Lamivudine Resistance Research Articles

Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial

Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks. One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks. At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 ml/min/1.73 m2 by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm2) at the femur (-2.48%, p <0.001). Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. (ClinicalTrials.gov No, NCT01639066 and NCT01639092). In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.

Viral quasispecies of hepatitis B virus in patients with YMDD mutation and lamivudine resistance may not predict the efficacy of lamivudine/adefovir rescue therapy.

The association between hepatitis B virus (HBV) quasispecies (QS) and the efficacy of nucleos(t)ide analog therapy is currently not well defined, particularly in the case of lamivudine (LAM)/adefovir (ADV) combination rescue therapy for patients with chronic HBV infection (CHB) presenting with LAM resistance. In the present study, 16 CHB patients with the rtM204I/V mutation in the tyrosine-methionine-aspartate-aspartate motif of the C domain of the polymerase gene who switched to LAM/ADV treatment due to LAM resistance were assessed. HBV DNA was isolated from these patients and the reverse transcriptase (RT) region was sequenced. The QS heterogeneity and distribution was analyzed, the mutation sites were recorded and the phylogenetic trees were constructed. The results indicated that QS heterogeneity and distribution in the RT and S regions were not significantly different between responders (RS) and non-RS (NRS) at baseline (P>0.05), except for the higher frequency of a dominant strain in the RT region at the nucleotide level in the RS group (P=0.039). In addition, in NRS, no significant difference in QS heterogeneity or distribution in these regions was identified at six months vs. the baseline. Furthermore, although in the non-responder group the frequency of the LAM resistance-associated mutations (rtM204V/I) decreased at 6 months compared with the baseline, it did not disappear in any of the patients after six months of treatment. Analysis of individual patients did not indicate any consistent selection of specific HBV mutants during LAM/ADV rescue therapy. In conclusion, the baseline HBV QS within the RT and S regions may not be a valid predictor of the response to LAM/ADV rescue treatment in CHB patients with LAM resistance.

Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir.

Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. A total of 103 TDF-treated patients were included as follows: age 64years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD ) was <60mL/min, 37 (36%) because blood phosphate (P) levels were <2.5mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4months thereafter. During 46 (4-115)months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10mg/dL (P<0.0001), eGFRMDRD from 54 to 65mL/min (P=0.002), P from 2.2 to 2.6mg/dL (P<0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62mmol/L (P<0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P=0.018). Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment.

Primary resistance of hepatitis B virus to nucleoside and nucleotide analogues.

Nucleoside and nucleotide analogues (NUCs) targeting hepatitis B virus are capable of selecting resistant viruses upon long-term administration as monotherapies. The prevalence of resistance-associated substitutions (RASs) and fitness-associated substitutions at baseline of NUC therapy and their impact on treatment responses remain unknown. A total of 232 treatment-naïve patients chronically infected with hepatitis B virus (HBV) consecutively referred for the first time to one of French reference centres were included. The nearly full-length HBV reverse transcriptase was sequenced by means of deep sequencing, and the sequences were analysed. RASs were detected in 25% of treatment-naïve patients, generally representing low proportions of the viral quasispecies. All amino acid positions known to be associated with HBV resistance to currently approved NUCs or with increased fitness of resistant variants were affected, except position 80. RASs at positions involved in lamivudine, telbivudine and adefovir resistance were the most frequently detected. All patients with RASs detectable by next-generation sequencing at baseline who were treatment-eligible and treated with currently recommended drugs achieved a virological response. The presence of pre-existing HBV RASs has no impact on the outcome of therapy if potent drugs with a high barrier to resistance are used.

Evaluation of drug resistance mutations in patients with chronic hepatitis B.

Mutations occurring in viral polymerase gene of hepatitis B virus (HBV) due to the use of nucleos(t)id analogs reduce the activity of the drugs by causing antiviral resistance. In this study, it was aimed to evaluate mutations responsible for drug resistance and drug resistance mutation rates in patients followed up by the diagnosis of chronic hepatitis B (CHB). A total of 318 CHB patients were included in the study. HBV mutations were detected using the INNO-LiPA commercial kit based on the reverse hybridization principle. Drug resistance mutation was detected in 46.86% (149/318) of the patients. The rates of drug resistance were found 36.79% (117/318) for lamivudine resistance, 12.58% (40/318) for entecavir (ETV), and 7.86% (25/318) for adefovir. In 10 patients, the possible tenofovir (TDF) resistance (3.14%) was found. Single-drug and double-drug resistances were detected in 34.59% and in 11.01% of the patients, respectively. Triple drug resistance was detected in only 1.26% of the patients. Unlike various studies in Turkey and in other countries, remarkable resistance to ETV and TDF were found in this study. The high rate of the probable TDF resistance was striking, with 3.14%.

