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Chang Y, Kim SG, Jeong SW, Jang JY, Yoo JJ, Lee SH, Kim YS, Kim HS, Lee HW, Park S. Efficacy and Safety of Tenofovir Disoproxil Orotate in Chronic Hepatitis B Patients Previously Treated with Tenofovir Disoproxil Fumarate: Multicenter, Open-Label, Prospective Study. J Clin Med 2021; 10:jcm10235628. [PMID: 34884330 PMCID: PMC8658686 DOI: 10.3390/jcm10235628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/20/2021] [Accepted: 11/25/2021] [Indexed: 11/16/2022] Open
Abstract
Background/Aim: We aimed to demonstrate the efficacy and safety of tenofovir disoproxilorotate (TDO) compared with that of tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B. Methods: This multicenter, open-label, prospective clinical trial (KCT0004185) was conducted to evaluate the efficacy and safety of TDO on switching from TDF for 24 weeks in virologically suppressed chronic hepatitis B patients. The primary efficacy endpoint was the maintenance of virologic response. Safety was assessed by evaluating major adverse events, changes in renal function, and occurrence of hepatocellular carcinoma (HCC). Results: TDO treatment was not inferior in terms of virological response when compared with that on TDF treatment, with a noninferiority margin of −10% (risk difference, −3.17%; 95% confidence interval, −7.5–1.15%). The biological response of TDO was also comparable to that of TDF, with no significant difference in the proportion of patients with normalized alanine transaminase levels. After 24 weeks of treatment, hepatitis B core-related antigen (HBcrAg) significantly decreased to a mean titer of 3.91 log U/mL from 4.15 log U/mL at baseline (p = 0.01). There were no cases of grade 3 or higher adverse events and HCC. The mean estimated glomerular filtration rate increased from 91.09 mL/min to 93.34 mL/min (p = 0.056), and the mean serum level of phosphorus increased from 3.33 mg/dL to 3.44 mg/dL (p = 0.045), suggesting improvement in renal function with TDO treatment. Conclusion: In patients with chronic hepatitis B, the efficacy of TDO was noninferior to that of TDF, with a significant decrease in the HBcrAg titer and improved renal function.
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Affiliation(s)
- Young Chang
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
| | - Sang-Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Soung-Won Jeong
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
- Correspondence: (S.-W.J.); (H.-W.L.)
| | - Jae-Young Jang
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Sae-Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.-H.L.); (H.-S.K.)
| | - Young-Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Hong-Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.-H.L.); (H.-S.K.)
| | - Hyun-Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea
- Correspondence: (S.-W.J.); (H.-W.L.)
| | - Suyeon Park
- Department of Biostatistics, Soonchunhyang University Hospital, Seoul 04401, Korea;
- Department of Applied Statistics, Chung-Ang University, Seoul 06974, Korea
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Lin X, Liang C, Zou L, Yin Y, Wang J, Chen D, Lan W. Advance of structural modification of nucleosides scaffold. Eur J Med Chem 2021; 214:113233. [PMID: 33550179 PMCID: PMC7995807 DOI: 10.1016/j.ejmech.2021.113233] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 01/06/2021] [Accepted: 01/23/2021] [Indexed: 12/12/2022]
Abstract
With Remdesivir being approved by FDA as a drug for the treatment of Corona Virus Disease 2019 (COVID-19), nucleoside drugs have once again received widespread attention in the medical community. Herein, we summarized modification of traditional nucleoside framework (sugar + base), traizole nucleosides, nucleoside analogues assembled by other drugs, macromolecule-modified nucleosides, and their bioactivity rules. 2'-"Ara"-substituted by -F or -CN group, and 3'-"ara" substituted by acetylenyl group can greatly influence their anti-tumor activities. Dideoxy dehydrogenation of 2',3'-sites can enhance antiviral efficiencies. Acyclic nucleosides and L-type nucleosides mainly represented antiviral capabilities. 5-F Substituted uracil analogues exihibit anti-tumor effects, and the substrates substituted by -I, -CF3, bromovinyl group usually show antiviral activities. The sugar coupled with 1-N of triazolid usually displays anti-tumor efficiencies, while the sugar coupled with 2-N of triazolid mainly represents antiviral activities. The nucleoside analogues assembled by cholesterol, polyethylene glycol, fatty acid and phospholipid would improve their bioavailabilities and bioactivities, or reduce their toxicities.
