Hepatitis: Buti M

Buti M. · No affiliation provided · Enferm Infecc Microbiol Clin. · Pubmed #18358209 links to  free full text

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Buti M, Esteban R. · No affiliation provided · Ann Hepatol. · Pubmed #18007558 No free full text.

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Buti M. · No affiliation provided · An Med Interna. · Pubmed #15373717 No free full text.

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Buti M. · No affiliation provided · Gastroenterol Hepatol. · Pubmed #14733880 No free full text.

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Buti M. · No affiliation provided · Gastroenterol Hepatol. · Pubmed #12681121 No free full text.

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Buti M. · Servicio de Hepatología y Medicina Interna, Hospital General Universitario Vall d'Hebron, CIBER del Instituto de Salud Carlos II, Barcelona, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100229 links to  free full text

Abstract: At least 4 nucleos(t)ide analogs have been approved for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, entecavir, and telbivudine. The introduction of these drugs has radically changed the treatment of this disease. The advantages of these drugs are their oral administration, excellent tolerability and efficacy in all types of chronic hepatitis B (compensated and decompensated disease). The limitations are the need for prolonged treatments, which hampers adherence and can cause selection of HBV strains resistant to distinct drugs. The resistance rate differs for each of the drugs. Nucleotide analogs such as adefovir and tenofovir are useful in patients resistant to nucleoside analogs such as lamivudine, entecavir and telbivudine and vice versa. In cases of resistance to one of these drugs, combined treatment is advised.

Idris BI, Brosa M, Richardus JH, Esteban R, Schalm SW, Buti M. · Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. · Eur J Gastroenterol Hepatol. · Pubmed #18334876 No free full text.

Abstract: BACKGROUND: Chronic hepatitis B virus (HBV) infection can lead to fatal complications and death. Only a relatively small proportion of patients actually receive medication, and the majority requires long-term antiviral therapy that can result in the emergence of resistant strains of HBV. The study aimed to estimate the future burden of chronic hepatitis B in Spain over the next 20 years, the impact of current lamivudine treatment and the emergence of drug-resistant HBV. METHODS: We constructed a hypothetical cohort of people with active chronic HBV infection in Spain in 2005, and 'followed' the cohort for 20 years. The cohort was stratified with respect to factors that affect prognosis (i.e. hepatitis B e-antigen and histology-defined status). To estimate the burden, Markov mathematical simulation was performed based on three scenarios: natural history, treatment with antiviral drug (lamivudine) and treatment with a hypothetical drug with identical profiles to lamivudine but to which there is no resistance. RESULTS: We estimated that in 2005 there were around 111,000 individuals suffering from active chronic HBV infection. If the cohort is not treated, by the year 2025 there will be about 60,000 events of morbidity and 40,000 cases of liver-related deaths, with 1.84 billion euro expected to be consumed in providing care for the cohort. Treating 35% of the cohort with lamivudine will reduce the morbidity and mortality by 19 and 15%, respectively; whereas the hypothetical drug will reduce the morbidity and mortality by 27 and 24%. The cumulative cost savings resulting from the use of lamivudine and the hypothetical drug, respectively, are 160 and 300 million euro. Antiviral resistance accounts for a reduction of about one-third in the potential benefit of treatment, and almost a half of the potential cost saving. CONCLUSION: Chronic hepatitis B will pose a great burden in the future if the individuals with active disease are left untreated. Effective antiviral therapy and treatment coverage have substantial impact in reducing the future burden; however, antiviral resistance decreases treatment benefit considerably.

Zoulim F, Buti M, Lok AS. · INSERM, U871, 69003 Lyon, France. · J Viral Hepat. · Pubmed #17958640 No free full text.

