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INTRODUCTION AND OBJECTIVES: Covalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver biopsies. Hepatitis B core-related antigen (HBcrAg) levels in plasma/serum have been proposed to reflect intrahepatic cccDNA-levels and may therefore monitor treatment efficacy. This study aimed to validate the relationship between HBcrAg and other intrahepatic and circulating viral markers in CHB patients with high viral load, before and after combination treatment. MATERIALS AND METHODS: Plasma/serum levels of HBcrAg, HBsAg, HBV-DNA, and HBV pregenomic RNA (HBV-pgRNA), and intrahepatic cccDNA and HBV-DNA levels and fibrosis scores were measured in 89 CHB patients with HBV-DNA levels of >100,000 copies/mL (17,182 IU/mL). Measurements were done before and after a 48-week treatment with pegylated interferon alfa-2a and adefovir in a prospective study (ISRCTN77073364). RESULTS: Baseline HBcrAg-values correlated strongly with intrahepatic cccDNA (ρ 0.77, p < 0.001), intrahepatic HBV-DNA (ρ 0.73, p < 0.001) and plasma/serum HBV-DNA (ρ 0.80, p < 0.001), HBV-pgRNA (ρ 0.80, p < 0.001), and to lesser extend HBsAg (ρ 0.56, p < 0.001). Baseline HBcrAg-levels could not predict functional cure (FC) but HBcrAg-levels declined more strongly in patients who developed FC or HBeAg-loss. Furthermore, most correlations persisted at the end of treatment and follow-up. CONCLUSIONS: HBcrAg reflects cccDNA transcription activity more accurately than HBsAg and may replace HBV-DNA as a marker during future treatment regimens, especially when cccDNA transcription is targeted or nucleot(s)ide analogues are included in the treatment regime.

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The results of several new clinical trials that compared the effectiveness of entecavir (ETV) treatment with that of adefovir (ADV) treatment in patients with chronic hepatitis B (CHB) were published in recent years. However, the numbers of patients included in these clinical trials were too small to draw a clear conclusion as to whether ETV is more effective than ADV. Therefore, a new meta-analysis was needed to compare ETV with ADV for the treatment of CHB. A search of the Cochrane Central Register of Controlled Trials (CCTR), MEDLINE, the Science Citation Index, Embase, the China National Knowledge Infrastructure (CNKI), and the Wanfang Database for relevant studies published between 1966 and 2010 was performed. Trials comparing the use of ETV and ADV for the treatment of CHB were assessed. Of the 2,358 studies screened, 13 randomized controlled clinical trials comprising 1,230 patients (ETV therapy, 621; ADV therapy, 609) were analyzed. The serum hepatitis B virus (HBV) DNA clearance rate obtained in patients treated with ETV was significantly higher than that in patients treated with ADV at the 24th and 48th weeks of treatment (24 weeks: 59.6% vs. 31.8%, relative risk [RR], 1.82, 95% CI: 1.49-2.23; 48 weeks: 78.3% vs. 50.4%, RR, 1.61, 95% CI: 1.32-1.96). The serum HBeAg clearance rate, the HBeAg seroconversion rate, and the ALT normalization rate obtained for patients treated with ETV were also higher than the corresponding values for patients treated with ADV at the 48th week of treatment. The safety profiles were similar between patients treated with ETV and those treated with ADV. The evidence reviewed in this meta-analysis suggests that patients with hepatitis B have a greater likelihood of achieving a viral response and a biomedical response when treated with ETV than when treated with ADV.

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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.

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Se calcula que 400 millones de personas en todo el mundo están infectadas crónicamente con el virus de la hepatitis B (VHB). Colombia ha pasado a tener una prevalencia baja con un 2% de la población positiva para el antígeno de superficie de este virus (HBsAg); sin embargo, la prevalencia varía entre las distintas regiones. Los portadores de VHB tienen mayor riesgo de desarrollar hepatitis crónica, cirrosis hepática (CH), falla hepática y carcinoma hepatocelular (CHC). El tratamiento de la infección crónica por el VHB busca frenar por completo la replicación viral e inducir la remisión del daño hepático antes de que se desarrolle CH o CHC. Actualmente la terapia farmacológica se hace, entre otros medicamentos, con interferón pegilado alfa 2a, lamivudina, adefovir y entecavir. Los pacientes con hepatitis aguda no necesitan tratamiento, aquellos con falla hepática fulminante se deben evaluar para trasplante y el tratamiento de la infección crónica se debe elegir según la gravedad y características de la enfermedad. El seguimiento de los pacientes con infección aguda por el VHB se debe hacer cada 1-3 meses para detectar la progresión hacia hepatitis crónica; para ese propósito se miden los niveles de aminotransferasas, bilirrubinas, tiempo de protrombina, albúmina sérica, alfa-fetoproteína y ADN VHB; también se hacen recuento de plaquetas, biopsia hepática, ultrasonido abdominal y endoscopia digestiva superior. A los pacientes en tratamiento con interferón pegilado se les deben medir cada seis meses el antígeno e (HBeAg), su correspondiente anticuerpo (anti-HBe) y el ADN VHB. En quienes reciben lamivudina, adefovir, entecavir u otros antivirales, estas mediciones se hacen cada 3-6 meses. Se están estudiando otros fármacos tales como: emtricitabine, clevudine, tenofovir, telmivudina y beta L nucleósidos. Las estrategias inmunomoduladoras incluyen el uso de citoquinas y la vacunación.

