Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials.

BACKGROUND: Effective and well tolerated nucleos(t)ide analogue treatment exists for patients with chronic hepatitis B, although treatment is generally anticipated to be life-long, with concomitant costs and treatment-related side-effects. We aimed to characterise the outcomes of patients with persistent viral suppression who discontinued nucleotide analogue use after extended treatment. METHODS: The primary objective of this prespecified analysis was to evaluate the safety of stopping long-term tenofovir disoproxil fumarate therapy in patients enrolled in two (completed) randomised controlled studies, GS-US-174-0102 (ClinicalTrials.gov, number NCT00117676) and GS-US-174-0103 (ClinicalTrials.gov, number NCT00116805). In those studies, patients who had completed 8 years or more of nucleotide analogue treatment, were hepatitis B surface antigen (HBsAg)-positive with hepatitis B virus (HBV) DNA concentration of less than 29 IU/mL, and were unwilling or unable to continue therapy were required by protocol to enter a 24-week treatment-free follow-up (TFFU) phase. We present data for patients in the TFFU phase who were assessed at baseline and monitored every 4 weeks for changes in qualitative serum HBsAg, HBV DNA, and alanine aminotransferase (ALT) concentrations in addition to standard safety assessments. FINDINGS: Of 124 patients who entered the TFFU phase, 54 (44%) patients did not complete 24 weeks of follow-up (median 12 weeks; IQR 0-20). Overall, 32 (26%) patients reported an adverse event. Serious adverse events occurred in five (4%) patients, including elevated ALT concentrations in two patients, hepatic flare in two patients, and increased lipase in one patient. 38 (31%) of patients had grade 3 or higher laboratory abnormalities, the majority of which were ALT elevations (36 patients). Of the 106 hepatitis B e antigen (HBeAg)-negative patients who entered the TFFU phase, 63 (59%) were followed for 24 weeks. HBsAg loss was observed in five (5%) of the 106 HBeAg-negative patients who entered the TFFU phase, and 37 (35%) had both HBV DNA concentrations of less than 2000 IU/mL and ALT concentrations less than the ULN at TFFU week 24. 18 HBeAg-positive patients entered the TFFU phase, of whom seven (39%) were followed up for 24 weeks. Of these seven patients, none had HBsAg loss or HBV DNA of less than 2000 IU/mL and one (14%) had an ALT less than the ULN at week 24. INTERPRETATION: Within 24 weeks of stopping 8 years or more of nucleotide analogue therapy almost a third of patients experienced a grade 3 or higher laboratory abnormality. Although few patients achieved HBsAg loss, a subgroup of HBeAg-negative patients can achieve a low-replicative state within a short duration of follow-up. FUNDING: Gilead Sciences, Inc.

Current clinical evidence for nucleos(t)ide analogues in patients with HBV-related hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of death globally and is frequently seen following Hepatitis B virus (HBV) or Hepatitis C virus infection. Areas with high HBV infection rates, such as Asia and sub-Saharan Africa, are therefore also high-risk areas for HCC. Areas covered: This review identifies and discusses the current evidence from robust clinical trials which have investigated the benefits of Nucleos(t)ide analogue (NA) antiviral therapy in HBV-related HCC patients, including HCC patients that underwent liver transplantation and HCC patients with or without curative treatment. In addition, we assess how this evidence has influenced current clinical practice, with a particular focus on those areas of high HBV infection rates. Expert commentary: A number of studies have assessed whether NA antiviral treatment can improve the prognosis of HBV-related HCC patients. In this review we evaluate the current evidence, including that from trials in Asia, for antiviral NA treatments in HBV-related HCC patients. We also focus on those NAs with a high genetic barrier to resistance (i.e. ETV or TDF), on different therapeutic approaches, and on the future evidence that is required in this field.

