Is tenofovir disoproxil fumarate an all-powerful weapon in the treatment of chronic hepatitis B?

No abstract available.

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.

Virologic response is not durable after adefovir discontinuation in lamivudine-resistant chronic hepatitis B patients / 대한간학회지

BACKGROUND/AIMS: We investigated the durability of the biochemical and virologic responses after adefovir (ADV) discontinuation in lamivudine-resistant (LMV-R) chronic hepatitis B (CHB) patients, and the outcomes of ADV discontinuation compared to that of ADV maintenance. METHODS: The indication for ADV treatment cessation was an undetectable level of hepatitis B virus (HBV) DNA documented on two occasions at least 6 months apart. All patients received additional ADV for at least 12 months after the confirmation of undetectable HBV DNA (Cobas TaqMan PCR assay, <70 copies/mL). Of 36 patients who had a sufficient ADV therapeutic effect, 19 discontinued ADV treatment, while the others maintained it. A virologic rebound was arbitrarily defined as the redetection of HBV DNA at a level higher than 105 copies/mL. RESULTS: In the ADV discontinuation group, ADV treatment and additional therapy were administered for medians of 33 months (range, 12-47 months) and 18 months, respectively. The patients were followed for a median of 12 months (range, 3-30 months) after ADV cessation. During that period, 18 of 19 patients (95%) experienced viral relapse. Viral rebound was observed in six patients (32%). However, 12 of 18 patients (67%) exhibited serum HBV DNA levels of less than 105 copies/mL. Biochemical relapses were observed in four of the six patients with viral rebound. In the ADV maintenance group, patients were treated for a median of 53 months (range, 31-85 months), and 9 patients (53%) experienced viral breakthrough. CONCLUSIONS: During short-term follow-up after ADV discontinuation, most patients (95%) exhibited viral relapse, whereas and viral breakthrough occurred in about half of patients (53%) maintained on ADV therapy. Therefore, the durability of virologic response after ADV discontinuation in LMV-R patients was unsatisfactory. In addition, and viral breakthrough was not infrequent in the ADV continuation group.

Add on Lamivudine to Adefovir Monotherapy for the Treatment of Lamivudine-resistant Chronic Hepatitis B Patients / 대한소화기학회지

BACKGROUND/AIMS: Add on adefovir (ADV) to ongoing lamivudine (LAM) has been recommended as a standard therapy for the treatment of LAM resistance. In the past, switch to ADV monotherapy was suggested as an option for the treatment of LAM resistance, leading to frequent development of ADV resistance. However, ADV monotherapy has been still used in LAM-resistant patients because of low cost in Korea. The aims of this study were to evaluate the virologic response and virologic breakthrough during adding on LAM in LAM-resistant patients receiving ADV monotherapy. METHODS: The study population comprised 99 patients with LAM-resistance. We divided them into 3 groups (Group 1: switch to ADV monotherapy, N=58, Group 2: add on ADV to ongoing LAM, N=25, Group 3: add on LAM to ADV monotherapy, N=16). HBV DNA levels were assessed at baseline and every 3 months during therapy. Serum HBV DNA levels were measured by bDNA assay or the COBAS TaqMantrade mark HBV test. RESULTS: The median treatment duration for group 1, group 2, and group 3 was 42.0, 20.6, and 31.8 (18.7 mon. of ADV+13.1 mon. of LAM) months, respectively. Cumulative rate of virologic breakthrough in group 1 was 5.2%, 19.0%, and 25.9% at 12, 24, and 36 months of treatment, respectively. Virologic breakthrough was not detected in group 2 and group 3 (p=0.016, group 1 vs. group 2 or 3). In group 3, median serum HBV DNA levels were 4.22 log10 copies/mL prior to LAM administration. Median serum HBV DNA changes from baseline (log10 copies/mL) were -0.91, -1.93, -1.87 and -1.74 at week 12, 24, 36 and 48, respectively. CONCLUSIONS: Later add on LAM to ADV monotherapy prevented the development of ADV resistance in patients with LAM resistance effectively, comparable to ADV add on to continuing LAM therapy.

