Long-term Evaluation of Residual Viremia in a Clinical Trial of Dolutegravir Plus Lamivudine as Maintenance Treatment for Participants With and Without Prior Lamivudine Resistance.

In this pilot clinical trial, we evaluated rates of residual replication in persons without lamivudine resistance-associated mutations in proviral DNA population sequencing who switched to dolutegravir plus lamivudine. After 144 weeks, there was no signal of changes in residual viremia based on qualitative detection methods, irrespective of past lamivudine resistance. Clinical Trials Registration. NCT03539224.

Influence of Renal Function on the Single-Dose Pharmacokinetics of Besifovir, a Novel Antiviral Agent for theTreatment of Hepatitis B Virus Infection.

Per the well-known resistance of hepatitis B virus to nucleoside/nucleotide analogs, alternative treatment options with higher resistance barriers have been approved for use in both treatment-naïve and lamivudine-resistant hepatitis B virus infections. This phase I study was conducted in adults with normal and impaired renal function to evaluate the effect of renal impairment on the pharmacokinetics of besifovir, a prodrug of an acyclic nucleotide phosphonate, that is mainly cleared via renal excretion. An open-label, single-dose parallel-group clinical study was conducted in subjects with normal renal function and mild, moderate, and severe renal impairment. Subjects received a single oral dose of besifovir dipivoxil 150 mg, and serial blood and urine samples were collected for up to 72 hours after dosing to assess the pharmacokinetic characteristics of besifovir. The extent of plasma exposure of besifovir, detected as its major and active metabolites, LB80331 and LB80317, respectively, increased with worsening renal function. Compared to the subjects with normal renal function, the mean areas under the concentration-time curves of LB80331 increased by 1.5-, 2.5-, and 4.5-fold in subjects with mild, moderate, and severe impairment, respectively. LB80317 showed a 1.8-, 3.2-, and 6.2-fold increase in subjects with mild, moderate, and severe renal impairment compared to those with normal function. The ratios of LB80331 renal clearance and the average estimated glomerular filtration rate of each renal impairment group with respect to the normal group were similar. The increase in plasma exposure and decrease in renal clearance suggest the need to adjust dosage regimens in patients with moderate to severe renal impairment.

Hepatitis B virus genetic multiplicity and the associated HBV lamivudine resistance mutations in HBV/HIV co-infection in Western Kenya: A review article.

BACKGROUND: Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infections are common as the two viruses use same routes of transmission. Studies show that HIV infection modifies the natural course of chronic HBV infection, leading to more severe and progressive liver disease, and a higher incidence of cirrhosis, liver cancer and mortality. Therefore, determining HBV status and genotypes among HIV co-infected patients would improve their therapeutic management. OBJECTIVE: This article reviewed the HBV genetic multiplicity and the associated HBV Lamivudine resistance mutations in HBV/HIV co-infection in western Kenya. METHODS: Comprehensive literature searches and analysis were performed in peer-reviewed journals in the National council for biotechnology information (NCBI), PubMed, and Web of science using key words of HIV, Hepatitis B genotypes, HBV/HIV co-infection and Lamivudine resistance. RESULTS: HBV genotype A is predominant. D and E are also present in Kenya and neighboring countries in the region. HBV polymerase rtV173L, rtL180M, and rtM204V major substitutional mutations were identified. Currently, TDF + 3TC + DTG are recommended for treatment of HBV/HIV co-infection. CONCLUSION: Evidence shows that HBV/HIV co-infection places a heavy burden to the society. Along with ART regimen, HBV genotype is a major factor determining the course of disease and treatment outcome. Treating HIV in HBV/HIV co-infection with antiretroviral agents may result in a very high prevalence of HBV 3TC-resistance mutations. Therefore, improved screening for HBV and extended follow-up of HBV/HIV co-infected individuals is needed to better understand the impact of different ART regimens on clinical outcomes.

Comparison of replication competence of wild-type and lamivudine-resistant hepatitis B virus isolates from a chronic hepatitis B patient.