Abstract: Despite the recent progress in antiviral therapy of chronic hepatitis B, clinical experience has shown that antiviral drug resistance is inevitable with the administration of nucleoside analog monotherapy. The long-term persistence of the viral genome in infected cells and the high rate of spontaneous mutation is the basis for the selection of HBV mutants that are resistant to polymerase inhibitors. Selection of antiviral-resistant mutations leads to a rise in viral load and progression of liver disease. The incidence of antiviral resistance depends on the potency and genetic barrier to resistance of the antiviral drug, highlighting the importance of the choice if first line therapy. The determination of cross-resistance profile of each drug has allowed the design of rescue therapy for patients with virologic breakthrough. Early diagnosis and treatment intervention allow the majority of patients to maintain in clinical remission despite the occurrence of drug resistance. Clinical studies are ongoing to determine the best strategy to prevent or delay antiviral drug resistance and of its impact on liver disease.

Buti M, Rodriguez-Frias F, Jardi R, Esteban R. · Liner Unit, Hospital General Universitari Pall d'Hebron, Barcelona, Spain. · J Clin Virol. · Pubmed #16461229 No free full text.

Abstract: The hepatitis B virus (HBV), a member of the Hepadnaviridae family, is prone to mutations due to its asymmetric replication via reverse transcription of an RNA intermediate. The estimated mutation rate of the hepadnavirus genome is 2 x 10(4) base substitutions/site/year. This mutation rate is approximately 100 times higher than that of other DNA viruses but between 100 and 1000 times lower than that of RNA viruses. Analyses of both naturally occurring viral variants and in vitro mutagenesis studies have identified some mutations that have a role in viral latency, pathogenesis of liver disease, immune escape, and resistance to antiviral therapy.

Buti M, Casado MA, Fosbrook L, Esteban R. · Department of Hepatology, Hospital Vall d'Hebrón, Barcelona, Spain. · Pharmacoeconomics. · Pubmed #16235977 No free full text.

Abstract: BACKGROUND: Patients infected with chronic hepatitis C virus (HCV) genotype 1 are the least responsive to peginterferon (pegIFN) and ribavirin therapy. The monitoring of early virological response (EVR) is therefore an important tool for quickly identifying non-responders, permitting therapy discontinuation and avoiding adverse effects and costs. OBJECTIVE: To analyse the financial impact, in treatment-naive patients infected with HCV genotype 1, of two different measurement techniques for evaluating the EVR during pegIFN-alpha-2b plus ribavirin therapy, and to compare the results of a 48-week standard course of therapy with pegIFN-alpha-2b plus ribavirin without measuring EVR. METHODS: A budget impact model was constructed using a decision-tree analysis. EVR was defined as a >2 log decline in HCV RNA levels at week 12 either tested with two quantitative HCV RNA tests or undetectable HCV core antigen (HCV core Ag) protein levels at week 12 (one HCV core Ag test). Clinical data were taken from multicentre trials and costs from the published literature (euro, 2003 values). The analysis was carried out from the perspective of the Spanish healthcare system and therefore only direct costs were considered. The base-case scenario assumed that a potential study population of 18,504 people in Spain with chronic HCV genotype 1 would be eligible for treatment with pegIFN-alpha-2b plus ribavirin. RESULTS: In the base case, the most effective strategy was testing EVR by HCV core Ag. This resulted in 12,745 patients reaching a sustained virological response (SVR) at an overall cost of 243.98 million euro (19,142 euro per SVR). Conversely, quantitative HCV RNA testing resulted in 11,776 patients with an SVR at a cost of 232.73 million euro ( 19,763 euro per SVR). The incremental cost per successfully treated patient with HCV core Ag testing versus quantitative HCV RNA testing was 11,597 euro. One-way sensitivity analyses demonstrated that changes in the study parameters did not modify the outcomes, except when increasing the EVR or SVR of strategy 2 or when decreasing the EVR or SVR of strategy 3. CONCLUSION: This model suggests, with its underlying assumptions and data, that the assessment of EVR at week 12 by HCV core Ag testing in chronic HCV patients infected with genotype 1 permits identification of those patients expected to achieve an SVR with pegIFN-alpha-2b and ribavirin, resulting in a lower overall cost to the Spanish healthcare system than HCV RNA testing or no testing at all.