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Affiliation(s)
- Xia Lin
- Medical College, Guangxi University, Nanning, 530004, China; College of Chemistry and Chemical Engineering, Guangxi University, Nanning, 530004, China; Guangxi Medical College, Nanning, 530023, China
| | | | - Lianjia Zou
- Guangxi Medical College, Nanning, 530023, China
| | - Yanchun Yin
- Guangxi Medical College, Nanning, 530023, China
| | - Jianyi Wang
- Medical College, Guangxi University, Nanning, 530004, China; College of Chemistry and Chemical Engineering, Guangxi University, Nanning, 530004, China.
| | - Dandan Chen
- Guangxi Medical College, Nanning, 530023, China
| | - Weisen Lan
- College of Agriculture, Guangxi University, Nanning, 530004, China
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Choi JH, Kang MS, Lee CG, Wang NHL, Mun S. Design of simulated moving bed for separation of fumaric acid with a little fronting phenomenon. J Chromatogr A 2017; 1491:75-86. [PMID: 28249717 DOI: 10.1016/j.chroma.2017.02.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 02/15/2017] [Accepted: 02/19/2017] [Indexed: 10/20/2022]
Abstract
The production of fumaric acid through a biotechnological pathway has grown in importance because of its potential value in related industries. This has sparked an interest in developing an economically-efficient process for separation of fumaric acid (product of interest) from acetic acid (by-product). This study aimed to develop a simulated moving bed (SMB) chromatographic process for such separation in a systematic way. As a first step for this work, commercially available adsorbents were screened for their applicability to the considered separation, which revealed that an Amberchrom-CG71C resin had a sufficient potential to become an adsorbent of the targeted SMB. Using this adsorbent, the intrinsic parameters of fumaric and acetic acids were determined and then applied to optimizing the SMB process under consideration. The optimized SMB process was tested experimentally, from which the yield of fumaric-acid product was found to become lower than expected in the design. An investigation about the reason for such problem revealed that it was attributed to a fronting phenomenon occurring in the solute band of fumaric acid. To resolve this issue, the extent of the fronting was evaluated quantitatively using an experimental axial dispersion coefficient for fumaric acid, which was then considered in the design of the SMB of interest. The SMB experimental results showed that the SMB design based on the consideration of the fumaric-acid fronting could guarantee the attainment of both high purity (>99%) and high yield (>99%) for fumaric-acid product under the desorbent consumption of 2.6 and the throughput of 0.36L/L/h.
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Affiliation(s)
- Jae-Hwan Choi
- Department of Chemical Engineering, Hanyang University, Haengdang-dong, Seongdong-gu, Seoul, 04763, South Korea
| | - Mun-Seok Kang
- Department of Chemical Engineering, Hanyang University, Haengdang-dong, Seongdong-gu, Seoul, 04763, South Korea
| | - Chung-Gi Lee
- Department of Chemical Engineering, Hanyang University, Haengdang-dong, Seongdong-gu, Seoul, 04763, South Korea
| | - Nien-Hwa Linda Wang
- School of Chemical Engineering,480 Stadium Mall Drive, Purdue University, West Lafayette, IN 47907-2100, USA
| | - Sungyong Mun
- Department of Chemical Engineering, Hanyang University, Haengdang-dong, Seongdong-gu, Seoul, 04763, South Korea.
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Yu HM, Kwon SY, Kim J, Chung HA, Kwon SW, Jeong TG, Hee An S, Jeong GW, Yun SU, Min JK, Kim JH, Choe WH. Virologic response and safety of tenofovir versus entecavir in treatment-naïve chronic Hepatitis B patients. Saudi J Gastroenterol 2015; 21:146-51. [PMID: 26021773 PMCID: PMC4455144 DOI: 10.4103/1319-3767.157558] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS This study aimed to evaluate the antiviral response and safety of tenofovir (TDF) versus entecavir (ETV) in treatment-naïve CHB patients. PATIENTS AND METHODS We performed a retrospective cohort study of treatment-naive CHB patients who were treated with TDF or ETV. We analyzed virologic, biochemical, and serologic responses at 3, 6, and 12 months. RESULTS A total of 107 patients (TDF group = 49, ETV group = 58) were included. Baseline characteristics were similar between the two groups. The estimated proportion of complete virologic response (CVR) in the TDF or ETV group was 44.9% versus 39.7% at 6 months and 89.6% versus 83.2% at 12 months, respectively (P = 0.991). Viral breakthrough was not observed in both groups. One patient in the TDF group and two patients in the ETV group experienced HBeAg loss, respectively (P = 0.657). High HBV DNA level at baseline was a significant negative predictor of virologic response by Cox regression analysis (P = 0.007). The safety profile was similar between the two groups. There was no case with serious adverse event. CONCLUSIONS Both TDF and ETV were effective in achieving CVR and had a favorable safety profile in treatment-naïve CHB patients. High viral load at baseline was a negative predictive factor of CVR.