Clinical observation of continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B

Objective: To observe continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B. Methods: Data of patients with active stage of chronic hepatitis B over the past 6 years were collected and analyzed retrospectively. The incidence of drug resistance mutation and related factors between patients taking LAM or ETV continuously and intermittently were compared with those taking LAM or ETV. Data comparison was performed using χ(2) test. Results: Patients with HBV DNA≥10(5) copies / ml at the time of initial treatment had higher resistance mutation rates than those with HBV DNA < 10(5) copies / ml at either continuous or intermittent treatment, and patients with intermittent treatment had higher resistance mutation rates than those with continuous treatment. Simultaneously, the incidence of drug resistance mutation in LAM and ETV in the first, second and third years were significantly higher in intermittent treatment than that of continuous treatment (P < 0.05). There was a positive correlation between the frequency of drug withdrawal and the rate of drug resistance mutation. There were no individual difference and drug difference between LAM and ETV. Conclusion: In the treatment of chronic hepatitis B with oral nucleoside analogues, drug resistance may occur in either continuous or intermittent treatment. When comparing continuous with intermittent treatment, it suggests that intermittent is more likely to cause viral resistance mutation.

Discovery of the Novel Entecavir-Resistant Hepatitis B Virus Reverse Transcriptase A181C Substitution From an Integrated Genotypic Analysis.

Entecavir (ETV) is a first‐line therapy for chronic hepatitis B virus (HBV), demonstrating potent suppression of HBV DNA and a high barrier to viral resistance. Previous studies revealed that ETV‐resistant (ETVr) HBV DNA resulted from substitutions in the HBV reverse transcriptase (RT) at positions rtT184, rtS202, or rtM250 in combination with lamivudine resistance (LVDr) substitutions rtM204I/V±rtL180M. In vitro, viral variants exhibit varying degrees of ETV susceptibility and replication capacity depending on specific resistance substitutions. To explore the potential for additional pathways to ETVr, HBV RT sequences from 982 evaluable patients enrolled in 17 ETV clinical studies were analyzed. Thirty novel emergent substitutions at amino acid positions not previously associated with HBV nucleos(t)ide drug resistance were observed in at least 2 patients and were identified in patient‐derived HBV with a wild‐type, LVDr, or ETVr RT sequence. Phenotypic analysis of these substitutions indicated that they had no effect on ETV susceptibility. Phenotypic analysis was also performed on patient‐derived HBV RT sequences from 10 LVD‐naive and 13 LVD‐experienced patients with virologic breakthrough and emergent novel substitutions while on ETV treatment. One LVD‐experienced patient‐derived HBV RT harboring LVDr substitutions rtL180M+rtM204V with rtA181C displayed reduced ETV susceptibility (122‐fold greater than wild‐type HBV) and remained susceptible to adefovir and tenofovir. HBV harboring the rtA181C substitution without LVDr substitutions rtL180M+rtM204V remained susceptible to inhibition by ETV, adefovir, and tenofovir, although cross‐resistance to LVD and telbivudine was observed. Conclusion: An integrated genotypic analysis of HBV RT sequences from patients with chronic HBV treated with ETV led to the discovery of the novel ETVr substitution rtA181C. This substitution was always detected in combination with LVDr substitutions rtL180M+rtM204V in ETV‐treated patients.

Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study.

BackgroundDual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection.MethodsWe retrospectively analyzed patients with HIV-RNA ≤50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA ≥200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis.ResultsFour hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval [CI], 86.6–97.2) without M184V and 87.8% (95% CI, 78.4–97.2) with M184V (P = .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51–199 copies/mL) was 79.8% (95% CI, 67.8%–91.8%) with M184V vs 90.1% (95% CI, 84.0%–96.2%) without M184V (P = .016).ConclusionsPrevious selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips.

Shorter hepatitis B immunoglobulin administration is not associated to hepatitis B virus recurrence when receiving combined prophylaxis after liver transplantation.

