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Khan F, Ali H, Musharraf SG. Tenofovir disoproxil fumarate-mediated γ-globin induction is correlated with the suppression of trans-acting factors in CD34 + progenitor cells: A role in the reactivation of fetal hemoglobin. Eur J Pharmacol 2022; 927:175036. [PMID: 35618038 DOI: 10.1016/j.ejphar.2022.175036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 05/07/2022] [Accepted: 05/12/2022] [Indexed: 11/19/2022]
Abstract
Sickle-cell disease (SCD) and β-thalassemia are public health issues that affect people all over the world. Fetal hemoglobin (HbF) induction is a molecular intervention, including hydroxyurea, which has made an effort to improve current treatment. Tenofovir disoproxil fumarate (TDF) is formerly reported with improving levels of hemoglobin, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV). Hence, in this preclinical investigation, human peripheral whole blood-derived CD34+ progenitor cells were cultured to prove the efficacy of TDF on erythroid proliferation, differentiation, γ-globin gene expression regulation, and ultimately HbF production. We observed that TDF increased the proliferation of immature erythroid cells, delayed the terminal erythroid maturation without cytotoxicity as correlated with other HbF inducers. Here, the presented data show that TDF can induce HbF expression by up-regulating the γ-globin gene transcription up to 7.1 ± 0.46-fold and subsequently increased the F-cells (10.79 ± 1.9-fold) population in terminally differentiated erythroid cells. Furthermore, our findings demonstrated that TDF-mediated γ-globin gene induction and HbF production was associated with down-fold regulation of BCL11A and SOX6, and their corresponding trans-acting regulators, FOP, KLF1, and GATA1. Collectively, our findings suggest TDF as an effective inducer of HbF in CD34+ cells and pave the way to put forward the assessment of TDF as a new potential therapy in treating β-hemoglobinopathies.
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Affiliation(s)
- Faisal Khan
- Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Hamad Ali
- Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Department of Basic Medical Sciences, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad 44000, Pakistan
| | - Syed Ghulam Musharraf
- Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial. PLoS One 2021; 16:e0246272. [PMID: 33544759 PMCID: PMC7864465 DOI: 10.1371/journal.pone.0246272] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 01/09/2021] [Indexed: 11/19/2022] Open
Abstract
Objectives We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV. Design IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858). Methods IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir–maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented. Results Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value <0.001). Similarly, maternal hip bone mineral density declined significantly more through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference -2.29% (-3.20, -1.39) (p-value <0.001). Adjusting for covariates did not change the treatment effect. Conclusions Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis.
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Gollu G, Gummadi S. Simultaneous Quantification of Lamivudine, Tenofovir Disoproxil Fumarate and Doravirine in Pharmaceutical Dosage Form by Liquid Chromatography with Diode Array Detection. Pharm Chem J 2020. [DOI: 10.1007/s11094-020-02232-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Khan F, Ali H, Musharraf SG. Tenofovir disoproxil fumarate induces fetal hemoglobin production in K562 cells and β-YAC transgenic mice: A therapeutic approach for γ-globin induction. Exp Cell Res 2020; 394:112168. [PMID: 32653411 DOI: 10.1016/j.yexcr.2020.112168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 07/05/2020] [Indexed: 02/07/2023]
Abstract
Pharmacologic induction of fetal hemoglobin (HbF) is an effective strategy for treating β-hemoglobinopathies like β-thalassemia and sickle cell anemia by ameliorating disease severity. Hydroxyurea is the only FDA-approved agent that induces HbF, but significant nonresponders and toxicity limit its clinical usefulness. This study relates preclinical investigation of Tenofovir disoproxil fumarate (TDF) as a potential HbF inducing agent, using human erythroleukemia cell line and a β-YAC mouse model. Erythroid induction of K562 cells was studied by the benzidine/H2O2 reaction, total hemoglobin production was estimated by plasma hemoglobin assay kit, and γ-globin gene expression by RT-qPCR, whereas, fetal hemoglobin production was estimated by flow cytometry and immunofluorescence microscopy. We observed significantly increased γ- globin gene transcription and HbF expression mediated by TDF in K562 cells. Subsequent treatment of β-YAC transgenic mice with TDF confirmed HbF induction in vivo through an increase in γ-globin gene expression and in the percentage of HbF positive red blood cells. Moreover, TDF showed no cytotoxic effect at HbF inducing concentrations. These data support the potential development of TDF for the treatment of hematological disorders, including β-thalassemia and sickle cell anemia.
