Lamivudine-resistant Patients Research Articles

Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression.

Hepatitis B virus (HBV) X gene (HBx) mutants can develop during the natural course of chronic HBV infection. However, little is known about whether the emergence of HBx mutants during long-term antiviral therapy is an adaptation of HBV to antiviral stress. This study was to identify HBx mutants that emerged in patients experiencing Lamivudine resistance or suboptimal treatment. Forty-six Lamivudine-resistant patients and 46 patients with suboptimal treatment responses to Entecavir were enrolled in this study. HBx mutants were identified by sequence analysis and their roles in the HBV replication cycle were characterized. We show that deletion/truncation/insertion mutations were only detected in the Lamivudine resistance group, while synonymous mutations were found in both groups. Follow-up analyses revealed that five patients in the Lamivudine group developed hepatocellular carcinoma, while patients in the Entecavir group did not. These mutants were characterized by a significant decrease in transactivation of the pre-S1 promoter, and varying effects on transactivation of the X promoter. Co-transfection of HBx-mutant plasmid and HBV replication-competent clone into HepG2 cells resulted in increased nuclear-to-cytoplamic HBV core antigen, HBV-DNA ratios, and nuclear covalently closed circular DNA (cccDNA). Antiviral drug sensitivity assays revealed that these mutants exhibited a compensatory effect to counteract antiviral drug suppression, resulting in elevated secretory HBV-DNA levels. Our study demonstrates that HBx mutants can emerge during Lamivudine or Entecavir therapy. These mutants exhibit altered transactivation of the HBV pre-S1 and X promoters, leading to increased cccDNA levels to compensate for replication suppression.

Long-term data on entecavir treatment for treatment-naive or lamivudine-resistant chronic hepatitis B infection in kidney transplant recipients.

Entecavir (ETV) showed short-term efficacy and safety in HBsAg-positive kidney transplant recipients (KTRs), but long-term data are lacking. We retrospectively reviewed 30 HBsAg-positive KTRs who received ETV during 2007-2017. Eighteen treatment-naïve (Group I) and 12 lamivudine-resistant (Group II) patients received ETV for 48.4±35.2 and 66.0±26.0months, respectively. Both groups show significant HBV DNA decline, but Group I achieved earlier undetectability after 11.9±9.6months (compared with 28.8±24.2months in Group II, P=.033). Group I showed higher rates of undetectable HBV DNA (89%, 94%, 94%, 100%, and 100% at 12, 24, 36, 48, and 60months, respectively, compared with 25%, 50%, 50%, 91%, and 91% in Group II, P=.003). ALT normalized after 6.0±1.9 and 6.8±2.1months in Group I and Group II, respectively. Four patients (33.3%) in Group II developed drug resistance (2 had persistent viraemia and 2 had virological breakthrough, at 40.3±15.0months). Group II showed higher liver stiffness after 5years (7.7±4.1kPa, compared with 5.0±1.6kPa in Group I, P=.046) and incidence of cirrhosis (4 patients [33.3%], compared with 1 [5.6%] patient in Group I, P=.049). Two patients (one in each group) developed hepatocellular carcinoma. Renal allograft function remained stable during follow-up of 63.2±33.4months for both groups. There was no difference in patient and graft survival between two groups at 5years (P=.62 and .36, respectively). ETV showed favorable long-term efficacy and tolerability in treatment-naïve KTRs. One-third of lamivudine-resistant subjects showed non-response or viral breakthrough after ETV treatment.