In lamivudine-refractory chronic hepatitis B (CHB) patients, discontinuation of lamivudine therapy may lead to loss of lamivudine-resistant hepatitis B virus (HBV) and reappearance of wide-type HBV as dominant strains, yet the underlying mechanism remains unclear. In this study, we cloned wide-type and lamivudine-resistant HBV genomes from the sera of a CHB patient who stopped lamivudine therapy after occurrence of resistant virus and determined the biologic properties of the two isolates in hepatoma cell lines. Sequencing reverse transcriptase region of HBV revealed that the patient developed lamivudine-resistant mutations (rtV173 L, rtL180 M, and rtM204 V) 36 months after the start of lamivudine therapy, and lamivudine-resistant mutants reversed to wild-type after the treatment was stopped for 8 months. Our data showed that the wild-type and mutant isolates had similar transcriptional and translational activity. However, comparison of intracellular and released HBV DNA levels showed that replication efficiency of the mutant virus was approximately 50% of wild-type HBV, while the infectivity of released virus was not affected by the lamivudine-resistant mutations. In conclusion, the reversion of lamivudine-resistant mutants to wild-type HBV after discontinuation of lamivudine in hepatitis B patients may be attributed to better replication fitness of wild-type HBV.

Lamivudine-resistant rtL180M and rtM204I/V are persistently dominant during combination rescue therapy with entecavir and adefovir for hepatitis B.

Adefovir (ADV) sequential monotherapy was included in the 2005 Asia-Pacific guidelines for the management of patients with lamivudine (LAM) resistance. However, following the development of ADV resistance, the proportion of resistant variants during combined rescue therapy with ADV and entecavir (ETV) were unknown. The present study characterized the dynamics of resistant variants in patients with chronic hepatitis B (CHB) and LAM-resistant variants during antiviral therapy consisting of ADV monotherapy followed by ADV-ETV combination therapy. A total of 3 patients were selected from a cohort of 55 patients with CHB due to developing ADV resistance. The patients had been previously treated with LAM (100 mg daily) for 21-24 months. At the initiation of sequential monotherapy with ADV, LAM-resistant variants (rtM204V/I and rtL180M) were detected in the three patients. These patients developed ADV resistance during 19-30 months of ADV sequential monotherapy, and then switched their antiviral regimen to ADV-ETV combination therapy. During ADV monotherapy and ADV-ETV combination therapy, the patients were monitored every 3 months for the first year of therapy, and then every 6 months thereafter. A total of 30 serum samples were collected from the patients throughout the monitoring period. In total, 10 mutants that were associated with commonly-used antiviral drugs were detected by pyrosequencing. During ADV sequential monotherapy, LAM-resistant variants were gradually decreased, whereas ADV-resistant rtA181V/T and rtN236T variants gradually increased in the viral population. During 30-41 months of ADV-ETV combination therapy, viral load reduction was 2.59-3.28 log10 copies/ml; ADV-resistant variants rtA181T/V and rtN236T were undetectable following 11-24 months of combination therapy; and rtL180M and rtM204I/V remained dominant in the viral population. In conclusion, the results of the present study suggested that, in patients with LAM and ADV-resistant variants that developed during LAM-ADV sequential monotherapy, ETV-ADV combination therapy may partially inhibit the replication of HBV DNA; however, LAM-resistant rtL180M and rtM204I/V variants remained predominant following 30-41 months combination therapy.

Development and validation of an oligonucleotide ligation assay to detect lamivudine resistance in hepatitis B virus.

Treatment of chronic hepatitis B virus (HBV) infection with lamivudine-monotherapy rapidly selects mutant variants in a high proportion of individuals. Monitoring lamivudine resistance by consensus sequencing is costly and insensitive for detection of minority variants. An oligonucleotide ligation assay (OLA) for HBV lamivudine-resistance was developed and compared to consensus sequencing. Both assays detected drug resistance mutations in 35/64 (54.7%) specimens evaluated, and OLA detected minority mutants in an additional six (9.4%). OLA may offer a sensitive and inexpensive alternative to consensus sequencing for detection of HBV drug resistance in resource-limited settings.

Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine: Insight from Multiple Molecular Dynamics Simulations.

Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3) variation in the overall enzyme motion as evident from the PCA for both systems, and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.

Tenofovir rescue therapy in chronic hepatitis B patients who failed previous nucleoside analogue treatment.

BACKGROUND: Tenofovir (TDF) is considered as the first line therapy for chronic hepatitis B. This study presents the results of TDF monotherapy in patients who failed previous nucleoside analogue treatment. METHODS: The study included 29 patients treated with TDF 245 mg once daily for 18 months after lamivudine monotherapy (LAM arm: n = 15) or sequential therapy with lamivudine and entecavir (LAM → ETV arm: n = 14). The previous antiviral therapy was discontinued due to lack of efficacy. All patients had HBV DNA between 2.1 and 8.23 log10 IU/ml and 15 were HBeAg-positive, while 45% of patients had increased ALT activity. Undetectable HBV DNA (<20 IU/ml) at months 3, 6, 12 and 18 was the primary endpoint in the study, while HBeAg/HBsAg loss/seroconversion and ALT normalisation were secondary endpoints. RESULTS: Primary nonresponse to TDF was not observed. HBV DNA was undetectable in 80, 80, 80 and 93% in LAM arm and 50, 71, 86 and 86% in LAM → ETV arm patients, at 3, 6, 12 and 18 months of TDF therapy, respectively. One patient achieved anti-HBeAg seroconversion. 86.5% of patients had normal ALT activity at the end of the study. The baseline HBV DNA load, HBeAg status and the length of the duration of TDF therapy appeared significantly associated with the response to the therapy. HBV DNA clearance occurred faster in HBeAg-negative patients than in those positive for HBeAg. CONCLUSIONS: TDF is an effective antiviral medication in patients with previous exposure to LAM or LAM and ETV. Final proportion of patients who achieved undetectable HBV DNA and had normal ALT activity in both arms, was similar.

Inferior graft survival of hepatitis B core positive grafts is not influenced by post-transplant hepatitis B infection in liver recipients--5-year single-center experience.

Nonoptimal liver grafts, and among them organs from anti-HBc+ donors, are increasingly used for liver transplantation. In this retrospective study including 1065 adult liver transplantations performed between 1977 and 2012, we analyzed long-term patient and graft survival and occurrence of HBV infection. A total of 52 (5.1%) patients received an anti-HBc+ graft. The 10-year graft and patient survival of these recipients were 50.9% and 59.0% compared to 72.0% and 76.5% (P = 0.001; P = 0.004) of patients receiving anti-HBc- grafts, respectively. Cox regression model showed that high urgency allocation (P = 0.003), recipient age (P = 0.027), anti-HCV+ recipients (P = 0.005), and anti-HBc+ organs (P = 0.048) are associated with decreased graft survival. Thirteen of 52 (25.0%) patients receiving anti-HBc+ grafts developed post-transplant HBV infection within a mean of 2.8 years. In this study, antiviral prophylaxis did not have significant impact on HBV infection, but long-term survival (P = 0.008). Development of post-transplant HBV infection did not affect adjusted 10-year graft survival (100% vs. 100%; P = 1). Anti-HBc+ liver grafts can be transplanted with reasonable but inferior long-term patient and graft survival. The inferior graft survival is not, however, related with post-transplant HBV infection as long as early diagnosis and treatment take place.