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Affiliation(s)
- Faisal Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Hamad Ali
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Syed Ghulam Musharraf
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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Yang J, Sheng G, Xiao D, Shi H, Wu W, Lu H, Cao H, Li L. The frequency and skewed T-cell receptor beta-chain variable patterns of peripheral CD4(+)CD25(+) regulatory T-cells are associated with hepatitis B e antigen seroconversion of chronic hepatitis B patients during antiviral treatment. Cell Mol Immunol 2016; 13:678-687. [PMID: 26899927 PMCID: PMC5037272 DOI: 10.1038/cmi.2015.100] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 11/07/2015] [Accepted: 11/08/2015] [Indexed: 02/08/2023] Open
Abstract
The frequency and T-cell receptor beta-chain variable (TCRBV) patterns of peripheral CD4(+)CD25(+) regulatory T-cells (Tregs) are ambiguously altered in chronic hepatitis B (CHB) patients following tenofovir disoproxil fumarate (TDF) treatment. Moreover, the clinical significance of these parameters in relation to hepatitis B e antigen (HBeAg) seroconversion (SC) is largely unknown. In this study, the circulation of Tregs in HBeAg-positive CHB patients was determined by flow cytometry, and the molecular profiles of frequent TCRBV patterns of Tregs were analyzed using a gene melting spectral pattern. The parameters, such as Treg frequency, the number of skewed TCRBV patterns, hepatitis B virus (HBV) DNA levels, and alanine aminotransferase (ALT) levels, were analyzed by comparing their associations in seroconverting and non-seroconverting patients following TDF treatment. The Treg frequency was significantly correlated with the ALT level in seroconverting but not in non-seroconverting patients. Similarly, skewed TCRBV patterns were remarkably associated with HBV DNA levels in the SC group. Six TCRBV families (BV3, BV11, BV12, BV14, BV20, and BV24) were more prevalent than other TCRBV members in seroconverting patients pretreated with TDF, while BV12, BV15, and BV22 were predominant in non-seroconverting patients during TDF treatment. Taken together, the preferential TCRBV patterns may be associated with immune responses related to SC. The dynamic frequency and skewed TCRBV patterns of peripheral Tregs could contribute to predicting SC in CHB patients. Moreover, the conserved TCRBV complementarity-determining region (CDR3) motif may be targeted to develop personalized immunotherapy for CHB patients.
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MESH Headings
- Adult
- Alanine Transaminase/metabolism
- Amino Acid Motifs
- Antigens, CD/metabolism
- Antiviral Agents/pharmacology
- Antiviral Agents/therapeutic use
- Complementarity Determining Regions/immunology
- Conserved Sequence
- DNA, Viral/blood
- Hepatitis B e Antigens/immunology
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/virology
- Humans
- Interleukin-2 Receptor alpha Subunit/metabolism
- Kinetics
- Longitudinal Studies
- Lymphocyte Count
- Middle Aged
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Seroconversion/drug effects
- T-Lymphocytes, Regulatory/immunology
- Young Adult
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Abstract
Viruses are major pathogenic agents causing a variety of serious diseases in humans, other animals, and plants. Drugs that combat viral infections are called antiviral drugs. There are no effective antiviral drugs for many viral infections. However, there are several drugs for influenza, a couple of drugs for herpesviruses, and some new antiviral drugs for treatment of HIV and hepatitis C infections. The arsenal of antivirals is complex. As of March 2014, it consists of approximately 50 drugs approved by the FDA, approximately half of which are directed against HIV. Antiviral drug creation strategies are focused on two different approaches: targeting the viruses themselves or targeting host cell factors. Direct virus-targeting antiviral drugs include attachment inhibitors, entry inhibitors, uncoating inhibitors, protease inhibitors, polymerase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and integrase inhibitors. Protease inhibitors (darunavir, atazanavir, and ritonavir), viral DNA polymerase inhibitors (acyclovir, valacyclovir, valganciclovir, and tenofovir), and an integrase inhibitor (raltegravir) are included in the list of Top 200 Drugs by sales for the 2010s.
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Liu Y, Zhang Y, Yuan J, Zeng W, Zhang G, Yao S, Li H, Yang M, Deng Y, Zou R, Li S, Xiao J. Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures. Hepatol Res 2015; 45:E43-52. [PMID: 25429855 DOI: 10.1111/hepr.12454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 02/08/2023]
Abstract
AIM In this prospective study, we aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Chinese chronic hepatitis B (CHB) patients after multiple nucleoside/nucleotide analog (NA) treatment failures. METHODS A total of 115 Chinese CHB patients with suboptimal response to two or more NA treatments were included in this study. All patients were changed to TDF (300 mg/day, oral administration) antiviral treatment for at least 72 weeks. Hepatitis B virus (HBV) polymerase (P) gene mutation screening for each patient was performed. In addition, virological, biochemical responses and estimated glomerular filtration rate (eGFR) of each patient at weeks 12, 24, 48 and 72 of TDF treatment were evaluated. RESULTS Seventy-six out of 115 patients had drug-resistance mutations (R(+) ), including 27 with adefovir (ADV)-associated mutations (35.5%) and 49 with lamivudine (LMV)-associated mutations (64.5%). For all included patients, complete viral response (CVR) of HBV DNA (<100 IU/mL) was 57.4%, 69.6%, 74.8% and 86.1% at weeks 12, 24, 48 and 72 of TDF treatment, respectively. Alanine aminotransferase normalization and hepatitis B e-antigen seroclearance occurred in 77.3% and 23.2%, respectively, after 72-week TDF treatment. CVR at weeks 12, 24 and 48 was observed more commonly in patients with baseline HBV DNA of less than 10(6) IU/mL. There was no significant reduction of eGFR induced by the TDF treatment. CONCLUSION Seventy-two-week treatment with TDF in Chinese CHB patients with previously multiple NA treatment failures exhibited effective and safe outcomes, which were independent of baseline mutations conferring ADV or LMV resistance.