Antiviral effect of initial combination therapy with adefovir dipivoxil and lamivudine vs adefovir dipivoxil added to ongoing lamivudine therapy after lamivudine resistance in patients with hepatitis B-related decompensated cirrhosis

Antiviral effect of initial combination therapy with adefovir dipivoxil and lamivudine <i>vs</i> adefovir dipivoxil added to ongoing lamivudine therapy after lamivudine resistance in patients with hepatitis B-related decompensated cirrhosis

Efficacy and Safety of Tenofovir Disoproxil Furmarate for Patients with Lamivudine-Resistant Hepatitis B Virus Infection

AIM: Tenofovir disoproxil fumarate (TDF) has potent antiviral efficacy and lack of resistance during long-term use in chronic hepatitis B (CHB) patients. The purpose of this study was to evaluate antiviral efficacy and safety of TDF in lamivudine-resistant CHB patients. METHODS: We performed a retrospective study of consecutive CHB patients who had detectable HBV DNA (>50IU/mL) and documented lamivudine-resistant mutations during antiviral treatment. Patients who had adefovir or entecavir-resistant HBV infection were excluded. They were treated with TDF monotherapy or combination with lamivudine more than 6 months. We analyzed virologic response (HBV DNA <20 IU/mL), biochemical and serologic responses to the TDF treatment and adverse events. RESULTS: A total of 101 CHB patients (HBeAg-positive 86%, mean baseline HBV DNA 3.29 log10IU/ mL) were enrolled. They were treated with TDF (n=74) or combination with lamivudine (n=27) for median duration of 20 months. The proportion of patients achieving virologic response at 6 months and 12 months was 80.2%, and 89.7%, respectively. The mean change from baseline in HBV DNA was –2.05 log10IU/mL, and –2.14 log10IU/mL, respectively. Multivariate Cox regression analysis showed that baseline HBV DNA level was a significant predictive factor of virologic response at 12 months. (HR=0.645; 95% CI 0.504-0.826; p=0.001). Two patients (2.4%) showed HBeAg loss, and no patient lost HBsAg during the treatment period. Serious adverse events or renal impairment was not observed. CONCLUSION: TDF is safe and effective for complete viral suppression in patients with lamivudine-resistant HBV infection.

Efficacy of tenofovir-based rescue therapy in patients with lamivudine-resistant hepatitis B virus: A systematic review and meta-analysis

Currently, there are no conclusive results on the efficacy of Tenofovir disoproxil fumarate (TDF) monotherapy in chronic hepatitis B (CHB) patients with lamivudine-resistant (LAM-R). The aim of this study was to compare the efficacy between TDF and TDF-based combination therapy against LAM-R HBV in CHB patients. Randomized and non-randomized control trials directly comparing TDF and TDF-based therapy for treatment of LAM-R CHB patients, were searched in Pubmed, Medline, EMBASE, database up to June 15, 2015. The data were analyzed with Review Manager (v.5.3). Five articles (683 patients in total) met entry criteria. The overall efficacy of tenofovir-based combination therapy was not significantly better with regard to the rates of virological response (85.5% vs. 81.5%; RR=0.95, 95%CI=0.88-1.03, P=0.25), ALT normalization (61.9% vs.72.0%; RR=1.18, 95%CI=0.96-1.44, P=0.11) and HBeAg loss (17.0% vs. 18.1%; RR=1.40, 95%CI=0.78-2.49, P=0.26) compared with TDF monotherapy through 48-week treatment. Additionally, subgroup analysis showed that no significant difference was determined as TDF group compared to TDF-based group at 48weeks, in terms of rates of HBV DNA undetectability, ALT normalization and HBeAg loss in the treatment of LAM-R patients with prior failure of LAM monotherapy. Moreover, the rates of HBV DNA suppression between groups were similar through 24 or 48weeks of treatment in LAM-R patients with prior failure of LAM/ADV therapy. TDF monotherapy is as effective as TDF-based combination therapy in maintaining viral suppression in LAM-R patients with prior failure of LAM or LAM/ADV therapy.

The case of chronic hepatitis B treatment with tenofovir: an update for nephrologists.

