HCV infection in contributing to HCV elimination.
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Affiliation(s)
- Marianne Martinello
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia.
| | - Behzad Hajarizadeh
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
| | - Jason Grebely
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
| | - Gregory J Dore
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
| | - Gail V Matthews
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
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11
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Tan YW, Tao Y, Liu LG, Ye Y, Zhou XB, Chen L, He C. Epidemiological features of chronic hepatitis C infection caused by remunerated blood donors: A nearly 27-year period survey. World J Gastroenterol 2018; 24:1250-1258. [PMID: 29568205 PMCID: PMC5859227 DOI: 10.3748/wjg.v24.i11.1250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 02/01/2018] [Accepted: 02/09/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To understand the prevalence of hepatitis C virus (HCV) infection in blood donors over a nearly 27-year interval and to explore the factors that affect the outcome of HCV infection. METHODS A retrospective and cross-sectional study was conducted. The participants, mostly plasma donors, were selected from three administrative villages in the Jiangsu province in Eastern China. A questionnaire was administered among the villagers who had a history of blood donation from the late 1980s to the early 1990s. All participants underwent physical examination, liver B-ultrasonography, and liver stiffness measurement. In addition, 10 mL of blood was collected from each participant to measure simple liver function parameters (albumin, alanine aminotransferase, aspirate aminotransferase), blood factors (platelet), and for hepatitis B surface antigen, antiHCV, and antihuman immunodeficiency virus detection. HCV RNA detection, HCV genotyping, and other tests were carried out in antiHCV-positive patients. RESULTS After a median of 27 years (25-31 years) from the last blood donation to the time of survey, a total of 1694 participants were investigated, and the antiHCV-positive individuals were categorized into three groups: blood donors (n = 12, 3.3%), plasma donors (n = 534, 68.5%), and mixed donors (n = 324, 58.8%). A total of 592 (68.05%) patients had detectable HCV RNA, and 91.9% had genotype 1b. A total of 161 (27.2%, 161/592) patients with chronic HCV were considered to have cirrhosis with a liver stiffness measurement level higher than 12 kPa. Multiple logistic (binary) regression analysis results showed that platelet and IgG levels were associated with cirrhosis. CONCLUSION The nearly 27-year interval investigation revealed that chronic hepatitis C infection is a very serious public health problem in Eastern China. Plasma donation and subsequent return of blood cells to the donor are the main causes of hepatitis C infection. The main HCV genotype is 1b. Nearly 28% of cases progressed to cirrhosis. Age, especially over 60 years, and regular drinking habits were risk factors associated with cirrhosis.
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Affiliation(s)
- You-Wen Tan
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Yan Tao
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Long-Gen Liu
- Department of Hepatology, The Third People’s Hospital of Changzhou, Changzhou 213001, Jiangsu Province, China
| | - Yun Ye
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Xin-Bei Zhou
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Li Chen
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
| | - Cong He
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
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12
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Naggie S, Marks KM, Hughes M, Fierer DS, Macbrayne C, Kim A, Hollabaugh K, Roa J, Symonds B, Brainard DM, McHutchison JG, Peters MG, Kiser JJ, Chung R. Sofosbuvir Plus Ribavirin Without Interferon for Treatment of Acute Hepatitis C Virus Infection in HIV-1-Infected Individuals: SWIFT-C. Clin Infect Dis 2017; 64:1035-1042. [PMID: 28329053 DOI: 10.1093/cid/cix025] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 01/12/2017] [Indexed: 12/14/2022] Open
Abstract
Background Historically, acute hepatitis C virus (HCV) infection was treated with shorter durations of interferon-containing therapies. In the era of direct-acting antivirals (DAAs), it is unclear whether the efficacy of treatment achieved in chronic infection can be maintained with abbreviated courses of therapy during the acute phase. Methods The sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals (SWIFT-C) is an open-label, 2-cohort clinical trial in which the first cohort assessed for the safety and efficacy of 12 weeks of sofosbuvir plus ribavirin for the treatment of acute HCV infection in participants with chronic human immunodeficiency virus type 1 (HIV-1) infection. This is a preplanned analysis of the first cohort, which had a planned accrual of 17 participants. Results Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2 280 000 IU/mL (interquartile range, 272 000-4 230 000). Ten participants (59%) achieved the primary outcome of SVR12 (90% confidence interval, 36%-78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment. Conclusion Sofosbuvir-ribavirin for 12 weeks for the treatment of acute HCV genotype-1 infection in HIV-1-infected persons results in a high relapse rate. Preliminary studies of DAA combination therapies suggest improved response rates, although the adequate duration of therapy remains unclear. Clinical Trials Registration NCT02128217.
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Affiliation(s)
- Susanna Naggie
- Duke University Medical Center, Durham, North Carolina, USA
| | | | - Michael Hughes
- Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | | | | | - Arthur Kim
- Massachusetts General Hospital, Boston, USA
| | | | - Jhoanna Roa
- Social & Scientific Systems, Inc., Silver Spring, Maryland, USA
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14
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Abstract
Ultrasound elastography, also termed sonoelastography, is being used increasingly in clinical practice to aid the diagnosis and management of diffuse liver disease. Elastography has been shown to be capable of differentiating advanced and early-stage liver fibrosis, and consequently a major application in clinical liver care includes progression to cirrhosis risk stratification through (1) assessment of liver fibrosis stage in HCV and HBV patients, (2) distinguishing non-alcoholic steatohepatitis from simple steatosis in non-alcoholic fatty liver disease patients, and (3) prognostic evaluation of liver disease is autoimmune liver disease. In addition, elastographic characterization of focal liver lesions and evaluation of clinically significant portal hypertension have the potential to be clinically useful and are areas of active clinical research.
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Affiliation(s)
- Manish Dhyani
- Department of Radiology, Massachusetts General Hospital (MGH), Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA,
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Doyle JS, Deterding K, Grebely J, Wedemeyer H, Sacks-Davis R, Spelman T, Matthews G, Rice TM, Morris MD, McGovern BH, Kim AY, Bruneau J, Lloyd AR, Page K, Manns MP, Hellard ME, Dore GJ. Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort. J Viral Hepat 2015; 22:1020-32. [PMID: 26098993 PMCID: PMC4618180 DOI: 10.1111/jvh.12429] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 05/06/2015] [Indexed: 12/21/2022]
Abstract
Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention to treat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13-4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making.
