Resistant Chronic Hepatitis Research Articles

Adefovir Dipivoxil-induced Fanconi's Syndrome and Osteomalacia Following Multiple Bone Fractures in a Patient with Chronic Hepatitis B

We herein present the case of a 66-year-old Japanese man with Fanconi's syndrome. He had been receiving adefovir dipivoxil (ADV) for the treatment of entecavir (ETV)-resistant chronic hepatitis B (CHB) for four years in his 8-year treatment of hepatocellular carcinoma (HCC), but was referred to our hospital after increased levels of bone pain in his ribs, knees, and ankles. Renal dysfunction, hypophosphatemia, and increased levels of bone alkaline phosphatase were found by a hematology test after admission for treatment of HCC. Radiography and 99m Tc-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy revealed multiple insufficiency fractures in the ribs, knees, ankles, and heels. After switching from ADV to tenofovir disoproxil fumarate (TDF) and treatment with calcitriol and sodium dihydrogenphosphate, the patient's serum phosphate levels slightly increased and renal dysfunction did not improve, but after six months his clinical symptoms disappeared. To detect and prevent adverse effects from ADV, physicians and pharmacists should carefully monitor renal function and serum phosphate levels in patients with hepatitis B virus (HBV) treated for a long time with ADV.

Step-down Strategy in Antiviral Resistant Chronic Hepatitis B Patients Who Achieved Viral Suppression With Rescue Combination Therapy

In the treatment of chronic hepatitis B (CHB) patients with drug resistance, rescue combination therapy leads to viral suppression in almost all patients. However, once it is achieved, lifelong maintenance especially, by using combination therapy is not always possible in a significant proportion of patients. At present, there is no consensus on whether it is possible to switch to monotherapy from combination therapy. However, there is robust evidence to support step-down therapy, which involves switching from combination therapy to monotherapy in antiviral resistant CHB patients who achieve complete viral response from combination therapy. We review the evidence in favor of switching to monotherapy in antiviral resistant CHB patients who achieve complete viral response by combination therapy.

Efficacy of entecavir-based rescue therapy in lamivudine-resistant chronic hepatitis B patients in China: a retrospective study.

Limited studies have investigated the antiviral efficacy of entecavir (ETV)-based rescue therapy in lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients. We retrospectively analyzed the efficacy of entecavir (ETV) monotherapy versus ETV-tenofovir disoproxil fumarate (TDF) combination therapy in 220 LAM-resistant CHB patients. Among 220 patients, 114 patients were treated with ETV monotherapy and 106 were treated with ETV-TDF combination therapy for at least 24 months. There were no significant differences between the two groups in baseline characteristics. During the follow-up of 24 months, virologic response (VR) occurred in 146 (66.4%) patients (58 patients belonged to the ETV monotherapy group and 88 patients belonged to the ETV-TDF combination group). The VR rates were different between the ETV and ETV-TDF groups (32.5% vs. 57.5% at 6 months, 50.0% vs. 77.4% at 12 months; and 50.9% vs. 83.0% at 24 months, P<0.001). In addition, both groups showed no difference in terms of the biochemical and HBeAg response. The rates of viral breakthrough at 6, 12 and 24 months were significantly different between ETV and ETV-TDF groups (2.63%, 4.39% and 9.65% vs. 0.00%, 0.94% and 1.89% at 6, 12 and 24 months, respectively). The ETV-TDF group was superior to the ETV group in achieving a virologic response. Moreover, the ETV-TDF was lower than the ETV group in achieving the initial viral breakthrough and genotypic mutations. Therefore, ETV-TDF combination therapy might be a better regimen than ETV monotherapy in the subgroup of LAM-resistant Chinese patients with CHB.

Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study

Long-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB). LAM-R CHB patients were randomised 1:1 to receive TDF 300mg or FTC 200mg and TDF 300mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA<69IU/ml (<400copies/ml) at week 96 (primary efficacy endpoint) was reported previously. Here we present week 240 follow-up data. Overall, 280 patients were randomised to receive TDF (n=141) or FTC/TDF (n=139), and 85.4% completed 240weeks of treatment. At week 240, 83.0% of patients in the TDF arm, and 82.7% of patients in the FTC/TDF treatment arm had HBV DNA<69IU/ml (p=0.96). Rates of normal alanine aminotransferase (ALT) and normalised ALT were similar between groups (p=0.41 and p=0.97 respectively). Hepatitis B e antigen loss and seroconversion at week 240 were similar between groups, (p=0.41 and p=0.67 respectively). Overall, six patients achieved hepatitis B surface antigen (HBsAg) loss and one patient (FTC/TDF arm) had HBsAg seroconversion by week 240. No TDF resistance was observed up to week 240. Treatment was generally well tolerated, and renal events were mild and infrequent (∼8.6%). The mean change in bone mineral density at week 240 was -0.98% and -2.54% at the spine and hip, respectively. TDF monotherapy was effective and well tolerated in LAM-R CHB patients for up to 240weeks. The goal of oral antiviral treatment for chronic hepatitis B (CHB) is to achieve and maintain undetectable HBV DNA levels. Treatment options with enhanced potency, and low risk of resistance development for patients infected with lamivudine resistant (LAM-R) HBV are required. Tenofovir disoproxil fumarate (TDF) monotherapy was effective and well tolerated without TDF resistance development in CHB patients with LAM-R, for up to 240weeks. Clinical trial number: NCT00737568.

Is the tenofovir based therapy almighty for previous treatment failure in chronic hepatitis B?

Is the tenofovir based therapy almighty for previous treatment failure in chronic hepatitis B?

Tenofovir-based rescue therapy in chronic hepatitis B patients with suboptimal responses to adefovir with prior lamivudine resistance.

We evaluated the efficacy of tenofovir (TDF)-based rescue therapy and compared the outcomes of TDF monotherapy and TDF-based nucleoside analog (NA) combination therapy in patients with suboptimal response (SOR) to adefovir (ADV) with or without NAs in lamivudine (LAM)-resistant chronic hepatitis B. All study subjects received ADV with or without NAs due to prior LAM resistance, and were then switched to TDF-based rescue therapy due to SOR (hepatitis B virus DNA >20 IU/ml after at least 6 months of therapy). A total of 125 patients were eligible. The overall cumulative proportion of complete virologic response (CVR) was 64 of 74 patients (86.5%) at 48 weeks of treatment. During the follow-up period of 48 weeks, there was no significant difference in CVR rate (P = 0.750) between the TDF monotherapy (n = 18) and the TDF with NA groups (n = 107). Patients with ADV genotypic mutations showed inferior antiviral responses to TDF compared with the patients without ADV genotypic mutations, but this was not statistically significant (P = 0.069). Partial virological response to prior ADV therapy showed higher CVR rates compared to patients with non-response at 12 weeks (P = 0.013), but there was no significant difference after 24 (P = 0.076) and 48 weeks (P = 0.198) of treatment. TDF monotherapy is as effective as TDF plus NA combination therapy in patients with SOR to ADV-based rescue therapy and LAM resistance. TDF, with or without NAs, was effective even in cases of ADV resistance.

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies.

To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients. Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by real-time PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a log-rank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively. Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors. If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.

Tenofovir rescue therapy in pregnant females with chronic hepatitis B.