Antiviral Efficacy of Lamivudine/Adefovir Combination Therapy in Chronic Hepatitis B Patients with Resistance to Lamivudine and Adefovir Consecutively / 대한소화기학회지

BACKGROUND/AIMS: The aim of this study was to elucidate the antiviral efficacy of lamivudine (LMV)-adefovir (ADV) combination therapy in chronic hepatitis B patients who showed resistance to LMV and ADV consecutively. METHODS: A retrospective review was performed in eighteen patients with chronic hepatitis B who developed virologic breakthroughs during LMV-ADV sequential mono-therapy and treated with LMV-ADV combination therapy. RESULTS: The median duration of follow up was 17 months (range, 6-27) after the start of LMV-ADV combination therapy. Mean HBV DNA level in log10 IU/mL was 6.08+/-0.95, 4.05+/-1.66, 3.17+/-1.58, 3.18+/-2.16, and 2.35+/-1.52 at 0, 3, 6, 12, and 24 months, respectively. Sixteen patients (88.9%) showed HBV DNA reduction below detection limit (<20,000 IU/mL). HBeAg seroconversion was observed in one patient (7.1%) after 8 months of combination therapy. Virologic breakthrough occurred in only one patient after 21 months of combination therapy. Viral rebound occurred in two patients at 12 months and 14 months of combination therapy. Normalization of serum ALT was achieved in twelve patients (66.7%). Primary non-response was observed in two cases (11.1%). CONCLUSIONS: LMV-ADV combination treatment was effective in 88.9% of patients with resistance to LMV and ADV in a short-term follow up. It may be applied as a bridge therapy until another effective antiviral regimen becomes available.

Treatment of Hepatitis B Virus Resistant to Lamivudine and Adefovir / 대한소화기학회지

No abstract available.

Virologic response to adefovir dipivoxil monotherapy is not durable in HBeAg-positive, lamivudine-resistant chronic hepatitis B patients / 대한간학회지

BACKGROUNDS/AIMS: It has been shown that adefovir dipivoxil is an effective antiviral agent in the treatment of chronic hepatitis B (CHB), not only in wild-type hepatitis B virus (HBV) infection, but also in lamivudine-resistant (LAMV-R) cases. However, little is known about the durability of the virologic response to adefovir in LAMV-R CHB patients. METHODS: Fifteen HBV e-antigen (HBeAg)-positive, LAMV-R CHB patients showed a virologic response to adefovir monotherapy. These patients received additional adefovir for at least a further 12 months. The virologic relapse rate after discontinuation of adefovir was evaluated. In addition, predictive factors associated with virologic relapse were investigated. RESULTS: The median level of serum HBV DNA before adefovir administration was 7,457,840 IU/mL (range 107,920-99,524,960 IU/mL). The median duration of adefovir treatment was 30 months (range 14-46 months). During a median follow-up period of 14 months after discontinuation of adefovir, the 1-, 2-, 3-, 6-, and 12-month cumulative relapse rates were 26.7%, 53.3%, 73.3%, 80%, and 80%, respectively. High pretreatment HBV DNA levels were found to be the only factor that was predictive of off-therapy relapse. CONCLUSIONS: Our data suggest that the adefovir-monotherapy-induced virologic response is not durable in most patients with LAMV-R HBeAg-positive CHB, especially in those with a high pretreatment HBV DNA level.

Development of Clevudine Resistance after Switching from Lamivudine in a Patient with Chronic Hepatitis B / 대한소화기학회지

Clevudine is a nucleoside analog of the unnatural beta-L configuration which has potent antiviral activity against hepatitis B virus (HBV). Clevudine is expected to have similar pattern of resistance profile as lamivudine. However, there was no report on the mutation associated with clevudine resistance in patients with chronic hepatitis B. We report a case of young male patient with chronic hepatitis B who presented with clevudine resistance. The patient had received lamivudine therapy for 5 months with reduced serum HBV DNA levels. Then, lamivudine was switched to clevudine monotherapy. After the 6 months of clevudine therapy, the patient developed virologic breakthrough (>1.0x10(8) copies/mL) as well as biochemical breakthrough, which was associated with the presence of rtM204I plus rtL80I mutant. After switching from clevudine to adefovir, the viral load decreased with biochemical improvement.

