Clinical characteristics and chronicity of acute hepatitis B induced by lamivudine-resistant strains

Whether resistant hepatitis B virus (HBV) strains are transmissible and can lead to chronic infection remains to be studied. The aim of this study was to investigate the clinical characteristics of patients with acute hepatitis B caused by lamivudine (LAM)‐resistant strains. Sera were collected from 234 Chinese patients with acute hepatitis B. LAM‐resistance mutations were identified by direct polymerase chain reaction (PCR) sequencing. LAM‐resistant HBV variants were detected in 11 of the 234 (4.7%) patients. Among these patients, six harbored the rtM204I mutation, two harbored the rtL180M + rtM204I mutations, one harbored the rtM204I + rtM204V mutations, one harbored the rtL80I + rtM204I mutations, and one harbored the rtV173L + rtL180M + rtM204V mutations. Three patients were infected with genotype B HBV and eight patients were infected with genotype C HBV. Two patients infected with viruses with LAM‐resistance mutations developed severe acute hepatitis. One patient developed chronic hepatitis B. This patient was infected with genotype C HBV that had LAM‐resistance mutations (rtL180M + rtM204I). The patient was diagnosed with an occult hepatitis B virus infection based on the presence of HBV DNA in the liver and the absence of detectable hepatitis B surface antigen (HBsAg) in the serum. LAM‐resistant HBV strains in China are transmissible, can cause acute hepatitis B, and can even progress to chronic infection in China. J. Med. Virol. 84:1558–1561, 2012. © 2012 Wiley Periodicals, Inc.     

Case report: management and HBV sequencing in a patient co-infected with HBV and HIV failing tenofovir

Nucleos(t)ide analogs such as tenofovir, lamivudine, or emtricitabine are active against both HBV and HIV. Tenofovir confers potent and durable HBV‐DNA suppression but the best strategy in case of resistance of HBV to tenofovir remains unknown. A case of a 22‐year‐old patient with co‐infection with HBV and HIV transmitted perinatally is reported. After prolonged and intermittent treatment of HIV with lamivudine and tenofovir, HBV became resistant to lamivudine. Subsequently, clinical resistance to tenofovir occurred, manifesting as HBV‐DNA breakthrough. The non‐compliance was reasonable excluded and HIV‐RNA remained constantly suppressed. Entecavir (1 mg daily) was added and the combination therapy resulted in a rapid and continuous suppression of HBV‐DNA for over 12 months. The treatment was well‐tolerated and safe. No known mutations, such as rtA181T/V associated with rtN236T or A194T that are associated with reduced susceptibility or resistance to tenofovir were detected. However, a unique and complex HBV substitution pattern was found: with a development of rtR192PR mutation at the time of virological failure. Adding entecavir to failing therapy with tenofovir and emtricitabine was feasible, well‐tolerated and resulted in virological success. The rtR192PR, which is located in the B domain near the rtA194T, occurring in a context of a very complex substitutions patterns, might be associated with resistance to tenofovir. J. Med. Virol. 84:1340–1343, 2012. © 2012 Wiley Periodicals, Inc.     

Reactivation of occult hepatitis B virus infection following cytotoxic lymphoma therapy in an anti‐HBc negative patient

Screening hepatitis B virus (HBV) surface antigen (HBsAg) and HBV core antibody (anti‐HBc) is recommended prior to cytotoxic or immunosuppressive therapy. This case describes an anti‐HBc negative, DNA positive occult HBV infection in a 71‐year‐old Caucasian male following rituximab‐based treatment for follicular lymphoma. Pre‐screening serology indicated negative HBsAg and anti‐HBc. However, following sequential treatment cycles the patient developed weak HBsAg with a low HBV DNA load (<1,000 IU/ml), but remained anti‐HBc negative. The DNA load peaked 5 months later (>1 × 10⁶ IU/ml) and he was subsequently treated with Tenofovir. Currently the patient remains anti‐HBc negative, and is anti‐HBe negative, anti‐HBs negative, HBeAg positive. No clinical or biochemical evidence of hepatitis has occurred. Sequencing and phylogenetic analysis identified the HBV genosubtype as D4, most probably acquired some years ago during a stay in Papua New Guinea, in spite of prior hepatitis B vaccination. Four amino acid substitutions were detected within the HBsAg loop yet none in the core protein. This case questions the dependability of anti‐HBc testing and highlights the role of HBV DNA testing prior to and throughout cytotoxic or immunosuppressive regimes. As this case exemplifies, vaccination protects against clinical infection but may not exclude seronegative occult infection with the possibility of reactivation. J. Med. Virol. 85:597–601, 2013. © 2013 Wiley Periodicals, Inc.     