To evaluate the safety and efficacy of tenofovir monotherapy in pregnant females resistant to lamivudine or telbivudine. The effect of tenofovir on the fetus was also assessed. The clinical data of 17 females were reviewed in this study. Adverse events and pregnancy outcomes from January 1, 2011 to June 30, 2013 were evaluated in the Department of Gynecology and Obstetrics of Beijing Ditan Hospital, Capital Medical University, Beijing, China. These pregnant females developed lamivudine (LAM)- or telbivudine (LdT)-resistant chronic hepatitis B and received tenofovir (TDF) therapy (300 mg/d), and its curative effect, maternal and perinatal adverse events, fetal growth and development, and neonatal prognosis were evaluated. The median hepatitis B virus (HBV) DNA level in the pregnant females with LAM or LdT resistance was 5.9 (range, 4.2-7.2) log10 copies/mL before the initiation of TDF. Ten of these females had abnormal alanine aminotransferase (ALT) levels. The patients were treated with TDF for a median of 24 wk (range, 12-40 wk). Fourteen females (82.4%) had an HBV DNA level of <500 copies/mL at the time of delivery. This decrease was statistically significant (P<0.0001). Serum ALT levels were normalized in all subjects with an elevated serum ALT level at baseline (P=0.0003). There were no significant changes in serum creatinine and phosphorus levels during TDF treatment. In addition, no adverse events related to TDF treatment were observed. Seventeen females delivered 17 live infants, and all infants had good Apgar scores. The mean birth weight was 3226.5±331.7 g, and the mean length at birth was 50.4±1.1 cm. The growth and development of the infants was normal at birth, and no infants had birth defects related to TDF treatment. Eleven infants completed HBV vaccination and had no evidence of vertical transmission. The use of TDF in pregnant females with chronic HBV and LAM or LdT resistance was safe and effective.

Different mechanism of selection of adefovir-resistant mutant viruses during adefovir monotherapy in patients with lamivudine-resistant chronic hepatitis B

Background: Adefovir (ADV) resistance is more frequent in lamivudine (LMV)-resistant chronic hepatitis B (CHB) patients than in nucleos(t)ide analogue-naïve patients. The majority of LMV-resistant mutants harbor the rtM204V/I mutation, while a minor fraction harbor the rtA181V/T mutation. We aimed to elucidate the mechanism of the high rate of ADV resistance in LMV-resistant patients during ADV therapy. Methods: We performed a clonal analysis of HBV reverse transcriptase in treatment-naïve (n=3) and LMV-resistant patients before ADV therapy (n=14). Dynamic changes in the viral population (n=9) during ADV therapy were also analyzed. Results: Before ADV therapy, rtA181V/T was observed in 30 of 680 clones (4.4%) from 7 patients with LMV resistance under dominant rt204V/I mutation and in one of 150 clones in treatment-naïve patients. The rtA181V/T mutation was more frequently found in clones from LMV-resistant patients than in treatment-naïve patients (p=0.029). The rtN236T mutation was not observed in any clone. During ADV therapy, most rtM204V/I mutants were replaced by wild type in all 3 patients without the rtA181V/T mutation and in one patient with the rtA181V/T mutation. Subsequently, wild type was replaced by the rtN236T and/or rtA181V/T mutant. In patients with the rtA181V/T mutation (n=6), the rtA181V/T mutant overtook the rtM204V/I mutant in 3 of 4 patients with ADV resistance. In 2 patients without ADV resistance, most of the viral population was replaced by wild type by the last follow-up. Conclusion: The high rate of ADV resistance in patients with LMV-resistance might be attributable to preexisting rtA181V/T mutant virus.

Efficacy of Adefovir-Based Combination Therapy for Patients with Lamivudine- and Entecavir-Resistant Chronic Hepatitis B Virus Infection

Treatment strategies for entecavir (ETV)-resistant chronic hepatitis B (CHB) patients are not yet well established. The aim of this study was to evaluate overall antiviral efficacy and to compare the efficacy of combination therapy with adefovir (ADV) plus nucleoside analogues (lamivudine [LAM], telbivudine [LdT], or ETV) in patients infected with LAM- and ETV-resistant hepatitis B virus (HBV) variants. Virologic, biochemical, and serologic responses during combination therapy with ADV plus nucleoside analogues were assessed. Propensity score analysis was used to select a matched group of patients for the comparison of rescue therapy regimens. A total of 67 consecutive patients were analyzed. Complete virologic suppression was achieved in 27 patients. The overall cumulative incidence of complete virologic suppression at month 24 was 47.4%: 44.3% in the LAM or LdT plus ADV group and 51.4% in the group given ETV and ADV. There was no significant difference between these two groups (P = 0.234). The cumulative incidences of complete virologic suppression were still comparable between the two groups selected and matched using the propensity score model (P = 0.419). Virologic breakthrough was observed in 9 patients, and rtA181V substitution was newly detected in one patient. Hepatitis B e antigen (HBeAg) negativity and lower baseline HBV DNA level were associated with complete virologic suppression in univariate analysis. In multivariate analysis, lower baseline HBV DNA level remained an independent predictor. In conclusion, combination therapy with ADV plus nucleoside analogues fails to show sufficient antiviral efficacy in CHB patients with resistance to both LAM and ETV. Further study is warranted to evaluate the efficacy of a more potent tenofovir-based regimen in such patients.

