Low-level viremia in nucleoside analog-treated chronic hepatitis B patients / 中华医学杂志(英文版)

Low-level viremia (LLV) was defined as persistent or intermittent episodes of detectable hepatitis B virus (HBV) DNA (<2000 IU/mL, detection limit of 10 IU/mL) after 48 weeks of antiviral treatment. Effective antiviral therapies for chronic hepatitis B (CHB) patients, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), have been shown to inhibit the replication of HBV DNA and prevent liver-related complications. However, even with long-term antiviral therapy, there are still a number of patients with persistent or intermittent LLV. At present, the research on LLV to address whether adversely affect the clinical outcome is limited, and the follow-up treatment for these patients is open to question. At the same time, the mechanism of LLV is not clear. In this review, we summarize the incidence of LLV, the association between LLV and long-term outcomes, possible mechanisms, and management strategies in these patient populations.

Influence of Treg cells and HBV genotype on sustained response and drug resistance in the treatment with nucleoside drugs

We aimed to investigate the influence of regulatory T cells including CD4+CD25+, CD8+CD28- and hepatitis B virus (HBV) genotype on sustained virological response and tolerance of nucleoside drugs. One hundred and thirty-seven patients were enrolled. Lamivudine was administered to 84 patients. Entecavir was administered to the other 53 patients. Before treatment, biochemical tests, HBV DNA load, HBV serum level, HBV genotype, PB CD3+, CD4+, CD8+, CD4+CD25+/CD3+, and CD8+CD28-/CD3+ frequencies were measured. Based on HBV DNA loads after 4 weeks of therapy, patients were divided into response group and suboptimal response group. The lamivudine group received treatment continuously, and then patients were categorized into non-resistance group and resistance group. Compared with the suboptimal response and resistance groups for lamivudine, CD4+CD25+/CD3+ levels were higher in the response and non-resistance groups (t=4.372, P=0.046; t=7.262, P=0.017). In the non-resistance group, CD8+CD28-/CD3+ frequency was lower than in the resistance group (t=5.527, P=0.037). Virus load and hepatitis B E antigen (HBeAg)-positive rate were significantly lower than in the response and resistance group (t=2.164, P=0.038; X2=4.239, P=0.040; t=2.015, P=0.044; X2=16.2, P=0.000). Incidence of drug resistance was high in patients with virogene type C. For the virological response to entecavir, CD8+CD28-/CD3+ level was significantly lower than that of the suboptimal response group (t=6.283, P=0.036). Response and suboptimal response groups were compared in CD3+, CD4+, CD8+, CD4+CD25+/CD3+ and virus genotype, and differences were not statistically significant (P>0.05). Baseline regulatory T cells including CD4+CD25+/CD3+ and CD8+CD28-/CD3+ frequencies have a relationship with the incidence of rapid virological response and the resistance to nucleoside drugs. Patients with HBV genotype C receiving lamivudine more often underwent drug resistance. Antiviral efficacy and the resistance to lamivudine were closely correlated with baseline factors; the same cannot be found for entecavir.

High efficacy of adefovir and entecavir combination therapy in patients with nucleoside-refractory hepatitis B / 대한간학회지

BACKGROUND/AIMS: Newly developed and potent antiviral agents suffer from the problem of drug resistance. Multidrug resistance is a major impediment in the treatment of patients with chronic hepatitis B (CHB). In line with American Association for the Study of Liver Diseases guidelines, adefovir dipivoxil (ADV) add-on therapy is recommended in the case of lamivudine resistance, while tenofovir disoproxil fumarate (TDF) is recommended for ADV or entecavir (ETV) resistance. TDF is currently not available in Korea. ADV+ETV combination therapy may be a viable alternative to TDF in patients with either ADV or ETV resistance. However, the efficacy of ADV+ETV combination therapy in patients with CHB and multidrug resistance is unclear. This study investigated the efficacy of ADV+ETV combination therapy in patients with multidrug resistance. METHODS: Twenty-five patients were enrolled and were administered ADV+ETV combination therapy for at least 6 months. Blood was drawn at baseline and at 3, 6, 9, and 12 months after commencing treatment, and the following blood parameters were analyzed: alanine transaminase, hepatitis B e-antigen (HBeAg), anti-hepatitis B e-antigen, and hepatitis B virus (HBV) DNA levels. The initial virological response (IVR) was defined as an HBV DNA level of or =5.0 log) dropped from 76% at baseline to only 5% after 6 months of treatment. The biochemical response rate during the first 6 months was 71%. HBeAg was lost in 2 patients (10%). CONCLUSIONS: ADV+ETV combination therapy induced a good IVR in CHB patients who were refractory to more than 2 antiviral agents. This regimen may be a good alternative to TDF in Korea, where that drug is not available.

