Undetectable Hepatitis B Virus DNA Levels Research Articles

#2336 Hepatitis-B virus related membranous nephropathy presenting as nephrotic syndrome treated with tenofovir

Abstract Background The prevalence of Hepatitis B virus (HBV) related nephropathy particularly membranous nephropathy follows geographic HBV prevalence patterns. Hepatitis B virus infection occurs throughout the world and is endemic in developing countries such as Africa, Eastern Europe, the Middle East, Central Asia, China, Southeast Asia, the Pacific islands and the Amazon basin of South America. Vertical transmission from mother to child often predominates in endemic areas. Membranous glomerulonephritis is the most common histological renal lesion associated with hepatitis B virus infection. Treatment options for renal patients with chronic HBV infection are complex, being dictated by the overall clinical picture and best conducted by multidisciplinary approach and thorough renal monitoring. Therapeutic guidelines are very limited, mostly case series are available in this setting. Anti-viral treatment is indicated in hepatitis B surface antigen (HBsAg)-positive patients with evidence of active liver disease based on aminotransferases and serum HBV DNA levels of 2000-20 000 IU/ml have been proposed as the threshold to start treatment Aim To present a case of young healthy male with chronic HBV infection with nephrotic syndrome and Membranous Nephropathy who developed reactivation after discontinuation of Tenofovir. Case A 32-year old man presented with generalized edema 5 months ago associated with dipstick proteinuria. The swelling has progressed and now associated with walking difficulty thus sought consult and was then admitted. His mother had been hypertensive for more than a decade and work up revealed that she is positive for anti-HBS and negative for HBsAg. His father is negative for HBsAg. His childhood and past medical history is unremarkable. He is a non-smoker, non alcoholic and no history of illicit drug use. He is monogamous and not promiscuous. He has 6 siblings and two of his brothers are hypertensives and found to have chronic Hepatitis B infection. His complement levels were low, ANA and ASO titers were negative. His creatinine was 1.06 mg/dl, BUN- 11.77 mg/dl, SGPT-161 U/L (NV: < 42 U/L), albumin- 1.50 g/dl (NV: 3.5-5.0 g/dl). Total cholesterol- 443.30 mg/dl, Triglycerides 330.46 mg/dl. Urine PCR-4,369 mg/g. Hepatitis profile revealed reactive for HBsAg and HBeAg. His HBV viral load was 170 000 000 IU/ml (989 400 000 copies/ml). His HIV screening was negative. A kidney biopsy was performed which revealed Membranous Glomerulonephritis. He was given Tenofovir 300 mg daily for 6 months. His repeat HBV viral load was < 20 IU/ml (< 116 copies/ml) and his 24 h urinary protein was 1,891 mg/24H. His albumin was 4.57 g/dl and his creatinine remained stable at 0.96 mg/dl while his SGPT went back to normal at 40 U/L. A repeat HBeAg revealed 0.55 which could be a possible seroconversion. Tenofovir was discontinued for 6 months however patient came back with persistent proteinuria associated with high HBV DNA titer. A repeat 24H-urine protein showed 1,182 mg/24H. Tenofovir was resumed and Enalapril was continued. Follow up check up 3 months after revealed urine PCR was 850 mg/g and his kidney function remained stable. He is advised to continue Tenofovir with frequent follow up until he becomes HBsAg-negative. Recommendation We recommend that antiviral treatment in this subset of population requires prolong treatment until persistent seroconversion of HBeAg and persistent undetectable HBV DNA level or have lost HBsAg even if the patient does not develop hepatitis B surface antibody. This recommendation of prolong treatment are still developing and requires further investigation.

