ANTECEDENTES:

El carcinoma hepatocelular (CHC) es una causa significativa de muerte, especialmente en Asia y África subsahariana. La extracción del cáncer mediante cirugía u otras técnicas se considera el tratamiento de primera línea para el CHC en etapa inicial, pero la recidiva del CHC es el principal problema posoperatorio. El principal factor de riesgo del CHC es la infección por el virus de la hepatitis B (HBV). La lamivudina y el adefovir dipivoxil son eficaces y tolerables para la hepatitis B crónica al suprimir la carga viral y reducir la fibrosis en el hígado.

OBJETIVOS:

Evaluar los efectos beneficiosos y perjudiciales de la administración posoperatoria de lamivudina con o sin adefovir dipivoxil en pacientes con CHC tratado quirúrgicamente y con infección crónica por el HBV o con un estado de portador del HBV.

MÉTODOS DE BÚSQUEDA:

Se hizo una búsqueda sistemática en el Registro de Ensayos Controlados del Grupo Cochrane Hepatobiliar (Cochrane Hepato-Biliary Group), en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) en The Cochrane Library, MEDLINE, EMBASE y en Science Citation Index Expanded (SCI Exp) en octubre 2011. Se buscaron ensayos adicionales mediante la revisión de las listas de referencias de los artículos pertinentes.

CRITERIOS DE SELECCIÓN:

En esta revisión, se incluyeron los ensayos clínicos aleatorios que compararon la administración de lamivudina con y sin adefovir dipivoxil en pacientes con CHC tratados con ablación (quirúrgica o mediante otras técnicas) y con infección crónica por el HBV o con un estado de portador del HBV, independientemente del estado de publicación, idioma y cegamiento. Se planificó extraer los datos sobre los efectos perjudiciales informados en los estudios cuasialeatorios o los estudios de cohortes cuando se recuperaron con los resultados de la búsqueda.

OBTENCIÓN Y ANÁLISIS DE LOS DATOS:

Dos autores seleccionaron de forma independiente los estudios para su inclusión y extrajeron y analizaron los datos. Se informó descriptivamente el tipo y número de eventos adversos.

RESULTADOS PRINCIPALES:

No se pudieron incluir ensayos aleatorios en esta revisión sistemática. Por lo tanto, no fue posible seguir el protocolo publicado previamente ni realizar metanálisis.
Mediante las búsquedas de ensayos clínicos aleatorios, se recuperaron cuatro ensayos de cohortes con 230 pacientes. Estos ensayos se leyeron para encontrar datos sobre los efectos perjudiciales, es decir, los eventos adversos. La hepatitis intercurrente fue un evento adverso grave atribuible a la lamivudina. En los cuatro estudios de cohorte, no se informaron eventos adversos que parecieran haber sido causados por la administración de lamivudina o adefovir dipivoxil.

CONCLUSIONES DE LOS AUTORES:

No se encontraron pruebas de ensayos aleatorios sobre los efectos beneficiosos o perjudiciales de la lamivudina con o sin adefovir dipivoxil para el CHC posoperatorio. Se deben realizar ensayos clínicos aleatorios con un gran número de pacientes y un período de seguimiento largo para dirigir la práctica clínica.

To determine whether adefovir (ADV) in combination with entecavir (ETV) is more effective than with lamivudine (LAM) in patients with lamivudine-resistant chronic HBV infection, electronic databases were searched through May 10th, 2013 to obtain relevant trials which met the inclusion criteria. Meta-analysis was performed on randomized controlled trials (RCTs) and non-randomized studies. Four trials containing a total of 323 patients were included. Serum HBV DNA reductions after 3 and 6 months of treatment in the ETV + ADV group were greater than that of LAM + ADV group (mean difference (MD) = 0.90, 95% confidence interval (CI): 0.74-1.07, P < 0.00001; MD = 0.81, 95% CI.: 0.57-1.06, P < 0.00001). The rate of 6 months HBV DNA undetectability with ETV and ADV was higher than that of LAM and ADV (relative risk (RR) = 1.63, 95% CI.: 1.14-2.34, P < 0.007). There were higher rates of serum ALT normalization than those in LAM + ADV group after 6 months of treatment (RR = 1.40, 95% CI.: 1.11-1.77, P < 0.005). The ETV + ADV group had lower viral breakthrough and genotypic mutation rates than LAM + ADV group after 12 months of treatment (RR = 0.24, 95% CI.: 0.10-0.58, P = 0.002). The combination of ETV plus ADV is a more effective rescue therapy than LAM add-on ADV in patients with LAM-resistant HBV.

