T-cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice.

BACKGROUND & AIMS: Current antiviral therapies control but rarely eliminate HBV, leaving chronic HBV carriers at risk of developing hepatocellular carcinoma (HCC). Lacking or dysfunctional virus-specific adaptive immunity prevents control of HBV and allows the virus to persist. Restoring antiviral T-cell immunity could lead to HBV elimination and cure of chronically infected patients. METHODS: We constructed bispecific T-cell engager antibodies that are designed to induce antiviral immunity through simultaneous binding of HBV envelope proteins (HBVenv) on infected hepatocytes and CD3 or CD28 on T cells. T-cell engager antibodies were employed in co-cultures with healthy donor lymphocytes and HBV-infected target cells. Activation of the T-cell response was determined by detection of pro-inflammatory cytokines, effector function (by cytotoxicity) and antiviral effects. To study in vivo efficacy, immune-deficient mice were transplanted with HBVenv-positive and -negative hepatoma cells. RESULTS: The 2 T-cell engager antibodies synergistically activated T cells to become polyfunctional effectors that in turn elicited potent antiviral effects by killing infected cells and in addition controlled HBV via non-cytolytic, cytokine-mediated antiviral mechanisms. In vivo in mice, the antibodies attracted T cells specifically to the tumors expressing HBVenv resulting in T-cell activation, tumor infiltration and reduction of tumor burden. CONCLUSION: This study demonstrates that the administration of HBVenv-targeting T-cell engager antibodies facilitates a robust T-cell redirection towards HBV-positive target cells and provides a feasible and promising approach for the treatment of chronic viral hepatitis and HBV-associated HCC. LAY SUMMARY: T-cell engager antibodies are an interesting, novel therapeutic tool to restore immunity in patients with chronic hepatitis B. As bispecific antibodies, they bind envelope proteins on the surface of the hepatitis B virus (HBV) and CD3 or CD28 on T cells. This way, they induce a potent antiviral and cytotoxic T-cell response that leads to the elimination of HBV-positive cells. These bispecific T-cell engager antibodies are exciting therapeutic candidates for chronic hepatitis B and HBV-associated hepatocellular carcinoma.

Hepatitis B-C and human immunodeficiency virus: seroprevalence and associated factors among health students in Saudi Arabia.

OBJECTIVES: To assess the seroprevalence of Hepatitis B (HBV), Hepatitis C (HCV), and Human Immunodeficiency Virus (HIV) among newly admitted health track students in a large university in the Eastern Province of Saudi Arabia, and determine the students' immunity against HBV, and bloodborne viral infection risk factors or practices among them. METHODS: Information about the 1145 students, vaccination history, and exposure to bloodborne viral infections risk factors/practices were collected using a structured questionnaire during August 2020. The results of serological data were obtained from students' electronic files. RESULTS: All students tested negative for HBV, HCV, and HIV infections. The seroprevalence of positivity against HBV was 25.8%, and the frequencies of students with protective levels of anti-HBV were inversely related to their age. The majority (70.8%) of students had 1 or 2 identifiable risk factors for bloodborne diseases, and the most frequent risk factor was history of dental intervention. Female students were more than four-times likely to be in the high-risk group for bloodborne infections than males (OR = 4.4; 95% CI: 3.3-5.9). Being from the Central Province of Saudi Arabia (OR = 1.9; 95% CI: 1.2-3.1) and having a mother's educational level of master or doctorate (OR = 3.0; 95% CI: 1.3-6.7) were found to be independent predictors of being in the high-risk group. On the other hand, having a family member in the healthcare field was found as a predictor of being in the low-risk group for bloodborne diseases (OR = 0.7; 95% CI: 0.5-0.9). CONCLUSION: About three-fourth of students in this study were susceptible to HBV. Our findings stress the need to develop policies to raise awareness regarding bloodborne infectious diseases, in addition to expanding access to HBV vaccination for healthcare staff, especially in older ages.

Trend of 25-hydroxycholesterol and 27-hydroxycholesterol plasma levels in patients affected by active chronic hepatitis B virus infection and inactive carriers.