Tenofovir is a nucleotide acting both as an inhibitor of human immunodeficiency (HIV) reverse transcriptase and as a competitor for hepatitis B virus (HBV) RNA-directed DNA polymerase. Approved worldwide in 2001, tenofovir is used as a component of highly active antiretroviral therapy (HAART) in patients with HIV infection. Since 2008, it has also been indicated for treatment of chronic HBV infection or HIV/HBV co-infection. The aim of the treatment consists in suppressing viral replication, thus reducing hepatic complications and improving patient survival. Furthermore, tenofovir could represent an effective therapeutic option in lamivudine-resistant HBV patients. Tenofovir is eliminated unchanged through urine via glomerular filtration (80%) and proximal tubular secretion (20%). Thus, alterations in renal clearance may interfere with tenofovir pharmacokinetics and systemic drug concentrations, modifying the therapeutic response. Hence, a renal overload of tenofovir in patients with a pre-existing kidney impairment could result in a worsening of renal function. Following a brief introduction on HBV infection and its therapeutic options, we review the latest evidence, to our knowledge, on renal toxicity of tenofovir in HBV patients and on drug management.

Prediction of prognosis to lamivudine in patients with spontaneous reactivation of hepatitis B virus-related acute-on-chronic liver failure: Using virologic response at week 4

Background/aimsCurrent results had demonstrated lamivudine (LAM) contributed to improve liver function and short-term prognosis in patients with hepatitis B virus-related acute-on-chronic liver failure (ACLF), but data concerning the outcome of long-term prognosis are limited. Our objective was to explore the prediction value of early viral response for prognosis and LAM resistance in ACLF patients with lamivudine treatment within 96weeks. MethodsOne hundred and forty consecutive subjects were recruited, 76 patients were treated with LAM and supportive treatment (LAM group) and 64 patients only received supportive treatment (non-NAs group). All the patients were followed up until death or 96weeks. The primary end point was overall survival rate at 96weeks, as well as the relationship between the virologic response at weeks 4 or 12 and prognosis and resistance at 96weeks. ResultsAt 96weeks, the cumulative survival was higher in the LAM group than that in the non-NA group (43/76 (56.58%) vs 9/64 (14.06%), respectively, p=0.000). The survival rate of patients achieved complete viral response (CVR) at week 4 was higher than that of those with partial virologic response (PVR) during the 96-week follow-up (27/29 [93.10%] vs 16/45 [35.56%], p=0.000). In CVR patients, there was a significant improvement in model for end-stage liver failure (MELD) scores compared to PVR. Logistic recurrence indicated that both 4-week CVR and MELD scores were an independent predictor of the 96-week survival. Twelve patients developed LAM resistance (22.22%); all of them came from the PVR at 4weeks. ConclusionLAM can significantly improve the long-term survival rate, and 4weeks CVR can predict the long-term clinical outcome and LAM-resistant in patients with HBV-related ACLF.

Entecavir 1 mg versus combined lamivudine/adefovir dipivoxil in chronic HBV Egyptian patients resistant to LAM monotherapy, non-randomised controlled study

Background and study aimsThe development of antiviral-resistant mutations with long-term treatment remains a major concern in the treatment of chronic hepatitis B virus (HBV) infection. The study aimed to compare the therapeutic efficacy of entecavir 1mg versus combined lamivudine/adefovir dipivoxil (Lam/Adv) in chronic HBV patients resistant to lamivudine monotherapy. Patients and methodsThis study included two groups of lamivudine-resistant patients who received lamivudine 100mg for 1–3years. Group 1 was composed of 25 cases (52% HBeAg+ve) who received combined Lam/Adv, and group 2 was composed of 13 patients (30.8% HBeAg+ve) who received entecavir 1mg. Pre-enrolment assessment included biochemical, serological and quantitative HBV-DNA testing as well as HBeAg and hepatitis B envelope antibody (HBeAb) assessment. Evaluation was done at 3, 6, 12, 24 and 36months of treatment by the same parameters. Hepatitis B surface antigen and antibody (HbsAg and HBsAb) were assessed after each year of treatment. ResultsAt the end of 36months of treatment, 16 cases (69%) in group 1 completed the study period, versus 13 (100%) in group 2. Two cases in group 1 underwent HBeAg seroconversion, accompanied by HBV-DNA undetectability, at 6 and 12months, respectively; no cases were seroconverted in group 2. Both treatments achieved improvement in alanine aminotransferase (ALT), bilirubin and alpha-foetoprotein equally at the end of the study. HBV-DNA undetectability was better achieved in group 2 when compared to group 1. HBeAg seroconversion was only achieved in two cases in group 1, whereas no cases lost HBeAg in group 2. None of our cases achieved HbsAg seroconversion or loss at the end of the study period. ConclusionThe entecavir 1-mg monotherapy group achieved better HBV-DNA undetectability starting at 3months of treatment when compared to the Lam/Adv group; however, both lines of treatment showed almost similar results over the rest of the study period. HBeAg seroconversion was only achieved in two cases in the combined Lam/Adv group, whereas no cases lost HBeAg in the other group.