OBJECTIVES:

The aim of the current study was to compare the effectiveness of adefovir dipivoxil (ADV) monotherapy with that of combination ADV and lamivudine (LAM) therapy in the treatment of LAM-resistant chronic hepatitis B (CHB).

METHODS:

Publications on the effectiveness of ADV monotherapy versus the combination of ADV and LAM therapy for the treatment of LAM-resistant CHB were identified by a search (up to year 2010) of the PubMed, HealthStar, ScienceDirect, and VIP databases. Biochemical response data (alanine aminotransferase normalization rate) and virological response data (serum hepatitis B virus DNA undetectable rate) were extracted and combined to obtain an integrated result.

RESULTS:

The literature search yielded 11 articles, six of which reported randomized controlled trials; the remaining five reported prospective cohort studies. The summary odds ratio (OR) values of the biochemical response at 3, 6, 12, and >12 months were 1.60 (p=0.06), 1.30 (p=0.18), 1.77 (p=0.008), and 3.35 (p<0.00001), respectively. The summary OR values of the virological response at 3, 6, 12, and >12 months were 1.46 (p=0.21), 1.68 (p=0.04), 1.16 (p=0.54), and 1.87 (p=0.01), respectively.

CONCLUSIONS:

The effectiveness of the combination therapy was not obviously predominant over the monotherapy in short duration therapies; however, the combination therapy had a great advantage over monotherapy in both biochemical and virological response when the therapy duration was prolonged to >12 months.

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.

RECORD STATUS:

None

CITATION:

Stachnik M. Adefovir dipivoxil for treatment of hepatitis B. University HealthSystem Consortium (UHC). Drug Monograph. 2003

Background and Aim: Adefovir dipivoxil (ADV) is effective in lamivudine (LAM)-resistant hepatitis B e antigen-negative (HBeAg-) chronic hepatitis B (CHB). However, it is unclear whether LAM treatment should be continued in these patients. We aimed to compare the long-term efficacy of adding ADV to ongoing LAM treatment versus switching to ADV monotherapy in LAM-resistant HBeAg- CHB. Methods: Sixty LAM-resistant patients with HBeAg- CHB were randomly assigned (3:1) to combination therapy (10 mg ADV once daily plus ongoing LAM at 100 mg once daily [n = 45]) or 10 mg ADV monotherapy once daily (n = 15). Virological and biochemical responses were defined as hepatitis B virus (HBV)-DNA <400 copies/mL and as normalization of alanine aminotransferase levels, respectively. Results: The median follow-up time was 53 months (range 20-60 months). A virological response was observed in 38/45 (84.4%) and 11/15 (73.3%) patients in the ADV/LAM and ADV monotherapy groups, respectively (P = 0.56). Biochemical response rates were higher in the ADV/LAM group than in the ADV monotherapy group (90.9% vs 57.1%, respectively; P = 0.01). In the ADV/LAM group, serum HBV-DNA remained undetectable in all patients who achieved a virological response (n = 38). In the ADV monotherapy group, virological breakthrough occurred in four of the 11 patients who achieved a virological response (36.4%; P < 0.001 vs the ADV/LAM group, log-rank test). In addition, two patients in each group who did not achieve a virological response eventually developed ADV resistance. Conclusions: Adding ADV to LAM is more effective than switching to ADV monotherapy in LAM-resistant patients with HBeAg- CHB. © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

OBJECTIVE:

To evaluate the efficacy of adefovir monotherapy (ADF) versus adefovir-Matrine combination therapy (ADF+M) for chronic hepatitis B.

METHODS:

Such databases as The Cochrane Library, MEDLINE, PubMed, CBM, CNKI, WanFang and VIP Database were searched from the date of their establishment to July 2010, and the references of all included studies were also traced so as to identify randomized controlled trials (RCTs) of ADF versus ADF+M. Quality assessment and data extraction were conducted in accordance with the Cochrane Handbook 5.0.2 by two reviewers independently. Meta-analyses were conducted by using RevMan 5.0 software.