Bone scintigraphy and secondary osteomalacia due to nephrotoxicity in a chronic hepatitis B patient treated with tenofovir / Gammagrafía ósea y oseteomalacia secundaria a nefrotoxicidad en una paciente con hepatitis B tratada con tenofovir

Tenofovir is a nucleotide analogue used for the treatment of chronic hepatitis B and HIV infection. The safety of tenofovir is high but it has been described that tenofovir produces tubular toxicity and Fanconi's syndrome in some HIV-infected patients. To our knowledge this is the first documented case of bone involvement in Fanconi's syndrome in a patient treated with tenofovir for chronic hepatitis B without HIV coinfection. Bone scintigraphy has proven to be very useful for the diagnosis of secondary osteomalacia. Normalization of the bone scan after the withdrawal of the drug and the decline in alkaline phosphatase and phosphate serum levels reinforce the cause-effect relationship (AU)

El tenofovir es un análogo de nucleótido que se utiliza para el tratamiento de la hepatitis B y de la infección por VIH. La seguridad del fármaco es muy alta, pero se ha descrito que en algunos pacientes VIH produce toxicidad tubular y síndrome de Fanconi. En nuestro conocimiento este es el primer caso en el que se documenta afectación ósea en síndrome de Fanconi en una paciente tratada con tenofovir por hepatitis B. En este contexto la gammagrafía ósea ha resultado ser de gran utilidad para el diagnóstico de osteomalacia secundaria. La normalización de la gammagrafía ósea y de los valores séricos de fosfato y fosfatasa alcalina tras la retirada del fármaco refuerza la relación causa-efecto (AU)

Effectiveness of hepatitis B treatment in clinical practice.

It is important to examine the effectiveness of current therapies for chronic hepatitis B in clinical practice, given the therapeutic advances over the past 15 years. A 2010 Institute of Medicine report on hepatitis and liver cancer stated that the public and health care providers have a lack of knowledge and awareness about viral hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of hepatitis B treatment, based on results from clinical trials, and discuss the effectiveness of these treatments in clinical practice. We also discuss why having efficacious treatments alone would have a small impact on the global health burden of hepatitis B, and highlight the importance of educating the public and the medical community and coordination of care.

Activation of distinct P2Y receptor subtypes stimulates insulin secretion in MIN6 mouse pancreatic beta cells.

Extracellular nucleotides and their receptor antagonists have therapeutic potential in disorders such as inflammation, brain disorders, and cardiovascular diseases. Pancreatic beta cells express several purinergic receptors, and reported nucleotide effects on insulin secretion are contradictory. We studied the effect of P2Y receptors on insulin secretion and cell death in MIN6, mouse pancreatic beta cells. Expression of P2Y(1) and P2Y(6) receptors was revealed by total mRNA analysis using RT-PCR. MIN6 cells were stimulated in the presence of 16.7 mM glucose with or without P2Y(1) and P2Y(6) agonists, 2-MeSADP and Up(3)U, respectively. Both the agonists increased insulin secretion with EC(50) values of 44.6+/-7.0 nM and 30.7+/-12.7 nM respectively. The insulin secretion by P2Y(1) and P2Y(6) agonists was blocked by their selective antagonists MRS2179 and MRS2578, respectively. Binding of the selective P2Y(1) receptor antagonist radioligand [125I]MRS2500 in MIN6 cell membranes was saturable (K(D) 4.74+/-0.47 nM), and known P2Y(1) ligands competed with high affinities. Inflammation and glucose toxicity lead to pancreatic beta cell death in diabetes. Flow cytometric analysis revealed that Up(3)U but not 2-MeSADP protected MIN6 cells against TNF-alpha induced apoptosis. Overall, the results demonstrate that selective stimulation of P2Y(1) and P2Y(6) receptors increases insulin secretion that accompanies intracellular calcium release, suggesting potential application of P2Y receptor ligands in the treatment of diabetes.

Hepatitis B virus resistance to nucleos(t)ide analogues.