The combination of hepatitis B immunoglobulin and a nucleos(t)ide analogues has markedly reduced the rate of hepatitis B virus recurrence after liver transplantation; however, the optimal duration of hepatitis B immunoglobulin has not been clarified. This lack of consensus perpetuates the use of different strategies. The aim of this study was to evaluate the risk factors associated to hepatitis B virus recurrence after liver transplantation in a large cohort of patients under different hepatitis B immunoglobulin regimens. Retrospective multicentre analysis of hepatitis B virus-related liver transplantation recipients receiving combined prophylaxis (hepatitis B immunoglobulin + nucleos(t)ide analogues). The strategy of short-term hepatitis B immunoglobulin was compared to lifelong administration. Hepatitis B virus recurrence was defined as positive HBsAg after liver transplantation. Three hundred and thirty-eight patients were analysed. After a median follow-up period of 72months, 37 patients (11%) developed hepatitis B virus recurrence. Hepatocellular carcinoma recurrence and lamivudine resistance after liver transplantation were the only factors independently associated to hepatitis B virus recurrence (HR 5.4 [2.3-12] and 9.3 [4.2-20] respectively P<.001). HBsAg reappearance after hepatitis B virus recurrence was transient (16 patients), persistent (15) or alternant (6). The hepatitis B immunoglobulin regimen did not have an impact on the rate or evolution of hepatitis B virus recurrence. Overall, patient survival was good and not influenced by hepatitis B virus recurrence (82% at 5years). Fulminant liver failure, hepatitis C coinfection or hepatocellular carcinoma at liver transplantation were independent risk factors for lower survival. Liver transplantation is an effective treatment for hepatitis B virus-related liver disease. Since the introduction of combined prophylaxis the rate of hepatitis B virus recurrence is very low. However, lifelong hepatitis B immunoglobulin administration does not seem necessary to reduce hepatitis B virus recurrence.

Antiviral therapy in hepatitis B virus-infected children with immune-tolerant characteristics: A pilot open-label randomized study

Chronic infection with hepatitis B virus (HBV) in children is a serious health problem worldwide. How to treat children with immune-tolerant chronic hepatitis B infection, commonly characterized by hepatitis B e antigen (HBeAg) positivity, high viral load, normal or mildly elevated alanine aminotransferase and no or minimal inflammation in liver histology, remains unresolved. This trial aims to study the benefits of antiviral therapy in children with these characteristics. This is a pilot open-label randomized controlled study. From May 2014 to April 2015, 69 treatment-naive chronically HBV-infected children, aged 1 to 16 years, who had immune-tolerant characteristics were recruited to this trial and randomly assigned, in a 2:1 ratio, to treatment group and control group. Patients in the treatment group received either interferon-α (IFN) monotherapy or consecutively received IFN monotherapy, combination therapy of IFN and lamivudine (LAM), and LAM therapy alone. All patients were observed until week 96. At baseline, epidemiological, biochemical, serological, virological and histological indices were consistent across the treatment and control groups. Of the 46 patients in the treatment group, 73.91% had undetectable serum HBV DNA, 32.61% achieved HBeAg seroconversion and 21.74% lost hepatitis B surface antigen (HBsAg) at the endpoint. No LAM resistance emerged at week 96. In the control group, only one (4.35%) patient underwent spontaneous HBeAg seroconversion and had undetectable serum HBV DNA during observation, and moreover, none developed HBsAg clearance. For all patients, no serious adverse events were observed. Antiviral treatment with a sequential combination of IFN and LAM resulted in a significant improvement in the rates of undetectable serum HBV DNA, HBeAg seroconversion and HBsAg loss in children with chronic HBV infection and immune-tolerant characteristics. There is a lack of data regarding treatment of immune-tolerant chronic hepatitis B (CHB). It remains unresolved how children with immune-tolerant CHB should be treated. This paper reports the outcomes from a pilot open-label randomized controlled trial on antiviral therapy in children with immune-tolerant characteristics. It shows that a sequential combination of interferon-α and lamivudine was beneficial.

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

Oral Nucleos(t)ide Analogs Alone After Liver Transplantation in Chronic Hepatitis B With Preexisting rt204 Mutation.