Clinical utility of entecavir for chronic hepatitis B in Chinese patients

The People’s Republic of China has one of the highest rates of hepatitis B virus (HBV) infection. This review summarizes recent data from studies of entecavir, one of the recommended first-line oral therapies for treating chronic hepatitis B, in Chinese HBV-infected patients. Long-term treatment with entecavir is efficacious and well tolerated, and studies comparing entecavir with other nucleos(t)ide therapies, such as lamivudine, adefovir, and telbivudine, demonstrate superior antiviral effects for entecavir therapy and comparable safety profiles. Entecavir monotherapy and combination treatment with other nucleos(t) ide analogs has been shown to be efficacious in the treatment of lamivudine-resistant and adefovir-resistant patients with HBV infection, as well as in patients with multidrug-resistant disease. Entecavir has also been shown to be effective in patients with HBV-associated clinical morbidity, including cirrhosis and liver failure, as well as in preventing recurrence of HBV following liver transplantation and in preventing reactivation of HBV after immunosuppres-sive therapy. Although the cost of anti-HBV therapy is a particular concern in the People’s Republic of China, a number of studies have recently demonstrated that entecavir (particularly long-term therapy) represents a more cost-effective treatment strategy compared with other nucleos(t)ide therapies. Further research is required to assess the effects of entecavir combination therapy on hepatitis B surface antigen clearance, and in drug-resistant patients in the People’s Republic of China.

Baseline CD4+ T-Cell Counts Predict HBV Viral Kinetics to Adefovir Treatment in Lamivudine-Resistant HBV-Infected Patients with or without HIV Infection

Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. Methods: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. Results: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. Conclusion: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV.

Adding adefovir vs. switching to entecavir for lamivudine‐resistant chronic hepatitis B (ACE study): a 2‐year follow‐up randomized controlled trial

Management of lamivudine-resistant chronic hepatitis B (CHB) remains challenging, as inappropriate choice of treatment may cause multidrug resistance. Until now, randomized trials directly comparing adding adefovir and switching to entecavir monotherapy have not been reported. This multicentre prospective randomized study was designed to compare the efficacy of these two strategies. Two hundred and nineteen lamivudine-resistant CHB patients were randomized to either adefovir-lamivudine combination group or entecavir monotherapy group (n = 110 vs. 109), and followed up for 24 months. One hundred and eighty patients completed this study. At month 24, virological response rate [hepatitis B virus (HBV) DNA <60 IU/ml] was higher in the adefovir-lamivudine combination group compared with entecavir group (56.7% vs. 40%, P = 0.025), although biochemical and serological response rates were not significantly different. Genotypic resistance (9.2% vs. 24.6%, P = 0.005) and combined viral breakthrough (2.0% vs. 17.6%, P < 0.001) were more frequent in the entecavir group. However, by subgroup analysis, virological response rates were not significantly different between the two therapies in HBeAg-positive patients (44.9% vs. 35.7%, P = 0.268) or in patients with high baseline HBV DNA (≥7 log IU/ml) (40.7% vs. 31.3%, P = 0.320) at month 24. This study showed that adefovir-lamivudine combination provides significantly higher antiviral efficacy and the lower resistance rate compared with the entecavir monotherapy in the management of lamivudine-resistant CHB. However, it had limited efficacy in HBeAg-positive patients or in patients with high baseline HBV DNA.