Cost-effectiveness of telbivudine versus lamivudine for chronic hepatitis B

BACKGROUND AND AIM: Chronic hepatitis B is a highly prevalent disease worldwide, leading to serious consequences if not properly treated. Six treatment options for chronic hepatitis B are currently provided by the Brazilian public health system. Telbivudine is a nucleoside analogue that is neither included in the Brazilian clinical protocol nor in the therapeutic guidelines for chronic hepatitis B. OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of telbivudine for the viewpoint of the Brazilian public system, comparing it to lamivudine. METHODS: A Markov model was used to project lifetime complications and costs of treatment with lamivudine or telbivudine for chronic hepatitis B in both HBeAg-positive and HBeAg-negative patients. To evaluate disease progression, probabilities and utilities of virologic response, virologic resistance, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, treatment, interruption of treatment, death and seroconversion were collected in systematic reviews. Costs were collected in DATASUS, ABC da Saúde and scientific literature. RESULTS: Higher rate of virologic response and seroconversion was obtained with telbivudine, and also higher values of quality adjusted life years. However lamivudine is associated with lower costs and also lower cost-effectiveness values. The incremental cost-effectiveness ratios for telbivudine, when compared with lamivudine, were US$ 30,575 and US$ 40,457, respectively for HBeAg-positive and HBeAg-negative patients. CONCLUSION: In chronic hepatitis B lamivudine is a more cost-effective or even cost-saving strategy when compared with telbivudine.

New Insight for HBV DNA and HBsAg Quantitation during Antiviral Therapy in Patients with Chronic Hepatitis B / 대한소화기학회지

Over the past decade, advances in the antiviral therapy in patients with chronic hepatitis B have enabled the sustained suppression of hepatitis B viral replication and the prevention of progressive liver disease. Hepatitis B surface antigen (HBsAg) has been used to diagnose patients with hepatitis B virus infection. Recently, test for quantitative HBsAg titers are available and on-treatment HBsAg quantitations are used to predict treatment outcome. Serum HBV DNA levels have been shown to predict natural course of chronic hepatitis B infection. The HBV DNA levels have been reported to be positively correlated with the development of cirrhosis, hepatocellular carcinoma and related death. The baseline and on-treatment levels of HBV DNA are important factors for predicting treatment outcomes. In this article, we will discuss the role of HBV DNA and HBsAg quantitation during antiviral therapy.

Eficácia do adefovir dipivoxil, entecavir e telbivudina para o tratamento da hepatite crônica B: revisão sistemática / The efficacy of adefovir dipivoxil, entecavir and telbivudine for chronic hepatitis B treatment: a systematic review

INTRODUÇÃO: A hepatite crônica B é uma das doenças infecciosas mais frequentes no mundo e constitui um grave problema de saúde pública MÉTODOS: Para avaliar a eficácia dos análogos de núcleosídeo/nucletídeo utilizados no seu tratamento (adefovir dipivoxil, entecavir e telbivudina) foi conduzida uma revisão sistemática de ensaios clínicos randomizados. Foram consultadas, dentre outras, as bases de dados PubMed e LILACS RESULTADOS: Foram selecionados 29 artigos entre os publicados de janeiro/1970 até dezembro/2009 CONCLUSÕES: Todos os análogos de núcleosídeo/nucletídeo apresentam eficácia superior ou similar à lamivudina. O entecavir pode ser indicado para o tratamento da hepatite B crônica como alternativa à lamivudina em pacientes HBeAg positivo e negativo virgens de tratamento, considerando seu baixo potencial de resistência viral. A adição de adefovir à lamivudina apresentou bons resultados em pacientes resistentes à lamivudina. O uso de entecavir e telbivudina nesses pacientes apresenta risco de resistência cruzada. Telbivudina é um dos mais recentes antivirais disponíveis, mas resistência antiviral já documentada representa limitação ao seu uso como opção terapêutica à lamivudina. Eventos adversos aos análogos de núcleosídeo/nucletídeo foram similares em características, gravidade e incidência quando comparados à lamivudina e placebo.