Patients with chronic hepatitis B (CHB) can be successfully treated using nucleos(t)ide analogs (NA), but drug-resistant hepatitis B virus (HBV) mutants frequently arise, leading to treatment failure and progression to liver disease. There has been much research into the mechanisms of resistance to NA and selection of these mutants. Five NA have been approved by the US Food and Drug Administration for treatment of CHB; it is unlikely that any more NA will be developed in the near future, so it is important to better understand mechanisms of cross-resistance (when a mutation that mediates resistance to one NA also confers resistance to another) and design more effective therapeutic strategies for these 5 agents. The genes that encode the polymerase and envelope proteins of HBV overlap, so resistance mutations in polymerase usually affect the hepatitis B surface antigen; these alterations affect infectivity, vaccine efficacy, pathogenesis of liver disease, and transmission throughout the population. Associations between HBV genotype and resistance phenotype have allowed cross-resistance profiles to be determined for many commonly detected mutants, so genotyping assays can be used to adapt therapy. Patients that experience virologic breakthrough or partial response to their primary therapy can often be successfully treated with a second NA, if this drug is given at early stages of these events. However, best strategies for preventing NA resistance include first-line use of the most potent antivirals with a high barrier to resistance. It is important to continue basic research into HBV replication and pathogenic mechanisms to identify new therapeutic targets, develop novel antiviral agents, design combination therapies that prevent drug resistance, and decrease the incidence of complications of CHB.

Tenofovir: farmacología e interacciones / Tenofovir: pharmacology and interactions

Tenofovir es un análogo de los nucleótidos y, por ello, presenta un mecanismo de acción diferente al de los análogos a los nucleósidos. Se administra por vía oral en forma de éster disoproxil, que es desesterificado para alcanzar una biodisponibilidad, que supera el 20%, y que aumenta ligeramente si el fármaco se ingiere con grasas. Presenta una distribución tisular amplia, facilitada por el pequeño tamaño de la molécula y su escasa fijación a proteínas, y se elimina en su práctica totalidad en forma activa por la orina, a través de filtración glomerular y secreción tubular activa. Esta circunstancia obliga a realizar un ajuste de la dosis cuando hay insuficiencia renal. De forma característica, presenta una semivida intracelular que supera en más de 10 veces a la plasmática. Su perfil farmacocinético le configura como un fármaco con poco potencial de producir o de presentar interacciones con otros fármacos. Así, dentro de los antirretrovirales se ha descrito un aumento de la biodisponibilidad de didanosina que conlleva la recomendación de utilizarlo en dosis inferior a la habitual, mientras que puede utilizarse sin ajustes con otros inhibidores análogos y no análogos. Tampoco parece alterar la farmacocinética de los fármacos inhibidores de la proteasa, aunque éstos pueden producir un aumento ligero de la biodisponibilidad de tenofovir que parece tener escasa trascendencia clínica. Se ha señalado la ausencia de interacciones con otros fármacos no antirretrovirales(AU)

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported(AU)

Datos clínicos I. Experiencia clínica de tenofoviren combinaciones con inhibidores no análogos de la transcriptasa inversa / Clinical data I. Clinical experience with tenofovir in combination with nonnucleoside analogue transcriptase inhibitors

La aparición del tratamiento antirretroviral de granactividad ha supuesto una drástica mejora en elpronóstico de los pacientes infectados por el virus deinmunodeficiencia humana. La gran eficacia de lostratamientos antirretrovirales ha desplazado el interéshacia nuevos aspectos de la terapéutica, como ladosificación 1 vez al día de los antirretrovirales, el uso ydiseño de nuevas combinaciones de dosis fijas defármaco y el perfil de seguridad de los fármacos. Eltenofovir disoproxil fumarato (TDF) es un análogo denucleótido inhibidor de la transcriptasa inversa que seadministra 1 vez al día y que en combinación es uno delos fármacos recomendados en pautas de inicio por lamayoría de las guías de práctica clínica. En la actualidad,se dispone de una experiencia de más de 5 años queconfirma que el TDF en combinación con los inhibidoresno análogos de la transcriptasa inversa es un fármacocómodo, seguro, altamente eficaz y adecuado pararegímenes una vez al día con escaso número de comprimidos(AU)