There is currently limited data regarding the use of oral antiviral therapy alone without hepatitis B immune globulin for chronic hepatitis B patients with preexisting lamivudine (LAM) resistance (LAM-R) undergoing liver transplantation. This is a cohort study determining the effectiveness and long-term outcome in this group of patients. Fifty-seven consecutive chronic hepatitis B patients with preexisting rt204 LAM-R mutations or virological load refractory to LAM undergoing liver transplantation were included, with a median follow-up of 73 months. Fifty-five (96.5%) patients received a regimen that included the use of nucleotide analogs. The cumulative rate of hepatitis B surface antigen seroclearance at 1, 5, and 10 years was 82%, 88%, and 91%, respectively. At the time of transplantation, 39 (72%) patients had detectable hepatitis B virus (HBV) DNA, with a median of 4.5 log copies/mL. The cumulative rate of HBV undetectability was 91% at 1 year, increasing to 100% by 5 years. After 1 year of liver transplantation, over 90% of the patients had undetectable HBV DNA, and from 8 years onward, 100% had undetectable HBV DNA. The overall long-term survival was excellent, with a 12-year survival of 87%. There was no HBV-related graft loss, and no retransplantation or deaths due to HBV reactivation. Oral antiviral therapy alone without hepatitis B immune globulin is highly effective in preventing HBV reactivation and graft loss from recurrent hepatitis B after liver transplantation in patients with preexisting LAM resistance HBV. The long-term outcome was excellent, with survival of 87% at 12 years after transplantation, without any mortality related to HBV reactivation.

Treatment Efficacy and Safety of Tenofovir Disoproxil Fumarate-Based Therapy in Chronic Hepatitis B Patients for 3 Years: A Single Center Prospective Cohort Study

Introduction: To evaluate the efficacy and safety of Tenofovir (TDF)-based therapy in naïve and treatment-experienced chronic hepatitis B (CHB) patients for 3 years in a single-center. Methods: A total of 148 CHB patients treated with TDF-based therapy at Daejeon St. Mary's hospital were prospectively enrolled from Jan, 2013 to Jan, 2014. We compared the virological response and evaluated the safety of treatment-naïve and experienced CHB patients. Results: An overall complete virologic response (CVR) was achieved in 79.2 %, 84.0 %, and 90.8% of patients at week 48, 96 and 144, respectively. In the HBeAg (+) population (n=87), 88.5 % of patients achieved CVR, while in the HBeAg (-) patients (n=61), 94.2 % achieved CVR at week 144. In treatment-naïve populations (n=63), CVR of HBeAg positive patients (n=28) at week144 showed 96.2%. HBeAg loss or seroconversion rate at week 144 showed 25.0%, respectively. In treatmentnaïve HBeAg negative CHB (n=35), CVR at week 144 showed 93.3%. In treatment-experienced populations (n=85), overall CVR showed in 74.4 %, 82.2 %, and 87.8% of patients at week 48, 96 and 144, respectively. In a subgroup analysis, CVR at week 144 was present in 100 %, 71.4%, 84.6%, and 94.4% of participants in the lamivudine-resistant (LAM-R) group, adefovir-resistant (ADV-R) group, multidrug-resistant (MDR) group, and suboptimal response group, respectively. Of note, 3-year CVR in MDR patients were improved compared to 2-year CVR (84.6% vs. 69.2%). In safety, there were no significant decrement of serum estimated glomerular filtration rate (eGFR), calcium, and phosphorus level. Aspartate aminotransferase to platelet ratio index (APRI) score were significantly improved during treatment. Conclusion: TDF demonstrated sustained viral suppression, a favorable safety, and no evidence of resistance development through 3 years of treatment. Significant improvement in underlying hepatic function including serologic markers of fibrosis was observed following 3 years of treatment.

Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression.