HIV–HBV vaccine escape mutant infection with loss of HBV surface antibody and persistent HBV viremia on tenofovir/emtricitabine without antiviral resistance

We report a case of acute hepatitis B virus genotype A vaccine escape mutant infection with loss of HBV vaccine-induced seropositivity in a HIV-1 infected patient. His HBV is unresponsive to tenofovir/emtricitabine treatment demonstrated by persistent viremia despite lacking known resistance mutations and while having an undetectable HIV-1 viral load.     

Prophylaxis for Hepatitis B Virus Reactivation after Allogeneic Stem Cell Transplantation in the Era of Drug Resistance and Newer Antivirals: A Systematic Review and Meta-Analysis

Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are at a very high risk of hepatitis B virus reactivation (HBVr). Lamivudine is commonly used as prophylaxis against HBVr in high-risk patients undergoing allo-HSCT. Unfortunately, its efficacy is diminishing due to the development of HBV mutant drug-resistant strains. With the availability of newer antiviral agents such as entecavir, telbivudine, adefovir, and tenofovir, it is important to assess their role in HBVr prophylaxis. A comprehensive search of 7 databases was performed to evaluate efficacy of antiviral prophylaxis against HBVr in allo-HSCT patients (PubMed/Medline, Embase, Scopus, Cochrane Library, Web of Science, CINAHL, and ClinicalTrials.gov (June 21, 2017)). We identified 10 studies, with 2067 patients undergoing allo-HSCT; these primarily evaluated the use of lamivudine and entecavir as prophylaxis against HBVr in patients undergoing allo-HSCT because there were little or no data about adefovir, telbivudine, or tenofovir as prophylaxis in this specific patient population. Thus, included studies were categorized into 2 main prophylaxis groups: lamivudine and entecavir. Results of our meta-analysis suggest that entecavir is very effective against HBVr, although further clinical trials are required to test efficacy of new antivirals and explore the emerging threat of drug resistance.     

Fatal liver failure with the emergence of hepatitis B surface antigen variants with multiple stop mutations after discontinuation of lamivudine therapy

Treatment of chronic hepatitis B virus (HBV) infection with lamivudine is effective and well-tolerated. However, discontinuation of the treatment is associated frequently with acute exacerbation of liver diseases. A patient suffering from acute liver failure after discontinuation of lamivudine treatment is described. The patient was treated with lamivudine for 4 months and ceased the treatment without consulting. After receiving lamivudine, the patient developed anti-HBs and became negative for hepatitis B surface antigens (HBsAg). However, HBV DNA reappeared to a level of 6.47 x 10(5) copies/ml. The patient died due to acute liver failure. Sequencing of HBV isolates revealed that mutations including G145R and stop codons occurred within the HBsAg coding region. In conclusion, HBV replication resumed after the uncontrolled cessation of lamivudine treatment in this patient and may have triggered the process leading to liver failure. Anti-HBs antibody appeared and may be the selective force for the emergence of HBV mutants.     

Snapshot on drug‐resistance rate and profiles in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice

While the selection of complex HBV drug‐resistance patterns on therapeutic failure can compromise the efficacy of anti‐HBV therapies, recent data show that patients failing treatment without drug‐resistance have a rate of virological success close to drug‐naive patients. The goal of this study is defining, in clinical practice, the burden of drug‐resistance mutations in a cohort of patients treated with anti‐HBV drugs. Prevalence and patterns of drug‐resistance were analyzed by RT‐sequencing in 204 patients infected chronically: 148 experiencing virological rebound (defined as an increase in serum HBV‐DNA > 20 IU/ml after achieving virological success [HBV‐DNA < 20 IU/ml]), and 56 null/partial responders (always detectable serum HBV‐DNA [>20 IU/ml] within 48 weeks of therapy). The highest rate of drug‐resistance was observed in patients experiencing virological rebound (prevalence, 79.1%). Conversely, almost half (46.4%) null/partial responders have no evidence of drug‐resistance. The rate of drug‐resistance was higher in patients treated with lamivudine (76.8% [109/142]) and telbivudine (83.3% [5/6]), followed by adefovir (62.5% [15/24]), and entecavir (52.2% [12/23]). Complex mutational patterns characterized by the co‐presence of rtM204V/I‐rtA181T/V (impairing the efficacy of all anti‐HBV drugs) were detected in four patients (2.7%) with virological rebound. Drug‐resistance is the main cause of failure to therapy in patients experiencing virological rebound, supporting the need of rapid switch to anti‐HBV drugs with higher genetic barrier and potency (entecavir/tenofovir). Conversely, nearly half of null/partial responders shows no evidence of drug‐resistance mutations, maintaining high chance of achieving therapeutic success with the same class of drug. In this setting, genotypic resistance may help in selecting patients still carrying wild‐type viruses, that may take major benefits from antiviral treatment. J. Med. Virol. 85: 996–1004, 2013. © 2013 Wiley Periodicals, Inc.     