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Affiliation(s)
- Hyung Min Yu
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea,Address for correspondence: Dr. So Young Kwon, Department of Internal Medicine Gastroenterology, Konkuk University Hospital, Hwayang-dong, Kwangjin-gu, Seoul, Korea - 143 729, South Korea. E-mail:
| | - Jiwan Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Hyun Ah Chung
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Se Woong Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Taek Gun Jeong
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Sang Hee An
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Gyung Won Jeong
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Seon Ung Yun
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Jae Ki Min
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, South Korea
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5
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A Rapid and Sensitive LC Method for Determination of Diastereomeric Purity of Tenofovir Alafenamide. Chromatographia 2014. [DOI: 10.1007/s10337-014-2745-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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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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Gao L, Trinh HN, Li J, Nguyen MH. Tenofovir is superior to entecavir for achieving complete viral suppression in HBeAg-positive chronic hepatitis B patients with high HBV DNA. Aliment Pharmacol Ther 2014; 39:629-37. [PMID: 24467455 PMCID: PMC3999385 DOI: 10.1111/apt.12629] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 11/16/2013] [Accepted: 01/01/2014] [Indexed: 01/10/2023]
Abstract
BACKGROUND Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the two first-line anti-viral therapies for chronic hepatitis B (CHB); however, there are limited studies directly comparing their effectiveness. AIM To compare the effectiveness of ETV and TDF in nucleos(t)ide-naïve CHB patients with high hepatitis B virus (HBV) DNA levels, defined as serum HBV DNA greater than 6 log10 IU/mL. METHODS We performed a retrospective multicentre cohort study of adult CHB patients who were seen between 2009 and 2012 at four Northern California community gastroenterology and hepatology clinics. RESULTS We identified 59 consecutive patients treated with TDF and 216 patients treated with ETV. Pre-treatment characteristics were similar between the two groups. Among HBeAg-negative patients, there was no significant difference in viral suppression rates between ETV and TDF (P = 0.72). In contrast, among HBeAg-positive patients, those treated with TDF achieved viral suppression significantly more rapidly than those treated with ETV (P < 0.0001); the Kaplan-Meier estimated probability of complete suppression was 18% vs. 11% at 6 months, 51% vs. 28% at 12 months and 72% vs. 39% at 18 months respectively. Multivariate Cox proportional hazards analysis indicated that treatment with TDF compared to ETV was a significant predictor of viral suppression, but only for HBeAg-positive patients (HR = 2.59; 95% CI 1.58-4.22; P < 0.001). CONCLUSION Tenofovir is significantly more effective than entecavir for achieving complete viral suppression in HBeAg-positive, nucleos(t)ide-naïve chronic hepatitis B patients with HBV DNA greater than 6 log10 IU/mL.
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Affiliation(s)
- Linyi Gao
- Department of Chemistry, Stanford University, Stanford, CA, USA;
| | | | - Jiayi Li
- Palo Alto Medical Foundation, Mountain View, CA, USA;
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA;
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8
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Aljofan M, Netter HJ, Aljarbou AN, Hadda TB, Orhan IE, Sener B, Mungall BA. Anti-hepatitis B activity of isoquinoline alkaloids of plant origin. Arch Virol 2013; 159:1119-28. [PMID: 24311152 DOI: 10.1007/s00705-013-1937-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Accepted: 10/29/2013] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) is the causative agent of B-type hepatitis in humans, a vaccine-preventable disease. Despite the availability of effective vaccines, globally, 2 billion people show evidence of past or current HBV infection, of which 350 million people are persistently infected, with an estimated annual increase of 1 million. There is no cure for chronic HBV infections, which are associated with cirrhotic liver failure and with an increased risk of developing hepatocellular carcinoma. Hepatitis antiviral research has focused primarily on the development of inhibitors of viral polymerase through the use of nucleoside analogues. Therefore, there is an urgent need for the development of non-nucleoside compounds to be used as an alternative or to complement the current therapy. To address this need, 18 isoquinoline alkaloids were evaluated for their potential antiviral activity against HBV in vitro.