Clinical outcomes of liver transplantation in human immunodeficiency virus/hepatitis B virus coinfected patients in China

BackgroundHighly active antiretroviral therapy (HAART) has been able to improve the immune system function and survival of human immunodeficiency virus (HIV) patients. However, Patients coinfected with HIV and hepatitis B virus (HBV) are more likely to develop end-stage liver disease (ESLD) than those infected with HBV alone. Consequently, liver transplantation is often required for these patients. This study evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-HBV coinfected patients in China.MethodsWe conducted a retrospective analysis on all HIV-HBV coinfected patients that underwent OLT from April 1, 2019 to December 31, 2021 and their outcomes were compared to all HBV monoinfected patients undergoing OLT during the same period. Patient outcomes were determined, including cumulative survival, viral load, CD4 T-cell count and postoperative complications.ResultsThe median follow-up of HIV recipients was 36 months after OLT (interquartile range 12–39 months). Almost all patients had stable CD4 T-cell count (> 200 copies/ul), undetectable HBV DNA levels, and undetectable HIV RNA load during follow-up. The 1-, 2-, and 3-year posttransplant survival rates were 85.7% for the HIV group (unchanged from 1 to 3 years) versus 82.2%, 81.2%, and 78.8% for the non-HIV group. Cumulative survival among HIV-HBV coinfected recipients was not significantly different from the HBV monoinfected recipients (log-rank test P = 0.692). The percentage of deaths attributed to infection was comparable between the HIV and non-HIV groups (14.3% vs. 9.32%, P = 0.665). Post OLT, there was no significant difference in acute rejection, cytomegalovirus infection, bacteremia, pulmonary infection, acute kidney injury, de novo tumor and vascular and biliary complications.ConclusionsLiver transplantation in patients with HIV-HBV coinfection yields excellent outcomes in terms of intermediate- or long-term survival rate and low incidence of postoperative complications in China. These findings suggest that OLT is safe and feasible for HIV-HBV coinfected patients with ESLD.Trial registrationChinese Clinical Trial Registry (ChiCTR2300067631), registered 11 January 2023.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double‐blind, double‐dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty‐seven (71 in group A) patients with HBeAg‐positive CHB and 46 (21 in group A) patients with HBeAg‐negative CHB completed the 240‐week treatment and follow‐up. Baseline characteristics were well balanced between the two groups. For the HBeAg‐positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg‐negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long‐term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Hepatitis B virus core-related antigen (HBcrAg) as a prognostic marker for the development of hepatocellular carcinoma: A mini systematic review of the literature.

Chronic hepatitis B (CHB) infection is a risk factor for hepatocellular carcinoma (HCC). Previous studies showed that elevated levels of Hepatitis B Virus (HBV) DNA and HBsAg are associated with increased HCC risk in patients with chronic HBV infection. Multiple studies showed that high levels of HBV DNA and Hepatitis B Surface Antigen (HBsAg) are associated with higher HCC risk in CHB patients. Patients treated with antiviral therapy may have undetectable or low levels of HBV DNA and HBsAg loss. However, HCC may develop in some patients with low-level HBV DNA and HBsAg seroconversion. In this study, we evaluated the role of HBcrAg in predicting HBV related HCC development. We searched PubMed, Scopus, and Web of Science databases using keywords (hepatitis B core-related antigen, hepatocellular carcinoma, liver neoplasm, hepatocellular and hepatic cancer, to identify studies assessing serum level of HBcrAg in patients with CHB and HCC. The search resulted in 184 studies. Seven studies were included: Four of which were retrospective cohort studies, and the rest were prospective cohort, case controls. Six of them reported a higher HBcrAg positivity rate in the HCC group when compared with the HBV DNA assay, yet with similar hazard ratio (HR) in predicting the incidence of HCC. However, four studies found that HBcrAg positivity was an independent risk factor for HCC development with a HR ranging from 3.27 to 7.05. HBV-related HCC has many proposed biomarkers in its prediction, yet our findings revealed HBcrAg to may have superiority over other biomarkers. High quality studies with bigger sample size research is needed to understand the potential role of HBcrAg in CHB induced HCC.

Clinical Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels.