Redetection of HBV lamivudine-resistant mutations in a patient under entecavir therapy, who had been treated sequentially with nucleos(t)ide analogues

Development of hepatitis B virus (HBV)-resistant strains following nucleos(t)ide analog treatment is a major medical concern. This report describes a case of an adult patient with chronic HBV infection, sequentially treated with the nucleos(t)ide analogues, lamivudine, adefovir, and entecavir. During monotherapy with lamivudine, the patient developed lamivudine-resistant variants, which were undetectable during adefovir dipivoxil monotherapy. Twenty-two months after discontinuing lamivudine therapy, the resistant variants were again detected while the patient was receiving entecavir monotherapy. Genotypic analysis by sequencing the HBV polymerase was confirmed with the INNO-LiPA method. The results of this study suggest that entecavir treatment reselected residual lamivudine-resistant HBV variants, possibly because lamivudine-resistant HBV is less susceptible to entecavir than the wild-type virus. Despite the presence of these variants, the patient has had a complete virological response.     

Telbivudine and adefovir combination therapy for patients with chronic lamivudine-resistant hepatitis B virus infections

We evaluated second-line salvage therapy with adefovir + telbivudine (group 1), adefovir followed by adefovir + telbivudine (group 2), or lamivudine + adefovir followed by adefovir + telbivudine (group 3) in hepatitis B patients with an inadequate virologic response to lamivudine treatment. Simple linear regression analysis showed that for each additional month of treatment, the most significant reduction in viral load occurred in group 1 (HBV DNA [Log₁₀ IU/mL]: group 1, ?0.149; group 2, -0.081; group 3, ?0.123). Generalized estimating equation analysis revealed that compared to group 1, hepatitis B virus (HBV) DNA levels were 1.203 and 0.443 Log₁₀ IU/mL higher in groups 2 and 3, respectively. Overall, a significant reduction in viral load (?0.060 Log₁₀ IU/mL) was observed for each additional month of treatment. Adefovir + telbivudine treatment resulted in a significant reduction in HBV DNA levels. Moreover, telbivudine treatment resulted in a significant reduction in viral load (?0.050 Log₁₀ IU/mL) compared to lamivudine treatment after the emergence of lamivudine resistance.     

Entecavir: a new treatment option for chronic hepatitis B.

Because of the slow kinetics of viral clearance and the spontaneous genetic variability of hepatitis B virus (HBV), antiviral therapy of chronic hepatitis B remains a clinical challenge. Despite the recent development of lamivudine, adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic HBV infection, there is still a major need for new antiviral compounds. Entecavir, a guanosine analog, has been recently approved in US for the therapy of chronic hepatitis B and its registration is expected soon in Europe. Extensive studies have been performed to characterize its antiviral activity in enzymatic and tissue culture models, as well as in animal models of HBV infection. In clinical trails, entecavir administration was associated with a significantly more potent viral suppression compared to lamivudine, and a significant advantage in terms of biochemical and histological improvement compared to lamivudine. Entecavir was tolerated as well as lamivudine in these phase III trials. No case of resistance was detected after two years of therapy in nucleoside naive patients. Treatment of patients with lamivudine failure requires a higher dosage of entecavir and induces a significant decline in viraemia levels. However, 10% of these patients developed entecavir resistance after two years of therapy. The availability of entecavir as a new treatment option is providing clinicians more choice to keep both viral replication and liver disease under control. This provides new hope for improved treatment concepts for chronic HBV infection.     