Previous studies have indicated that the drug-resistant mutations of hepatitis B virus (HBV) are a major obstacle to antiviral therapy. However, it is still unclear whether there are pre-existent resistance mutations in patients with HBV infection and the relationship between drug-resistant mutation, genotypes, and progression of hepatitis B disease. A total of 357 treatment-naïve patients with HBV infection were involved in this retrospective study. The drug-resistant mutations of HBV reverse transcriptase domain were screened by direct gene sequencing. Lamivudine (LAM) resistance was detected in 8 patients (3.7%) with chronic hepatitis B (CHB), 13 (11.7%) patients with liver cirrhosis (LC), and 6 (21.4%) patients with hepatocellular carcinoma (HCC). Adefovir(ADV)-resistant mutations were detected in 10 (4.6%) patients with CHB, 15 (13.5%) patients with LC and 4 (14.5%) patients with HCC. Both LAM and ADV resistant mutations were detected in 2 patients (0.9%) with CHB, 1 patient (0.9%) with LC and 1 patient (3.6%) with HCC. Significant differences (p <0.01) were observed in the drug-resistance rates among patients with CHB, LC and HCC. Meanwhile, all the drug-resistant mutations were found in patients with HBV genotype C. This study demonstrated higher risk of pre-existing drug-resistant mutations in patients with HBV genotype C comparing to patients with HBV genotype B. Likewise, increasing prevalence of pre-existing drug-resistant mutations was shown, alongside with the progression of the disease.

Role of Cell-Penetrating Peptides in Intracellular Delivery of Peptide Nucleic Acids Targeting Hepadnaviral Replication.

Peptide nucleic acids (PNAs) are potentially attractive antisense agents against hepatitis B virus (HBV), although poor cellular uptake limits their therapeutic application. In the duck HBV (DHBV) model, we evaluated different cell-penetrating peptides (CPPs) for delivery to hepatocytes of a PNA-targeting hepadnaviral encapsidation signal (ε). This anti-ε PNA exhibited sequence-specific inhibition of DHBV RT in a cell-free system. Investigation of the best in vivo route of delivery of PNA conjugated to (D-Arg)8 (P1) showed that intraperitoneal injection to ducklings was ineffective, whereas intravenously (i.v.) injected fluorescein-P1-PNA reached the hepatocytes. Treatment of virus carriers with i.v.-administered P1-PNA resulted in a decrease in viral DNA compared to untreated controls. Surprisingly, a similar inhibition of viral replication was observed in vivo as well as in vitro in primary hepatocyte cultures for a control 2 nt mismatched PNA conjugated to P1. By contrast, the same PNA coupled to (D-Lys)4 (P2) inhibited DHBV replication in a sequence-specific manner. Interestingly, only P1, but not P2, displayed anti-DHBV activity in the absence of PNA cargo. Hence, we provide new evidence that CPP-PNA conjugates inhibit DHBV replication following low-dose administration. Importantly, our results demonstrate the key role of CPPs used as vehicles in antiviral specificity of CPP-PNA conjugates.

Clade homogeneity and low rate of delta virus despite hyperendemicity of hepatitis B virus in Ethiopia

BackgroundAlthough hepatitis B virus (HBV) is hyperendemic and heterogeneous in its genetic diversity in Ethiopia, little is known about hepatitis D virus (HDV) circulating genotypes and molecular diversity.MethodsA total of 321 hepatitis B surface antigen (HBsAg) positives (125 HIV co-infected, 102 liver disease patients and 94 blood donors) were screened for anti-HDV antibody. The anti-HDV positive sera were subjected to Real time PCR for HDV-RNA confirmation. The non coding genome region (spanning from 467 to 834 nucleotides) commonly used for HDV genotyping as well as complete HDV genome were sequenced for genotyping and molecular analysis.ResultsThe anti-HDV antibody was found to be 3.2% (3) in blood donors, 8.0% (10) in HIV co-infected individuals and 12.7% (13) in liver disease patients. None of the HIV co-infected patients who revealed HBV lamivudine (3TC) resistance at tyrosine-methionine/isoleucine-aspartate-aspartate (YM(I)DD) reverse transcriptase (RT) motif with concomitant vaccine escape gene mutants was positive for anti-HDV antibody. The HDV viremia rate was 33.3%, 30.0% and 23.1% in respect to the above study groups. All the six isolates sequenced were phylogenetically classified as HDV genotype 1 (HDV-1) and grouped into two monophyletic clusters. Amino acid (aa) residues analysis of clathrin heavy chain (CHC) domain and the isoprenylation signal site (Py) at 19 carboxyl (C)-terminal amino acids (aa 196–214) and the HDV RNA binding domain (aa 79–107) were highly conserved and showed a very little nucleotide variations. All the sequenced isolates showed serine at amino acid position 202. The RNA editing targets of the anti-genomic HDV RNA (nt1012) and its corresponding genomic RNA (nt 580) showed nucleotides A and C, respectively.ConclusionsThe low seroprevalence and viraemic rates of HDV in particular during HIV-confection might be highly affected by HBV drug resistance selected HBsAg mutant variants in this setting, although HDV-1 sequences analysis revealed clade homogeneity and highly conserved structural and functional domains. Thus, the potential role of HBV drug resistance associated polymerase mutations and concomitant HBsAg protein variability on HDV viral assembly, secretion and infectivity needs further investigation.