Highly active antirretroviral therapy has transformed theprognosis of patient infected with humanimmunodeficiency virus. The efficacy of these drugs hasshifted the clinicians` attention to other therapeuticaspects like QD regimens, fixed dose combinations andclinical safety. Tenofovir disoproxil fumarate(TDF) is anucleoside monophosphate (nucleotide) analogue that inhibits reverse trascriptase enzyme. It’s administered ina q.d. regimen and it’s recommended by most of theclinical guidelines as a start regimen in combination withtwo other drugs. Currently more than 5 years of clinicalexperience is accumulated and confirmed that acombination of tenofovir and a nonnucleoside analoguetranscriptase inhibitor is a comfortable, safe, highlyeffective and low pill burden regimen(AU)

Datos clínicos II. Experiencia clínica de tenofovir en combinaciones con inhibidores de proteasa / Clinical data II. Clinical experience of tenofovir DF in combination with protease inhibitors

Tenofovir (TDF) es uno de los fármacos de elección en las combinaciones de tratamiento antirretroviral de primera línea. La mayor parte de la información acerca de su eficacia y seguridad en este escenario se originó inicialmente en ensayos clínicos en los que se combinaba con no análogos de nucleósidos. Este hecho, así como la posible interacción de TDF con algunos inhibidores de proteasa (IP) y la sospecha de que esta combinación pudiera incrementar el riesgo de nefrotoxicidad, hace imprescindible analizar la experiencia clínica disponible de la combinación de TDF (asociado a emtricitabina u otro análogo de nucleósido) con un IP. En esta revisión se presentan los datos de eficacia y seguridad procedentes en su mayoría de ensayos clínicos. Tomados en su conjunto, estos estudios aportan suficiente información para poder afirmar que la combinación de TDF con IP es eficaz y segura, lo que justifica su elección en el tratamiento de primera línea o en el rescate tras el fracaso virológico(AU)

Tenofovir is one of the drugs of choice in first-line combinations of antiretroviral therapy. Most data on safety and efficacy in this scenario initially came from clinical trials in which tenofovir was combined with non-nucleoside reverse transcriptase inhibitors. Because of this, as well as the possible interaction of tenofovir with some protease inhibitors and the suspicion that this combination could increase the risk of nephrotoxicity, analysis of the clinical experience available on the combination of tenofovir (associated with emtricitabine or another nucleoside analogue) with a protease inhibitor is essential. The present review reports data on efficacy and safety, mainly from clinical trials. Taken together, these studies provide sufficient information to indicate that the combination of tenofovir and protease inhibitors is safe and effective, justifying its selection in first-line therapy or rescue therapy after virological failure(AU)

Tenofovir: farmacología e interacciones / Tenofovir: pharmacology and interactions

Tenofovir es un análogo de los nucleótidos y, por ello, presenta un mecanismo de acción diferente al de los análogos a los nucleósidos. Se administra por vía oral en forma de éster disoproxil, que es desesterificado para alcanzar una biodisponibilidad, que supera el 20%, y que aumenta ligeramente si el fármaco se ingiere con grasas. Presenta una distribución tisular amplia, facilitada por el pequeño tamaño de la molécula y su escasa fijación a proteínas, y se elimina en su práctica totalidad en forma activa por la orina, a través de filtración glomerular y secreción tubular activa. Esta circunstancia obliga a realizar un ajuste de la dosis cuando hay insuficiencia renal. De forma característica, presenta una semivida intracelular que supera en más de 10 veces a la plasmática. Su perfil farmacocinético le configura como un fármaco con poco potencial de producir o de presentar interacciones con otros fármacos. Así, dentro de los antirretrovirales se ha descrito un aumento de la biodisponibilidad de didanosina que conlleva la recomendación de utilizarlo en dosis inferior a la habitual, mientras que puede utilizarse sin ajustes con otros inhibidores análogos y no análogos. Tampoco parece alterar la farmacocinética de los fármacos inhibidores de la proteasa, aunque éstos pueden producir un aumento ligero de la biodisponibilidad de tenofovir que parece tener escasa trascendencia clínica. Se ha señalado la ausencia de interacciones con otros fármacos no antirretrovirales

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported

Datos clínicos I. Experiencia clínica de tenofovir en combinaciones con inhibidores no análogos de la transcriptasa inversa / Clinical data I. Clinical experience with tenofovir in combination with nonnucleoside analogue transcriptase inhibitors