The efficacy of adefovir dipivoxil monotherapy and the incidence of genotypic resistance to adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B infection / 대한간학회지

BACKGROUND/AIMS: Adefovir dipivoxil (ADV) is a nucleotide analogue that inhibits wild-type hepatitis B virus (HBV) and lamivudine (LMV)-resistant HBV mutants. The aim of this study was to elucidate the efficacy of ADV monotherapy and the incidence of genotypic resistance to ADV in patients with LMV-resistant chronic HBV infection. METHODS: This study involved 124 patients with chronic HBV infection who had received ADV monotherapy due to the presence of LMV-resistant HBV mutants. The efficacy of ADV was evaluated by the normalization of serum alanine aminotransferase (ALT) level and by the reduction of serum HBV DNA level (with cutoff levels of 2x10(4) IU/mL and 2x10(2) IU/mL). The cumulative rate of HBeAg loss or seroconversion was assessed in HBeAg-positive patients. The development of mutations in the reverse trancriptase region of HBV DNA polymerase was evaluated by direct sequencing analysis during ADV monotherapy. RESULTS: The mean serum HBV DNA level was 5.94 log10IU/mL. At 12 and 24 months after ADV monotherapy, the cumulative rates of serum ALT normalization were 69.4% and 75.5%, respectively, and those of serum HBV DNA reduction were 79.8% and 89.2% for a cutoff level of 2x10(4) IU/mL, and 44.2% and 59.0% for a cutoff of 2x10(2) IU/mL. The mean serum HBV DNA levels at 12 and 24 months were significantly lower than baseline, at 3.24 and 3.04 log10IU/mL, respectively (P<0.001). At 12 months after ADV treatment, the cumulative rates of HBeAg loss and seroconversion were 15.8% and 10.5%, respectively, and the rtN236T and rtA181T/V mutants in HBV DNA polymerase were identified in 25% and 64% of patients, respectively. CONCLUSIONS: Although ADV monotherapy is effective, it leads to a high rate of mutations of HBV DNA reverse transcriptase gene in patients with chronic HBV infections who have LMV-resistant HBV mutants.

Factors affecting initial virologic response and emergence of resistant mutants after adefovir treatment in lamivudine-resistant chronic hepatitis B patients / 대한간학회지

BACKGROUND/AIMS: Adefovir dipivoxil (adefovir) effectively inhibits both wild-type and lamivudine-resistant hepatitis B virus (HBV) replication. The development of adefovir resistance is both delayed and infrequent compared with lamivudine resistance. The aim of this study was to characterize the serologic, biochemical, and virologic response to adefovir, and to explore the factors affecting initial virologic response (IVR, defined as a decrease in serum HBV below 4 log10copies/mL after 6 month of treatment) and adefovir resistance in lamivudine resistant HBV-infected patients. METHODS: This study population comprised 76 patients with lamivudine-resistance who had received adefovir for more than 12 months between March 2004 and December 2006. The adefovir-resistant mutant was assayed at 6 months and 12 months during adefovir administration. Restriction-fragment mass polymorphism analysis was used for detecting YMDD and adefovir mutants. RESULTS: After adefovir administration, an IVR was observed in 31% of the patients with lamivudine resistance. Factors associated with an IVR were HBeAg negativity (P=0.04) and the presence of liver cirrhosis (P=0.04). Age, sex, pretreatment levels of alanine aminotransferase and aspartate aminotransferase, pretreatment HBV DNA levels, presence of precore mutation, and type of YMDD mutants were not related to an IVR during adefovir treatment. The prevalence of adefovir resistance was 5% and 13% at 6 months and 12 months after therapy, respectively. Mixed infection of the precore mutant was a risk factors for the emergence of adefovir resistance (P=0.01). CONCLUSIONS: Lamivudine-resistant HBV patients exhibiting HBeAg negativity and liver cirrhosis were more likely to achieve an IVR after adefovir therapy. Adefovir resistance was associated with mixed infection of the precore mutant.