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Affiliation(s)
- Yingxia Liu
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Ying Zhang
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Jing Yuan
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Wen Zeng
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Guoliang Zhang
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Simin Yao
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Huijuan Li
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Min Yang
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Yong Deng
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Rongrong Zou
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Shaxi Li
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Jia Xiao
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
- Department of Anatomy, The University of Hong Kong, Hong Kong, China
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Ng HH, Stock H, Rausch L, Bunin D, Wang A, Brill S, Gow J, Mirsalis JC. Tenofovir disoproxil fumarate: toxicity, toxicokinetics, and toxicogenomics analysis after 13 weeks of oral administration in mice. Int J Toxicol 2015; 34:4-10. [PMID: 25568137 PMCID: PMC4334733 DOI: 10.1177/1091581814565669] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against HIV and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50-1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology end points. Plasma levels and systemic exposure of tenofovir increased less than dose proportionally and were similar on days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, after 4 and 13 weeks, cytomegaly was observed in mice treated with 1000 mg/kg of TDF, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression.
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Affiliation(s)
- Hanna H Ng
- Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Howard Stock
- Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Linda Rausch
- Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Deborah Bunin
- Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Abraham Wang
- Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Shirley Brill
- Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Jason Gow
- Biosciences Division, SRI International, Menlo Park, CA, USA
| | - Jon C Mirsalis
- Biosciences Division, SRI International, Menlo Park, CA, USA
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Ahn SS, Chon YE, Kim BK, Kim SU, Kim DY, Ahn SH, Han KH, Park JY. Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide-naïve chronic hepatitis B patients in Korea: data from the clinical practice setting in a single-center cohort. Clin Mol Hepatol 2014; 20:261-266. [PMID: 25320729 PMCID: PMC4197174 DOI: 10.3350/cmh.2014.20.3.261] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 09/02/2014] [Accepted: 09/11/2014] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIMS This study assessed the antiviral efficacy and safety of tenofovir disoproxil fumarate (TDF) for up to 12 months in Korean treatment-naïve chronic hepatitis B (CHB) patients. METHODS A total of 411 treatment-naïve CHB patients who had been treated with TDF for at least 3 months (median 5.6) were consecutively enrolled. Clinical, biochemical, virological parameters and treatment adherence were routinely assessed every 3 months. RESULTS The median age was 51.3 years, 63.0% of the patients were male, 49.6% were HBeAg (+), and 210 patients had liver cirrhosis. The median baseline HBV DNA was 5.98 (SD 1.68) log10 IU/mL. Among the patients completing week 48, 83.3% had a complete virologic response (CVR, <12 IU/mL by HBV PCR assay), and 88.2% had normalized levels of alanine aminotransferase (ALT). The cumulative probabilities of CVR at 3, 6, 9 and 12 months were 22.8%, 53.1%, 69.3% and 85.0%. During the follow-up period, 9.8% patients achieved HBeAg loss and 7.8% patients achieved HBeAg seroconversion. There was no virological breakthrough after initiating TDF. The most common TDF-related adverse event was gastrointestinal upset, and three patients discontinued TDF therapy. However, no serious life-threatening side effect was noted. CONCLUSIONS In a clinical practice setting, TDF was safe and highly effective when administered for 12 months to Korean treatment-naïve CHB patients.
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Affiliation(s)
- Sung Soo Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Young Eun Chon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Fernández-Rodríguez CM, Gutiérrez-García ML. Prevention of hepatocellular carcinoma in patients with chronic hepatitis B. World J Gastrointest Pharmacol Ther 2014; 5:175-182. [PMID: 25133046 PMCID: PMC4133443 DOI: 10.4292/wjgpt.v5.i3.175] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 04/01/2014] [Accepted: 07/12/2014] [Indexed: 02/06/2023] Open
Abstract
Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma (HCC). Globally, over half a million people each year are diagnosed with HCC, with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus (HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC, the molecular basis for this association has not been fully elucidated. In addition, a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis, recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agents in achieving profound and durable suppression of HBV DNA levels while improving liver function and histology, robust evidence of other long-term clinical outcomes, such as prevention of HCC, are limited.
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