Some hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients show undetectable serum HBV DNA levels at HCC diagnosis. The risk of HBV reactivation and its impact on clinical outcomes are not well-unknown. This retrospective cohort study included a total of 985 HBV-related HCC patients with undetectable serum HBV DNA levels (< 12IU/mL) at HCC diagnosis (112 were antiviral treatment (AVT)-naïve; 873 were receiving AVT). Incidence and risk factors for HBV reactivation (re-detection of HBV DNA in serum) during follow-up, as well as its association to overall survival, were assessed. During a median of 33.4months of follow-up (range: 0.2-124.2months), HBV reactivation was observed in 279 patients. HBV reactivation rate was significantly lower for patients receiving AVT than AVT-naïve patients (three-year cumulative incidence rate: 27.3% versus 56.0%; P < 0.001). In multivariable-adjusted analysis, the risk of HBV reactivation was lower for those receiving AVT compared to AVT-naïve patients (adjusted hazard ratio: 0.39, 95% confidence interval: 0.29-0.54). Overall survival was significantly lower for those experiencing HBV reactivation than those who did not (71.5% and 85.7% at five-year) and was associated with higher risk of overall mortality (adjusted hazard ratio: 5.15, 95% confidence interval: 3.60-7.38). More than half of AVT-naïve patients experienced HBV reactivation within three years, which was associated with increased risk of overall mortality. The risk of HBV reactivation was lower for those receiving AVT, suggesting that prompt AVT needs to be considered for AVT naïve HBV-related HCC patients with undetectable HBV DNA levels.

Tenofovir alafenamide for prevention and treatment of hepatitis B virus reactivation and de novo hepatitis

Background and AimAdministration of tenofovir alafenamide (TAF) as prevention or treatment of hepatitis B virus (HBV) reactivation is not well known. The aim of this study is to reveal the efficacy and safety of TAF against HBV reactivation.MethodsEntecavir (ETV) and TAF were given to 66 and 11 patients, respectively, as prophylaxis against or treatment of HBV reactivation during chemotherapy or immune suppression therapy from January 2010 to June 2020. The antiviral effects and safety were assessed.ResultsAt week 24, the antiviral effects on patients receiving ETV and TAF were similar in terms of reduction of HBV DNA (−2.83 ± 1.45log IU/mL vs −3.05 ± 2.47log IU/mL; P = 0.857) and achieving undetectable levels of HBV DNA (78.8 vs 90.9%; P = 0.681). There was no significant difference in the decrease in the estimated glomerular filtration rate (eGFR) between the two groups (−0.62 ± 11.2 mL/min/1.73 m2 vs −3.67 ± 13.2 mL/min/1.73 m2; P = 0.291).ConclusionTAF is safe and effective against HBV reactivation.

APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients

Chronic hepatitis B virus (HBV) infection is currently incurable. Long-term treatment with potent and safe nucleos(t)ide analogs (NAs) can reduce hepatocellular carcinoma (HCC) and cirrhosis-related complications through profound viral suppression. However, indefinite therapy raises several crucial issues with pros and cons. Because seroclearance of hepatitis B surface (HBsAg) as functional cure is not easily achievable, a finite therapy including sequential 48-week pegylated interferon therapy may provide an opportunity to facilitate HBsAg seroclearance by the rejuvenation of exhausted immune cells. However, the cost of stopping NA is the high incidence of virological relapse and surge of alanine aminotransferase (ALT) levels, which may increase the risk of adverse outcomes (e.g., decompensation, fibrosis progression, HCC, or liver-related mortality). So far, the APASL criteria to stop NA treatment is undetectable HBV DNA levels with normalization of ALT; however, this criterion for cessation of treatment is associated with various incidence rates of virological/clinical relapse and more than 40% of NA-stoppers eventually receive retreatment. A very intensive follow-up strategy and identification of low-risk patients for virological/clinical relapse by different biomarkers are the keys to stop the NA treatment safely. Recent studies suggested that decreasing HBsAg level at the end-of-treatment to < 100-200IU/mL seems to be a useful marker for deciding when to discontinue NAs therapy. In addition, several viral and host factors have been reviewed for their potential roles in predicting clinical relapse. Finally, the APASL guidance has proposed rules to stop NA and the subsequent follow-up strategy to achieve a better prognosis after stopping NA. In general, for both HBeAg-positive and HBeAg-negative patients who have stopped treatment, these measurements should be done every 1-3months at the minimum until 12months.

Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus.

Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.