La aparición del tratamiento antirretroviral de gran actividad ha supuesto una drástica mejora en el pronóstico de los pacientes infectados por el virus de inmunodeficiencia humana. La gran eficacia de los tratamientos antirretrovirales ha desplazado el interés hacia nuevos aspectos de la terapéutica, como la dosificación 1 vez al día de los antirretrovirales, el uso y diseño de nuevas combinaciones de dosis fijas de fármaco y el perfil de seguridad de los fármacos. El tenofovir disoproxil fumarato (TDF) es un análogo de nucleótido inhibidor de la transcriptasa inversa que se administra 1 vez al día y que en combinación es uno de los fármacos recomendados en pautas de inicio por la mayoría de las guías de práctica clínica. En la actualidad, se dispone de una experiencia de más de 5 años que confirma que el TDF en combinación con los inhibidores no análogos de la transcriptasa inversa es un fármaco cómodo, seguro, altamente eficaz y adecuado para regímenes una vez al día con escaso número de comprimidos

Highly active antirretroviral therapy has transformed the prognosis of patient infected with human immunodeficiency virus. The efficacy of these drugs has shifted the clinicians` attention to other therapeutic aspects like QD regimens, fixed dose combinations and clinical safety. Tenofovir disoproxil fumarate(TDF) is a nucleoside monophosphate (nucleotide) analogue that inhibits reverse trascriptase enzyme. It¿s administered in a q.d. regimen and it¿s recommended by most of the clinical guidelines as a start regimen in combination with two other drugs. Currently more than 5 years of clinical experience is accumulated and confirmed that a combination of tenofovir and a nonnucleoside analogue transcriptase inhibitor is a comfortable, safe, highly effective and low pill burden regimen

Datos clínicos II. Experiencia clínica de tenofovir en combinaciones con inhibidores de proteasa / Clinical data II. Clinical experience of tenofovir DF in combination with protease inhibitors

Tenofovir (TDF) es uno de los fármacos de elección en las combinaciones de tratamiento antirretroviral de primera línea. La mayor parte de la información acerca de su eficacia y seguridad en este escenario se originó inicialmente en ensayos clínicos en los que se combinaba con no análogos de nucleósidos. Este hecho, así como la posible interacción de TDF con algunos inhibidores de proteasa (IP) y la sospecha de que esta combinación pudiera incrementar el riesgo de nefrotoxicidad, hace imprescindible analizar la experiencia clínica disponible de la combinación de TDF (asociado a emtricitabina u otro análogo de nucleósido) con un IP. En esta revisión se presentan los datos de eficacia y seguridad procedentes en su mayoría de ensayos clínicos. Tomados en su conjunto, estos estudios aportan suficiente información para poder afirmar que la combinación de TDF con IP es eficaz y segura, lo que justifica su elección en el tratamiento de primera línea o en el rescate tras el fracaso virológico

Tenofovir is one of the drugs of choice in first-line combinations of antiretroviral therapy. Most data on safety and efficacy in this scenario initially came from clinical trials in which tenofovir was combined with non-nucleoside reverse transcriptase inhibitors. Because of this, as well as the possible interaction of tenofovir with some protease inhibitors and the suspicion that this combination could increase the risk of nephrotoxicity, analysis of the clinical experience available on the combination of tenofovir (associated with emtricitabine or another nucleoside analogue) with a protease inhibitor is essential. The present review reports data on efficacy and safety, mainly from clinical trials. Taken together, these studies provide sufficient information to indicate that the combination of tenofovir and protease inhibitors is safe and effective, justifying its selection in first-line therapy or rescue therapy after virological failure

Tratamiento de la toxicidad renal en el paciente positivo al virus de la inmunodeficiencia humana. Qué medir, cómo medirlo y con qué frecuencia / Management of renal toxicity in HIV-positive patients. What to measure, how to measure it and frequency