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Affiliation(s)
- Joseph S. Doyle
- Centre for Population Health, Burnet Institute, Melbourne, Australia,School of Population Health and Preventive Medicine, Monash University, Melbourne, Australia,Department of Infectious Diseases, The Alfred Hospital, Melbourne, Australia
| | - Katja Deterding
- Hannover Medical School, Hannover, Germany,Hep-Net Study House: German Network of Competence on Viral Hepatitis, Germany
| | | | - Heiner Wedemeyer
- Hannover Medical School, Hannover, Germany,Hep-Net Study House: German Network of Competence on Viral Hepatitis, Germany,German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Rachel Sacks-Davis
- Centre for Population Health, Burnet Institute, Melbourne, Australia,School of Population Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Tim Spelman
- Centre for Population Health, Burnet Institute, Melbourne, Australia
| | | | - Thomas M. Rice
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
| | - Meghan D. Morris
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
| | | | | | | | - Andrew R. Lloyd
- School of Medical Sciences, UNSW Australia, Sydney, Australia
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
| | - Michael P. Manns
- Hannover Medical School, Hannover, Germany,Hep-Net Study House: German Network of Competence on Viral Hepatitis, Germany,German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Margaret E. Hellard
- Centre for Population Health, Burnet Institute, Melbourne, Australia,School of Population Health and Preventive Medicine, Monash University, Melbourne, Australia,Department of Infectious Diseases, The Alfred Hospital, Melbourne, Australia
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Zhang B, Nguyen NH, Yee BE, Yip B, Ayoub WS, Lutchman GA, Nguyen MH. Treatment of Acute Hepatitis C Infection with Pegylated Interferon and Ribavirin in Patients Coinfected with Human Immunodeficiency Virus: A Systematic Review and Meta-Analysis. Intervirology 2015; 58:242-9. [PMID: 26402746 PMCID: PMC8262400 DOI: 10.1159/000437427] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 07/05/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/AIMS Of the 35 million human immunodeficiency virus (HIV)-positive patients worldwide, 10-40% are coinfected with chronic hepatitis C virus (HCV). Compared to HCV-monoinfected patients, those coinfected experience decreased spontaneous HCV clearance, accelerated liver fibrosis, and a decreased response to anti-HCV therapy. We conducted a meta-analysis to estimate the efficacy of treating acute HCV in HIV-positive patients with peginterferon and ribavirin combination therapy. METHODS Two authors independently searched MEDLINE and EMBASE (2014) for English articles, and reviewed bibliographies and abstracts from major liver and HIV conferences (2011-2013). Original studies featuring at least 10 treatment-naive, HIV-positive adults infected with acute HCV and treated with peginterferon and ribavirin were included. Analyses were calculated using a random-effects model. Heterogeneity was assessed using the Cochrane Q test (p < 0.05) and the I(2) statistic (>50%). RESULTS From 12 studies (450 patients), the pooled sustained virological response (SVR) was 71.4% (95% CI 64.7-77.4; Q statistic = 22.20, p = 0.023, I(2) = 50.44). The rapid virological response (RVR; 7 studies, 196 patients) was 47.4% (95% CI 40.6-54.7), and the early virological response (EVR; 9 studies, 283 patients) was 82.8% (95% CI 67.0-92.0). The probability of an SVR was 93.1% (95% CI 84.9-97.0) in those who obtained an RVR (6 studies, 82 patients) and 85.9% (95% CI 78.7-91.0) if an EVR (7 studies, 168 patients) was reached. CONCLUSION Peginterferon with ribavirin is an effective option for treating acute HCV in HIV-positive patients, especially if they achieve an RVR or an EVR.
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Affiliation(s)
- Bing Zhang
- School of Medicine, University of California, San Diego, La Jolla, Calif
| | - Nghia H. Nguyen
- School of Medicine, University of California, San Diego, La Jolla, Calif
| | - Brittany E. Yee
- School of Medicine, University of California, San Diego, La Jolla, Calif
| | - Benjamin Yip
- Department of Internal Medicine, University of California, Irvine, Orange, Calif
| | - Walid S. Ayoub
- Department of Gastroenterology/Hepatology, Cedars-Sinai Medical Center, Los Angeles, Calif
| | - Glen A. Lutchman
- Division of Gastroenterology/Hepatology, Stanford University Medical Center, Palo Alto, Calif., USA
| | - Mindie H. Nguyen
- Division of Gastroenterology/Hepatology, Stanford University Medical Center, Palo Alto, Calif., USA
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17
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Matsuura K, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis C virus infection. J Med Virol 2015. [PMID: 26211651 DOI: 10.1002/jmv.24334] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The clinical course of hepatitis C virus (HCV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HCV infection. Recent genome-wide association studies identified several host genetic factors influencing treatment efficacy or clinical course in HCV infection. A landmark discovery was that IFNL3-IFNL4 variants are strongly associated with responses to interferon-based treatment. Genetic variants in IFNL3-IFNL4 as well as those in HLA class II loci influence the spontaneous clearance of acute HCV infection. Interestingly, these genetic variants also affect the activity of hepatitis, or disease progression in chronic hepatitis C. In addition, polymorphisms in apoptosis-related genes such as RNF7, TULP1, and MERTK are associated with fibrosis progression, and DEPDC5 and MICA variants are associated with HCV-related hepatocellular carcinoma. Understanding the genetic factors associated with the clinical course of HCV infection is essential for personalized treatment and surveillance of disease progression and hepatocellular carcinoma.
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Affiliation(s)
- Kentaro Matsuura
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.,Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.,Department of Transfusion Medicine, Clinical CenterInfectious Disease and Immunogenetics Section, National Institutes of Health, Bethesda, Maryland
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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Martinello M, Matthews GV. Enhancing the detection and management of acute hepatitis C virus infection. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2015; 26:899-910. [PMID: 26254495 DOI: 10.1016/j.drugpo.2015.07.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 06/07/2015] [Accepted: 07/07/2015] [Indexed: 12/23/2022]
Abstract
Acute HCV infection refers to the 6-month period following infection acquisition, although this definition is somewhat arbitrary. While spontaneous clearance occurs in approximately 25%, the majority will develop chronic HCV infection with the potential for development of cirrhosis, end stage liver disease and hepatocellular carcinoma. Detection of acute HCV infection has been hampered by its asymptomatic or non-specific presentation, lack of specific diagnostic tests and the inherent difficulties in identifying and following individuals at highest risk of transmitting and acquiring HCV infection, such as people who inject drugs (PWID). However, recognition of those with acute infection may have individual and population level benefits and could represent an ideal opportunity for intervention. Despite demonstration that HCV treatment is feasible and successful in PWID, treatment uptake remains low with multiple barriers to care at an individual and systems level. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment, treatment and prevention in this group are urgently needed. As the therapeutic landscape of chronic HCV management is revolutionised by the advent of simple, highly effective directly-acting antiviral (DAA) therapy, similar opportunities may exist in acute infection. This review will discuss issues surrounding improving the detection and management of acute HCV infection, particularly in PWID.