Long-Term Efficacy of Entecavir Plus Adefovir Combination Therapy versus Entecavir Monotherapy in Adefovir Refractory Chronic Hepatitis B Patients with Prior Lamivudine Resistance

Objectives: We investigated the long-term efficacy of entecavir (ETV) + adefovir (ADV) combination therapy versus ETV monotherapy in lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients who failed to respond to ADV rescue therapy. Methods: A total of 91 ADV refractory patients with prior LAM resistance received ETV (1.0 mg/day) + ADV (10 mg/day) combination therapy (group A, n = 45) or ETV (1.0 mg/day) monotherapy (group B, n = 46) for more than 48 weeks. Results: The rates of undetectable serum hepatitis B virus DNA levels (≤20 IU/ml) at weeks 48 and 96 were not significantly different between group A and group B (31.1 vs. 23.9% at week 48, p = 0.442, and 44.7 vs. 34.5% at week 96, p = 0.457). However, the incidence of virological breakthrough in group A was significantly lower than that in group B (0 vs. 17.4% at week 48, p = 0.006, and 2.6 vs. 44.8% at week 96, p < 0.001). ETV monotherapy was the only independent factor significantly associated with virologic breakthrough (p = 0.015). Conclusions: ETV + ADV combination therapy is a better therapeutic option than ETV monotherapy for ADV refractory CHB patients with prior LAM resistance.

Partial Virological Response to Adefovir Add-On Lamivudine Rescue Therapy in Patients with Lamivudine-Resistant Chronic Hepatitis B

Background/Aims: In patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB) receiving adefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. Methods: 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. Results: 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBV DNA <500 IU/ml) at week 48. Conclusions: This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48.

Treatment of lamivudine-resistant chronic hepatitis B infection: a multicenter retrospective study

Objectives.To compare the efficacy of rescue therapies in lamivudine (LAM)-resistant chronic hepatitis B (CHB) infections including: (1) adefovir dipivoxil (ADV) monotherapy, (2) ADV plus LAM combination therapy and (3) entecavir (ETV) 1.0 mg monotherapy. Materials and methods.The authors designed a multicenter-retrospective study. Eight institutions participated in the study from Korea. Results. A total of 343 LAM-resistant CHB patients were enrolled. The proportion of patients with undetectable serum hepatitis B virus (HBV) DNA levels at month 24 after the initiation of rescue therapy was higher in the ADV plus LAM combination therapy group (39/64, 60.9%) than in the ADV monotherapy (50/126, 39.7%) and ETV 1.0 mg monotherapy (19/48, 39.6%) groups (p = 0.014). Mean serum HBV DNA levels at 24 months were 2.07 ± 1.21 log10 IU/ml in the ADV plus LAM combination therapy group, 2.74 ± 1.74 log10 IU/ml in the ADV monotherapy group and 3.08 ± 1.97 log10 IU/ml in the ETV 1.0 mg monotherapy group (p = 0.014). In multivariate analysis, a finding of undetectable serum HBV DNA level at 6 months and ADV plus LAM combination therapy (vs. ADV) was an independent factor for predicting undetectable serum HBV DNA at month 24 (odds ratio, 1.003; 95% confidence interval, 1.000–1.006; p = 0.026). Conclusions.ADV plus LAM combination therapy is more effective in reducing viral load than switching to ADV or ETV 1.0 mg in patients with LAM-resistant CHB.