Predictors and kinetics of occult hepatitis B virus infection in HIV-infected persons

It has been proposed that occult hepatitis B virus (HBV) infection, defined as detectable HBV‐DNA in serum with undetectable surface antigen (HBsAg^?), is associated with raised transaminases in HIV‐infected persons. The aim of this study was to determine the prevalence of occult HBV infection in two independent cohorts, and investigate its predictors, association with alanine‐aminotransferase (ALT) levels and response to antiretroviral therapy. Sera from HBsAg^? persons with core antibody (anti‐HBc⁺) were tested by real‐time PCR. Overall, 5.2% of patients were HBsAg⁺ and 39% HBsAg^?/anti‐HBc⁺. The prevalence of occult HBV infection was 48/343 (14.0%; 95% CI 10.7–18.1%), and 27/196 (13.8%) and 21/147 (14.3%) in the two cohorts. Median HBV‐DNA load was 342 (51–147,500) and 60 (25–33,850) copies/ml respectively. HBV‐DNA detection was associated with absence of surface antibody (anti‐HBs), but not with CD4 or ALT levels. Among 11 HBV‐DNA⁺ persons who started antiretroviral therapy containing lamivudine or lamivudine/tenofovir, HBV‐DNA was repeatedly undetectable over median 19 (3–43) months. However, HBV‐DNA detection was intermittent among drug‐naïve persons. Occult HBV infection is common in HBsAg^?/anti‐HBc⁺ HIV‐infected patients and predicted by undetectable anti‐HBs. The intermittent nature of HBV‐DNA detection poses a diagnostic challenge, but no association is observed with ALT levels. J. Med. Virol. 79:1464–1471, 2007. © Wiley‐Liss, Inc.     

基因芯片法检测HBV多位点变异和基因分型的临床价值

目的运用基因芯片技术检测临床乙肝患者血清中HBV病毒的相关耐药基因突变及基因分型,评价该方法在监测HBV耐药及基因分型中的作用。方法在使用不同核苷类药物的260例乙肝患者血清中,采用寡核苷酸探针芯片检测其携带的HBV相关耐药基因变异情况及基因型。并随机挑取40例第2次扩增产物进行DNA序列分析。结果经基因芯片检测到拉米呋啶耐药31例（19．4％）,阿德福韦酯耐药6例（6％）。260例患者中C基因型180例（69．2％）,B型59例（22．7％）,BC混合型21例（8．1％）。结论基因芯片法可同时检测针对拉米呋啶、阿德福韦酯、恩替卡韦、替比呋啶的多重耐药基因位点以及基因分型,与基因测序法比较,结果完全一致,是一种可靠的检测方法,可为临床抗病毒药物的科学选择提供参考。     

Hepatitis C virus superinfection in hepatitis B virus chronic carriers: a reciprocal viral interaction and a variable clinical course.

BACKGROUND: The virological and clinical impact of hepatitis C virus (HCV) superinfection in chronic hepatitis B virus (HBV) carriers has been poorly characterized. OBJECTIVE: To evaluate the viral interaction, clinical presentation and course of the disease in four HBsAg/HBV-DNA positive chronic hepatitis patients who developed acute HCV infection. STUDY DESIGN: To evaluate clinical, virological and laboratory data for at least 6 months from the onset of acute HCV infection in patients with chronic HBV infection. RESULTS: Three patients with acute HCV infection had a normal clinical course, but the remaining patient had severe disease with ascites and a marked decrease in prothrombin activity. In all cases, plasma HBV-DNA, which had been detectable prior to the HCV infection, was no longer detectable when the acute HCV infection occurred. The inhibition exerted by HCV on HBV-DNA persisted throughout the follow-up period in three patients, but was temporary in the one patient who experienced an acute exacerbation of chronic HBV infection. HCV-RNA became persistently undetectable in two patients and reduced to low levels in the other two. CONCLUSIONS: Acute HCV infection in the four HBV chronic carriers was characterized by a reciprocal inhibition of HBV-HCV genomes and, in one case, by a severe course of disease.     

Reactivation of lamivudine-resistant occult hepatitis B in an HIV-infected patient undergoing cytotoxic chemotherapy.

BACKGROUND: Reactivation of occult hepatitis B virus (HBV) infection is a well-known complication of cytotoxic chemotherapy. Lamivudine prophylaxis is recommended to reduce the incidence and severity of hepatitis in this context. CASE REPORT: An HIV-infected patient positive for HBs antigen became positive for HBc antibody alone under lamivudine given as part of antiretroviral therapy. He was treated with chemotherapy for non-Hodgkin's lymphoma while under lamivudine. Then, he developed HBV-related hepatitis that led to delay chemotherapy. He received adefovir that induced a dramatic decline in HBV DNA load and a normalisation of hepatic enzyme levels. However, the patient died of a relapse of lymphoma. Retrospective analysis of stored plasma samples showed evidence of lamivudine-resistant occult hepatitis before the onset of chemotherapy and reactivation of the HBV mutant. CONCLUSION: To our knowledge, this is the first report of occult hepatitis reactivation due to lamivudine-resistant mutant selected under lamivudine therapy in an HIV-infected patient. Our study underlines the need to carefully investigate lamivudine resistance in HIV-infected patients with occult infection under lamivudine therapy. Those patients should be monitored with the addition of anti-viral agents effective against the mutant strain.     