La enfermedad renal crónica en pacientes con infección por el virus de la inmunodeficiencia humana se está poniendo de manifiesto como una de las comorbilidades más frecuentes, por lo que, actualmente, su estudio es un campo abierto. Las manifestaciones que pueden aparecer son muy variadas, por lo que se debe tener alto índice de vigilancia y ya desde la primera visita del paciente realizar los estudios adecuados para descartarla y evitar el empeoramiento con las medidas diagnósticas o terapéuticas que posteriormente se deban aplicar. Uno de los problemas más habituales es la nefrotoxicidad de algunos fármacos y cada vez son más frecuentes los casos descritos asociados a tenofovir. Sin embargo, la experiencia clínica con este fármaco es muy extensa y su toxicidad renal es poco habitual, tanto en ensayos clínicos como en la práctica clínica. Lo importante es conocer bien qué es lo que puede ocurrir, los factores colaboradores y controlar de manera adecuada a los pacientes

Chronic kidney disease in patients with HIV is being recognized as one of the most frequent comorbidities of this disease and consequently much research is currently being performed in this area. The possible manifestations are highly varied and consequently a high index of suspicion is required. Appropriate investigations should be performed from the moment patients first seek care to rule out renal disease and to prevent worsening, with the diagnostic or therapeutic measures that may subsequently be required. One of the most common problems is nephrotoxicity caused by some drugs and cases associated with tenofovir are becoming more frequently described. However, there is wide clinical experience with this drug and renal toxicity associated with its use is uncommon both in clinical trials and in clinical practice. Familiarity with what may happen, the associated factors and appropriate patient management are essential

Conclusiones / No disponible

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Análogos de nucleósidos y nucleótidos en el tratamiento de la hepatitis crónica por el virus B / Nucleoside and nucleotide analogs in the treatment of chronic hepatitis B

Hay al menos 4 análogos de los nucleótidos/nucleósidos aprobados para el tratamiento de la hepatitis crónica por virus de la hepatitis B (HBC): lamivudina, adefovir dipivoxil, entecavir y telbivudina. La introducción de estos fármacos ha supuesto un cambio radical en el tratamiento de esta enfermedad. Las ventajas de estos fármacos son la administración oral, la excelente tolerancia y la eficacia en todos los tipos de HBC (enfermedad hepática compensada y descompensada). Las limitaciones son la necesidad de tratamientos prolongados que dificultan la adhesión y pueden ocasionar la selección de cepas del virus de la hepatitis B resistentes a los distintos fármacos. La tasa de resistencias es diferente para cada uno de los fármacos. Los análogos de nucleótidos, como el adefovir y el tenofovir, son útiles en pacientes con resistencia a análogos de nucleósidos, como lamivudina, entecavir y telbivudina, y viceversa. En casos de resistencia a uno de estos fármacos se aconseja el tratamiento combinado(AU)

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(AU)

Análogos de nucleósidos y nucleótidos en el tratamiento de la hepatitis crónica por el virus B / Nucleoside and nucleotide analogs in the treatment of chronic hepatitis B

Hay al menos 4 análogos de los nucleótidos/nucleósidos aprobados para el tratamiento de la hepatitis crónica por virus de la hepatitis B (HBC): lamivudina, adefovir dipivoxil, entecavir y telbivudina. La introducción de estos fármacos ha supuesto un cambio radical en el tratamiento de esta enfermedad. Las ventajas de estos fármacos son la administración oral, la excelente tolerancia y la eficacia en todos los tipos de HBC (enfermedad hepática compensada y descompensada). Las limitaciones son la necesidad de tratamientos prolongados que dificultan la adhesión y pueden ocasionar la selección de cepas del virus de la hepatitis B resistentes a los distintos fármacos. La tasa de resistencias es diferente para cada uno de los fármacos. Los análogos de nucleótidos, como el adefovir y el tenofovir, son útiles en pacientes con resistencia a análogos de nucleósidos, como lamivudina, entecavir y telbivudina, y viceversa. En casos de resistencia a uno de estos fármacos se aconseja el tratamiento combinado

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

Tratamiento del paciente con hepatitis crónica por el virus de la hepatitis B / Clinical management of patients with chronic hepatitis B virus infection