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Affiliation(s)
- Marianne Martinello
- The Kirby Institute, University of New South Wales, Wallace Wurth Building, Sydney, NSW 2052, Australia.
| | - Gail V Matthews
- The Kirby Institute, University of New South Wales, Wallace Wurth Building, Sydney, NSW 2052, Australia
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19
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Rossotti R, Baiguera C, Travi G, Pazzi A, Orso M, Puoti M. Acute HCV Infection: Diagnosis, Epidemiology and Current Treatment Options. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2015. [DOI: 10.1007/s40506-015-0045-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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20
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Occupational Exposures among Healthcare Workers: New Methods for Prevention and Recommended Postexposure Prophylaxis for HIV and Hepatitis B and C. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2015. [DOI: 10.1007/s40506-014-0036-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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21
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Sulkowski MS. Management of acute and chronic HCV infection in persons with HIV coinfection. J Hepatol 2014; 61:S108-19. [PMID: 25443339 DOI: 10.1016/j.jhep.2014.08.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/10/2014] [Accepted: 08/12/2014] [Indexed: 01/13/2023]
Abstract
Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection.
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Affiliation(s)
- Mark S Sulkowski
- Johns Hopkins University, School of Medicine, Baltimore, MD, United States.
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22
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23
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KASL clinical practice guidelines: management of hepatitis C. Clin Mol Hepatol 2014; 20:89-136. [PMID: 25032178 PMCID: PMC4099340 DOI: 10.3350/cmh.2014.20.2.89] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 05/20/2014] [Indexed: 12/16/2022] Open
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Santantonio T, Fasano M, Sagnelli E, Tundo P, Babudieri S, Fabris P, Toti M, Di Perri G, Marino N, Pizzigallo E, Angarano G. Acute hepatitis C: a 24-week course of pegylated interferon α-2b versus a 12-week course of pegylated interferon α-2b alone or with ribavirin. Hepatology 2014; 59:2101-9. [PMID: 24442928 DOI: 10.1002/hep.26991] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 11/19/2013] [Accepted: 12/23/2013] [Indexed: 01/01/2023]
Abstract
UNLABELLED Therapy of acute hepatitis C (AHC) has not yet been standardized and several issues are still unresolved. This open, randomized, multicenter trial aimed to assess the efficacy and safety of a 24-week course of pegylated IFN (Peg-IFN) alpha-2b versus a 12-week course of Peg-IFN alpha-2b alone or with ribavirin (RBV) in AHC patients. One hundred and thirty HCV acutely infected patients who did not spontaneously resolve by week 12 after onset were consecutively enrolled and randomized to receive Peg-IFN alpha-2b monotherapy (1.5 μg/kg/week) for 24 or 12 weeks (arm 1, n = 44 and arm 2, n = 43, respectively) or in combination with RBV (10.6 mg/kg/day) for 12 weeks (arm 3, n = 43). The primary endpoint was undetectable HCV RNA at 6-month posttreatment follow-up (sustained virological response; SVR). All patients were followed for 48 weeks after therapy cessation. HCV RNA levels were determined by real-time polymerase chain reaction (limit of detection: 15 IU/mL) at the central laboratory at baseline, week 4, end of treatment, and 6 and 12 months posttreatment. Using an intent-to-treat analysis, overall SVR rate was 71.5%. In particular, an SVR was achieved in 31 of 44 (70.5%), 31 of 43 (72.1%), and 31 of 43 (72.1%) patients in arms 1, 2, and 3, respectively (P = 0.898). Sixteen patients (12.3%) prematurely discontinued therapy or were lost to follow-up; thus, sustained response rates with per-protocol analysis were 81.6%, 81.6%, and 81.6% for patients in arms 1, 2, and 3 respectively. With multivariate analysis, virologic response at week 4 of treatment was an independent predictor of SVR. Peg-IFN alpha-2b was well tolerated. CONCLUSION Peg-IFN alpha-2b induces a high SVR in chronically evolving AHC patients. Response rates were not influenced by combination therapy or treatment duration.
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Sagnelli E, Santantonio T, Coppola N, Fasano M, Pisaturo M, Sagnelli C. Acute hepatitis C: clinical and laboratory diagnosis, course of the disease, treatment. Infection 2014; 42:601-10. [PMID: 24619833 DOI: 10.1007/s15010-014-0608-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 02/24/2014] [Indexed: 02/06/2023]
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Affiliation(s)
- J Harrison
- Imperial College Healthcare NHS Trust, London, UK.
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27
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Abstract
The acute phase of hepatitis C (HCV) infection is typically defined as the initial 6 months following exposure to the virus; however, in some individuals, the acute phase of the infection can last much longer (Orland et al. Hepatology 33:321-27, 2001). Although some patients have symptoms of acute hepatitis, most infected individuals are entirely asymptomatic. As a result, many patients are unaware of the infection until it progresses to chronic infection, and may not develop symptoms until decades later with the onset of decompensated cirrhosis or hepatocellular carcinoma (HCC). A substantial proportion (20-40%) of infected patients clear the virus during the acute phase. Interferon-based treatment is also much more likely to be successful in the acute phase of infection but is relatively poorly tolerated. Therefore, recognition of acute HCV infection is critical to prioritize those patients who do not spontaneously clear the infection for immediate therapy. However, the promise of highly effective well-tolerated all-oral therapies in development may alter the management approach. This review will focus on the epidemiology, natural history, diagnosis, and treatment of acute HCV infection.
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Affiliation(s)
- Suraj A Sharma
- Toronto Center for Liver Disease, Sandra Rotman Centre for Global Health, University Health Network, University of Toronto, 6B-Fell Pavilion, 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada
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Lee TH, Tillmann HL, Patel K. Individualized therapy for hepatitis C infection: focus on the interleukin-28B polymorphism in directing therapy. Mol Diagn Ther 2014; 18:25-38. [PMID: 24022240 DOI: 10.1007/s40291-013-0053-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus—a major global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma—affects millions of people worldwide. Pegylated interferon (Peg-IFN) and ribavirin (RBV) had been the standard treatment for a decade until availability of the protease inhibitors in 2011. However, current antiviral therapy is still IFN-based and is associated with significant side effects and variable treatment response. Thus, various host and viral factors have been evaluated before and during treatment for the prediction of sustained virologic response to antiviral therapy. In 2009, genome-wide association studies found the single-nucleotide polymorphisms, located near the host interleukin-28B (IL28B) gene that encodes IFN-λ3, to be the best pretreatment predictor of virologic response to Peg-IFN and RBV therapy in chronic hepatitis C genotype 1 patients. Additionally, inosine triphosphatase (ITPA) gene variants were found to be associated with RBV-induced hemolytic anemia, which could affect treatment dose for selected patients. IL28B, ITPA, and other treatment predictors allowed for a potential individualized approach to treat hepatitis C. In the era of increased overall virologic response rates and good tolerability of the rapidly developing non-IFN oral direct-acting antiviral therapy regimens, the need for individualized treatment is likely to diminish. Various predictors of response, including IL28B will likely be of reduced importance in the near future.