RESULTS:

A total of 24 RCTs involving 2 092 patients were included. The results of meta-analyses showed that at the end of the treatment for both six months and 12 months, respectively, the ADF+M group was superior to ADF group with a significant difference in both the HBeAg seroconversion rate as the primary outcome (six months: RR=2.05, 95%CI 1.53 to 2.74; 12 months: RR=2.13 95%CI 1.74 to 2.60) and the secondary outcome such as HBV-DNA negative conversion, HBeAg negative conversion, ALT normalization, HBV-DNA variation, complete response and HBsAg negative conversion, etc.

CONCLUSION:

As the current evidence shows, ADF+M therapy is superior to ADF therapy for chronic hepatitis B. The significant difference can even be observed at the end of the treatment for six months. However, the results should be interpreted with caution because of the low quality of the included studies. High-quality, large-scale RCTs are needed to further prove the results.

RECORD STATUS:

None

CITATION:

Canadian Coordinating Office for Health Technology Assessment. Adefovir dipivoxil for hepatitis B virus infection. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 2003

Chronic viral hepatitis B remains a global public health concern. Currently, several drugs, such as tenofovir and adefovir, are recommended for treatment of patients with chronic hepatitis B. tenofovir is a nucleoside analog with selective activity against hepatitis b virus and has been shown to be more potent in vitro than adefovir. But the results of trials comparing tenofovir and adefovir in the treatment of chronic hepatitis B were inconsistent. However, there was no systematic review on the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B. To evaluate the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B we conducted a systematic review and meta-analysis of clinical trials. We searched PUBMED, Web of Science, EMBASE, CNKI, VIP database, WANFANG database, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Review. Finally six studies were left for analysis which involved 910 patients in total, of whom 576 were included in tenofovir groups and 334 were included in adefovir groups. At the end of 48-week treatment, tenofovir was superior to adefovir at the HBV-DNA suppression in patients[RR = 2.59; 95%CI(1.01-6.67), P = 0.05]. While there was no significant difference in the ALT normalization[RR = 1.15; 95%CI(0.96-1.37), P = 0.14], HBeAg seroconversion[RR = 1.32; 95%CI(1.00-1.75), P = 0.05] and HBsAg loss rate[RR = 1.19; 95%CI(0.74-1.91), P = 0.48]. More high-quality, well-designed, randomized controlled, multi-center trails are clearly needed to guide evolving standards of care for chronic hepatitis B.

OBJECTIVE:

To study the effect of different doses of adefovir dipivoxil on renal function of patients with chronic hepatitis B(CHB).

METHODS:

Renal function of 309 patients with CHB who were treated with different doses of adefovir dipivoxil was examined and compared with 276 CHB patients who were not treated with adefovir dipivoxil.The doses of adefovir dipivoxil were half dose,constant dose,1.5 times doses and double doses.

RESULTS:

There was no significant difference in the abnormal rate of creatinine between the constant group and the control group(2.46% vs.2.53%),while the abnormal rate of creatnine in the double doses group was remarkable higher than that in the constant group(2.46% vs.5.48%,P0.001).If choosing the concentration of uric acid more than 430 μmol /L as abnormal,the abnormal rate of uric acid in constant group was significant higher than that in double doses group(9.36% vs 5.48%,P0.01).However,if the concentration of uric acid more than 392 μmol /L was set as abnormal,there was no significant difference of abnormal rate of uric acid among control group,constant group and double doses group (10.5%,12.8% and 10.96% respectively,P0.05). Compared with control group,both of abnormal rates of urea nitrogen in half dose group and 1.5 times doses group were significantly different(19.05% vs 14.28% and 4.71% vs 14.28% respectively).

CONCLUSION:

The major impact of adefovir dipivoxil on renal function is that double doses of adefovir dipivoxil might induce elevation of creatinine value with 5.48%. Regular monitoring renal function could guranteed safety of long term treatment of high-dose adefovir dipivoxil.The cut-off value of renal function should follow uniform labrotory standard in different units.