Entecavir Monotherapy Prevents Hepatitis B Virus Recurrence After Liver Transplant for Chronic Hepatitis B Patients: A Long-Term Retrospective Study

Limited data are available on the use of oral antiviral therapy, particularly the long-term use of entecavir monotherapy in patients with hepatitis B virus (HBV)-related diseases after liver transplant (LT). The clinical data on consecutive patients who underwent LT for HBV-related diseases from 2011 to 2019 were prospectively collected and retrospectively analyzed. All patients received entecavir monotherapy alone during the follow-up period; viral serology/load and liver biochemical tests were performed regularly. Among the total of 89 patients were patients with decompensated cirrhosis (n=27 [30%]), acute-on-chronic HBV (n=21 [24%]), and hepatocellular carcinoma (HCC) (n=41 [46%]). The median age of the patients was 50 years (range, 42-58 years), and the median follow-up was 37 months (range, 1-96 months). Before LT, 45 (51%) patients did not receive, whereas 44 (49%) were currently receiving, oral antiviral therapy. At the time of LT, serum level of HBV DNA of 34 (38%) patients was >20 IU/mL, with the median level being 270,000 IU/mL (range, 4270-2,020,000), and 53 patients (59%) had undetectable levels of HBV DNA (≤20 IU/mL). The cumulative rate of hepatitis B surface antigen loss was 79.8%, 100%, and 100% after 1 month, 1 year, and 5 years, respectively. Hepatitis B surface antigen positivity returned after seroclearance in 1 patient, who died of HCC recurrence with an undetectable level of HBV DNA. The overall survival rates at 1, 3, and 5 years after LT were 94.51%, 86.84%, and 85.27%, respectively. During the follow-up period, no entecavir adverse reactions or dose reductions were observed. Long-term entecavir monotherapy was highly effective in preventing HBV reactivation and HBV-related diseases.

CccDNA Maintenance in Chronic Hepatitis B - Targeting the Matrix of Viral Replication.

Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma, despite an effective prophylactic vaccine and well-tolerated and effective oral antivirals. Both the incapacity of the immune system to clear hepatitis B virus (HBV) infection and the unique replication strategies adopted by HBV are considered key determinants of HBV chronicity. In this regard, the formation of the HBV DNA minichromosome, the covalently closed circular DNA (cccDNA), in the nucleus of infected hepatocytes, is essential not only for the production of all viral proteins but also for HBV persistence even after long-term antiviral therapy. Licensed polymerase inhibitors target the HBV reverse transcriptase activity, control the disease with long-term therapy but fail to eliminate the cccDNA. Consequently, the production of viral RNAs and proteins, including the hepatitis B surface antigen (HBsAg), is not abolished. Novel therapeutic efforts that are in the pipeline for early clinical trials explore novel targets and molecules. Such therapeutic efforts focus on achieving a functional cure, which is defined by the loss of HBsAg and undetectable HBV DNA levels in serum. Since a true cure of HBV infection requires the elimination of the cccDNA from infected cells, comprehension of the mechanisms implicated in cccDNA biogenesis, regulation and stability appears necessary to achieve HBV eradication. In this review, we will summarize the state of knowledge on cccDNA metabolism, focusing on insights suggesting potential weak points of the cccDNA that may be key for the development of therapeutic approaches and design of clinical trials aiming at lowering cccDNA loads and activity.

Efficacy and safety of tenofovir alafenamide fumarate for preventing mother-to-child transmission of hepatitis B virus: a national cohort study.

Data on tenofovir alafenamide fumarate (TAF) for preventing mother-to-child transmission of hepatitis B virus (HBV) are lacking. To investigate the efficacy and safety of TAF therapy for preventing hepatitis B mother-to-child transmission. Mothers with chronic HBV infection, positive for hepatitis B e-antigen and with HBV DNA >200 000 IU/mL received TAF for preventing mother-to-child transmission were enrolled retrospectively from multiple centres with data collection on mother-infant dyads up to postpartum week 24-28. Primary measurements were the mother-to-child transmission rate and infants' malformation rate. Secondary assessments included maternal HBV DNA reduction at delivery, and maternal or infant adverse events during follow up. Among 71 mothers enrolled, the mean (±SD) age was 30.3 (±2.2) years. TAF was initiated during the second or third trimester and continued to delivery with a mean (±SD) duration of 12.8 (±4.0) weeks. At delivery, 85.9% (61/71) of the mothers achieved HBV DNA <200 000 IU/L. Seventy-three infants (two sets of twins) were born from mothers treated with TAF and none had congenital defects or malformations. All infants received HBV immunoglobulin and vaccine at birth with additional HBV vaccinations at one and six months. At age 24-28 weeks, all infants had negative hepatitis B surface antigen and undetectable levels of HBV DNA (<100 IU/mL). Body weight, height, and head circumferences were comparable to national standards for physical development. No severe adverse effects were reported in either mothers or infants. TAF for highly viraemic mothers effectively prevented mother-to-child transmission of hepatitis B. There were no safety concerns for either mothers or infants with 24-28 weeks of follow up.