Hepatitis B virus (HBV) infection is a global health problem with different immunological phases and therapeutic approaches. The serological condition of inactive carrier (IC) was recently well defined as a clinical and virological stable status, in which specific treatment is usually deferred, while the active chronic hepatitis B (CHB) condition requires an immediate treatment strategy. Recently, a possible broad antiviral effect of oxysterols, in particular 25-hydroxycholesterol (25OHC) and 27-hydroxycholesterol (27OHC), was observed, as most likely linked to the positive modulation of innate immunity, but no clear evidence is available about their possible role in chronic HBV infection. Thus, we examined the relationship between the plasma levels of oxysterols and the disease condition of 40 HBV patients, without treatment at the start of the study. Of these, 33 were ICs and 7 were active CHB subjects. A marked reduction of 25OHC and 27OHC plasma levels was detectable in all active CHB recruited patients, while the plasma values observed in ICs all remained within the physiological range. No difference was observed between the two groups of patients with regard to the plasma levels of 24-hydroxycholesterol (24OHC). Further, the plasma level of 27OHC ≥ 140 µg/L was shown to be predictive of an inactive carrier status. This cohort study points to 27OHC as a good candidate biomarker to differentiate active and inactive CHB status. An increasing bulk of research reports is supporting the very likely contribution of this oxysterol to the immunological control of chronic hepatitis B.

Efficacy of Nucleotide/Nucleoside Analogues and Hepatitis B Immunoglobulin Therapy in Blocking Mother-to-Child Transmission of Hepatitis B in an Eastern Chinese Group.

The objective of this study was to investigate the efficacy and potential side-effects of nucleotide/nucleoside analogues and hepatitis B immunoglobulin injection of newborns in blocking mother-to-child transmission of hepatitis B virus in the middle and late pregnancy period. 238 cases of enrolled pregnant women were divided into the Telbivudine group, the Tenofovir group, the Lamivudine group, and the hepatitis B immunoglobulin (HBIG) group. Enrolled patients received corresponding therapies. Clinical and laboratory data were collected. Results showed that the levels of HBV DNA of the enrolled pregnant women in the Telbivudine, Tenofovir, and Lamivudine groups decreased rapidly after 12 weeks of drug intervention compared with those in the control. HBsAg positive rate in newborns and in children 24 weeks after birth was 0/60, 0/60, 0/60, 3/30, and 11/28 in the Telbivudine, Tenofovir, Lamivudine, HBIG, and control groups, respectively. No significant side-effects were identified after following up to 12 months after birth. Our results show that routine HBV vaccine plus HBIG injections is insufficient in blocking mother-to-child HBV transmission. Administration of nucleotide/nucleoside analogues or HBIG at pregnancy is suggested to maximize the blocking of vertical HBV transmission.

Evaluation of HBV, HCV, and HIV seroprevalence in patients with plasma cell disorders.

Hepatitis B (HBV) and hepatitis C (HCV) viruses are hepatotropic and lymphotropic viruses that can proliferate either in lymphocytes and monocytes or hepatocytes.The aim of this study was to evaluate the seroprevalence of HBV, HCV, and human immunodeficiency virus (HIV) in patients with plasma cell disorders. We also aimed to compare patients with plasma cell disorders and chronic lymphocytic leukemia (CLL) in terms of HBV, HCV, and HIV seropositivity.This is a retrospective study. The patients who had patient file in the Multiple Myeloma Outpatient Unit of our hospital and were followed in our outpatient unit between January 1, 2012 and September 15, 2019, with diagnoses of either of the plasma cell disorders were included in the study. In addition, 272 CLL patients who were admitted to the Leukemia Outpatient Unit of our hospital were also enrolled in the study. The 2 disease groups were compared in terms of HBV, HCV, and HIV seropositivity.A statistically significant relationship was found between disease groups according to hepatitis B surface antigen (P < .05). Hepatitis B positivity were found to be more common in CLL patients. There was also a statistically significant relationship between the disease groups in terms of hepatitis B e antigen positivity (P = .001).We found that hepatitis B surface antigen positivity rate in CLL patients was higher than in patients with plasma cell disorders. Seroprevalence of HBV, HCV, and HIV was found to be very low in patients with plasma cell disorders.

Present and future management of viral hepatitis B and C in children.