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Jones L, Atkinson A, Bates G, McCoy E, Porcellato L, Beynon C, McVeigh J, Bellis MA. Views and experiences of hepatitis C testing and diagnosis among people who inject drugs: systematic review of qualitative research. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2013; 25:204-11. [PMID: 24332457 DOI: 10.1016/j.drugpo.2013.11.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 10/30/2013] [Accepted: 11/11/2013] [Indexed: 11/26/2022]
Abstract
BACKGROUND Many developed countries are facing a major challenge to improve identification of individuals acutely and chronically infected with hepatitis C virus (HCV) infection. We explored the views and experiences of people who inject drugs (PWID) in relation to HCV testing, and diagnosis through a review and synthesis of qualitative research. METHODS Based on the thematic synthesis of qualitative research. Searches were conducted in 14 databases and supplemented by reference checking, hand searching of selected journals, and searches of relevant websites. Studies of any qualitative design that examined the views and experiences of, and attitudes towards, HCV testing and diagnosis among PWID or practitioners involved in their care were included. Key themes and sub-themes were systematically coded according to the meaning and content of the findings of each study which proceeded to the preparation of a narrative account of the synthesis. RESULTS 28 qualitative studies were identified. We identified a number of overarching descriptive themes in the literature, finding overall that PWID hold complex and differing views and experiences of testing and diagnosis. Three major themes emerged: missed opportunities for the provision of information and knowledge; shifting priorities between HCV testing and other needs; and testing as unexpected and routine. Evidence of missed opportunities for the provision of knowledge and information about HCV were clear, contributing to delays in seeking testing and providing a context to poor experiences of diagnosis. Influenced by the nature of their personal circumstances, perceptions of the risk associated with HCV and the prioritisation of other needs acted both to encourage and discourage the uptake of HCV testing. Undergoing HCV testing as part of routine health assessment, and an unawareness of being testing was common. An unexpected positive diagnosis exacerbated anxiety and confusion. CONCLUSION This review has identified that there are modifiable factors that affect the uptake of HCV testing and experiences of HCV diagnosis among PWID. Intervention development should focus on addressing these factors. There is a need for further research that engages PWID from a diverse range of populations to identify interventions, strategies and approaches that they consider valuable.
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Affiliation(s)
- L Jones
- Centre for Public Health, Faculty of Education, Health and Community, Liverpool John Moores University, 15-21 Webster Street, Liverpool L3 2ET, UK.
| | - A Atkinson
- Centre for Public Health, Faculty of Education, Health and Community, Liverpool John Moores University, 15-21 Webster Street, Liverpool L3 2ET, UK
| | - G Bates
- Centre for Public Health, Faculty of Education, Health and Community, Liverpool John Moores University, 15-21 Webster Street, Liverpool L3 2ET, UK
| | - E McCoy
- Centre for Public Health, Faculty of Education, Health and Community, Liverpool John Moores University, 15-21 Webster Street, Liverpool L3 2ET, UK
| | - L Porcellato
- Centre for Public Health, Faculty of Education, Health and Community, Liverpool John Moores University, 15-21 Webster Street, Liverpool L3 2ET, UK
| | - C Beynon
- Centre for Public Health, Faculty of Education, Health and Community, Liverpool John Moores University, 15-21 Webster Street, Liverpool L3 2ET, UK
| | - J McVeigh
- Centre for Public Health, Faculty of Education, Health and Community, Liverpool John Moores University, 15-21 Webster Street, Liverpool L3 2ET, UK
| | - M A Bellis
- Public Health Wales, Haydn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
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Beinhardt S, Payer BA, Datz C, Strasser M, Maieron A, Dorn L, Grilnberger-Franz E, Dulic-Lakovic E, Stauber R, Laferl H, Aberle JH, Holzmann H, Krall C, Vogel W, Ferenci P, Hofer H. A diagnostic score for the prediction of spontaneous resolution of acute hepatitis C virus infection. J Hepatol 2013; 59:972-7. [PMID: 23850880 DOI: 10.1016/j.jhep.2013.06.028] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 05/30/2013] [Accepted: 06/26/2013] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development of viral persistence and need for early antiviral treatment. METHODS 136 patients (74 male; 35 ± 15 years) were analyzed. From variables predictive of spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cut-offs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cut-offs were: (I) presence of IL28B C/C (p=0.027), (II) age (p=0.031; cut-off: 35 years), (III) peak-bilirubin (p=0.018; cut-off: 6 mg/dl), (IV) HCV-RNA decline within 4 weeks (p<0.001;cut-off: >2.5 log), (V) serum IP-10 (p=0.003; cut-off: 546 pg/ml), (VI) presence of CD4(+) Th1 cells (p=0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA decline of ≥ 1 log 10 but <2.5 log 10 to 1 point, a decline of ≥ 2.5 log 10 to 2 points. Three scores were evaluated (Score 1: I-IV; Score 2: I-V; Score 3: I-VI). RESULTS A cut-off of ≥ 3 points out of 5 in Score 1 (AUROC: 0.82; DeLong 95% CI: 0.76-0.93) predicted spontaneous clearance with a sensitivity of 71% (95% CI: 0.53-0.86) and specificity of 87% (95% CI: 0.73-0.95). PPV and NPV were 79% and 82%. Corresponding findings for Score 2 including IP-10 (AUROC: 0.93; DeLong 95% CI: 0.86-0.93) at a cut-off of ≥ 4 were: sensitivity 81%, specificity 95% (PPV: 100%; NPV: 77%). A cut-off of ≥ 5 in Score 3 (AUROC: 0.98; DeLong 95% CI: 0.95-1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV: 100%; NPV: 88%). CONCLUSIONS The scores enable a reliable discrimination between AHC-patients with high potential for spontaneous clearance from candidates for early therapeutic intervention due to marginal chance of spontaneous resolution.