La hepatitis crónica por virus de la hepatitis B es aún un problema importante de salud pública, agravado por el creciente fenómeno de la inmigración procedente de zonas con elevada prevalencia de infección por este virus. Durante los últimos años se ha producido un avance notable en los métodos diagnósticos, el conocimiento de la historia natural de la enfermedad y las opciones terapéuticas, incluido el trasplante hepático, lo que se ha traducido en una mejoría en la supervivencia de los pacientes. Todo ello ha ido acompañado de un incremento en la complejidad de la toma de decisiones. Actualmente hay 6 tratamientos aprobados para la hepatitis B, incluidas 2 formulaciones de interferón, el estándar y el pegilado, y 4 análogos de nocleótidos/nucleósidos, lamivudina, adefovir, entecavir y telbivudina, y 2 más que se utilizan en pacientes coninfectados con el virus de la inmunodeficiencia humana, tenofovir y emtricitabina. Sin embargo, ninguno de los tratamientos actuales es capaz de erradicar el virus, por lo que con frecuencia es preciso recurrir a tratamientos prolongados, con el consiguiente riesgo de generar variantes del virus resistentes. Por ello y por la heterogeneidad de la historia natural de la enfermedad, aún no se han establecido con claridad las indicaciones de tratamiento y en qué parámetros deben basarse, cuál es el fármaco o la combinación de fármacos ideal o qué criterios deben seguirse para continuar, modificar o interrumpir el tratamiento. Por tanto, a pesar de los enormes progresos realizados, aún persisten numerosas incógnitas que hacen que el tratamiento clínico de estos pacientes constituya un auténtico reto

Chronic hepatitis B is still a major public health problem, aggravated by the growing phenomenon of immigration from areas with a high prevalence of infection with this virus. In the last few years, marked progress has been achieved in diagnostic methods, knowledge of the natural history of the disease and in therapeutic options, including liver transplantation, which has improved survival in these patients. These advances have been accompanied by an increase in the complexity of decision making. Six treatments have currently been approved for hepatitis B, including two interferon formulations ¿ standard and pegylated ¿ and four neucleos(t)ide analogs, lamivudine, adefovir, entecavir and telbivudine, as well as two further drugs that are used in patients coinfected with HIV, tenofovir and emtricitabine. However, none of the current treatments is able to eradicate the virus and consequently prolonged treatments are often required with the consequent risk of generating resistance. For this reason, as well as the heterogeneity of the natural history of the disease, there is a lack of consensus on the indications for treatment and the parameters in which treatment should be based, the most suitable drug or drug combination, and the criteria to be used to continue, modify or suspend treatment. Therefore, despite the enormous progress made, numerous questions remain that make the clinical management of these patients a major challenge

Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine.

We determined the clinical outcome of hepatitis e antigen (HBeAg)-negative chronic hepatitis B patients treated with long-term nucleos(t)ide analog therapy starting with lamivudine. We evaluated 201 such patients treated for 3.8 +/- 1.4 years and 2 historical similar cohorts: 1 treated with interferon-alfa (n = 209) and 1 untreated (n = 195). Virological or biochemical remission rate at 48 months under lamivudine was 34% or 36%, respectively, whereas adefovir was administered in 79 patients with virological-biochemical breakthroughs or no response. Of the lamivudine-treated patients, 4 died, 1 underwent a transplantation, and another 8 developed major events, all having advanced fibrosis at baseline and all but 1 having experienced breakthroughs or no response. At 5 years, survival was 96%, and major event-free survival was 93%. The major event-free survival was significantly better in patients with than in those without virological remission under lamivudine. At the end of follow-up, both survival and major event-free survival were independently associated with type of and response to treatment, being significantly better in patients under long-term antiviral therapy or interferon sustained responders than in interferon non-sustained responders or untreated cases (5-year survival: 96% or 98% vs. 88% or 90%, respectively). In conclusion, in HBeAg-negative chronic hepatitis B, long-term nucleos(t)ide analog therapy starting with lamivudine significantly improves survival and reduces the risk of major complications, compared with interferon non-sustained responders or untreated patients. In such patients with advanced fibrosis, close follow-up for lamivudine resistance and prompt onset of additional antiviral therapy is required or the ab initio use of agent(s) with low resistance rates should be considered.