Having a hepatitis B virus (HBV) or hepatitis C virus (HCV) infection places a child at higher risk for subsequent chronic hepatitis B (CHB) or chronic hepatitis C (CHC) infection. The risk of mother-to-child transmission is higher for HBV (20% to 90%) than for HCV (<5%). Perinatal HBV infection generally causes CHB infection while perinatal HCV infection has a certain rate of spontaneous viral clearance (around 20% to 30%). Of the two, only HBV infection can benefit from passive/active perinatal immunoprophylaxis. The risk of CHB in children with HBV horizontal transmission decreases with age, whereas HCV transmission among teenagers commonly results into a long-life infection and CHC infection. Children with CHB or CHC should be carefully assessed for the need for antiviral treatment. When treatment cannot be deferred, pediatric CHB infection has different first-line treatment options: standard interferon (for children aged≥1 year), pegylated interferon (for children aged≥3 years), and the oral nucleotide analogues entecavir (for children aged≥2 years) and tenofovir (for children aged≥12 years). The choice of treatment depends on the child's age, virus genotypes, previous treatment failure and presence of contraindications. Expected responsiveness rate is 25% of hepatitis B e-antigen clearance, with both standard interferon and nucleotide analogues. Direct antiviral agents are first-line treatment for CHC infection in children aged 3 years or older. Hepatitis C virus sustained virus response is as high as 97%. Therefore, if direct antiviral agents can be proven to be safe and well tolerated in very young children, HCV eradication could be planned after the first screening.

Hepatitis B Virus: From Diagnosis to Treatment.

Hepatitis B infection is still a global concern progressing as acute-chronic hepatitis, severe liver failure, and death. The infection is most widely transmitted from the infected mother to a child, with infected blood and body fluids. Pregnant women, adolescents, and all adults at high risk of chronic infection are recommended to be screened for hepatitis B infection. The initial analysis includes serological tests that allow differentiation of acute and chronic hepatitis. Molecular assays performed provide detection and quantification of viral DNA, genotyping, drug resistance, and precore/core mutation analysis to confirm infection and monitor disease progression in chronic hepatitis B patients. All patients with chronic hepatitis B should be treated with antiviral medications and regularly monitored for efficient treatment. The current treatment is based on nucleos(t)ide analogs and pegylated interferons that save lives by decreasing liver cancer death, liver transplant, slow or reverse the progression of liver disease as well as the virus infectivity.

High Level of Hepatitis B Core-Related Antigen Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection of Intermediate Viral Load.

BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC). Serum levels of HB core-related antigen (HBcrAg) have been associated with active replication of HBV. We investigated whether HBcrAg levels are associated with development of HCC, especially in patients who do not require antiviral treatment. METHODS: We collected data from 2666 adults positive for hepatitis B surface antigen (HBsAg), infected with HBV genotypes B or C, and without liver cirrhosis, who had long-term follow-up at the National Taiwan University Hospital from 1985 through 2000. None of the patients received antiviral treatment during the follow-up. Baseline levels of HBV DNA, HBsAg, and HBcrAg were determined retrospectively and participants were followed for a mean of 15.95 years. The primary end point was an association between serum level of HBcrAg and HCC development. RESULTS: HCC developed in 209 patients in the cohort (incidence rate, 4.91 cases/1000 person-years). We found a positive association between baseline level of HBcrAg and HCC development; HBcrAg level was an independent risk factor in multivariable analysis. In the subgroup of hepatitis B e antigen-negative patients with HBV DNA levels from 2000 to 19,999 IU/mL (intermediate viral load [IVL]) and normal levels of alanine aminotransferase, HBcrAg levels of 10 KU/mL or more identified patients at increased risk of HCC (hazard ratio, 6.29; confidence interval, 2.27-17.48). Patients with an IVL and a high level of HBcrAg had a risk for HCC that did not differ significantly from that of patients with a high viral load (≥20,000 IU/mL). Patients with an IVL but a low level of HBcrAg had a low risk of HCC, with an annual incidence rate of 0.10% (95% confidence interval, 0.04%-0.24%). CONCLUSIONS: In a long-term follow-up study of 2666 patients with chronic HBV infection (genotypes B or C), level of HBcrAg is an independent risk factor of HCC. Moreover, HBcrAg level of 10 KU/mL identifies patients with an IVL who are at high risk for HCC.

Evaluation of HBV-Like Circulation in Wild and Farm Animals from Brazil and Uruguay.