Buti M, Esteban R. · Liver Unit, Hospital General Universitari Vall d'Hebron, Barcelona, Spain. · Drugs. · Pubmed #16033287 No free full text.

Abstract: The management of chronic hepatitis B (CHB) has improved dramatically over the last decade with the development of new drugs such as lamivudine and adefovir dipivoxil, in addition to the now standard interferon (IFN)-alpha therapy. These new drugs can achieve a significant reduction or inhibit replication of hepatitis B virus (HBV) DNA during therapy. However, in the majority of patients, particularly in those who are hepatitis B e antigen (HBeAg)-negative, the sustained off-therapy suppression of HBV DNA is rare. For this reason, several new antiviral and immunomodulatory agents are currently being evaluated. Among the immunomodulatory agents, pegylated IFNalpha (peginterferon-alpha) has been shown to be more effective for HBeAg-positive CHB than either lamivudine or standard IFNalpha monotherapy, particularly in those patients infected by HBV genotypes A and B. The new antivirals entecavir, tenofovir disoproxil fumarate and telbivudine exhibit a more potent viral inhibitory effect than the currently approved drugs (IFNs, lamivudine and adefovir dipivoxil). However, the emergence of viral resistance has been witnessed and this could be one of the major limitations to the clinical use of these new drugs, particularly during prolonged therapy. In HBeAg-negative patients it is more and more common for oral antiviral therapy to be administered for prolonged periods, as the sustained off-therapy response rates of short-term therapy are very low. Different studies are currently evaluating combination therapy, using lamivudine with adefovir dipivoxil or peginterferon-alpha with lamivudine; the preliminary results show virological responses no better than those achieved by monotherapy. However, as combination therapy is associated with a low likelihood of developing HBV drug resistance, this could result in a higher virological response during prolonged therapy. In the near future the most realistic therapeutic option for the majority of patients with CHB will be long-term use of these new, more potent antiviral drugs, if they can achieve good safety profiles while maintaining low resistance rates at affordable costs.

Buti M. · Servicio de Hepatología-Medicina Interna, Hospital General Universitari Vall d'Hebron, Paseo Vall d'Hebron, 119, 08035 Barcelona, España. · Gastroenterol Hepatol. · Pubmed #15195531 No free full text.

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Buti M. · Liver Unit, Hospital General Universitari Vall d'Hebron, Barcelona, Spain. · Ann Hepatol. · Pubmed #15115961 No free full text.

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Buti M, Esteban R. · Liver Unit, Hospital General Universitari Vall d'Hebron, Paseo Valle de Hebron 119, Barcelona 08035, Spain. · J Hepatol. · Pubmed #14708692 No free full text.

Abstract: To summarize, the future of chronic hepatitis B therapy seems to be the combination of different drugs. Ideally, the optimal drugs to combine would meet the following criteria: they should be orally applicable, they should have an excellent safety profile and the duration of therapy should limited. Currently, the drugs most likely to fulfill these criteria are the nucleoside analogs.

Buti M, Esteban R. · Liver Unit, Hospital General Universitari Vall d' Hebron, Barcelona, Spain. · Drugs Today (Barc). · Pubmed #12698207 No free full text.

Abstract: In chronic hepatitis B therapy there are new and exciting developments in antivirals such as nucleotide analogues. Adefovir is the latest drug approved for therapy of chronic hepatitis B. This agent has a potent in vitro and in vivo effect against herpes virus, retroviruses and hepadnaviruses. In the hepatitis B virus setting, adefovir dipivoxil inhibits both the wild type and HBV lamivudine-resistant strains. Adefovir is an oral drug and the recommended dose for chronic hepatitis B is 10 mg daily. The safety profile of this dose is excellent but higher doses can produce renal tubular damage, particularly when the drug is used for prolonged therapy. Up to now, no evidence of HBV resistance to adefovir dipivoxil has been detected, and this constitutes one of its main advantages as it permits longer duration of therapy. Adefovir is an important new addition to current first-line treatments for HBeAg and anti-HBe-positive chronic hepatitis B, as well as being rescue therapy for lamivudine-resistant HBV strains.