Impact of Lamivudine-Based Antiretroviral Treatment on Hepatitis B Viremia in HIV-Coinfected South Africans.

This prospective study investigated the impact of lamivudine-containing antiretroviral therapy (ART) on HIV-positive patients in South Africa with baseline hepatitis B virus (HBV) infection. Follow-up samples from 56 HBV/HIV co-infected patients, 25 with occult HBV infection (OBI) and 31 with chronic HBV infection (CHB), were available for analysis. HBV viral loads were quantified at 6, 12, 18, and 24 months post-ART initiation by the COBAS TaqMan HBV Test 48 assay, and the HBV polymerase gene was amplified with an in-house nested polymerase chain reaction assay. During 24 months of lamivudine-based ART, 6 of 8 (75%) OBI and 4 of 6 (67%) CHB patients achieved undetectable levels of HBV DNA, while 2 patients had persistent HBV DNA levels ≥ 2 × 105 despite lamivudine-based ART for 24 months. HIV viremia was undetectable in all patients at 12 months, suggesting high adherence to ART. Several lamivudine-associated HBV resistance mutations, including L180M, A181T, M204I, and M204V, were observed. Sequence analysis also revealed a rare genotype G infection. While resource-limited settings may use lamivudine-based ART because of availability and low cost, antivirals with dual therapy against HBV and HIV (e.g., lamivudine and tenofovir) should always be recommended with the regular monitoring of HBV viremia levels.

Can we cure hepatitis B virus with novel direct-acting antivirals?

Current treatments against chronic hepatitis B (CHB) include pegylated interferon alpha (Peg-IFNα) and nucleos(t)ide analogs (NAs), the latter targeting the viral retrotranscriptase, thus inhibiting de novo viral production. Although these therapies control infection and improve the patient's quality of life, they do not cure HBV-infected hepatocytes. Acomplete HBV cure is currentlynot possible because of the presence of the stable DNA intermediate covalently closed circular DNA (cccDNA). Current efforts are focused on achieving a functional cure, defined by the loss of Hepatitis B surface antigen (HBsAg) and undetectable HBV DNA levels in serum, and onexploring novel targets and molecules that are in the pipeline for early clinical trials. The likelihood of achieving a long-lasting functional cure, with no rebound after therapy cessation, is higher using combination therapies targeting different steps in the hepatitis B virus (HBV) replication cycle. Noveltreatments and their combinations are discussed for their potential to cure HBV infection, as well as exciting new technologies that could directly target cccDNA and cure without killing the infected cells.

The association of vitamin D with hepatitis B virus replication: Bystander rather than offender

Low vitamin D is frequent in hepatitis B virus (HBV)-infected patients and several studies show an inverse association of serum vitamin D level with HBV viral load. However, the causal relationship remains unclear. HBV carriers receiving regular 6-month surveillance without current antiviral treatment or cirrhosis were invited to participate into this trial. The markers of HBV replication included serum HBV DNA and quantitative HBsAg (qHBsAg) levels. Those with undetectable HBV DNA or sufficient vitamin D levels, cancer or electrolyte imbalance were excluded. The eligible subjects were randomized to receive either vitamin D supplement 2000 IU per day for 2 months (vitamin D group) or none (control group). A total of 196 HBV carriers (93 males and 103 females; mean age 51.9±10.0 years) were screened. Of them, 28 patients had undetectable serum HBV DNA levels, which is defined as spontaneous viral clearance. The vitamin D levels were not different between patients with detectable HBV DNA and those without (p=0.18). After exclusion, 149 patients were randomized to two groups: 75 in vitamin D group and 74 in control group. After 2 months vitamin D supplement, the serum vitamin D levels were significantly higher in the vitamin D group than the control group (p<0.001). However, the serum qHBsAg and HBV DNA levels were comparable between these two groups. There is no causal relationship between vitamin D and HBV replication. The role of liver reserve on serum vitamin D levels in patients with chronic HBV infection needs further investigation.