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Affiliation(s)
- Mohamad Aljofan
- Department of Microbiology, School of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, 3800, Australia,
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9
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Pradat P, Le Pogam MA, Okon JB, Trolliet P, Miailhes P, Brochier C, Maynard M, Bailly F, Zoulim F, Cotte L. Evolution of glomerular filtration rate in HIV-infected, HIV-HBV-coinfected and HBV-infected patients receiving tenofovir disoproxil fumarate. J Viral Hepat 2013; 20:650-7. [PMID: 23910650 DOI: 10.1111/jvh.12088] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/16/2013] [Indexed: 12/13/2022]
Abstract
We aimed to compare the evolution of estimated glomerular filtration rate (eGFR) in HIV-, HIV-HBV- and HBV-infected patients treated with tenofovir disoproxil fumarate (TDF). Three groups of patients receiving TDF > 12 months were recruited: 194 HIV-infected patients, 85 HIV-HBV-coinfected patients and 50 HBV-infected patients. eGFR was estimated using the Modification of the Diet in Renal Disease (MDRD) equation. Multivariate regression models were constructed to estimate factors associated with eGFR decrease from baseline. A total of 329 patients were studied. Median follow-up was 2.7 years. Median eGFR decrease was -4.9 (-16.6 to +7.2) mL/min/1.73 m(2) . After multivariate stepwise regression analysis, age (P = 0.0002), non-African origin (P < 0.0001), baseline eGFR (P < 0.0001) and TDF duration (P = 0.02) were associated with eGFR decrease in the whole population, while hypertension, diabetes and type of infection were not. Age (P < 0.0001), non-African origin (P = 0.0004), baseline eGFR (P < 0.0001) and TDF duration (P = 0.007) remained associated with eGFR decline in HIV and HIV-HBV-infected patients, while other variables including HIV risk factor, CDC stage, CD4 and HIV-RNA levels were not. Age (P = 0.03), non-African origin (P = 0.004), baseline eGFR (P < 0.0001) and baseline HBV-DNA > 2000 IU/mL (P = 0.04) were associated with eGFR decline in HBV and HIV-HBV-infected patients, while other variables including HBV risk factor and fibrosis stage were not. Estimated glomerular filtration rate decline under TDF therapy appears mainly associated with older age, non-African origin, higher baseline eGFR and longer TDF administration but not with the type of viral infection. Regular follow-up of renal function, especially tubular function is recommended during TDF therapy.
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Affiliation(s)
- P Pradat
- Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Service d'Hépatologie, Lyon, France.
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Roux L, Priet S, Payrot N, Weck C, Fournier M, Zoulim F, Balzarini J, Canard B, Alvarez K. Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: synthesis, antiviral activity and decomposition study. Eur J Med Chem 2013; 63:869-81. [PMID: 23603046 DOI: 10.1016/j.ejmech.2013.02.039] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 01/30/2013] [Accepted: 02/26/2013] [Indexed: 12/25/2022]
Abstract
9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12.
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Affiliation(s)
- Loïc Roux
- Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR CNRS 7257, Equipe Chimie Médicinale et Virologie Structurale, Université Aix-Marseille, Parc scientifique de Luminy, 163 av. de Luminy, 13288 Marseille Cedex 9, France
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11
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Kim YJ, Sinn DH, Gwak GY, Choi MS, Koh KC, Paik SW, Yoo BC, Lee JH. Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures. World J Gastroenterol 2012; 18:6996-7002. [PMID: 23322999 PMCID: PMC3531685 DOI: 10.3748/wjg.v18.i47.6996] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 05/31/2012] [Accepted: 06/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients after multiple failures.
METHODS: A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue (NA) treatments were included. Study subjects were treated with TDF alone (n = 13) or in combination with lamivudine (LAM, n = 12) or entecavir (ETV, n = 4) for ≥ 6 mo. Complete virologic response (CVR) was defined as an achievement of serum hepatitis B virus (HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment. Safety assessment was based on serum creatinine and phosphorus level. Eleven patients had histories of LAM and adefovir dipivoxil (ADV) treatment and 18 patients were exposed to LAM, ADV, and ETV. Twenty-seven patients (93.1%) were hepatitis B e antigen (HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL. The median treatment duration was 16 mo (range 7 to 29 mo).
RESULTS: All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it. Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV. One patient had a resistance to both ADV and ETV. The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%, respectively. Although one patient failed to achieve CVR, serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL, achieving near CVR. No patients in this study showed viral breakthrough or primary non-response during the follow-up period. The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%, 12%, and 27% at 6, 12, and 18 mo of treatment, respectively. Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations. History of prior exposure to specific antiviral agents did not make a difference to treatment outcome. Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV. No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed. There were no other adverse events related to TDF therapy observed in the study subjects.
CONCLUSION: TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.