Efficacy and safety of peginterferon alfa-2a in patients with lamivudine-resistant HBeAg-positive chronic hepatitis B

Lamivudine resistance develops in up to 80% of patients with chronic hepatitis B (CHB) after 5 years of treatment. Cross-resistance between nucleoside/nucleotide analogues limits management options in these patients. To investigate the role of pegylated interferon-α2a as rescue therapy in these patients, the efficacy and safety of pegylated interferon-α2a between treatment-naive patients and lamivudine-resistant patients with hepatitis B e antigen (HBeAg)-positive CHB were compared. A total of 150 HBeAg-positive CHB patients were stratified according to prior treatment. Lamivudine-resistant patients (n=64) and treatment-naive patients (n=86) received pegylated interferon-α2a once-weekly for 48 weeks and were followed-up for an additional 24 weeks. Primary end points were HBeAg loss and HBV DNA <100,000 copies/ml at end of follow-up. A total of 65 (76%) treatment-naive patients and 49 (77%) lamivudine-resistant patients completed treatment and 24 weeks of follow-up. Rates of HBeAg loss were comparable at end of follow-up between treatment-naive patients and lamivudine-resistant patients (20.9% and 23.4%, respectively; P=0.8423). Similarly, rates of HBV DNA<100,000 copies/ml were comparable at end of follow-up between treatment-naive patients and lamivudine-resistant patients (20.9% and 21.9%, respectively; P=1.000). There was no statistically significant difference in alanine aminotransferase normalization rates between treatment-naive patients and lamivudine-resistant patients (36.0% and 29.7%, respectively; P=0.4848). A total of one patient in each group achieved hepatitis B surface antigen (HBsAg) loss and seroconversion. The most common adverse events were those known to occur with pegylated interferon-α2a therapy, and safety profiles were similar between both patient populations. Pegylated interferon-α2a may be effective as a rescue therapy in patients with lamivudine-resistant HBeAg-positive CHB.

The short-term efficacy of entecavir in lamivudine-resistant chronic hepatitis B: influence of sequential adefovir-refractoriness.

Sequential antiviral therapy for chronic hepatitis B may lead to the selection of multidrug-resistant mutation. This study was carried out to assess the efficacy of entecavir in patients that have experienced adefovir monotherapy failure after the development of lamivudine resistance. Fifty-three patients with confirmed genotypic lamivudine-resistant chronic hepatitis B were treated with entecavir. Thirty patients were switched to entecavir directly (LAM-ETV group), whereas the remaining 23 were adefovir-refractory patients who were switched to entecavir (LAM-ADV-ETV group). These 23 patients included 9 patients with inadequate response (ADV-I subgroup) and 14 that exhibited adefovir resistance (ADV-R subgroup). Significantly greater reductions in HBV DNA levels were observed after 24, 48 and 72 weeks of entecavir therapy in the LAM-ETV group than in the LAM-ADV-ETV group, respectively. However, between these two groups at 48 and 72 weeks, no significant differences were observed in cumulative proportions of virological response or breakthrough, respectively. Furthermore, efficacy of entecavir was not significantly different in the ADV-I and ADV-R subgroups. Four patients in the LAM-ETV group and six patients in the LAM-ADV-ETV group developed genotypic resistance to entecavir. Entecavir therapy is less effective in adefovir-refractory patients with prior lamivudine resistance than in lamivudine-resistant patients.

Do different lamivudine‐resistant hepatitis B genotypes carry the same risk of entecavir resistance?