Возможность использования количественного определения HBsAg при хронической HBV-инфекции с дельта-агентом

We have conducted a pilot study to identify the association between the HBsAg level and activity of the pathological process in the liver, as well as possibility of quantitative assessment of HBsAg for monitoring chronic liver diseases caused by hepatitis B virus (HBV) and hepatitis D virus (HDV). Objective. To assess the possibility of using HBsAg levels as a predictor of disease activity and prognosis in patients with chronic HBV infection with delta-agent. Patients and methods. We analyzed serum specimens from 30 patients with HDV and HBV co-infection. Among 15 patients with chronic hepatitis B with delta-agent, there were 5 HBV DNA positive and 10 HBV DNA negative. Among patients with liver cirrhosis, HBV DNA was detected in 11 individuals, while 4 individuals had undetectable HBV DNA levels. Results. We found that mean HBsAg level in patients with chronic HBV infection and negative HBV DNA was 1.9 ± 0.56 IU/mL. Mean HBsAg level in patients with chronic HBV infection with delta-agent and positive HBV DNA was 4.3 ± 0.62 IU/mL (p &lt; 0.05). High HBsAg levels correlated with elevated ALT in patients with chronic hepatitis B and delta-agent. Patients with liver cirrhosis caused by HDV had normal ALT levels, but elevated bilirubin concentrations regardless of HBV DNA presence and HBsAg level. Conclusion. High levels of HBsAg can be considered as a predictor of active disease in patients with chronic HBV infection with delta-agent and also a marker of transformation of chronic hepatitis B with delta-agent into liver cirrhosis. Key words: chronic hepatitis B with delta agent, liver cirrhosis, enzyme-linked immunosorbent assay, HBsAg levels, polymerase chain reaction

3173 Spontaneous HBsAg Seroclearance in a Patient With Chronic Hepatitis B: Do We Need Surveillance?

INTRODUCTION: Hepatitis B virus (HBV) infection is a global health problem despite an effective vaccination program, routine antenatal screening, and perinatal care. Among the individuals infected with the HBV, about 5 % of adults and 90% of children become chronic carriers. A small percentage of carriers undergo spontaneous seroclearance of Hepatitis B surface antigen (HBsAg). We present a case of spontaneous HBsAg seroclearance in a chronic hepatitis B carrier. CASE DESCRIPTION/METHODS: A 60-year-old Hispanic male with a history of chronic hepatitis B presented to the hepatology clinic for regular follow-up. He was asymptomatic with no stigmata of chronic liver disease. He had been followed in the clinic for nine years. He was HBsAg positive, hepatitis B surface antibody detectable at 6.9 mIU/ml, hepatitis B e antigen (HBeAg) negative, hepatitis B e antibody positive, undetectable HBV DNA levels, and alpha-fetoprotein 17.2 ng/ml. He persistently had normal liver enzymes. Five months after the last positive HBsAg, routine serology showed loss of HBsAg. CT Abdomen with contrast liver protocol showed no evidence of cirrhosis and hepatocellular carcinoma (HCC). The liver biopsy showed no evidence of fibrosis. The patient is on surveillance with a follow-up in 6 months for repeat serology. DISCUSSION: Chronic hepatitis B carriers are at risk of developing decompensated liver cirrhosis and hepatocellular carcinoma. The rate of HBsAg spontaneous seroclearance is estimated to be 1–3% per year. The long-term outcome after HBsAg seroclearance is excellent if there is no pre-existing cirrhosis or viral superinfection. HBsAg carriers who are negative for HBeAg or negative for HBV DNA are more likely to clear HBsAg from serum. AASLD guidelines recommend HCC surveillance in chronic hepatitis B infection, but its usefulness in patients after HBsAg seroclearance without any liver injury remains controversial. Few retrospective studies recommend surveillance in high-risk patients, which include male patients, patients with cirrhosis, HCV superinfection, age ≥50 years at the time of seroclearance and family history of HCC. Surveillance in patients who do not have any risk factors may not be cost effective as the incidence of adverse liver events among them is rare. Our patient had chronic hepatitis B for nine years and underwent spontaneous seroclearance of HBsAg with negative HBeAg and undetectable HBV DNA. He has no evidence of cirrhosis or viral superinfection, thus having a favorable long-term prognosis.