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Wang C, Fan R, Sun J, Hou J. Prevention and management of drug resistant hepatitis B virus infections. J Gastroenterol Hepatol 2012; 27:1432-40. [PMID: 22694205 DOI: 10.1111/j.1440-1746.2012.07198.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the past decade, broadened therapeutic options of oral direct antiviral agents for the treatment of chronic hepatitis B infection include: Lamivudine, Adefovir Dipivoxil, Telbivudine, Entecavir and Tenofovir Disoproxil Fumarate. These direct oral antiviral agents effectively suppress the replication of the virus and reduce the risk of potential liver-related complications. However, prolonged use of these nucleos(t)ide analogues has been associated with drug resistance that compromises the initial clinical benefits. Moreover, the oncogenic risk of mutations due to prolonged nucleos(t)ide analogue therapy needs to be further investigated by in vitro and in vivo studies. In the current era of potent nucleotide analogues, new data are emerging, we are still facing the pool of patients who have developed resistance to the prior generation of nucleos(t)ide analogues. This paper aims to focus on incidence of antiviral drug resistance and virological breakthrough, prudent selection of initial therapy, on-treatment monitoring for drug resistance and revise treatment strategies for patients with resistant virus.
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Affiliation(s)
- Cheng Wang
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
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13
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De Clercq E. Tenofovir: Quo Vadis Anno 2012 (Where Is It Going in the Year 2012)
? Med Res Rev 2012; 32:765-85. [PMID: 22581627 DOI: 10.1002/med.21267] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Erik De Clercq
- Rega Institute for Medical Research; KU Leuven; Minderbroedersstraat; 10, B-3000 Leuven Belgium
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Si-Ahmed SN, Pradat P, Zoutendijk R, Buti M, Mallet V, Cruiziat C, Deterding K, Dumortier J, Bailly F, Esteban R, Wedemeyer H, Janssen HL, Zoulim F. Efficacy and tolerance of a combination of tenofovir disoproxil fumarate plus emtricitabine in patients with chronic hepatitis B: a European multicenter study. Antiviral Res 2011; 92:90-5. [PMID: 21767570 DOI: 10.1016/j.antiviral.2011.07.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/29/2011] [Accepted: 07/04/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) is used extensively to treat HIV infection and also has potent activity against hepatitis B virus (HBV) infection. The aim of this study was to assess the efficacy and tolerance of TDF + FTC in patients with chronic hepatitis B (CHB). METHODS Seventy eight consecutive CHB patients from five European centers were included. All started a TDF + FTC combination between October 2005 and March 2010. Virological, biochemical, and clinical data were recorded during follow-up. Tolerance was also monitored. Patients were classified into either treatment simplification (TS), where efficacy of the previous treatment was obtained at TDF + FTC initiation, and treatment intensification (TI), where the previous line of therapy had failed. RESULTS TDF + FTC was given as a TI to 54 patients (69%) and as a TS to 24 (31%). Among patients with TI, 83% were males. The median baseline HBV-DNA was 4.4 log10 IU/mL, and median alanine-transaminase (ALT) was 1.10 × ULN. Sixty percent were HBeAg positive, 47% had significant fibrosis (≥ F3 Metavir equivalent), and 29% had confirmed cirrhosis. Median treatment duration was 76 weeks (interquartile range 60-116). Kaplan-Meier analysis showed that, 48 weeks after TI, the probability of being HBV-DNA becoming undetectable was 76%, and reached 94% at week 96. No viral breakthrough occurred. Patients with TS (87% males, median baseline HBV-DNA 1.1 log10 IU/mL, median ALT 0.79 × ULN, 33% HBeAg positive, 61% with significant fibrosis) were treated for a median duration of 76 weeks. In this subgroup, all patients but one remained HBV-DNA undetectable and no ALT flare-up occurred during follow-up. Creatinine levels did not show kidney-function deterioration in either group of patients. CONCLUSIONS After a median follow-up of > 76 weeks, the TDF + FTC combination showed encouraging antiviral efficacy and a good safety profile in all patients with CHB. TDF + FTC may represent an interesting clinical option to simplify therapy and increase the barrier to resistance, which should be assessed in the long term.
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15
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Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K. Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication. Eur J Med Chem 2011; 46:4281-8. [PMID: 21803462 PMCID: PMC7115536 DOI: 10.1016/j.ejmech.2011.06.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 06/21/2011] [Accepted: 06/22/2011] [Indexed: 12/31/2022]
Abstract
9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
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Affiliation(s)
- Karine Barral
- Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR CNRS 6098, Equipe Réplicases Virales: Structure, Mécanisme, et Drug-design, Universités Aix-Marseille I et II, Parc scientifique de Luminy, 163 av de Luminy, 13288 Marseille Cedex 9, France
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