INTRODUCTION: Chronic hepatitis B is one of the most frequent infectious disease in the world and represents a serious problem of public health METHODS: A systematic review of randomized clinical trials was conducted to evaluate the efficacy of the nucleoside/nucleotide analogues (adefovir, entecavir and telbivudine) used for the treatment of chronic hepatitis B. The databases PubMed and LILACS were consulted, among others RESULTS: Twenty nine articles published between January/1970 to December/2009 were selected CONCLUSIONS: All nucleoside/nucleotide analogues demonstrate upper or similar efficacy to lamivudine. The entecavir can be appropriate for patients with chronic hepatitis B, HBeAg positive and negative treatment-naive as alternative to lamivudine, considering its low potential of viral resistance. The addition of adefovir to lamivudine presented good results in lamivudine resistant patients. The use of entecavir and telbivudine in those patients presents risk of crossed resistance. TBV is one of the most recent antivirals available, but antiviral resistance already documented represents limitation to its use as therapeutic option to LAM. Adverse events of nucleoside/nucleotide analogues were similar in characteristics, gravity and incidence when compared to the lamivudina and placebo.

Hepatitis crónica viral / Chronic viral hepatitis

Los Virus Hepatitis B (VHB) y Hepatitis C (VHC) en la actualidad son infecciones frecuentes en el hombre, afectando a una proporción significativa de la población mundial. Estos son causa frecuente de hepatitis aguda y crónica, cirrosis hepática, hepatocarcinoma y trasplante hepático. En 105 últimos años ha habido un gran progreso en el conocimiento de la epidemiología e historia natural de la infección con el VHB y VHC. Además, se han logrado grandes avances en su tratamiento y con numerosas drogas actualmente en evaluación.

Hepatitis B (HBV) and Hepatitis C (HCV) virus are common viral infections, affecting at a large worldwide population. These viruses are frequent cause of acute and chronic hepatitis, cirrhosis, hepatocellular carcinoma and liver transplantation. In the last few years, the knowledge of the epidemiology and natural history of HBV and HCV infections have markedly improved. Furthermore, considerable progress have been achieved in the efficacy of treatment and several new drugs are currently under evaluation.

Treatment of chronic hepatitis B: will entecavir and telbivudine do the trick?

Rapid evolution and development in the treatment strategy of chronic hepatitis B (CHB) has taken place in the last decade. Six agents have been so far approved by the FDA for the management of HBV infection including two parenteral drugs (interferon alpha2b and pegylated interferon alpha-2a) and four oral nucleotide/nucleosides (lamivudine, adefovir dipivoxil, entecavir, and telbivudine). The two parenteral drugs have significant side effects and limited rates of HBeAg seroconversion. Lamivudine and Adefovir have been plagued by significant levels of drug resistance.The newer drugs entecavir and telbivudine have been in focus recently with claims of increased potency, with low side effects and lesser drug resistance. While these new drugs are definitely a welcome addition to the family of antiviral drugs against HBV, they are not necessarily a cure for all the evils of their predecessors.

Management of Antiviral-Resistant Chronic Hepatitis B Virus Infection / 대한소화기학회지

Substantial progress has been made in the treatment of chronic hepatitis B during the past decade. Nucleos(t)ide analogues are now widely used due to their convenience, less side effects, and considerable response rates. However, development of antiviral resistance is a major problem being considered as the most important factor for the treatment failure. Viral breakthrough associated with selection of antiviral-resistant hepatitis B virus (HBV) is usually followed by biochemical breakthrough, clinical deterioration, and even progressive liver failure. Therefore, appropriate management of antiviral resistance is critical for improving treatment outcomes. Strategies for the management of antiviral-resistant chronic HBV infection are described herein considering recently published guidelines. Lamivudine/telbivudine resistance can be managed by adding adefovir. Switching to adefovir or entecavir is also a viable option. However, careful follow-up of viral load is mandatory to detect any primary or secondary treatment failure in case of sequential monotherapy. Interferon or peg-interferon therapy can also be considered in case of young patients with compensated liver disease. For adefovir resistance, lamivudine can be added, but adding or switching to entecavir is a more reasonable option. Likewise, adding or switching to adefovir can be considered for entecavir resistance. Adding or switching to tenofovir needs to be considered upon availability. Experiences for clevudine resistance are still lacking, and need to be studied further upon the isolation of clinically resistant strains. To avoid emergence of resistant mutations, antiviral therapy should be initiated after careful balance of risk and benefit, and the most potent antiviral agent with the lowest resistance rate should be selected.