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Affiliation(s)
- Sandra Beinhardt
- Internal Medicine III, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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Spada E, Amoroso P, Taliani G, Zuccaro O, Chiriacò P, Maio P, Maio G, Esposito ML, Mariano C, Rinaldi R, Bellissima P, Tosti ME, Del Porto P, Francavilla R, Mellace V, Garbuglia AR, Folgori A, Mele A. Role of IL28B gene polymorphism and cell-mediated immunity in spontaneous resolution of acute hepatitis C. Clin Infect Dis 2013; 57:803-11. [PMID: 23784926 PMCID: PMC3749747 DOI: 10.1093/cid/cit402] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 06/06/2013] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND A single-nucleotide polymorphism (SNP; rs12979860) near the IL28B gene has been associated with spontaneous and treatment-induced hepatitis C virus clearance. We investigated predictors of spontaneous disease resolution in a cohort of patients with acute hepatitis C (AHC), analyzing epidemiological, clinical and virological parameters together with IL28B.rs12979860 genotypes and cell-mediated immunity (CMI). METHODS Fifty-six symptomatic AHC patients were enrolled and followed prospectively. CMI was measured in 31 patients at multiple time points by interferon-γ enzyme-linked immunospot assay and was correlated to the IL28B.rs12979860 SNP. RESULTS Eighteen patients had a self-limiting AHC that was associated with female sex (P = .028), older age (P = .018), alanine aminotransferase level >1000 U/L (P = .027), total bilirubin level >7 mg/dL (P = .036), and IL28B.rs12979860 genotype CC (P = .030). In multivariate analysis, only CC genotype was independently associated with self-limiting AHC (odds ratio, 5.3; 95% confidence interval, 1.1-26.5). Patients with the CC genotype with self-limiting AHC had a stronger (P = .02) and broader (P = .013) CMI than patients with the CT genotype with chronically evolving AHC. In patients with chronically evolving disease, CC genotype was associated with a broader CMI compared to CT genotype (P = .028). A negative CMI was more frequently associated with CT genotype among persistently infected patients (P = .043) and with persistent infection among CT patients (P = .033). CONCLUSIONS . Self-limiting AHC was independently associated with CC genotype. The correlation between IL28B.rs12979860 genotypes and CMI is suggestive of a possible important role of CMI in favoring hepatitis C virus clearance in CC patients.
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Affiliation(s)
- Enea Spada
- National Centre of Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanità, Rome, Italy.
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Mangia A, Ripoli M. Insulin resistance, steatosis and hepatitis C virus. Hepatol Int 2013; 7 Suppl 2:782-9. [PMID: 24587848 PMCID: PMC3918408 DOI: 10.1007/s12072-013-9460-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 06/30/2013] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have shown an increased occurrence of metabolic disorders such as insulin resistance (IR) and steatosis in patients with hepatitis C virus (HCV) infection. IR is believed to represent one of the central clinical features of the "metabolic syndrome" and the major pathogenetic factor for type 2 diabetes mellitus. In patients with chronic HCV hepatitis, IR may have several dangerous consequences such as accelerated progression of liver fibrosis, resistance to antiviral therapy and development of hepatocellular carcinoma. According to recent evidence, the global epidemic of metabolic disorders related to incorrect diets will lead physicians to deal with 1.2 billion patients with diabetes in the world in 2025. Given the high prevalence of HCV infection in several countries, metabolic manifestations will contribute to increasing morbidity and mortality in patients with HCV chronic infection in the near future. HCV treatment, shown able to decrease both the occurrence of HCV-related IR and diabetes, may reduce the risk of the associated morbidities.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Maria Ripoli
- Liver Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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Mangia A, Santoro R, Copetti M, Massari M, Piazzolla V, Spada E, Cappucci G, Missale G, Mottola L, Agostinacchio E, Mauro LD, Zuccaro O, Maio P, Pellegrini F, Folgori A, Ferrari C. Treatment optimization and prediction of HCV clearance in patients with acute HCV infection. J Hepatol 2013; 59:221-8. [PMID: 23587473 DOI: 10.1016/j.jhep.2013.04.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Revised: 04/04/2013] [Accepted: 04/06/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The lack of consensus on the optimal timing, regimen, and duration of treatment, in patients with acute HCV infection, stimulates the research on both favourable outcome predictors and individualized treatment regimens. This study aimed at investigating the impact of IL28B SNP rs12979860 alone or in combination with HLA class II alleles in both predicting spontaneous viral clearance and individualizing treatment strategies for patients with HCV persistence, after acute HCV exposure. METHODS 178 patients with AHC, consecutively treated with interferon alone or in combination with ribavirin, starting within or after 48 weeks from the diagnosis of AHC, were tested for IL28B SNPs and HLA class II alleles. RESULTS Spontaneous viral clearance was achieved in 28% of 169 patients available for genetic testing. Factors associated with HCV elimination were jaundice (OR 2.75, 95% CI 1.31-5.77) and IL28B CC (OR 3.87, CI 1.71-8.51), but not HLA alleles. In CT/TT patients without jaundice, NPV for virus persistence was 98%. In patients with IL28B CT/TT, starting treatment 48 weeks after the onset was significantly associated with lower rates of response (28% vs. 100%, p=0.027). By contrast, no significant differences in the rate of SVR were observed for CC carriers who started treatment later (65% vs. 85%, p=1.0). CONCLUSIONS In patients with acute HCV hepatitis, lack of viral clearance may be predicted by absence of jaundice and IL28B CT/TT genotype; in patients with these characteristics, treatment needs to be started immediately.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
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Tillmann HL, Smith AD. Treatment of Acute Hepatitis, Severe Acute Hepatitis, and Acute Liver Failure. VIRAL HEPATITIS 2013:468-485. [DOI: 10.1002/9781118637272.ch34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Perzynski AT, Terchek JJ, Blixen CE, Dawson NV. Playing the numbers: how hepatitis C patients create meaning and make healthcare decisions from medical test results. SOCIOLOGY OF HEALTH & ILLNESS 2013; 35:610-627. [PMID: 23009649 DOI: 10.1111/j.1467-9566.2012.01516.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
In this article we describe how patients assign meanings to medical test results and use these meanings to justify their actions. Evidence is presented from lay interpretations of medical tests for monitoring hepatitis C viral infection (HCV) to show how numeracy becomes embodied in the absence of physical symptoms. Illness narratives from 307 individuals infected with HCV were collected from the internet and analysed qualitatively. As part of standard medical care, chronically infected HCV patients are required to have periodic blood tests for laboratory testing. The lab results are presented numerically and compared with established physiological standards. HCV patients' knowledge and interpretations of test results have important consequences for their health behaviour and their medical decisions. In their stories, the patients described their decisions to begin, delay or stop treatment and developed strategies to alter their diet, exercise and use alternative therapies according to changes in their test result. The perceived meanings of test results are powerful signifiers that are capable of altering the course of HCV patients' illness, lives and stories. An interpretive model of health numeracy has the advantage of promoting understanding between patients and healthcare providers over a model that views innumeracy as a skill deficit.
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Affiliation(s)
- Adam T Perzynski
- Center for Health Care Research and Policy, Case Western Reserve University at MetroHealth Medical Center, Cleveland OH 44109–1998, USA.