Entecavir switch is one of the treatment options for lamivudine-resistant hepatitis B (HBV) patients in Asia. This study examined the outcome of patients with different baseline resistance genotypes in a cohort study. In this study, 14 patients with chronic HBV were treated with entecavir 1 mg/day for 5 years. Enrolment criteria include: documented lamivudine resistant mutations, treatment with adefovir 10 mg/day for at least 24 weeks, and Child-Pugh score <7. Most had previous failed adefovir therapy and compensated cirrhosis of the liver. Clinical outcomes, liver biochemistries, and HBV DNA were monitored regularly. Patients with virologic breakthrough were rescued with add-on adefovir. At the end of the treatment period, the mean HBV DNA fell from 5.92 × 10(6) (baseline) to 3.67 × 10(1) IU/ml. The presence of a HBV polymerase rtM204V mutation at the baseline was found to be the major risk factor for adverse outcomes. Compared to the patients with the rtM204I mutant, patients with the rtM204V mutant had increased risk of virologic breakthrough (80% vs. 0%, P = 0.010) requiring add-on adefovir, slower virologic responses (log rank test, P = 0.0011), failure to reach undetectable HBV DNA levels (60% vs. 0%, P = 0.045), and higher risk of entecavir-resistance (60% vs. 0%, P = 0.045). All the patients with rtM204I and rtA181 mutants had undetectable HBV DNA from 18th month. In summary, lamivudine-resistant HBV patients with the rtM204V mutation have the highest risk of developing entecavir resistance, and entecavir monotherapy should be avoided. Those with the rtM204I and rtA181V mutations may have lower risks, but regular surveillance for viral breakthrough is required.

Comparison of rescue strategies in lamivudine-resistant patients with chronic hepatitis B

Lamivudine (LAM) resistance now poses a major problem in the management of patients with chronic hepatitis B virus (HBV) infection. We retrospectively collected clinical data on chronic HBV-infected patients who had developed LAM resistance under de novo LAM monotherapy and subsequently took nucleos(t)ide analogs as rescue strategy in our hospital. From initiation of rescue therapies to January 2012, incidence of antiviral drug resistance was 23.67%, 18%, 6.94% and 0% (P=0.007) in the group of switching to adefovir dipivoxil (ADV) monotherapy, switching to entecavir (ETV) monotherapy, adding on ADV and switching to combination of ADV and ETV. At month 12, the median levels of serum HBV DNA were respectively 9300IU/mL, 4648IU/mL, 2054IU/mL and 100IU/mL (P<0.001), and the cumulative rates of serum ALT normalization were respectively 75%, 84%, 93% and 100% (P=0.003). Additionally, the strategy of switching to ADV monotherapy induced more single rtA181T mutations. In conclusion, switching to ADV monotherapy has been widely used in real-world clinical practice in China, however, due to the high incidence of drug resistance, switching to neither ADV nor ETV monotherapy is optimal when LAM resistance occurs; combination of ADV and ETV is most effective, whereas the strategy of adding on ADV is rational for most of LAM-resistant Chinese patients with chronic hepatitis B.

Hepatitis B e antigen‐suppressing mutations enhance the replication efficiency of adefovir‐resistant hepatitis B virus strains

Hepatitis B e antigen (HBeAg) negative hepatitis B virus (HBV) infections caused by precore (PC) or basal core promoter (BCP) mutations are associated with disease progression and complications. PC or BCP mutations may enhance the replication capacity of distinct drug-resistance-associated polymerase mutations, but their effect on adefovir-resistant HBV mutants is unclear. Importantly, BCP mutations were an independent risk factor for virological breakthrough in lamivudine-resistant patients treated with adefovir. We aimed at addressing the functional consequences of PC and BCP mutations on the replication and drug susceptibility of adefovir-resistant HBV mutants. Therefore, HBV constructs with wild type (WT) or adefovir-resistant rtN236T, rtA181V and rtA181T mutations, with or without concomitant PC or BCP mutations, were analysed in vitro using molecular assays. The adefovir-resistant polymerase mutations rtN236T, rtA181V and rtA181T showed a drastically reduced viral replication compared with WT. Interestingly, additional PC or BCP mutations enhanced the reduced replication efficacy of adefovir-resistant constructs and restored HBV replication to WT level. HBV rtA181T mutants displayed abolished hepatitis B surface antigen (HBsAg) secretion, owing to a sW172* stop codon in the overlapping envelope gene. All rtN236T- or rtA181V/T-containing constructs, regardless of concomitant PC or BCP mutations, were resistant to adefovir, but remained susceptible to telbivudine, entecavir and tenofovir. In conclusion, adefovir drug resistance mutations reduced viral replication, which can be significantly increased by additional HBeAg-suppressing PC or BCP mutations. Because increased HBV replication in HBeAg-negative patients has been associated with an unfavourable clinical course, close monitoring appears indispensable during adefovir treatment in HBeAg-negative patients.