San Miguel R, Guillén F, Cabasés JM, Buti M. · Pharmacy Services, Hospital Virgen de la Luz, Cuenca, Spain. · Aliment Pharmacol Ther. · Pubmed #12197840 links to  free full text

Abstract: BACKGROUND: The efficacy of interferon-alpha plus ribavirin treatment for patients not responding to interferon monotherapy is not well established. AIM: To assess the efficacy and safety of combination therapy with interferon-alpha 2a/2b plus ribavirin by performing a meta-analysis of randomized clinical trials. METHODS: A systematic search of electronic databases for randomized clinical trials of interferon-alpha 2a/2b plus ribavirin was conducted independently by two investigators. Data abstraction was performed. The primary end-point was a sustained virological response. Estimates of the common odds ratio were calculated using a random effects model. RESULTS: Of the 127 identified studies, 46 were considered for evaluation and 10 were included (1728 patients). The pooled sustained virological response was 12.6% (95% CI, 9.5-16.3%) for combination therapy vs. 2% (95% CI, 0.9-4.0%) for interferon monotherapy, with a common odds ratio of 5.49. Higher doses of interferon, a longer duration of therapy (48 weeks) and genotypes other than 1 and 4 were associated with an improvement in response. More side-effects and discontinuations were observed with combination therapy than with interferon monotherapy. CONCLUSIONS: Non-responders to interferon may benefit from re-treatment with combination therapy, especially from a 48-week regimen.

Casado MA, Buti M, Fosbrook L, Esteban R. · Schering-Plough, S.A. Paseo de la Castellana, 143, 28046 Madrid. · Gastroenterol Hepatol. · Pubmed #11968346 No free full text.

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Olivé G, Buti M, Esteban-Mur R, Guardia J. · Servicio de Hepatología, Hospital General Universitario Vall d'Hebron, Barcelona. · Gastroenterol Hepatol. · Pubmed #11968344 No free full text.

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Buti M. · Servicio de Hepatología, Hospital General Universitario Vall d'Hebron. Barcelona, Universidad Autónoma. Barcelona, Spain. · Gastroenterol Hepatol. · Pubmed #11481072 No free full text.

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Olive G, Buti M, Esteban R. · Servicio de Hepatología, Hospital Universitario Vall d'Hebron, Barcelona. · Rev Clin Esp. · Pubmed #11387827 No free full text.

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Buti M, Esteban R. · University General Hospital Valle de Hebron, Barcelona, Spain. · Forum (Genova). · Pubmed #10717258 No free full text.

Abstract: An important group of patients with chronic hepatitis C do not respond to interferon (IFN) therapy. Compared with untreated patients with chronic hepatitis C, non-responders have a higher percentage of cirrhosis, are more frequently infected by genotype 1 and usually have a viral load above 2 x 106 copies/ml. Also, patients with cirrhosis have lower life expectancy and higher risk of clinical complications, and therefore, are most in need of effective treatment strategies. There is no evidence that the re-treatment of non-responders with a standard regimen of IFN or more prolonged IFN therapy achieves a sustained biochemical or virological response. Between 20% and 40% of non-responder patients treated with IFN therapy for more than two years had an hepatic improvement in liver histology associated with a decrease in hepatitis C virus-ribonucleic acid levels. In contrast, combination therapy with IFN and ribavirin for six months now results in sustained response rates between 6% and 29% depending on the viral genotype and the presence or absence of cirrhosis. Patients infected with genotype 2 and 3 have a higher probability of achieving a sustained virological response than those infected by genotype 1. Currently, different studies are underway to determine whether high-dose IFN and/or induction therapy combined with ribavirin for more prolonged periods of time could increase the sustained response rate in non-responders. No other drugs appear to be efficacious in these patients, except the combination of IFN, ribavirin and amantadine which has shown interesting results in a preliminary trial but they need to be confirmed in further studies. These findings suggest that combination therapy is beneficial and can be recommended for some non-responder patients until other new therapies are available.