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Samala NR, Ghany MG. Acute hepatitis C: to treat or not to treat. THE LANCET. INFECTIOUS DISEASES 2013; 13:467-8. [PMID: 23523673 DOI: 10.1016/s1473-3099(13)70075-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Niharika R Samala
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1800, USA
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Kim AY, Nagami EH, Birch CE, Bowen MJ, Lauer GM, McGovern BH. A simple strategy to identify acute hepatitis C virus infection among newly incarcerated injection drug users. Hepatology 2013; 57:944-52. [PMID: 23111904 PMCID: PMC3712277 DOI: 10.1002/hep.26113] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 10/14/2012] [Indexed: 01/17/2023]
Abstract
UNLABELLED Acute hepatitis C virus (HCV) infection is underdiagnosed because most patients are asymptomatic. The majority of new infections occur among people who inject drugs (PWID), many of whom have a history of incarceration. In a previous pilot study, we identified symptomatic HCV cases, mainly among Caucasian inmates. We designed a cross-sectional study to evaluate whether risk factor-based screening of newly incarcerated inmates would enhance identification of asymptomatic acute HCV infection and elucidate any demographic shifts in HCV acquisition. From October 2006 to March 2008, 6,342 inmates underwent health assessments and 3,470 inmates (55%) were screened. The racial distribution was as follows: African American, 24.0%; Caucasian, 49.5%; Hispanic, 22.2%. One hundred seventy-one inmates (4.9%) were classified as high-risk. After further evaluation, 35 (20.5%) inmates were diagnosed with acute HCV with a mean age of 29 years; 62.9% were female and 91% were Caucasian. No African Americans were diagnosed with acute HCV. Our case-finding rate was 1.9 patients/month nearly a three-fold increase compared with our historical control period with a higher proportion of asymptomatic cases. We estimate a prevalence of ∼1.0% (95% confidence interval, 0.7%-1.4%) of acute HCV infections among newly incarcerated inmates. CONCLUSION Within the correctional system, systematic screening based on risk factors successfully identifies acute HCV infection among PWID, including asymptomatic patients. Our data also reflect changing nationwide patterns of injection drug use that vary by age, ethnicity, and race, leading to a marked reduction of acute HCV infections among African Americans compared with non-Hispanic whites. The nationwide implementation of this simple low-cost strategy in prison-based settings could identify more than 7,000 acute HCV infections among PWID, provide insight into changing epidemiologic trends, and facilitate appropriate therapeutic and preventive interventions.
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Affiliation(s)
- Arthur Y Kim
- Division of Infectious Diseases, Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Harvard University Center for AIDS Research, Boston, MA 02114, USA.
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Deutsch M, Papadopoulos N, Hadziyannis ES, Koskinas J. Clinical characteristics, spontaneous clearance and treatment outcome of acute hepatitis C: a single tertiary center experience. Saudi J Gastroenterol 2013; 19:81-5. [PMID: 23481134 PMCID: PMC3632015 DOI: 10.4103/1319-3767.108479] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND AIMS Acute hepatitis C is rarely diagnosed due to its predominantly asymptomatic course. However, early treatment results in viral eradication in a high number of patients thus, preventing chronicity. The aim of our study was to describe our experience with patients with acute hepatitis C virus (HCV) infection who presented and followed-up in our liver unit, pointing on treatment strategy, and outcome. PATIENTS AND METHODS Retrospective, descriptive study of 30 patients with acute HCV infection (26 males and 4 females) with a mean age of 32 years. RESULTS The source of infection was mainly injection drug use in 17/30 (56.7) and medical procedures 6/30 (20%). Twenty patients (66.6%) were symptomatic. HCV-ribonucleic acid (RNA) was detectable at presentation in 26 (86.7%) patients. The genotype distribution was: 13/26 (50%) genotype 1, 3/26 (11.5%) genotype 2, 8/26 (30.8%) genotype 3 and 2/26 (7.7%) genotype 4. Totally, 9 patients (30%) experienced spontaneous viral eradication. No significant differences could be documented between patients who spontaneously cleared the virus and those who had viral persistence. Thirteen patients (44%) were treated with peginterferon-based regimen. All patients (100%) achieved non-detectable HCV-RNA and had normal serum alanine aminotransferase levels at the end of the treatment. Eleven patients achieved sustained virologic response (SVR), one relapsed and one was lost to follow-up. The overall SVR rate was 84.6%. None of the patients required dose reduction or stopped the treatment due to side effects. CONCLUSION In conclusion, early initiation of anti-viral treatment in patients with acute hepatitis C results in high-SVR rates (independently of genotype) and is well-tolerated.
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Affiliation(s)
- Melanie Deutsch
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Greece
| | - Nikolaos Papadopoulos
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Greece,Address for correspondence: Dr. Nikolaos Papadopoulos, 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, 114 Vas. Sophias Ave., 115 27 Athens,, Greece E-mail:
| | - Emilia S. Hadziyannis
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Greece
| | - John Koskinas
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Greece
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Hajarizadeh B, Grebely J, Dore GJ. Case definitions for acute hepatitis C virus infection: a systematic review. J Hepatol 2012; 57:1349-60. [PMID: 22796896 DOI: 10.1016/j.jhep.2012.07.007] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 07/03/2012] [Accepted: 07/05/2012] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Case definitions for recent hepatitis C virus (HCV) infection vary considerably between studies. The aim of this systematic review was to characterize case definitions for recent HCV and explore the heterogeneity in studies performed to date. METHODS A systematic literature search of MEDLINE, SCOPUS, and ISI Web of Knowledge was performed covering all studies of recent HCV infection cited between January 2000 and June 2011. The criteria used by each study to define cases of recent HCV infection were extracted, structured, and analyzed. RESULTS Overall, 195 articles were included, with 87% (n=169) providing a clear case definition for recent HCV infection. The most frequently used individual criteria for defining a case included HCV antibody seroconversion (77%), alanine aminotransferase (ALT) elevation (68%), and HCV RNA detection (63%). In studies using HCV antibody seroconversion, the window period between the last negative and the first positive antibody test varied widely across studies (4 weeks to 4 years). Considerable diversity was also observed with respect to the ALT threshold used to characterize ALT elevations, ranging from 2 to 20 times the upper limit of normal. HCV antibody seroconversion was used as a single criterion in 41% of the studies, while all other studies used at least two criteria (range: 2-9). Epidemiology/surveillance studies mostly used a more sensitive case definition, whereas treatment studies, natural history studies, and diagnosis studies used more specific case definitions. CONCLUSIONS Marked heterogeneity in case definitions for recent HCV infection was observed. Although a single case definition for recent HCV is not warranted, a degree of standardization within specific study categories would enable improved cross-study comparison and more uniform evaluation of HCV prevention and management strategies.
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Affiliation(s)
- Behzad Hajarizadeh
- Viral Hepatitis Clinical Research Program, The Kirby Institute, The University of New South Wales (UNSW), Sydney, NSW, Australia.
