Browsing by Subject "Hepacivirus"

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    ItemOpen Access
    A minimal monitoring approach for the treatment of hepatitis C virus infection (ACTG A5360 [MINMON]): a phase 4, open-label, single-arm trial.
    (The lancet. Gastroenterology & hepatology, 2022-04) Solomon, Sunil S; Wagner-Cardoso, Sandra; Smeaton, Laura; Sowah, Leonard A; Wimbish, Chanelle; Robbins, Gregory; Brates, Irena; Scello, Christine; Son, Annie; Avihingsanon, Anchalee; Linas, Benjamin; Anthony, Donald; Nunes, Estevão Portela; Kliemann, Dimas A; Supparatpinyo, Khuanchai; Kityo, Cissy; Tebas, Pablo; Bennet, Jaclyn Ann; Santana-Bagur, Jorge; Benson, Constance A; Van Schalkwyk, Marije; Cheinquer, Nelson; Naggie, Susanna; Wyles, David; Sulkowski, Mark

    Background

    Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment.

    Methods

    ACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA >1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210.

    Findings

    Between Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment.

    Interpretation

    In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda.

    Funding

    US National Institutes of Health and Gilead Sciences.
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    Community-based HCV screening: knowledge and attitudes in a high risk urban population.
    (BMC Infect Dis, 2014-02-10) Norton, Brianna L; Voils, Corrine I; Timberlake, Sarah H; Hecker, Emily J; Goswami, Neela D; Huffman, Kim M; Landgraf, Anneka; Naggie, Susanna; Stout, Jason E
    BACKGROUND: In an attempt to curtail the rising morbidity and mortality from undiagnosed HCV (hepatitis C virus) in the United States, screening guidelines have been expanded to high-risk individuals and persons born 1945-1965. Community-based screening may be one strategy in which to reach such persons; however, the acceptance of HCV testing, when many high-risk individuals may not have access to HCV specific medications, remains unknown. METHODS: We set out to assess attitudes about HCV screening and knowledge about HCV disease at several community-based testing sites that serve high-risk populations. This assessment was paired with a brief HCV educational intervention, followed by post-education evaluation. RESULTS: Participants (n = 140) were surveyed at five sites; two homeless shelters, two drug rehabilitation centers, and a women's "drop-in" center. Personal acceptance of HCV testing was almost unanimous, and 90% of participants reported that they would still want to be tested even if they were unable to receive HCV treatment. Baseline hepatitis C knowledge was poor; however, the brief educational intervention significantly improved knowledge and increased acceptability of testing when medical access issues were explicitly stated. CONCLUSIONS: Despite inconsistencies in access to care and treatment, high-risk communities want to know their HCV status. Though baseline HCV knowledge was poor in this population, a brief on-site educational intervention improved both knowledge and acceptability of HCV testing and care. These data support the establishment of programs that utilize community-based screening, and also provide initial evidence for acceptance of the implementation of the recently expanded screening guidelines among marginalized communities.
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    Differential prevalence and geographic distribution of hepatitis C virus genotypes in acute and chronic hepatitis C patients in Vietnam.
    (PloS one, 2019-01) Le Ngoc, Chau; Tran Thi Thanh, Thanh; Tran Thi Lan, Phuong; Nguyen Mai, Trinh; Nguyen Hoa, Trang; Nghiem My, Ngoc; Le Van, Tan; Le Manh, Hung; Le Thanh, Phuong; Nguyen Van Vinh, Chau; Thwaites, Guy; Cooke, Graham; Heilek, Gabrielle M; Shikuma, Cecilia; Le, Thuy; Baker, Stephen; Rahman, Motiur; VIZIONS consortium