Buti M, Esteban R. · Hospital General Universitario Valle Hebron, Barcelona, Spain. · J Hepatol. · Pubmed #10622582 No free full text.

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Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. · Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, University of Paris 7 and INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hepatites Virales, Clichy, France. · N Engl J Med. · Pubmed #19052126 links to  free full text

Abstract: BACKGROUND: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS: Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

Buti M, Rodríguez Frías F, Calleja JL, Jardí R, Pons F, Crespo J, Casanovas T, Enríquez J, Carnicer F, Romero M, García Bengoechea M, Prieto M, García Samaniego J, Miras M, Pérez Roldán F, Rueda M, Esteban R. · Servicio de Hepatología, Hospital Universitari Vall d'Hebron, Barcelona, España. · Med Clin (Barc). · Pubmed #17988612 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: The extended treatment with lamivudine in patients with chronic hepatitis B is associated with the emergence of resistances. Patients with resistance to lamivudine show a loss of biochemical and virological responses and a higher progression of their liver disease. Adefovir dipivoxil, an analogue of the nucleotides, is effective for the treatment of patients with resistance to lamivudine. The aim of this study was to evaluate the efficacy, safety and resistance of adefovir dipivoxil in patients with chronic hepatitis B refractory to treatment with lamivudine. PATIENTS AND METHOD: One hundred and twenty hepatits B virus patients refractory to lamivudine were treated with adefovir dipivoxil. Seventy-four patients were followed up during two years. In all cases, the hepatitis B virus-DNA was determined by polymerase chain reaction, and in those cases without response to treatment, the presence of resistances to adefovir and lavimudine were studied. RESULTS: At the second year of treatment, we observed a biological response of 54.1%, a biochemical response of 62.2%, while an elimination of hepatitis B e antigen was seen in 21% cases. 20% patients developed resistance to adefovir dipivoxil, and the most frequent detected mutations were: A181V, A181T and N236T. Drug safety was excellent; in fact, only one adverse effect related to the drug was detected. CONCLUSIONS: Treatment with adefovir dipivoxil for 2 years in mono-therapy in patient who are previously non-responders to lavimudine is associated with a high biochemical and virologycal response with an excellent safety. At the second year of treatment, the adefovir dipivoxil resistance rate is 20%.

Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J. · Clinic of Internal Medicine II, Department of Medicine, Saarland University Hospital, Kirrbergerstrasse, 66421 Homburg/Saar, Germany. · J Hepatol. · Pubmed #16290907 No free full text.

Abstract: BACKGROUND/AIMS: Previous studies using standard interferon and ribavirin combination therapy suggested that patients infected with HCV-1 and a low pretreatment HCV-RNA level can be treated for 24 weeks without compromising sustained virologic response rates. The aim of the present study was to investigate this schedule in the era of pegylated interferon-alpha plus ribavirin. METHODS: Patients chronically infected with HCV-1 (n=235) and a screening viremia < or =600,000 IU/mL (real-time PCR) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. RESULTS: End-of-treatment and sustained virologic response rates were 80 and 50%, respectively. The 48-week historical control (Manns et al., Lancet 2001;358:958-65) had similar end-of-treatment (74%) but higher sustained virologic response rates (71%). This difference was due to a high virologic relapse rate after 24 weeks of therapy (37%) compared with the historical control (4%). A subset of patients who had undetectable serum HCV-RNA at treatment week 4, however, achieved similar sustained virologic response rate (89%) as in the control group (85%). CONCLUSIONS: HCV-1 infected patients with a low baseline HCV-RNA concentration who become HCV-RNA negative at week 4 may be treated for 24 weeks without compromising sustained virologic response rates.