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Naggie S. Management of hepatitis C virus infection: the basics. TOPICS IN ANTIVIRAL MEDICINE 2012; 20:154-61. [PMID: 23363693 PMCID: PMC3690573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Chronic hepatitis C virus (HCV) infection affects some 170 million people worldwide, including 3 to 4 million in the United States who are largely unaware of their infection status. HCV has 6 genotypes; genotype 1 is the most common in the United States and genotypes 1 and 4 are less responsive to interferon alfa-based therapy than the other genotypes. Treatment with available direct-acting antiviral (DAA) drugs has increased sustained virologic response (SVR) rates in genotype 1 infection and shortened duration of therapy in many patients, but at this time these agents must still be administered with peginterferon alfa and ribavirin to prevent rapid emergence of resistance. Baseline predictors of response to therapy continue to play a role with triple-drug combination therapy including the pharmacogenetic IL28B genotype, which differs in prevalence throughout the world. The stopping/futility rules are different for triple-drug combination therapy, allowing for earlier decision-making. Ultimately, SVR is the goal of HCV treatment because it dramatically reduces likelihood of poor long-term outcome, even among patients with histologically advanced disease. This article summarizes a basic review presented by Susanna Naggie, MD, at the IAS-USA live management of HCV continuing medical education program held in Atlanta in October 2012. This article is intended for practitioners who are new to HCV management or who are interested in reviewing the basics of HCV treatments.
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Grebely J, Morris MD, Rice TM, Bruneau J, Cox AL, Kim AY, McGovern BH, Shoukry NH, Lauer G, Maher L, Lloyd AR, Hellard M, Prins M, Dore GJ, Page K. Cohort profile: the international collaboration of incident HIV and hepatitis C in injecting cohorts (InC3) study. Int J Epidemiol 2012. [PMID: 23203695 DOI: 10.1093/ije/dys167] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study is an international multi-cohort project of pooled biological and behavioural data from nine prospective cohorts of people who inject drugs (PWID). InC(3) brings together researchers from Australia, Canada, USA and the Netherlands with expertise in epidemiology, biostatistics, clinical and behavioural sciences, virology and immunology to investigate research questions relevant to hepatitis C virus (HCV) and HIV outcomes. InC(3) was established to: (i) create a merged multi-cohort study of pooled data from well-characterized cohorts of PWID with prospective data on HIV and HCV infections, with a particular focus on HCV; (ii) facilitate new studies not possible within individual cohorts; and (iii) bring together researchers across disciplines to answer a broad range of research questions. Study cohorts identify acute HCV cases through follow-up of high-risk HCV antibody-negative PWID or through clinical referral networks. To date, data from 1986 to 2010 have been received from all contributing cohorts, with 821 HCV-infected and 1216 HCV-uninfected participants (overall, n = 2037). Data collected include demographics, host genetics, HCV ribonucleic acid testing, alanine aminotransferase testing, HIV/hepatitis B virus testing, HCV therapy, loss to follow-up and mortality. Potential collaborators should contact the InC(3) PI Dr Kimberley Page (kPage@psg.ucsf.edu) for further information.
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Affiliation(s)
- Jason Grebely
- The Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, New South Wales, Australia, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA, CRCHUM, Université de Montréal, Montreal, Quebec, Canada, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA, Harvard Medical School, Boston, MA, USA, Tufts Medical School, Boston, MA, USA, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia, Burnet Institute, Melbourne, Victoria, Australia, Cluster Infectious Diseases, Public Health Service, Amsterdam, Netherlands and Department of Internal Medicine, Academic Medical Center, Center for Infection and Immunity, Amsterdam, Netherlands
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Tohme RA, Xing J, Liao Y, Holmberg SD. Hepatitis C testing, infection, and linkage to care among racial and ethnic minorities in the United States, 2009-2010. Am J Public Health 2012; 103:112-9. [PMID: 23153151 DOI: 10.2105/ajph.2012.300858] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES We estimated rates and determinants of hepatitis C virus (HCV) testing, infection, and linkage to care among US racial/ethnic minorities. METHODS We analyzed the Racial and Ethnic Approaches to Community Health Across the US Risk Factor Survey conducted in 2009-2010 (n = 53,896 minority adults). RESULTS Overall, 19% of respondents were tested for HCV. Only 60% of those reporting a risk factor were tested, with much lower rates among Asians reporting injection drug use (40%). Odds of HCV testing decreased with age and increased with higher education. Of those tested, 8.3% reported HCV infection. Respondents with income of $75,000 or more were less likely to report HCV infection than those with income less than $25,000. College-educated non-Hispanic Blacks and Asians had lower odds of HCV infection than those who did not finish high school. Of those infected, 44.4% were currently being followed by a physician, and 41.9% had taken HCV medications. CONCLUSIONS HCV testing and linkage to care among racial/ethnic minorities are suboptimal, particularly among those reporting HCV risk factors. Socioeconomic factors were significant determinants of HCV testing, infection, and access to care. Future HCV testing and prevention activities should be directed toward racial/ethnic minorities, particularly those of low socioeconomic status.
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Affiliation(s)
- Rania A Tohme
- Division of Viral Hepatitis, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA.
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Feinstone SM, Hu DJ, Major ME. Prospects for prophylactic and therapeutic vaccines against hepatitis C virus. Clin Infect Dis 2012; 55 Suppl 1:S25-32. [PMID: 22715210 DOI: 10.1093/cid/cis362] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Natural cross-protective immunity is induced after spontaneous clearance of primary hepatitis C virus (HCV) infection. Although this suggests that effective prophylactic vaccines against HCV are possible, there are still several areas that require further study. Current data indicate that, at best, vaccine-induced immunity may not completely prevent HCV infection but rather prevent persistence of the virus. However, this may be an acceptable goal, because chronic persistence of the virus is the main cause of pathogenesis and the development of serious liver conditions. Therapeutic vaccine development is also highly challenging; however, strategies have been pursued in combination with current or new treatments in an effort to reduce the costs and adverse effects associated with antiviral therapy. This review summarizes the current state of HCV vaccines and the challenges faced for future development and clinical trial design.
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Affiliation(s)
- Stephen M Feinstone
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
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Doyle JS, Sacks-Davis R, Hellard ME. Acute Hepatitis C Infection: New Approaches to Surveillance, Treatment and Prevention. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s11901-012-0143-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Feld JJ. Treatment indication and response to standard of care with peginterferon and ribavirin in acute and chronic HCV infection. Best Pract Res Clin Gastroenterol 2012. [PMID: 23199502 DOI: 10.1016/j.bpg.2012.09.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Great strides have been made in the treatment of hepatitis C virus (HCV) infection in the past decade. Although there is much focus on the development of new direct-acting antivirals (DAA), interferon and ribavirin remain the backbone of therapy for both acute and chronic HCV infections. While DAA therapy will likely eventually largely replace interferon, in much of the world and for genotype non-1 patients, peginterferon and ribavirin remain first-line therapy. Interferon-based therapy is highly effective in acute HCV with high response rates with short courses of therapy. Unfortunately once infection progresses to chronicity, treatment success rates drop off considerably. The indications, pre-treatment evaluation and efficacy of peginterferon and ribavirin therapy in the treatment of acute and chronic HCV infection are discussed with strategies to improve outcomes and manage adverse events.