Efectividad de efavirenz versus lopinavir/ritonavir asociado a dos análogos nucleósidos como tratamiento de inicio en pacientes VIH positivos / Effectiveness of efavirenz versus lopinavir / ritonavir associated with two nucleoside analogues as initial therapy for HIV patients

Comparar la efectividad virológica e inmunológica, de dos esquemas, uno basado en efavirenz y el otro en lopinavir/ritonavir, ambos combinados con dos análogos nucleósidos, en pacientes con infección avanzada por VIH, sin tratamiento previo. Estudio observacional de cohorte. Falla virológica definida como carga viral >50 copias/mL en los intervalos 3 a 9, 10 a 16 y 22 a 28 meses después del inicio. Se determinó la variación de CD4+. Se realizó análisis univariado de variables asociadas falla virológica. Se aplicaron Chi², Sum Rank Testy Log Rank Test. 189 pacientes iniciaron tratamiento entre diciembre 2000 y abril 2004, 114 con efavirenz y 45 con lopinavir/ritonavir, combinados con dos análogos nucleósidos. Los grupos fueron comparables en características basales: edad en años (36,5 en efavirenz vs 36,9 en lopinavir/ritonavir, (P=0,78); CD4+ basal (183,3 en efavirenz vs. 143,7 en lopinavir/ritonavir, (P=0,14); carga viral basal (203,696 cop/mL en efavirenz vs 217,772 cop/mL en lopinavir/ritonavir, P=0,77). Para la cohorte completa 87 por ciento obtuvo valores de carga viral indetectable a los 6 meses, 58 por ciento al año y 48 por ciento a los 28 meses. El cambio en el valor de CD4+/mes (+10,5 en efavirenz vs + 9,5 en lopinavir/ritonavir, P=0,77) y el porcentaje de indetectabilidad fueron similares en ambos grupos, tomando en cuenta los pacientes que pudieron seguirse durante el período de observación, cuyo número fue disminuyendo a partir de la muestra inicial. Ambos esquemas fueron comparables en su efectividad en esta cohorte de pacientes en términos de variación de CD4+ y porcentaje de indetectabilidad de carga viral.

Diagnosis, antiretroviral therapy, and emergence of resistance to antiretroviral agents in HIV-2 infection: a review

Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are the causative agents of AIDS. HIV-2 is prevalent at moderate to high rates in West African countries, such as Senegal, Guinea, Gambia, and Cape Verde. Diagnosis of HIV-2 is made with a positive HIV-1/HIV-2 ELISA or simple/rapid assay, followed by one or two confirmatory tests specific for HIV-2. Following CD4+ T cell counts, HIV-2 viral burden and clinical signs and symptoms of immunodeficiency are beneficial in monitoring HIV-2 disease progression. Although non-nucleoside reverse transcriptase inhibitors are ineffective in treating HIV-2, nucleoside reverse transcriptase inhibitors and protease inhibitors can be effective in dual and triple antiretroviral regimens. Their use can decrease HIV-2 viral load, increase CD4+ T cell counts and improve AIDS-related symptoms. HIV-2 resistance to various nucleoside reverse transcriptase inhibitors and protease inhibitors, including zidovudine, lamivudine, ritonavir and indinavir, has been identified in some HIV-2 infected patients on antiretroviral therapy. The knowledge of HIV-2 peculiarities, when compared to HIV-1, is crucial to helping diagnose and guide the clinician in the choice of the initial antiretroviral regimen and for monitoring therapy success

Tratamiento antirretroviral / Antiretroviral therapy

En el presente trabajo se analizan los beneficios y limitaciones de la terapia antirretroviral de alta eficacia (HAART). Los objetivos de esta terapia son reducir la carga viral plasmática lo máximo posible y durante el mayor tiempo posible. Esto implica alcanzar niveles de carga viral no detectables con técnicas ultrasensibles. Se evalúan los resultados obtenidos con los principales esquemas de tratamiento asi como sus indicaciones y efectos adversos.

Tratamento de hepatites crônicas virais: uma atualização / Chronic viral hepatitis: an update

O autor realiza uma revisão da literatura sobre o tratamento atual das hepatites virais. Salienta, no caso da hepatite crônica pelo vírus B, a importância da vacinação, já que essa é uma doença que pode ser evitada. No seu tratamento, a droga mais aceita é o Interferon, a despeito da baixa eficácia. O papel dos análogos nucleosídios (lamivudina) ainda não está definido, restringindo-se o seu uso a protocolos, salvo em pacientes em programa de transplante hepático. No que tange ao tratamento da hepatite crônica pelo vírus C, a droga a ser ofertada também é o Inteferon. No entanto, pela baixa resposta terapêutica alcançada, abre-se uma perspectiva em sua associação com a Ribavirina

Atualizaçäo terapêutica em herpes simplex vírus / Therapeutic actualization in herpes virus

É apresentada uma revisäo das publicaçöes mais recentes sobre o herpes simplex vírus, com ênfase às relaçöes com transmissäo, tratamento e controle