Impact of Lamivudine plus Adefovir therapy in chronic hepatitis B Iranian patients, resistant to Lamivudine treatment alone, on disease inhibition: A pilot study

AIM: To evaluate the impact of combination therapy with Lamivudine and Adefovir for treatment of chronic hepatitis B in Lamivudine-resistant patients. METHODS: Among the 110 adult chronic hepatitis B Iranian patients whom were treated with Lamivudine, for 36 months, nineteen patients (17%) with no any biochemical and viral responses to Lamivudine alone, were selected and enrolled in the study. Due to resistancy, Adefovir was added to Lamivudine, and continued for 30 months. We measured HBV_DNA viral load and serum AST, ALT in 0, 12, 24, 30 and 0, 6, 12, 18, 24, 30 months, respectively. RESULTS: Between biochemical and viral characteristics, Repeated Measure analysis identified just biochemical markers— Aspartate Aminotransferase level (AST) (P = 0.002) and Alanine Aminotransferase level (ALT) (P = 0.007) —as predictors of response to treatment, while, viral marker—HBV DNA load—was not statistically significant (P = 0.128). CONCLUSIONS: Treatment for a long time, such as 21.5 ± 8.8 months, with Lami- vudine and Adefovir, can cause liver enzymes including AST and ALT, decreasing and being normal. But, this finding is not indicative, for HBV-DNA viral load.

Cost Effectiveness of Tenofovir Disoproxil Fumarate for the Treatment of Chronic Hepatitis B from a Canadian Public Payer Perspective

Previous research has demonstrated that tenofovir disoproxil fumarate (DF) is the most cost-effective nucleos(t)ide treatment for chronic hepatitis B (CHB) in the UK, Spain, Italy and France. However, to our knowledge, no published studies have yet evaluated the cost effectiveness of any treatments for CHB in a Canadian setting, where relative prices and management of CHB differ from those in Europe. Our objective was to determine the cost effectiveness of tenofovir DF compared with other nucleos(t)ide therapies licensed for CHB in Canada from the perspective of publicly funded healthcare payers. A Markov model was used to calculate the costs and benefits of nucleos(t)ide therapy in three groups of patients with hepatitis B e antigen (HBeAg)-positive and -negative CHB: nucleos(t)ide-naive patients without cirrhosis; nucleos(t)ide-naive patients with compensated cirrhosis; and lamivudine-resistant patients. Disease progression was modelled as annual transitions between 18 disease states. Transition probabilities, quality of life and costs were based on published studies. Health benefits were measured in QALYs. The reference year for costs was 2007 and costs and outcomes were discounted at 5% per annum. First-line tenofovir DF was the most effective nucleos(t)ide strategy for managing CHB, generating 6.85-9.39 QALYs per patient. First-line tenofovir DF was also the most cost-effective strategy in all patient subgroups investigated, costing between $Can43,758 and $Can48,015 per QALY gained compared with lamivudine then tenofovir. First-line tenofovir DF strongly dominated first-line entecavir. Giving tenofovir DF monotherapy immediately after lamivudine resistance developed was less costly and more effective than any other active treatment strategy investigated for lamivudine-resistant CHB, including second-line use of adefovir or adefovir + lamivudine. Probabilistic sensitivity analysis demonstrated 50% confidence that first-line tenofovir DF is the most cost-effective nucleos(t)ide strategy for treatment-naive patients with CHB, at a $Can50,000 per QALY threshold, and confirmed that first-line tenofovir DF has the highest expected net benefits. First-line tenofovir DF appears to be the most cost-effective nucleos(t)ide treatment for both cirrhotic and non-cirrhotic CHB patients in Canada, providing that society is willing to pay at least $Can48,015 per QALY gained, although sensitivity analyses highlighted uncertainty around the results.