Cost-effectiveness analysis of different rescue therapies in patients with lamivudine-resistant chronic hepatitis B in China

BackgroundSeveral rescue therapies have been used in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB); however, the economic outcome of these therapies is unclear. The object of the current analysis was to evaluate the lifetime cost-effectiveness of rescue therapies among patients with LAM-resistant CHB.MethodsA Markov model was developed to simulate the clinical course of patients with LAM-resistant CHB. From the perspective of Chinese health care, a lifetime cost-utility analysis was performedfor 4 rescue strategies: adefovir (ADV), entecavir (ETV) or tenofovir (TDF) monotherapy and combination therapy using LAM and ADV. A hypothetical cohort of 45-year-old patients with genotypic or clinical LAM-resistant CHB entered the model, and the beginning health state was LAM-resistant CHB without other complications. The transition probabilities, efficacy and resistance data for each rescue therapy as well as the costs and utility data were estimated from the literature. The discount rate (3%) utilized for costs and benefits. Sensitivity analyses were used to explore the impact of uncertainty on the results.ResultsIn LAM-resistant HBeAg-positive and HBeAg-negative CHB cohorts, TDF monotherapy and combination therapy were on the efficiency frontier for both positive and negative populations. Compared with no treatment, the use of combination therapy cost an additional $6,531.7 to gain 1 additional quality-adjusted life year (QALY) for HBeAg-positive patients and $4,571.7 to gain 1 additional QALY for HBeAg-negative patients. TDF monotherapy for HBeAg-positive patients, shows greater increase in QALYs but higher incremental cost-effectiveness ratio (ICER) in comparison with combination therapy. In probabilistic sensitivity analyses, combination therapy was the preferred option for health care systems with limited health resources, such as Chinese health care system.ConclusionIn Chinese patients with LAM-resistant CHB, combination therapy is a more cost-effective option than the competing rescue therapies.

Long‐term outcomes of add‐on adefovir dipivoxil therapy to ongoing lamivudine in patients with lamivudine‐resistant chronic hepatitis B

Add-on adefovir dipivoxil (ADV) therapy has been a standard rescue treatment for patients with lamivudine (LAM)-resistant chronic hepatitis B, but the overall benefits of long-term add-on ADV therapy are still limited. The aim of this study was to evaluate the long-term efficiency of add-on ADV treatment and to explore predictive factors associated with it. A total of 158 patients with LAM-resistant chronic hepatitis B were included in this retrospective, multicenter, nationwide study in Japan. After confirming LAM resistance, ADV was added to LAM treatment. Three types of events were considered as outcomes: virological response, hepatitis B e antigen (HBeAg) clearance and alanine aminotransferase (ALT) normalization. Virological response was defined as serum hepatitis B virus (HBV) DNA levels of less than 3 log copies/mL. Baseline factors contributing to these outcomes were examined by univariate and multivariate analyses. The median total duration of ADV treatment was 41 months (range, 6-84). The rate of virological response was 90.8% at 4 years of treatment; HBeAg clearance and ALT normalization were achieved by 34.0% and 82.7%, respectively, at the end of follow up. Each outcome had different predictive factors: baseline HBV DNA and albumin level were predictive factors for virological response, history of interferon therapy and ALT level for HBeAg clearance, and sex and baseline albumin level for ALT normalization. Long-term add-on ADV treatment was highly effective in LAM-resistant chronic hepatitis B patients in terms of virological and biochemical responses. Lower HBV replication and lower albumin level at baseline led to better outcomes.

