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 <4 log10 copies/mL after 6 months of combination therapy. RESULTS: The IVR rate was 76%. The proportion of patients with a high viral load (> 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.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Alanine Transaminase/blood ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Drug Resistance, Multiple, Viral ; Drug Therapy, Combination ; Female ; Genotype ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B Antibodies/blood ; Hepatitis B e Antigens/blood ; Hepatitis B, Chronic/*drug therapy ; Humans ; Male ; Middle Aged ; Nucleosides/therapeutic use ; Phosphonic Acids/*therapeutic use

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.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis ; Drug Resistance, Viral ; Female ; Follow-Up Studies ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/therapeutic use ; Male ; Middle Aged ; Phosphonic Acids/*therapeutic use ; Recurrence ; Risk Factors

Adefovir dipivoxil, an acyclic nucleoside analogue, has been approved for the treatment of patients with chronic hepatitis B. This agent is efficacious particularly in those who have developed lamivudine resistance. The report according to hypophosphatemia induced by low dose adefovir therapy is very rare. We report one case in which osteomalacia with hypophosphatemia developed in a patient with chronic hepatitis B on adefovir dipivoxil at a low dose, 10 mg daily. A 66-year-old man, who had been taking adefovir for more than 4 years due to lamivudine resistance, presented with muscle weakness and bone pain in both thighs. After 3 years of adefovir therapy, hypophosphatemia and elevated serum alkaline phosphatase levels had been noted. A bone scan showed multiple hot uptakes. All the image findings and clinical symptoms, such as bone pain and muscle weakness were improved after correcting the hypophosphatemia with oral phosphorous supplementation.
Adenine/adverse effects/*analogs & derivatives/therapeutic use ; Aged ; Alkaline Phosphatase/blood ; Antiviral Agents/*adverse effects/therapeutic use ; DNA, Viral/blood ; Dietary Supplements ; Hepatitis B, Chronic/*drug therapy ; Humans ; Hypophosphatemia/*chemically induced/complications ; Liver Cirrhosis/diagnosis ; Male ; Osteomalacia/*diagnosis/etiology ; Phosphates/blood ; Phosphonic Acids/*adverse effects/therapeutic use ; Whole Body Imaging

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.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Antiviral Agents/*pharmacology ; DNA, Viral/blood ; Drug Resistance, Viral ; Drug Therapy, Combination ; Female ; Hepatitis B e Antigens/blood ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/*therapeutic use ; Male ; Middle Aged ; Phosphonic Acids/*therapeutic use

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.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis ; Drug Resistance, Viral ; Female ; Hepatitis B e Antigens/*blood ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/*therapeutic use ; Male ; Middle Aged ; Phosphonic Acids/*therapeutic use ; Recurrence ; Retrospective Studies ; Risk Factors

BACKGROUND/AIMS: The purpose of this study was to evaluate the cost-effectiveness of 1 year and up to 5 years of antiviral treatment for chronic hepatitis B (CHB). METHODS: Two ten-health-state Markov models were developed for CHB patients. The proportion of patients remaining alive in each health state, and healthcare costs and quality-adjusted life years (QALYs) were determined during annual cycles of these Markov models. The total healthcare costs, life years, and QALYs over the 40-year time horizon of the model were calculated. The perspectives of the cost-effectiveness analysis were the Korean healthcare system and the healthcare needs of the CHB patient. RESULTS: Short-course therapy with alpha-interferon or 1-year treatment with pegylated interferon alpha-2a, lamivudine (LMV), or adefovir (ADV) had limited impact on disease progression. In contrast, either LMV-ADV or ADV-LMV as rescue medication administered for 5 years resulted in a more sustained decrease in the rate of disease progression. The cost-effectiveness threshold in Korea was estimated to be approximately 25,000,000 South Korean won. LMV administered for 1 year is cost-effective in comparison with no treatment for both HBeAg-positive and HBeAg-negative CHB patients, but longer duration antiviral therapies administered for up to 5 years in CHB patients were found to be highly cost-effective by international standards. CONCLUSIONS: Antiviral treatment of CHB with LMV or ADV for up to 5 years using the alternative antiviral agent as rescue medication appears to be a cost-effective strategy for both HBeAg-positive and HBeAg-negative CHB patients in Korea. Economic evaluation of antiviral therapies should be studied further and updated, particularly for newer agents.
Adenine/*analogs & derivatives/economics/therapeutic use ; Antiviral Agents/*economics/therapeutic use ; Cohort Studies ; Cost-Benefit Analysis ; Drug Therapy, Combination ; Hepatitis B e Antigens/blood ; Hepatitis B, Chronic/drug therapy/*economics ; Humans ; Interferon-alpha/*economics/therapeutic use ; Korea ; Lamivudine/*economics/therapeutic use ; Models, Statistical ; Phosphonic Acids/*economics/therapeutic use ; Quality of Life ; Severity of Illness Index

No abstract available.
Adenine/*analogs & derivatives/therapeutic use ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis ; Drug Resistance, Viral ; Drug Therapy, Combination ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/*therapeutic use ; Phosphonic Acids/*therapeutic use

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.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis ; Drug Resistance, Viral ; Drug Therapy, Combination ; Female ; Genotype ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/*therapeutic use ; Male ; Middle Aged ; Phosphonic Acids/*therapeutic use ; Time Factors

Adefovir dipivoxyl (ADV) effectively suppresses hepatitis B virus (HBV) replication but exhibits nephrotoxicity with severe hypophosphatemia when administered at a high dosage. This is the first report of severe hypophosphatemic osteomalacia induced by ADV at 10 mg/day. A 42-year-old man with HBV-related chronic liver disease presented with generalized bone pain, especially in the left ankle. He had been taking ADV for more than 1.5 years following a clinical breakthrough due to lamivudine-resistant HBV. Aggravating severe hypophosphatemia and elevated serum alkaline phosphatase levels with high bone fraction had been noted after 6 months of ADV therapy. Bone densitometry, simple bone X-rays, and a whole-body bone scan demonstrated osteoporosis and multiple areas with hot uptake, especially in the left ankle. All the image findings and symptoms improved after correcting the hypophosphatemia.
Absorptiometry, Photon ; Adenine/administration & dosage/adverse effects/*analogs & derivatives ; Adult ; Antiviral Agents/administration & dosage/*adverse effects ; Bone Density ; DNA, Viral/analysis ; Drug Resistance, Viral ; Hepatitis B virus/drug effects ; Hepatitis B, Chronic/complications/*drug therapy/virology ; Humans ; Hypophosphatemia/*chemically induced ; Lamivudine/therapeutic use ; Liver Cirrhosis/*virology ; Male ; Phosphonic Acids/administration & dosage/*adverse effects ; Tomography, X-Ray Computed

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.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Alanine Transaminase/blood ; Antiviral Agents/*therapeutic use ; Aspartate Aminotransferases/blood ; DNA, Viral/blood ; Drug Resistance, Viral/genetics ; Female ; Hepatitis B e Antigens/metabolism ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/*drug therapy/virology ; Humans ; Lamivudine/*therapeutic use ; Male ; Middle Aged ; Mutation ; Phosphonic Acids/*therapeutic use ; Polymorphism, Restriction Fragment Length