Despite vaccination campaigns around the world and the resolution of the disease in immunocompetent adults, it is estimated that 400 million people worldwide are chronically infected with the hepatitis B virus (HBV). The prevalence rate of this disease in the Colombian population is low, though variable among regions: only 2% are positive in tests for the surface antigen of this virus (HBsAg). Carriers of HBV have a higher risk of developing chronic hepatitis, cirrhosis (HC), liver failure and hepatocellular carcinoma (HCC). The aims of treatment for chronic HBV infection are to completely control viral replication and to induce remission of liver damage before HC or HCC may develop. Nowadays, pharmacological therapy of HBV infection is done, among others, with pegylated interferon alfa 2a, lamivudine, adefovir, and entecavir. Patients with acute hepatitis do not need to be treated, those with acute liver failure should be evaluated for transplantation, and therapy for chronic infection should be chosen according to the degree of severity and the characteristics of their disease. Patients with acute HBV infection should be monitored every 1 to 3 months in order to detect the progression toward chronic hepatitis; for that purpose the levels of aminotransferases, bilirubin, prothrombin time, serum albumin, alfa-fetoprotein and HBV DNA are determined, and platelet count, liver biopsy, abdominal ultrasonography and upper digestive endoscopy are carried out. In patients being treated with alfa 2ª pegylated interferon HBeAg, anti-HBe and HBV DNA must be measured every 6 months. These measurements should be made every 3 to 6 months in patients who use lamivudine, adefovir, entecavir or other antivirals. Other drugs with immunomodulatory or antiviral properties are being studied. The new antiviral agents include: emtricitabine, clevudine, tenofovir, telmivudine and beta L nucleosides. Immunomodulatory strategies include the use of cytokines and vaccination.

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El adefovir es un nucleótido que se utiliza por vía oral, sin resistencia conocida hasta los dos años de tratamiento. Actúa en los pacientes con hepatitis B crónica Age+ y Age-, es efectivo en resistentes a lamivudina. Es un medicamento bien tolerado en cirróticos descompensados y trasplantados. Se requiere ajuste de dosis con alteración de la función renal.

Adefovir is a nucleotide orally administrated with unknown resistance until two years of treatment. It is recommended for patients with chronic hepatitis B + and e -, it is resistant to Lamivudine. It is a well tolerated drug by decompensated, transplanted cirrhotic. Dose adjustment is required in renal impairment.

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Todos los pacientes con cirrosis y ADN HBV detectable deben recibir tratamiento antiviral. Se debe iniciar tratamiento con lamiduvina o adefovir dipivoxil. El interferón alfa, en cualquier presentación, está contraindicado. Se debe realizar monitoreo constante (cada 3 meses) de niveles de ADN HBV en los pacientes con lamiduvina para detectar resistencia a la droga. Cuando reaparece el ADN HBV o aumenta el mismo en 1 log10, se debe pensar que se está desarrollando resistencia contra lamiduvina. En caso de resistencia se debe iniciar tratamiento con adefovir dipivoxil. Los pacientes con adefovir dipivoxil deben tener monitoreo constante (cada 3 meses) de su función renal.

All cirrhotic patients and detectable DNA HBV must take antiviral treatment. Treatment should start with lamivudine or adenofir dipivoxil. Alpha interferon in any presentation is contraindicated. Constant monitoring (every 3 moths) of DNA HBV levels of patients with lamiduvine must be carried aout to detect drug resistance. When DNA HBV reappers or increases itself in 1 log10, it is believed that resistance against lamiduvine is being developed. In case of resistance, treatment with adenofir dipivoxil should be srted (every 3 months) of their renal function.

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