Infectious Diseases Risk While on Chronic, High-Dose Corticosteroids

Infectious Diseases Risk While on Chronic, High-Dose Corticosteroids

Characterization of occult hepatitis B virus infection among HIV positive patients in Cameroon

PurposeOccult hepatitis B infection (OBI) among HIV positive patients varies widely in different geographic regions. We undertook a study to determine the prevalence of occult hepatitis B infection among HIV infected individuals visiting a health facility in South West Cameroon and characterized occult HBV strains based on sequence analyses.MethodsPlasma samples (n = 337), which previously tested negative for hepatitis B surface antigen (HBsAg), were screened for antibodies against hepatitis B core (anti-HBc) and surface (anti-HBs) antigens followed by DNA extraction. A 366 bp region covering the overlapping surface/polymerase gene of HBV was then amplified in a nested PCR and the amplicons sequenced using Sanger sequencing. The resulting sequences were then analyzed for genotypes and for escape and drug resistance mutations.ResultsTwenty samples were HBV DNA positive and were classified as OBI giving a prevalence of 5.9%. Out of these, 9 (45%) were anti-HBs positive, while 10 (52.6%) were anti-HBc positive. Additionally, 2 had dual anti-HBs and anti-HBc reactivity, while 6 had no detectable HBV antibodies. Out of the ten samples that were successfully sequenced, nine were classified as genotype E and one as genotype A. Three sequences possessed mutations associated with lamivudine resistance. We detected a number of mutations within the major hydrophilic region of the surface gene where most immune escape mutations occur.ConclusionsFindings from this study show the presence of hepatitis B in patients without any of the HBV serological markers. Further prospective studies are required to determine the risk factors and markers of OBI.

A CROSS-SECTIONAL STUDY OF HEPATITIS B VIRUS INFECTION IN HIV-INFECTED CHILDREN IN WINDHOEK, NAMIBIA

BackgroundHepatitis B virus (HBV) remains endemic in Africa and an important co-morbidity in the HIV epidemic. The HIV treatment guidelines of the World Health Organisation (WHO) recommend tenofovir−lamivudine (or emtricitabine)...

Treatment Efficacy and Safety of Tenofovir-Based Therapy in Chronic Hepatitis B: A Real Life Cohort Study in Korea.

Background & AimsWe evaluated the efficacy and safety of Tenofovir disoproxil fumarate (TDF)-based therapy in naïve and treatment-experienced chronic hepatitis B (CHB) patients for 96 weeks in Korean real life practice.MethodsA total of 209 CHB patients with a prescription for TDF at the Seoul and Daejeon St. Mary’s hospitals were enrolled from December 2012 to October 2014. We compared the virological responses and evaluated the renal safety of treatment-naive and treatment-experienced patients.ResultsAn overall complete virological response (CVR) was achieved in 80.4% and 84.6% of patients at weeks 48 and 96, respectively. In a subgroup analysis, CVR at week 96 was present in 88.4%, 75.0%, 75.5%, and 83.3% of participants in the lamivudine-resistant (LAM-R) group, adefovir-resistant (ADV-R) group, multidrug-resistant (MDR) group, and suboptimal response group, respectively. In a multivariate analysis, ADV-R, MDR, hepatitis B virus DNA, and hepatitis B e antigen were independent predictors for CVR. With regard to renal safety, diabetes mellitus, cirrhosis, and an initial low estimated glomerular filtration rate were independent factors affecting creatinine elevation (≥0.5 mg/dL). Moreover, two patients with DM and cirrhosis experienced TDF-related Fanconi syndrome.ConclusionsTDF-based therapy demonstrated sustained viral suppression and favorable safety during a 2-year treatment period. The LAM-R and suboptimal response groups showed comparable efficacy to the naïve group, while the ADV-R and MDR groups were significantly associated with a low CVR. Close monitoring of renal safety should be mandatory when treating CHB patients receiving TDF, particularly those with DM and cirrhosis.