Management of Chronic Hepatitis B in Treatment-Naive Patients / 대한소화기학회지

Chronic hepatitis B (CHB) is a serious health problem in Korea. The natural history of chronic HBV infection has been divided into 4 phases: immune tolerance, immune clearance, inactive HBsAg carrier state and reactivation. During the phases of immune tolerance and inactive HBsAg carrier state, no treatment is required. Patients in the immune clearance or reactivation phases are candidates for therapy. In the last years, treatment effects of CHB have considerably improved. Several agents are currently approved for the treatment of CHB: interferon alpha, pegylated interferon alpha, lamivudine, adefovir, entecavir, telbivudine and clevudine in Korea. The treatment recommendations from the 2004 Korean Association for the Study of the Liver guideline on the management of CHB have been updated to incorporate new therapeutic options. What is uncertain is which agent or combination of agents is most effective, how long therapy should last, and which criteria should be used to start, continue, switch or stop therapy. Issues for consideration include efficacy, safety and incidences of resistance, and method of administration of antiviral therapy in treatment-naive patients.

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.

Dynamics of HBV DNA levels, HBV mutations and biochemical parameters during antiviral therapy in a patient with HBeAg-negative chronic hepatitis B.

Chronic hepatitis B virus (HBV) infection leads to long-term sequelae such as cirrhosis and hepatocellular carcinoma. Antiviral therapy aims at controlling the viral replication and thus, decreasing the likelihood of such complications. In this study, we evaluated the dynamics of biochemical and virological parameters over 10 years of antiviral therapy in a Thai patient with chronic HBeAg-negative HBV infection, who had relapsed after two courses of interferon alfa treatment. Lamivudine administration initially led to a significant reduction in alanine aminotransferase (ALT) and HBV DNA levels, but a subsequent emergence of YIDD mutants caused an ALT flare and a virus breakthrough. A 4-log HBV DNA decrease and normalization of the ALT level were achieved within 3 months of adefovir monotherapy without any relapse during follow-up exceeding 20 months. Thus, careful monitoring during treatment and knowledge of cross-resistance to antiviral salvage therapy are crucial for the management of patients with chronic hepatitis B.

Effect of Initial Virologic Response to Adefovir on the Development of Resistance to Adefovir in Lamivudine-resistant Chronic Hepatitis B / 대한간학회지

BACKGROUND/AIMS: Adefovir dipivoxil (ADV) resistance in patients with lamivudine-resistant chronic hepatitis B is not well understood. This study examined the initial virologic response (IVR) to ADV, the rate of ADV resistance and the factors associated with ADV resistance. METHODS: Eighty one lamivudine-resistant HBeAg-positive patients were enrolled in this study. IVR was defined as HBV DNA or = 4 log10 copies/mL after 6 months of therapy) were associated with ADV resistance.

Comparison of Clinical Outcome Between Patients Continuing and Discontinuing Lamivudine Therapy in Acute Exacerbation After Viral breakthrough During Lamivudine Therapy in Chronic Hepatitis B / 대한간학회지

BACKGROUNDS/AIMS: Continuation of lamivudine therapy is controversial for patients with chronic hepatitis B when viral breakthrough occurs. Moreover, the effect of continuous lamivudine therapy is unknown in patients with acute exacerbation after viral breakthrough. We assessed clinical course of acute exacerbation after viral breakthrough in patients who continued and discontinued lamivudine therapy. METHODS: Medical records of 109 patients with viral breakthrough during lamivudine therapy were reviewed. Of 40 patients with acute exacerbation (ALT level > 5 x ULN), adefovir dipivoxil was unavailable in 38 patients. These 38 patients (mean age 42.6 years; male/female, 34/6) were divided into continuation (n=21) and discontinuation (n=17) groups. Clinical courses of the 2 groups were compared. RESULTS: During follow-up period (mean, 27 months; range, 6-60 months), ALT levels decreased to 5 x ULN in 1 (5%) and 3 (18%), respectively, with no statistical significance (P=.417). CONCLUSIONS: When acute exacerbation of ALT levels occurs after viral breakthrough during lamivudine administration in patients with compensated chronic hepatitis B, continuation of lamivudine may have no advantage over discontinuation.

Resistance to Adefovir in Patients with Chronic Hepatitis B / 대한간학회지

No abstract available.