Correlation between pretreatment viral sequences and the emergence of lamivudine resistance in hepatitis B virus infection

The emergence of amino acid or nucleotide substitutions leads to lamivudine resistance in hepatitis B virus (HBV) infected patients. The aim of this study was to investigate whether viral sequences help predict the emergence of lamivudine resistance. The study subjects comprised 59 consecutive patients infected with HBV treated with daily therapy of 100 mg lamivudine. Among those, 32 patients with adequate pretreatment serum preservation were investigated for the correlation between viral amino acid substitutions and the appearance of lamivudine resistance with consideration of clinical background by determining dominant HBV full open reading frames. Viral resistance to lamivudine emerged in 28 of 59 patients (47%) in a median period of 2.45 years. Sequence comparisons of HBV genomes between patients who later developed lamivudine resistance and patients who did not revealed the existence of significant differences between the two groups in the pre‐S1 84 (P = 0.042), pre‐S2 1 (P = 0.017) and 22 (P = 0.015), and polymerase tp 95 (P = 0.046), judged by a log‐rank test. Viral sequence analyses revealed the presence of amino acid substitutions in HBV pre‐S1 and pre‐S2 that may be associated with the emergence of lamivudine resistance during chronic HBV infection. J. Med. Virol. 84:1360–1368, 2012. © 2012 Wiley Periodicals, Inc.     

Significance of liver histology in HBsAg‐positive,IgM anti‐HBc‐negative acute hepatitis B virus‐related hepatitis

Delladetsima I, Papatheodoridis G V, Tiniakos D G, Hatzakis A & Tassopoulos N C
(2012) Histopathology  61, 881–888 Significance of liver histology in HBsAg‐positive, IgM anti‐HBc‐negative acute hepatitis B virus‐related hepatitis Aims: The natural course of HBsAg‐positive, IgM anti‐HBc‐negative acute hepatitis B virus (HBV)‐related hepatitis is unclear. The aim of this study was to evaluate the prognostic significance of histological features and hepatic expression of HBV antigens in such patients. Methods and results: Fifty patients with HBsAg‐positive, IgM anti‐HBc‐negative acute hepatitis B who underwent liver biopsy during the acute hepatitis episode were studied [HBeAg seroconversion (n = 16), persistently positive for HBeAg (n = 9), and persistently negative for HBeAg (n = 25)]. Twenty‐six cases had features of typical acute hepatitis only (group A), and 24 cases had changes suggesting pre‐existing chronic hepatitis (group B). HBcAg and/or HBsAg immunoreactivity was detected less frequently in group A than in group B (31% versus 79%, P = 0.01). HBsAg clearance was observed in 24% of patients, almost exclusively in cases with HBeAg seroconversion. HBsAg loss was significantly more frequent in group A than in group B (52% versus 0%, P < 0.001), and in cases without rather than with immunohistochemical expression of HBV antigens (55% versus 0%, P < 0.001). In group A, HBsAg clearance was observed in 80%, 54% and 0% of patients with mild, moderate or severe acute hepatitis, respectively (P = 0.034). Conclusions: Histological information is very important for the prognosis of HBsAg‐positive, IgM anti‐HBc‐negative acute hepatitis B. HBeAg seroconversion with underlying typical acute hepatitis changes of mild to moderate severity without hepatic expression of HBV antigens strongly predicts subsequent HBsAg loss.     

Lamivudine treatment for severe acute HBV hepatitis

Treatment for acute hepatitis B is recommended in order to reduce the risk of progression to fulminant hepatitis and the need of OLT. We report our experience on treatment with high dose lamivudine, in patients with severe acute HBV infection. The diagnosis was based on clinical and virological findings and exclusion of other known causes of liver damage. The decision to treat was based on the prolongation of INR together with increasing values of bilirubin and ALT. Four patients received Lamivudine 200 mg/daily until clearance of serum HBV-DNA and then 100 mg/daily until clearance of HBsAg and appearance of anti-HBs antibodies. One patient received 100 mg/daily because of chronic renal impairment. The median period of hospitalization was 13 days, and none of the patients had complications, related either to underlying disease or to therapy. The complete normalization of serum transaminases and bilirubin occurred on average after 5.5 weeks and 3 weeks respectively. All patients cleared serum HBV-DNA within three months, lost HBeAg and HBsAg and seroconverted to anti-HBe; four patients developed anti-HBs at a protective titre. Early antiviral treatment attenuates the clinical and biochemical impairment leading to fast healing and promoting complete recovery.