Management of individuals with chronic hepatitis B virus infection and persistent normal or mildly elevated aminotransferase levels.

No consensus exists with respect to positive hepatitis B virus (HBV) DNA results and persistent normal or mildly elevated alanine aminotransferase (ALT). The aim of this study is to investigate the appropriate management and prognosis of these populations with chronic hepatitis B (CHB). A total of 235 subjects with positive HBV DNA results and persistent normal or mildly elevated ALT were enrolled in this study. Liver biopsy and liver stiffness measurements (LSM) were performed in all participants at baseline. Antiviral therapy was initiated in patients with significant hepatic inflammation (G ≥ 2) and/or fibrosis (S ≥ 2). The patients were divided into entecavir and adefovir groups based on HBV DNA load (>2000 IU/mL vs <2000 IU/mL). The liver biopsies were repeated at 72 weeks for the patients received antiviral therapy. We found that 112 subjects were hepatitis B e antigen (HBeAg) positive, and 123 subjects were negative. The corresponding median ALTs were 46 (39.5-52.5) and 48 (41.5-57.0) U/mL, respectively. G ≥ 2 and/or S ≥ 2 diseases were present in 48.8% (82/168) of the HBeAg-positive and 51.2% (86/168) of HBeAg-negative patients, respectively. In addition, 96 HBeAg-positive and 72 HBeAg-negative patients were divided into entecavir and adefovir groups. Meanwhile, liver biopsies had greater diagnostic accuracy for determining cirrhosis than LSM (0.711 vs 1.0, P < 0.0001). At the end of the study period, undetectable HBV DNA levels and normal ALT levels were observed in CHB-infected patients. Furthermore, the patients showed histologic improvement at 72 weeks compared with baseline measurements (G, 1.72 ± 1.00 vs 0.73 ± 0.88, P = 0.0002; S, 1.484 ± 0.90 vs 0.99 ± 1.13, P < 0.0001). Collectively, liver biopsy enhanced diagnostic accuracy for CHB-infected individuals with persistent normal or mildly elevated aminotransferase levels. Moreover, antiviral therapy can improve or regress the hepatic fibrosis and cirrhosis.

Level of Hepatitis B (HB) Core Antibody Associates With Seroclearance of HBV DNA and HB Surface Antigen in HB e Antigen-Seronegative Patients