Identification of hepatitis B virus rtS117F substitution as a compensatory mutation for rtM204I during lamivudine therapy

The replication defect of hepatitis B virus (HBV) lamivudine-resistant mutants can be restored by the development of compensatory mutations. Such mutations have long been recognized for the rtM204V mutant, while little is known about any compensatory mutation specific to the rtM204I mutant. The aim of this study was to search for previously unrecognized compensatory mutations following development of lamivudine-resistant mutants. Of 83 lamivudine-resistant patients, 49 and 34 patients harboured the rtM204I and rtM204V mutations, respectively. Serial serum samples obtained during the therapeutic course were submitted to sequence analysis. Site-directed mutagenesis experiments were performed to examine the functions of the identified associated mutations. Of the 49 patients carrying the rtM204I mutation, 5 subsequently developed an rtS117F substitution during the follow-up, whereas 4 harboured an rtN124D substitution prior to the development of the rtM204I mutation. Emergence of the rtS117F mutation was associated with an increase in hepatitis activity, whereas prior existence of the rtN124D mutation was associated with decompensated liver function upon development of the rtM204I mutation. Site-directed mutagenesis experiments showed that the rtS117F mutation by itself did not confer lamivudine resistance but it compensated for replication deficiency of the rtM204I mutant in HepG2 and Mahlavu cells. Additionally, virion and hepatitis B surface antigen secretion of the rtS117F mutant was significantly impaired. The rtS117F substitution served as a compensatory mutation for rtM204I. Emergence of the rtS117F mutation in lamivudine-resistant patients carrying rtM204I was associated with increased hepatitis activities. Prior existence of the rtN124D substitution was associated with liver decompensation upon development of the rtM204I mutation.

Frequency and Mutation Patterns of Resistance in Patients with Chronic Hepatitis B Infection Treated with Nucleos(t)ide Analogs in Add-On and Switch Strategies

: Background: Treatment for chronic hepatitis B (CHB) has improved over the last 10 years mainly due to the development of effective oral antiviral agents [nucleoside/nucleotide analogs (NUCs)].Objectives: The aim of the present study is to identify the frequency and major patterns of resistance to the hepatitis B virus (HBV) in a Turkish population of CHB patients treated with NUCs using add-on and switch therapy strategies.Patients and Methods: The investigation involved a total of 194 patients (88 were treated using add-on therapy, and 106 were treated using switch therapy). We analyzed the HBV polymerase gene by amplification and direct sequencing procedures.Results: Primary drug-resistance mutations were detected in 84 patients (43%; 42 in add-on therapy, and 42 in switch therapy) taking lamivudine (LAM), 10 patients (5%; 6 in add-on therapy, and 4 in switch therapy) taking entecavir (ETV), and 16 patients (8%; 8 in add-on therapy, and 8 in switch therapy) taking adefovir (ADV). The most common LAM and ETV resistance mutations were rtM204I/V, rtL180M and rtT184A/I/S, respectively, while rtA181T/V and rtN236T substitutions were the most frequently observed ADV resistance mutations.Conclusions: Patients with CHB who developed NUC resistance were managed using 2 different rescue strategies. The frequency and mutation pattern of resistance were similar in patients treated with add-on and switch strategies. These findings may be helpful in the management of rescue strategies in LAM-resistant patients. Implication for health policy/practice/research/medical education:Authors revealed of major drug resistance patterns and their frequencies in add-on and switch strategies in treatment of chronic hepatitis B virus. This article is an helpful for clinicians involved in the management of rescue strategies in lamivudine-resistant patients in chronic hepatitis B. Please cite this paper as:Sayan M, Akhan SC, Senturk O. Frequency and Mutation Patterns of Resistance in Patients with Chronic Hepatitis B Infection Treated with Nucleos(t)ide Analogs in Add-On and Switch Strategies. Hepat Mon.2011;11(10):835-42. DOI: 10.5812/kowsar.1735143X.775 © 2011 Kowsar M.P.Co. All rights reserved.