    BACKGROUND:The highest burden of disease from hepatitis C virus (HCV) is found in Southeast Asia, but our understanding of the epidemiology of infection in many heavily burdened countries is still limited. In particular, there is relatively little data on acute HCV infection, the outcome of which can be influenced by both viral and host genetics which differ within the region. We studied HCV genotype and IL28B gene polymorphism in a cohort of acute HCV-infected patients in Southern Vietnam alongside two other cohorts of chronic HCV-infected patients to better understand the epidemiology of HCV infection locally and inform the development of programs for therapy with the increasing availability of directly acting antiviral therapy (DAAs). METHODS:We analysed plasma samples from patients with acute and chronic HCV infection, including chronic HCV mono-infection and chronic Human Immunodeficiency Virus (HIV)-HCV coinfection, who enrolled in four epidemiological or clinical research studies. HCV infection was confirmed with RNA testing. The 5' UTR, core and NSB5 regions of HCV RNA positive samples were sequenced, and the genotype and subtype of the viral strains were determined. Host DNA from all HCV positive patients and age- and sex-matched non-HCV-infected control individuals were analysed for IL28B single nucleotide polymorphism (SNP) (rs12979860 and rs8099917). Geolocation of the patients were mapped using QGIS. RESULTS:355 HCV antibody positive patients were analysed; 54.6% (194/355) and 46.4% (161/355) were acute and chronic infections, respectively. 50.4% (81/161) and 49.6.4% (80/161) of chronic infections had HCV mono-infection and HIV-HCV coinfection, respectively. 88.7% (315/355) and 10.1% (36/355) of the patients were from southern and central regions of Vietnam, respectively. 92.4% (328/355) of patients were HCV RNA positive, including 86.1% (167/194) acute and 100% (161/161) chronic infections. Genotype could be determined in 98.4% (322/328) patients. Genotypes 1 (56.5%; 182/322) and 6 (33.9%; 109/322) predominated. Genotype 1 including genotype 1a was significantly higher in HIV-HCV coinfected patients compared to acute HCV patients [43.8% (35/80) versus 20.5% (33/167)], (p = <0.001), while genotype 6 was significantly higher in chronic HCV mono-infected patients [(44.4% (36/81) versus 20.0% (16/80)] (p = < 0.004) compared to HIV-HCV coinfected patients. The prevalence of IL28B SNP (rs12979860) homozygous CC was 86.46% (83/96) in control individuals and was significantly higher in acutely-infected compared to chronically-infected patients [93.2 (82/88) versus 76.1% (35/46)] (p = < 0.005). CONCLUSION:HCV genotype 6 is highly prevalent in Vietnam and the high prevalence in treatment naïve chronic HCV patients may results from poor spontaneous clearance of acute HCV infection with genotype 6.
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    Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing.
    (PLoS Pathog, 2012) Li, Hui; Stoddard, Mark B; Wang, Shuyi; Blair, Lily M; Giorgi, Elena E; Parrish, Erica H; Learn, Gerald H; Hraber, Peter; Goepfert, Paul A; Saag, Michael S; Denny, Thomas N; Haynes, Barton F; Hahn, Beatrice H; Ribeiro, Ruy M; Perelson, Alan S; Korber, Bette T; Bhattacharya, Tanmoy; Shaw, George M
    A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.
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    IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria.
    (PLoS One, 2014) Hwang, Kwan-Ki; Trama, Ashley M; Kozink, Daniel M; Chen, Xi; Wiehe, Kevin; Cooper, Abby J; Xia, Shi-Mao; Wang, Minyue; Marshall, Dawn J; Whitesides, John; Alam, Munir; Tomaras, Georgia D; Allen, Steven L; Rai, Kanti R; McKeating, Jane; Catera, Rosa; Yan, Xiao-Jie; Chu, Charles C; Kelsoe, Garnett; Liao, Hua-Xin; Chiorazzi, Nicholas; Haynes, Barton F