Although a low level of hepatitis B surface antigen (HBsAg) is a marker of hepatitis B virus (HBV) seroclearance, additional biomarkers are needed for more accurate prediction. We investigated whether quantification of antibody against HBV core protein (anti-HBc) can identify patients with undetectable levels of HBV DNA and HBsAg seroclearance among those who were HBV e antigen (HBeAg)-seronegative. We performed a retrospective analysis of data from a community-based cohort of individuals (30-65 years old) in Taiwan who were HBsAg seropositive, anti-HCV negative, and free of cirrhosis and/or liver cancer, recruited from 1991 through 1992, and evaluated every 6-12 months until June 30, 2004. We measured levels of anti-HBc in blood samples from 2500 participants who were seronegative for HBeAg. The first date at which a sample tested negative for HBV DNA or HBsAg, and remained negative in subsequent tests, was designated as the date of spontaneous HBV DNA undetectability or HBsAg seroclearance. We calculated cumulative incidences of HBV DNA undetectability and HBsAg seroclearance; associations between level of anti-HBc and undetectability of HBV DNA or HBsAg seroclearance were estimated by Cox proportional hazard regression. The effects of time on the associations between level of anti-HBc and HBsAg seroclearance was assessed by the area under the receiver operating characteristic curve (AUROC) analysis. After a 12-year follow-up period, higher proportions of subjects with levels of anti-HBc <3 log IU/mL had undetectable levels of HBV DNA (58%) and HBsAg seroclearance (53%) than subjects with higher levels of anti-HBc (29.6% and 19.8%, respectively) (P < .001). For subjects with levels of HBsAg <102 IU/mL and anti-HBc <3 log IU/mL, the adjusted rate ratio of HBV DNA undetectability was 16.45 (95% CI, 11.15-24.28) and of HBsAg seroclearance was 17.95 (95% CI, 12.49-25.81), compared to subjects with higher levels of HBsAg and anti-HBc. A model that included level of anti-HBc as a parameter identified subjects with HBsAg seroclearance within 10 years with an AUROC of 82%; this value was significantly higher than that from models that include only level of HBV DNA and HBsAg (P < .0001). In a retrospective analysis of a large cohort of patients with chronic HBV infection in Taiwan, we associated levels of anti-HBc <3 log IU/mL with undetectable HBV DNA and HBsAg seroclearance occurred within 10 years; patients who also have levels of HBsAg <102 IU/mL have greater odds. Combining data on levels of HBsAg, HBV DNA, and anti-HBc is able to identify HBeAg-seronegative patients who can achieve HBsAg seroclearance with an AUROC value of 82%.

Clinical impact of the early alanine amininotransferase flare during tenofovir monotherapy in treatment-naïve patients with chronic hepatitis B

Background/AimsLittle is known about the effect of early flares on response during first-line tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB). The aim of this study was to investigate the incidence and outcome of early alanine aminotransferase (ALT) flare in treatment-naive patients with CHB during long-term TDF monotherapy. MethodsOne hundred eighty-one treatment-naive CHB patients were treated with a 300-mg once-daily dose of TDF for more than 12 weeks. Virological markers of hepatitis B virus (HBV) and biochemical data were measured at baseline and every 4-12 weeks during the therapy. The proportion of patients with undetectable HBV DNA level (< 100 copies/mL) was noted. ResultsThe median age was 48.3 years and 122 patients (67.4%) were men. Hepatitis B envelope antigen (HBeAg) was positive in 101 patients (55.8%). No patient had cirrhosis. The median follow-up duration was 45 weeks (12-155 weeks). ALT flare (>5 × upper limit of the normal range) occurred in seven patients (3%) without viral breakthrough within the first 8 weeks after the start of TDF monotherapy. Among them, six patients were HBeAg-positive and one patient was HBeAg-negative. All cases of early ALT flares resolved within 4 weeks and virologic response was observed in all patients without interruption or discontinuation of treatment. ConclusionsContinuous TDF monotherapy was effective and safe in treatment-naive patients with CHB who experienced early ALT flares followed by a decrease in HBV DNA level.

Hepatitis B virus reactivation in HBV DNA-negative patients with hepatocellular carcinoma after transarterial chemoembolization

Objective To evaluate risk factors of hepatitis B virus (HBV) reactivation after transarterial chemoembolization (TACE) in patients with HBV-related hepatocellular carcinoma (HCC) with undetectable HBV DNA levels. Methods From August 2012 to Sepemter 2015, all patients who underwent TACE for HBV-related HCC with HBV DNA level less than 103 copies/ml in the First Affiliated Hospital of Soochow University were enrolled into the study. These patients were followed-up for at least 6 months after TACE to assess HBV reactivation. Univariate and multivariate logistic regression analyses were done to evaluate the risk factors related to HBV reactivation in these patients. Results With predetermined inclusion and exclusion criteria, 99 patients were enrolled into the study. Twenty-four patients (24.2%) developed HBV reactivation after TACE in the followed-up period. The level of transaminase was significantly higher in the HBV reactivation group than the non HBV reactivation group (P<0.05). HBeAg positivity and tumors more than 3 in number were independent risk factors of HBV reactivation. Conclusion HCC patients with undetectable levels of HBV DNA had a significant risk of HBV reactivation after TACE. Key words: Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Hepatitis B virus; Reactivation