Simple Scoring System Predicting Genotypic Resistance During Rescue Therapy for Lamivudine-Resistant Chronic Hepatitis B

In this study, we aimed to devise a simple scoring system predicting the risk of genotypic resistance (GR) to current rescue therapies for patients with lamivudine (LAM)-resistant chronic hepatitis B. LAM and adefovir (ADV) combination therapy should be recommended for an initial rescue therapy against LAM-resistant hepatitis B virus (HBV). However, there still are many LAM-resistant patients being treated with entecavir (ETV) or ADV monotherapy. This retrospective cohort study included consecutive patients treated for LAM-resistant chronic hepatitis B with ETV or ADV monotherapy, or LAM/ADV combination therapy. The cumulative probabilities of GR and virological responses and breakthrough according to clinical variables were analyzed by survival analyses and derived an index for future GR. A total of 224 patients were included (median treatment duration=117.9 wk). Using risk factors indentified on multivariable analyses, a simple index for future GR (Antiviral Resistance Prediction Index, ARPI) was developed with 3 clinical variables: the rescue therapy regimens (+0, ADV; +1, ETV; +2, LAM/ADV), HBV DNA reduction at 12 weeks (+0, <3 log10 copies/mL; +1, >3 log10 copies/mL), and the initial HBV DNA level (+0, >10 copies/mL; +1, <10 copies/mL). No patient with ARPI ≥2 exhibited GR, whereas 47% of the patients with an ARPI <2 developed GR by week 144 (P=0.005). The results of this study suggest that the ARPI is a simple and early index that can be used to determine the risk for subsequent GR during rescue therapy for LAM-resistant chronic hepatitis B.

RtL180M mutation of hepatitis B virus is closely associated with frequent virological resistance to adefovir dipivoxil therapy

We intended to investigate the effects of pre-existing mutations at reverse transcriptase region of hepatitis B virus (HBV) on the occurrence of virological breakthrough (VB) to adefovir dipivoxil (ADV) in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB). Ninety-seven patients with LAM-resistant CHB were treated with ADV at a dose of 10 mg daily, and were followed for a median period of 13 months. Just before the initiation of ADV therapy, the whole length of reverse transcriptase region of serum HBV-DNA was sequenced using direct sequencing. All patients had genotype C HBV and mutations in the YMDD motif, specifically, YIDD (65%), YVDD (28%), or both (7%). The rtL180M and rtL80V/I mutations were identified in 68% and 69%, respectively. The cumulative probability of VB was 19% and 27% at 1 and 2 years, respectively. There was no difference in the occurrence of VB with regard to types of YMDD mutation or rtL80V/I. However, interestingly, patients carrying rtL180M experienced VB during ADV monotherapy more frequently than those not carrying rtL180M (2-year cumulative probability of VB: 37% vs 3% at 2 years, P < 0.01). On multivariate Cox proportional hazards analysis, rtL180M (hazard ratio [HR]: 8.62, 95% confidence interval: 1.08-69.09, P = 0.042) and decrease in HBV-DNA for 1 year of treatment (HR: 0.69, 95% CI: 0.51-0.95, P = 0.024) are independently associated with VB. The rtL180M mutation of HBV, as well as a small decrease in HBV-DNA after 1 year of treatment might be closely associated with frequent occurrence of virological resistance to ADV in patients with LAM-resistant CHB.

A Combination anti-HBV regimen using lamivudine and other agents in treatment of resistant chronic hepatitis B