Outcome of adefovir add-on lamivudine rescue therapy of up to 5 years in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND AND AIM: We investigated the long-term efficacy of adefovir add-on lamivudine rescue therapy in lamivudine-resistant chronic hepatitis B and the optimal cutoff hepatitis B virus (HBV) DNA level that predicts complete virological response (CVR) among patients without CVR after 1 year of treatment. METHODS: We reviewed 167 lamivudine-resistant chronic hepatitis B patients who received adefovir add-on rescue therapy for up to 5 years. Multivariate analysis, area under the receiver operating characteristic curves, and Youden index were used. RESULTS: Median age was 47.0 years; 112 patients were male. Median baseline HBV DNA level was 6.6 log10 IU/mL; hepatitis B e antigen was positive in 130 (77.4%) patients. Five-year CVR, alanine aminotransferase normalization, hepatitis B e antigen seroconversion, and adefovir resistance rates were 86.9%, 92.5%, 16.7%, and 6.0%, respectively. One-year HBV DNA level independently associated with CVR. Optimal cutoff HBV DNA level to predict CVR among patients who failed to achieve CVR at 1 year was 800 IU/mL (area under receiver operating characteristic curve 0.752; sensitivity 49.3%, specificity 93.5%). During the 5-year treatment, 92.1% of patients with favorable response (HBV DNA < 800 IU/mL at 1 year) achieved CVR; 45.6% achieved CVR among suboptimal responders (HBV DNA ≥ 800 IU/mL at 1 year) (P < 0.001). CONCLUSION: Complete virological response or HBV DNA level < 800 IU/mL after 1 year adefovir add-on lamivudine rescue therapy can favorably predict CVR.

Switch to tenofovir-based therapy or to continue adefovir-based therapy in CHB patients with suboptimal response to adefovir-based combination?

No abstract available.

Entecavir plus tenofovir versus entecavir plus adefovir in chronic hepatitis B patients with a suboptimal response to lamivudine and adefovir combination therapy.

BACKGROUND/AIMS: We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy. METHODS: We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months. RESULTS: The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period. CONCLUSIONS: In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results.

Efficacy of Tenofovir-based Rescue Therapy in Lamivudine-resistant Chronic Hepatitis B Patients With Failure of Lamivudine and Adefovir Combination.

PURPOSE: In chronic hepatitis B patients, lamivudine (LAM) and adefovir (ADV) combination therapy is commonly used as a rescue therapy for LAM resistance, but it often results in incomplete viral suppression. We investigated the antiviral efficacy of tenofovir (TDF)/LAM combination therapy versus TDF monotherapy in LAM-resistant chronic hepatitis B (CHB) patients who failed to respond to LAM plus ADV rescue therapy. METHODS: Among 108 patients with LAM-resistant CHB who had a partial virologic response (VR) to LAM and ADV combination therapy, Eighty one patients were finally included in this study. FINDINGS: Resistance to ADV (ADV-R) was present in 32 patients (39.5%), and the remaining 49 patients (60.5%) had a partial virologic response to LAM/ADV combination (ADV-P). The study subjects were treated with TDF alone (n=15) or TDF/LAM combination (n=66). VR was achieved in 61 patients (75.3%). The rates of VR at 6 and 12 months were not significantly different between TDF monotherapy and TDF/LAM combination therapy groups (46.7 vs. 68.2% at 6 months, and 66.7 vs. 75.9% at 12 months, log-rank P=0.357). Treatment efficacy of TDF alone or TDF/LAM combination was not statistically different according to pre-existing ADV or LAM resistant strains. In multivariate analysis, absolute HBV DNA levels at the start of TDF rescue treatment (P<0.001; OR, 0.556; 95% CI, 0.422-0.731) were the only significantly associated with VR. IMPLICATIONS: TDF monotherapy was as effective as TDF/LAM combination therapy in maintaining viral suppression in patients with LAM-resistant patients who failed to respond to LAM/ADV combination therapy.

Long-term outcomes and dynamics of mutants associated with lamivudine-adefovir rescue therapy in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND/AIMS: To investigate the association between the baseline profiles and dynamics of hepatitis B virus (HBV) DNA polymerase gene mutations and the long-term virological response of lamivudine (LAM)-adefovir (ADV) combination therapy in patients with LAM-resistant chronic hepatitis B. METHODS: Seventy-five patients who received LAM-ADV combination therapy for more than 12 months were analyzed. Restriction fragment mass polymorphism assays were used to detect and monitor the dynamics of LAM- and ADV-resistant mutations. RESULTS: The median duration of LAMADV combination therapy was 26 months (range, 12 to 58 months). The baseline mutation profiles, rtM204I (p=0.992), rtM204I/V (p=0.177), and rtL180M (p=0.051), were not correlated with the cumulative virological response, and the baseline HBV DNA level (p=0.032) was the only independent predictive factor for cumulative virological response. Tests for LAM- and ADV-resistant mutations were performed in 12 suboptimal responders in weeks 48 and 96. The population of rtM204 mutants persisted or increased in 8 of 12 patients, and rtA181T mutants newly emerged as a minor population in four patients until 96 weeks. Nevertheless, the viral loads progressively decreased during rescue therapy, and these dynamics did not correlate with virological response. CONCLUSIONS: The baseline profile and dynamics of LAM-resistant mutations during LAM-ADV combination therapy are not associated with a virological response.