The origin of the hepatitis B virus is a subject of wide deliberation among researchers. As a result, increasing academic interest has focused on the spread of the virus in different animal species. However, the sources of viral infection for many of these animals are unknown since transmission may occur from animal to animal, human to human, animal to human, and human to animal. The aim of this study was to evaluate hepadnavirus circulation in wild and farm animals (including animals raised under wild or free conditions) from different sites in Brazil and Uruguay using serological and molecular tools. A total of 487 domestic wild and farm animals were screened for hepatitis B virus (HBV) serological markers and tested via quantitative and qualitative polymerase chain reaction (PCR) to detect viral DNA. We report evidence of HBsAg (surface antigen of HBV) and total anti-HBc (HBV core antigen) markers as well as low-copy hepadnavirus DNA among domestic and wild animals. According to our results, which were confirmed by partial genome sequencing, as the proximity between humans and animals increases, the potential for pathogen dispersal also increases. A wider knowledge and understanding of reverse zoonoses should be sought for an effective One Health response.

Automated Diagnosis of Hepatitis B Using Multilayer Mamdani Fuzzy Inference System.

In this research, a new multilayered mamdani fuzzy inference system (Ml-MFIS) is proposed to diagnose hepatitis B. The proposed automated diagnosis of hepatitis B using multilayer mamdani fuzzy inference system (ADHB-ML-MFIS) expert system can classify the different stages of hepatitis B such as no hepatitis, acute HBV, or chronic HBV. The expert system has two input variables at layer I and seven input variables at layer II. At layer I, input variables are ALT and AST that detect the output condition of the liver to be normal or to have hepatitis or infection and/or other problems. The further input variables at layer II are HBsAg, anti-HBsAg, anti-HBcAg, anti-HBcAg-IgM, HBeAg, anti-HBeAg, and HBV-DNA that determine the output condition of hepatitis such as no hepatitis, acute hepatitis, or chronic hepatitis and other reasons that arise due to enzyme vaccination or due to previous hepatitis infection. This paper presents an analysis of the results accurately using the proposed ADHB-ML-MFIS expert system to model the complex hepatitis B processes with the medical expert opinion that is collected from the Pathology Department of Shalamar Hospital, Lahore, Pakistan. The overall accuracy of the proposed ADHB-ML-MFIS expert system is 92.2%.

Association between hepatitis B virus infection and chronic kidney disease: A cross-sectional study from 3 million population aged 20 to 49 years in rural China.

Hepatitis B virus (HBV) infection can lead to different types of chronic kidney diseases (CKD) in clinical practice. However, HBV infection has been observed to have no significant association with CKD indicators in some epidemiological surveys. This research aims to estimate CKD prevalence in HBV infection population and clarify the relationship between HBV infection status and CKD.The participants aged 20 to 49 years were selected by multistage random sampling from January 1, 2010 to December 31, 2012 across 31 provinces and regions in rural China. The data was collected by standard questionnaire and physical check-up. Status of HBV infection was diagnosed as immune tolerant phase, hepatitis B envelope antigen -positive chronic HBV infection, inactive HBV carrier, hepatitis B envelope antigen -negative chronic HBV infection and resolved HBV infection based on serological markers, and the level of hepatic function, respectively.In total, 2,969,502 subjects were included in the study. In population aged 20 to 49 years in rural China, prevalence of HBV infection was 12.17%. Prevalence of proteinuria, hematuria, estimated glomerular filtration rate less than 60 mL/min/1.73m and CKD was 0.94%(95% CI = 0.91-0.97%) vs. 0.65%(95% CI = 0.64-0.66%), 1.92%(95% CI = 1.87-1.96%) vs. 1.19% (95% CI = 1.18-1.21%), 1.02%(95% CI = 0.99-1.06%) vs. 0.77% (95% CI = 0.76-0.78%), and 3.85%(95% CI = 3.78-3.91%) vs. 2.60%(95% CI = 2.58-2.62%) in population with HBV infection and without infection, respectively. Prevalence of CKD and indicators was higher in population in every status of HBV infection than in population without infection, respectively (all P < 0·0001). Every HBV infection status was a risk factor for CKD.CKD prevalence was higher in population in every status of HBV infection than without infection. HBV infection was a risk factor for CKD in population aged 20 to 49 years in rural China.

Interleukin-21 receptor gene polymorphism is associated with hepatitis B virus-related hepatocellular carcinoma in Chinese patients.