Background: Several difficulties remain in formulating treatment for chronic hepatitis B (CHB), 350 million people are chronically infected with HBV, Chronic infection with hepatitis B virus accounts for an enormous burden of disease worldwide, including up to half of all cases of cirrhosis, end stage liver disease , and hepatocellular carcinoma. Aim of the work: To maximize the elimination of the viral infection while minimizing or preventing damage to the liver cells and tissues and development of viral resistance to more antivirals. Patients and Methods: Eighty eight patients of chronic hepatitis B virus infection with resistance to lamivudine treatment as proved by quantitative PCR (more than 200 IU/ ml). Their age between (20-60) years, (85 males, and 3 females) were selected from the National Hepatology and Tropical Medicine Research Institute and were included in this study. The included patients were two groups, the first group 42 patients , were receiving Lamivudine, plus (Baraclude) Entecavir (tablet 0.5mg / day) treatment at the time of assessment. The second group 46 patients were receiving ( Hepsera tablet 10 mg / day ) Adefovir dipivoxil plus lamivudine (tablet). All the patients were subjected to the following : thorough history and clinical examination, abdominal ultrasonography and collection of blood samples for routine liver and kidney function investigations and serological assay for HBsAg, HBsAb, HBeAg, HBeAb, HBcAb quantitative HBV DNA (PCR). Results: Our results revealed significant differences between the two groups of patients of CHBV infection, resistant to Lamivudine drug, the first group were higher in response to a combination between Lamivudine + (Baraclude) Entecavir, than the second group who were receiving Lamivudine + (Hepsera) Adefovir dipivoxil combination therapy. Conclusion: Our study concluded that the clinical benefit is apparent with high percentage after a combination regimen using Lamivudine + Entecavir than a combination regimen using Lamivudine + Adefovir dipivoxil for the treatment of resistant chronic hepatitis B virus who were treated with Lamivudine only before. Recommendations: Optimal management of chronic hepatitis B,that may require long-term and sometimes lifelong treatment to maintain its clinical benefit is challenging. It is important to initiate treatment with a drug that has the least potential for induction of drug resistance as sequential monotherapy which may result in selection of multidrug resistant HBV mutatants.

Virological response to adefovir monotherapy and the risk of adefovir resistance

To evaluate virological response to adefovir (ADV) monotherapy and emergence of ADV-resistant mutations in lamivudine (LAM)-resistant chronic hepatitis B patients. Seventy-seven patients with documented LAM resistance who were treated with 10 mg/d ADV for > 96 wk were analyzed for ADV resistance. At week 48 and 96, eight (10%) and 14 (18%) of 77 LAM-resistant patients developed the ADV-resistant strain (rtA181V/T and/or rtN236T mutations), respectively. Hepatitis B virus (HBV) DNA levels during therapy were significantly higher in patients who developed ADV resistance than in those who did not. Incidence of ADV resistance at week 96 was 11%, 8% and 6% among patients with complete virological response (HBV DNA level < 60 IU/mL); 0%, 5% and 19% among patients with partial virological response (HBV DNA level ≥ 60 to 2000 IU/mL); and 32%, 34% and 33% among patients with inadequate virological response (HBV DNA levels > 2000 IU/mL) at week 12, week 24 and week 48, respectively. HBV DNA levels > 2000 IU/mL at week 24 showed best performance characteristics in predicting ADV resistance. Development of ADV resistance mutations was associated with HBV DNA levels, which could identify patients with LAM resistance who are likely to respond to ADV monotherapy.

Initial Virological Response and Viral Mutation with Adefovir Dipivoxil Added to Ongoing Lamivudine Therapy in Lamivudine-Resistant Chronic Hepatitis B

Although adefovir dipivoxil (ADV) has been used for antiviral treatment of lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients, the long-term efficacy of this treatment is not well understood. Initial virological response (IVR) has been reported to be an important factor in relation to the development of ADV-resistance. We therefore examined the factors associated with IVR and ADV mutation in these patients. Forty-nine LAM-resistant CHB patients with ADV add-on LAM therapy, 47% of whom were hepatitis B e-antigen (HBeAg)-positive with median treatment duration of 23 months, were enrolled in this study. Patients were classified into IVR and non-IVR groups on the basis of viral suppression status. Mutational analysis of the HBV polymerase/reverse transcriptase (rt) domain was performed by PCR-direct sequencing. Serum HBV DNA was undetectable (<2.6 log10 copies/mL) in 67, 82, and 84% of patients at 24, 48, and 96 weeks, respectively, after ADV add-on LAM therapy. IVR was achieved in 82% of patients, and ALT normalized at week 24 in 90% of IVR and 78% of non-IVR patients. The lower pretreatment HBV DNA level and virus-containing mutations other than double mutation of rtL180M + rtM204V were significantly associated with IVR (P=0.002 and P=0.014, respectively). ADV-resistant mutations in the RT motif, reported previously, were not detected. IVR is useful for predicting the antiviral efficacy of ADV and LAM combination therapy in LAM-resistant CHB.