Entecavir plus tenofovir versus entecavir plus adefovir in chronic hepatitis B patients with a suboptimal response to lamivudine and adefovir combination therapy

BACKGROUND/AIMS: We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy. METHODS: We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months. RESULTS: The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period. CONCLUSIONS: In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results.

Long-Term Outcomes and Dynamics of Mutants Associated with Lamivudine-Adefovir Rescue Therapy in Patients with Lamivudine-Resistant Chronic Hepatitis B

BACKGROUND/AIMS: To investigate the association between the baseline profiles and dynamics of hepatitis B virus (HBV) DNA polymerase gene mutations and the long-term virological response of lamivudine (LAM)-adefovir (ADV) combination therapy in patients with LAM-resistant chronic hepatitis B. METHODS: Seventy-five patients who received LAM-ADV combination therapy for more than 12 months were analyzed. Restriction fragment mass polymorphism assays were used to detect and monitor the dynamics of LAM- and ADV-resistant mutations. RESULTS: The median duration of LAM-ADV combination therapy was 26 months (range, 12 to 58 months). The baseline mutation profiles, rtM204I (p=0.992), rtM204I/V (p=0.177), and rtL180M (p=0.051), were not correlated with the cumulative virological response, and the baseline HBV DNA level (p=0.032) was the only independent predictive factor for cumulative virological response. Tests for LAM- and ADV-resistant mutations were performed in 12 suboptimal responders in weeks 48 and 96. The population of rtM204 mutants persisted or increased in 8 of 12 patients, and rtA181T mutants newly emerged as a minor population in four patients until 96 weeks. Nevertheless, the viral loads progressively decreased during rescue therapy, and these dynamics did not correlate with virological response. CONCLUSIONS: The baseline profile and dynamics of LAM-resistant mutations during LAM-ADV combination therapy are not associated with a virological response.

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.

Generation of a human hepatoma cell line supporting efficient replication of a lamivudine resistant hepatitis B virus.

Emergence of lamivudine (LAM) resistance causes treatment failure in patients with chronic hepatitis B and compromise the efficacy of subsequent salvage therapies with other nucleot(s)ide analogs (NAs). Establishment of cell-based assays supporting LAM-resistant hepatitis B virus (HBV) replication will not only provide tools for investigating the replication property, but also screening for antiviral agents efficiently inhibiting the replication of LAM-resistant HBV variants. Accordingly, a human hepatoma (HepG2)-derived cell line was established by stable transfection of a plasmid containing a 1.2 unit length of HBV genome harboring rtL180M and rtM204V mutations that confer LAM resistance. In addition to support efficient viral genome replication, the cell line also produces high levels of HBV virions and subviral particles. As expected, HBV DNA replication in this cell line is completely resistant to lamivudine, but sensitive to adefovir (ADV), entecavir (ETV) and tenofovir (TDF). The cell line is suitable for screening for antiviral agents that inhibit LAM-resistant HBV replication and inhibitors of HBsAg biosynthesis and secretion, which may reduce HBsAg antigenemia and ultimately help to restore host antiviral immune response against HBV and cure chronic HBV infection.

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

BACKGROUND AND STUDY AIMS: The 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 METHODS: This study included two groups of lamivudine-resistant patients who received lamivudine 100mg for 1-3 years. 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 36 months of treatment by the same parameters. Hepatitis B surface antigen and antibody (HbsAg and HBsAb) were assessed after each year of treatment. RESULTS: At the end of 36 months 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. CONCLUSION: The entecavir 1-mg monotherapy group achieved better HBV-DNA undetectability starting at 3 months 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.