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Affiliation(s)
- Jordan J Feld
- Toronto Western Hospital Liver Centre, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Canada.
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Deuffic-Burban S, Castel H, Wiegand J, Manns MP, Wedemeyer H, Mathurin P, Yazdanpanah Y. Immediate vs. delayed treatment in patients with acute hepatitis C based on IL28B polymorphism: a model-based analysis. J Hepatol 2012; 57:260-6. [PMID: 22521356 DOI: 10.1016/j.jhep.2012.03.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Revised: 03/06/2012] [Accepted: 03/12/2012] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Timing of treatment initiation in acute hepatitis C (AHC) patients is unclear. Spontaneous viral clearance argues for a "watch-and-wait" strategy. However, early initiation of treatment could increase the sustained virological response (SVR) rate. We compared three different HCV treatment initiation strategies in patients with AHC according to presence of clinical symptoms and IL28B polymorphism: (1) within 2 months after transmission (immediate initiation), (2) at 3 months (early initiation), and (3) at 4/5 months (delayed initiation). METHODS We calculated spontaneous HCV clearance probability based on the symptomatic (sAHC) and asymptomatic (aAHC) nature of disease and C/C or non-C/C genotype. We used different SVR probabilities according to delay between transmission and treatment. We estimated the probability of developing chronic hepatitis C (CHC). RESULTS The probability of developing CHC was lower for immediate treatment initiation (7.1% in C/C and 7.3% in non-C/C patients with sAHC; 6.6% in C/C and 7.1% in non-C/C patients with aAHC) than for delayed initiation (13.5% in C/C and 18.0% in non-C/C patients with sAHC; 14.6% in C/C and 18.5% in non-C/C patients with aAHC) regardless of the presence of symptoms or IL28B genotype. CONCLUSIONS In patients such as health care workers, in whom HCV is detected ≤ 2 months following transmission, treatment should be immediately initiated regardless of clinical symptoms and IL28B polymorphism. In those in whom HCV is detected>2 months after transmission, treatment 4/5 months after may be preferable because of a higher rate of spontaneous HCV clearance after 2 months and a poor HCV treatment efficacy's differential between months 3 and 4/5.
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Affiliation(s)
- Sylvie Deuffic-Burban
- Inserm ATIP-AVENIR Modélisation, aide à la décision et coût-efficacité en maladies infectieuses, Lille/Paris, France.
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Griffiths P. Wish list for viral vaccinologists. Rev Med Virol 2012; 22:281-4. [PMID: 22836674 DOI: 10.1002/rmv.1726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Omata M, Kanda T, Yu ML, Yokosuka O, Lim SG, Jafri W, Tateishi R, Hamid SS, Chuang WL, Chutaputti A, Wei L, Sollano J, Sarin SK, Kao JH, McCaughan GW. APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int 2012; 6:409-435. [PMID: 26201405 DOI: 10.1007/s12072-012-9342-y] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Accepted: 01/21/2012] [Indexed: 12/13/2022]
Abstract
The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the "APASL Consensus Statements and Management Algorithms for Hepatitis C Virus Infection" in December, 2010, in order to revise "Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection (J Gastroenterol Hepatol 22:615-633, 2007)". The working party consisted of expert hepatologists from the Asian-Pacific region gathered at Makuhari, Chiba, Japan on 19 December 2010. New data were presented, discussed and debated to draft a revision. Participants of the consensus meeting assessed the quality of cited studies. Finalized recommendations are presented in this review.
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Affiliation(s)
- Masao Omata
- Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan.
- The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Tatsuo Kanda
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ming-Lung Yu
- Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
- Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Osamu Yokosuka
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Seng-Gee Lim
- National University Hospital, Singapore, Singapore
| | | | - Ryosuke Tateishi
- The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | | | - Wan-Long Chuang
- Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Lai Wei
- Peking University People's Hospital, Beijing, China
| | - Jose Sollano
- University Santo Tomas Hospital, Manila, Philippines
| | | | - Jia-Horng Kao
- National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Geoffrey W McCaughan
- Royal Prince Alfred Hospital, Centenary Institute, University of Sydney, Sydney, Australia
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Beinhardt S, Aberle JH, Strasser M, Dulic-Lakovic E, Maieron A, Kreil A, Rutter K, Staettermayer AF, Datz C, Scherzer TM, Strassl R, Bischof M, Stauber R, Bodlaj G, Laferl H, Holzmann H, Steindl-Munda P, Ferenci P, Hofer H. Serum level of IP-10 increases predictive value of IL28B polymorphisms for spontaneous clearance of acute HCV infection. Gastroenterology 2012; 142:78-85.e2. [PMID: 22192885 DOI: 10.1053/j.gastro.2011.09.039] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2011] [Revised: 09/01/2011] [Accepted: 09/10/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Single nucleotide polymorphisms (SNPs) in IL28B and serum levels of interferon γ inducible protein 10 (IP-10) predict outcomes of antiviral therapy in patients with chronic hepatitis C. We associated IL28B SNPs rs12979860 and rs8099917, along with serum levels of IP-10, with outcomes of patients with acute hepatitis C (AHC). METHODS We studied 120 patients with AHC (64 male; 37 ± 16 years old) and 96 healthy individuals (controls). The IL28B SNPs rs12979860 and rs8099917 were detected using real-time polymerase chain reaction; serum concentrations of IP-10 were measured by enzyme-linked immunosorbent assays of 62 patients with AHC. RESULTS Hepatitis C virus was cleared spontaneously from 59 patients (49.2%). The IL28B rs12979860 C/C genotype was more frequent among patients with AHC than controls (62.5% vs 39.6%; P < .001) and among patients with spontaneous clearance than those without (74.6% vs 51.7%; P = .02) (positive predictive value, 60.3%). Patients with IL28B rs12979860 C/C more frequently developed jaundice (53.2% vs 27.6%; P = .022) than carriers of the T allele. The median level of IP-10 was lower among patients with AHC and spontaneous clearance (764 [113-2470] pg/mL) than those without spontaneous clearance (1481 [141-4412] pg/mL; P = .006). Based on receiver operating characteristic analysis, 540 pg/mL IP-10 was set as the cutoff for patients most likely to have spontaneous clearance (positive predictive value, 71.4%; negative predictive value, 65.9%). Including data on IP-10 levels increased the ability of the IL28B rs12979860 C/C to identify patients most likely to have spontaneous clearance (83% of those who had an IP-10 level <540 pg/mL and 32% who had an IP-10 level >540 pg/mL) (P < .01). CONCLUSIONS The combination of serum level of IP-10 and SNPs in IL28B can identify patients with AHC who are most likely to undergo spontaneous clearance and those in need of early antiviral therapy.
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Affiliation(s)
- Sandra Beinhardt
- Internal Medicine III, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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