A Case of Primary Neuroendocrine Carcinoma of Liver Presenting with Liver Abscess / 대한소화기학회지

Primary hepatic neuroendocrine cell carcinoma is a very rare tumor. We experienced a 75-year-old woman with primary hepatic neuroendocrine carcinoma presenting with pyogenic liver abscess. Abdominal CT scan revealed a multiseptated liver abscess and an enlarged lymph node in portocaval portion. We performed percutaneous drainage of the liver abscess, but the amount of drained pus did not decrease after 20 days. The follow-up abdominal CT scan showed that the cystic portion of liver abscess had been replaced by the solid tumor. Microscopic examination of the tumor tissue showed nests of epithelial cells with uniform round hyperchromatic nuclei and high nuclear to cytoplasmic ratio. Immunohistochemical staining was strongly positive for synaptophysin and chromogranin A.

Understanding hepatitis B.

Advances in molecular virology and availability of new antiviral agents have made a positive impact on the treatment of hepatitis B. It is important to know the natural history of hepatitis B virus as high amount of virus may remain in the body for long periods of time without any significant liver disease. Whilst reactivation or mutation of hepatitis B virus and immune clearance may be associated with liver injury leading at times to liver failure. Serological and virological tests are routinely available to systematically evaluate a patient who is detected to have Hepatitis B virus infection. International guidelines have been formulated to suggest appropriate selection of the patient and drug for effective treatment. Therapeutic strategies for total eradication of hepatitis B virus from the liver still remain elusive. However it is now possible to ameliorate liver disease and alter the natural history with effective long-term suppression of the hepatitis B virus. New formulations of existing drugs and newer antiviral agents are constantly being looked into in clinical trials in the pursuit of an ideal therapy.

Efficacy and Safety of Adefovir Dipivoxil in Patients with Decompensated Liver Cirrhosis with Lamivudine Resistance Compared to Patients with Compensated Liver Disease / 대한간학회지

BACKGROUND/AIMS: Adefovir dipivoxil is effective in patients with lamivudine-resistant hepatitis B virus (HBV). However, little is known about its role in Korean patients with decompensated liver cirrhosis. We retrospectively evaluated the efficacy and safety of adefovir dipivoxil in patients with decompensated liver cirrhosis with lamivudine resistance, and we compared this to the patients having compensated liver disease. METHODS: The patients with lamivudine-resistant chronic liver disease were enrolled and they received adefovir dipivoxil 10 mg daily. The clinical course and the biochemical and virological response of the decompensated cirrhosis group were compared with those of the patients with compensated liver disease group. RESULTS: One-hundred and one patients (the decompensated cirrhosis group, n=53; the compensated liver disease group, n=48) were evaluated. During the following up, 13 patients in the decompensated group and 4 patients in the compensated group dropped out of the treatment (P=0.011). After adefovir treatment, the proportion of patients with serum HBV DNA below 0.5 pg/mL in the decompensated group was less than that in the compensated group (50.9% vs. 83.3%, P=0.001), but the rates of normalized ALT, HBeAg loss and HBeAg seroconversion did not differ. The change of the Child-Pugh score in the decompensated group was 9.1 +/- 1.8 to 6.9 +/- 1.6 (P<0.001). The biochemical response in decompensated group was slower than that in the compensated group. Renal toxicity was not observed in either group. CONCLUSIONS: These results suggest that adefovir dipivoxil would be an effective and safe treatment for patients with decompensated liver cirrhosis with lamivudine resistance, but its effect might be limited and slower for decompensated cirrhosis.

Current Antiviral Therapy for Chronic Hepatitis B

During the past decade, major breakthroughs have been achieved in treatment of chronic hepatitis B. Currently, three therapeutic agents are approved for chronic hepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. In patients with HBeAgpositive chronic hepatitis B, all of these drugs achieve HBeAg loss (24-33%) and anti-HBe seroconversion (12-30%) rates that are superior to those observed in untreated controls. Interferon-alpha has several drawbacks, such as the parenteral administration and the development of frequent and potentially serious side effects. Lamivudine is a safe drug with rare and generally mild side effects. Lamivudine induces an initial virological remission in 70-90% of patients, but only 30-40% of patients remain in remission after the third year due to progressively increasing viral resistance. The main advantage of adefovir dipivoxil is the rare emergence of resistance, which has been identified in less than 2% of patients at 2 yr of treatment. Adefovir is also effective against lamivudine-resistant strains. This review will focus on the natural history and recently gained knowledge on the treatment of chronic hepatitis B.