BACKGROUND: We investigated the relationship between hepatitis B virus (HBV)-related pathogenesis and single nucleotide polymorphisms (SNPs) in interleukin-21 (IL-21)-JAK-STAT signaling pathway genes. METHODS: We used the high-resolution melting (HRM) method to genotype five SNPs (IL-21 rs2221903, IL-21 rs4833837, IL-21 receptor (IL-21R) rs2285452, JAK3 rs3008, and STAT3 rs1053023) in 546 HBV-infected patients and 353 healthy Chinese subjects. The HBV-infected patients were further divided into subgroups based on the HBV-related pathologies: chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC), and HBV-related hepatocellular carcinoma (HCC). RESULTS: There were no significant differences in the genotype and allele distributions of the five SNPs between the HBV-infected patients and healthy subjects. The genotype and allele frequencies were similar in the two groups for IL-21 rs2221903 (A>G, P = 0.83 and 0.67), rs4833837 (A>G, P = 0.80 and 0.49), IL-21R rs2285452 (G>A, P = 0.25 and 0.68), STAT3 rs1053023 (A>G, P = 1.00 and 0.96), and JAK3 rs3008 (C>T, P = 0.32 and 0.54). However, patients with the IL-21R rs2285452 AA genotype were more susceptible to HBV-related HCC than those with the IL-21R rs2285452 GA/GG genotype (P = 0.03, OR = 3.27, 95% CI = 1.16-9.20). The serological marker model of "HBsAg+, HBeAg+, HBcAb+" was predominant among patients with HBV infection. However, there was no association between the genotype's distribution of the five SNPs and the serological marker models (P > 0.05). CONCLUSIONS: These findings demonstrate that the IL-21R rs2285452 AA genotype increases the risk of HBV-related HCC in Chinese patients.

Booster immunity - diagnosis of chronic hepatitis B viral infection.

INTRODUCTION: Diagnosis of chronic hepatitis B virus (HBV) infection particularly its occult form requires monitoring and repeat serological and molecular studies. The aim of the study was to investigate the possible relation between the case of a family outbreak of hepatitis A and the finding that a member of this family was diagnosed with chronic hepatitis B. METHODOLOGY: A mother and her two sons, one previously diagnosed with chronic HBV infection, were hospitalized due to suspected acute hepatitis. Serological markers for hepatitis A, hepatitis B and hepatitis C were assessed. Additionally, HBV DNA was tested with a sensitive PCR. Hepatitis B vaccine was administered to the mother to differentiate resolved from occult HBV infection. RESULTS: A family outbreak of hepatitis A was confirmed, alongside a focus of chronic HBV infection. The serological profile for two brothers was HBsAg(+), anti-HBcIgM(-), anti-HBc(+), HBcAg(-)/anti-HBe(+). The mother was negative for all HBV markers except anti-HBc. HBV DNA was detected at a level of 461 IU/mL in the elder brother, 3647 IU/mL in the younger brother and was negative in the mother on two occasions. Her anti-HBc alone, having two sons with chronic HBV infection, and her lack of antibody response to hepatitis B vaccine despite being negative for HBV DNA, led to the diagnosis of probable occult HBV infection. CONCLUSION: Our results confirmed that a vaccination approach could facilitate diagnosis of chronic HBV infection in the presence of isolated anti-HBc. If it were not for a family outbreak of hepatitis A, this unexpected family HBV focus would not have been revealed.

Dynamics of hepatitis B virus serum markers in an acute hepatitis B patient in the incubation phase.

Patients with acute hepatitis B (AHB) usually present after developing symptoms; therefore, the temporal kinetics of viral markers during the incubation period have not been documented clearly. We describe an AHB infection before the onset of hepatitis, throughout the course of the disease and without anti-viral therapy. The patient initially visited our hospital for immunization against HBV and was found to be positive for viral markers: 0.0 IU/mL of anti-HBs, 0.06 S/CO of anti-HBc and 2.93 IU/mL of HBsAg. During the 14 days after his first visit, HBsAg, HBV DNA, HBe antigen and HBV core-related antigen, but not anti-HBc or anti-HBs, levels increased. On day 22, he developed acute hepatitis. The period of logarithmic viral replication was estimated to be 7.0 days. HBV genomic sequencing and phylogenetic analysis indicated transmission from the patient's wife. Although sexual intercourse could not be ruled, another possible route of transmission was the unusual occurrence of kissing his wife when she had macroscopic bleeding after tooth brushing, 2 months before his positive HBsAg result; the day of the episode being consistent with the calculated HBV replication velocity. This study reveals the temporal kinetics of viral markers during the incubation period of AHB.