    B-cell chronic lymphocytic leukemia (B-CLL) patients expressing unmutated immunoglobulin heavy variable regions (IGHVs) use the IGHV1-69 B cell receptor (BCR) in 25% of cases. Since HIV-1 envelope gp41 antibodies also frequently use IGHV1-69 gene segments, we hypothesized that IGHV1-69 B-CLL precursors may contribute to the gp41 B cell response during HIV-1 infection. To test this hypothesis, we rescued 5 IGHV1-69 unmutated antibodies as heterohybridoma IgM paraproteins and as recombinant IgG1 antibodies from B-CLL patients, determined their antigenic specificities and analyzed BCR sequences. IGHV1-69 B-CLL antibodies were enriched for reactivity with HIV-1 envelope gp41, influenza, hepatitis C virus E2 protein and intestinal commensal bacteria. These IGHV1-69 B-CLL antibodies preferentially used IGHD3 and IGHJ6 gene segments and had long heavy chain complementary determining region 3s (HCDR3s) (≥21 aa). IGHV1-69 B-CLL BCRs exhibited a phenylalanine at position 54 (F54) of the HCDR2 as do rare HIV-1 gp41 and influenza hemagglutinin stem neutralizing antibodies, while IGHV1-69 gp41 antibodies induced by HIV-1 infection predominantly used leucine (L54) allelic variants. These results demonstrate that the B-CLL cell population is an expansion of members of the innate polyreactive B cell repertoire with reactivity to a number of infectious agent antigens including intestinal commensal bacteria. The B-CLL IGHV1-69 B cell usage of F54 allelic variants strongly suggests that IGHV1-69 B-CLL gp41 antibodies derive from a restricted B cell pool that also produces rare HIV-1 gp41 and influenza hemagglutinin stem antibodies.
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    Testing and Clinical Management of Health Care Personnel Potentially Exposed to Hepatitis C Virus - CDC Guidance, United States, 2020.
    (MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports, 2020-07) Moorman, Anne C; de Perio, Marie A; Goldschmidt, Ronald; Chu, Carolyn; Kuhar, David; Henderson, David K; Naggie, Susanna; Kamili, Saleem; Spradling, Philip R; Gordon, Stuart C; Russi, Mark B; Teshale, Eyasu H
    Exposure to hepatitis viruses is a recognized occupational risk for health care personnel (HCP). This report establishes new CDC guidance that includes recommendations for a testing algorithm and clinical management for HCP with potential occupational exposure to hepatitis C virus (HCV). Baseline testing of the source patient and HCP should be performed as soon as possible (preferably within 48 hours) after the exposure. A source patient refers to any person receiving health care services whose blood or other potentially infectious material is the source of the HCP's exposure. Two options are recommended for testing the source patient. The first option is to test the source patient with a nucleic acid test (NAT) for HCV RNA. This option is preferred, particularly if the source patient is known or suspected to have recent behaviors that increase risk for HCV acquisition (e.g., injection drug use within the previous 4 months) or if risk cannot be reliably assessed. The second option is to test the source patient for antibodies to hepatitis C virus (anti-HCV), then if positive, test for HCV RNA. For HCP, baseline testing for anti-HCV with reflex to a NAT for HCV RNA if positive should be conducted as soon as possible (preferably within 48 hours) after the exposure and may be simultaneous with source-patient testing. If follow-up testing is recommended based on the source patient's status (e.g., HCV RNA positive or anti-HCV positive with unavailable HCV RNA or if the HCV infection status is unknown), HCP should be tested with a NAT for HCV RNA at 3-6 weeks postexposure. If HCV RNA is negative at 3-6 weeks postexposure, a final test for anti-HCV at 4-6 months postexposure is recommended. A source patient or HCP found to be positive for HCV RNA should be referred to care. Postexposure prophylaxis of hepatitis C is not recommended for HCP who have occupational exposure to blood and other body fluids. This guidance was developed based on expert opinion (CDC. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR Recommend Rep 2001;50[No. RR-11]; Supplementary Figure, https://stacks.cdc.gov/view/cdc/90288) and reflects updated guidance from professional organizations that recommend treatment for acute HCV infection. Health care providers can use this guidance to update their procedures for postexposure testing and clinical management of HCP potentially exposed to hepatitis C virus.