Analysis of clinical characteristics and S gene sequences in chronic asymptomatic HBV carriers with low-level HBsAg.

BACKGROUND: During the natural hepatitis B virus (HBV) infection process, some infected subjects are characterized by a sustained low serum HBV surface antigen (HBsAg) expression level. Most members in this population are chronic asymptomatic HBV carriers (ASCs). To elucidate the mechanism underlying low-level HBsAg expression in ASCs, we sequenced the HBV S gene in these patients to reveal specific sequence characteristics. METHODS: Overall, 1308 cases of chronic ASCs were grouped according to their HBsAg serum expression levels (10 IU/mL). The clinical characteristics of the population were analysed in detail. The HBV S gene was sequenced from 276 ASC cases with low-level HBsAg expression. Additionally, 100 of 1032 ASC cases with high-level HBsAg expression were randomly selected for HBV S gene sequencing based on age matching according to the low-level HBsAg group. A comparative analysis was conducted with the HBV S gene sequences from ASCs with low HBsAg expression and the HBV reference S gene sequences from ASCs with high HBsAg expression. RESULTS: The population with low-level HBsAg expression displayed the following primary clinical characteristics: mostly chronic asymptomatic HBV carriers, older age (mean age 55.09 years), HBsAg/anti-HBe/anti-HBc (core) positivity as the main serological pattern (97.1%), low HBV DNA replication (1.32 ± 1.60 log10 IU/mL), a low HBV-DNA positive rate (45.65%) and primarily genotype B (82.54%) and serotype adw (84.13%). The comparative analysis of the HBV S gene sequences from ASCs with low-level HBsAg showed significant mutations (including co-mutations) on both sides of the main hydrophilic region (MHR). CONCLUSION: Significant mutations in multiple regions and at multiple sites (including co-mutations) on both sides of the MHR may be one cause of the low HBsAg expression level in this population.

New viral biomarkers for Hepatitis B: Are we able to change practice?

The management of chronic hepatitis B virus (HBV) infection is challenged by its varying natural course and its stealthy nature. Not all HBV-infected patients will develop complications of infection; however, it is of utmost importance to identify patients who are at risk and require antiviral treatment and/or close surveillance. Hepatic inflammation and quantification of HBV DNA have guided treatment decisions in the last decade, and these guided interventions have been shown to reduce liver-related complications and death. Data on the quantification of additional HBV markers such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here, we review the current evidence of how to use these markers and discuss open issues that require additional research.

Switching to tenofovir vs continuing entecavir for hepatitis B virus with partial virologic response to entecavir: a randomized controlled trial.

Entecavir 0.5 mg (ETV) is widely used among treatment-naïve chronic hepatitis B (CHB) patients. However, 10%-30% of patients show partial virologic response (PVR) to the drug. If the hepatitis B virus (HBV) continues to replicate, the underlying liver disease may progress. Herein, we compared the efficacy of switching to tenofovir disoproxil fumarate (TDF) with that of continuing ETV in CHB patients with PVR to ETV. This was an open-label randomized controlled trial including CHB patients who had been receiving 0.5 mg of ETV for >12 months, but who still had detectable HBV DNA levels of >60 IU/mL without known resistance to ETV. Sixty patients were enrolled and 45 qualified for the study: Twenty-two patients were randomly assigned into the TDF group and 23 into the ETV group. After 12 months of treatment, the virologic response rate (HBV DNA <20 IU/mL) was significantly higher in the TDF group than in the ETV group, as measured using per-protocol analysis (55% vs 20%; P = .022) and intention-to-treat analysis (50% vs 17.4%; P = .020). The reduction in HBV DNA was greater (-1.13 vs -0.67 log10 IU/mL; P = .024), and the mean HBV DNA level was lower (1.54 vs 2.01 log10 IU/mL; P = .011) in the TDF group than in the ETV group. In conclusion, to achieve optimal response in CHB patients with PVR to ETV, switching to TDF would be a better strategy than continuing ETV. Appropriate modification of therapy would further improve the outcome of chronic HBV infection.