Wai-Kay Seto

Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score

BACKGROUND Therapy for chronic hepatitis B reduces the risk of progressing to hepatocellular carcinoma (HCC); however, there is no suitable and accurate means to assess risk. This study aimed to develop and validate a simple scoring system to predict HCC risk in patients with chronic hepatitis B. METHODS The development cohort consisted of 3584 patients without cirrhosis from the community-based Taiwanese REVEAL-HBV study (of whom 131 developed HCC during follow-up), and a validation cohort of 1505 patients from three hospitals in Hong Kong and South Korea (of whom 111 developed HCC during follow-up). We used Cox multivariate proportional hazards model to predict risk of HCC at 3, 5, and 10 years. Variables included in the risk score were sex, age, serum alanine aminotransferase concentration, HBeAg status, and serum HBV DNA level. We calculated the area under receiver operating curve (AUROC) and calibration of predicted and observed HCC risk. FINDINGS A 17-point risk score was developed, with HCC risk ranging from 0·0% to 23·6% at 3 years, 0·0% to 47·4% at 5 years, and 0·0% to 81·6% at 10 years for patients with the lowest and highest HCC risk, respectively. AUROCs to predict risk were 0·811 (95% CI 0·790-0·831) at 3 years, 0·796 (0·775-0·816) at 5 years, and 0·769 (0·747-0·790) at 10 years in the validation cohort, and 0·902 (0·884-0·918), 0·783 (0·759-0·806), and 0·806 (0·783-0·828), respectively, after exclusion of 277 patients in the validation cohort with cirrhosis. Predicted risk was well calibrated with Kaplan-Meier observed HCC risk. INTERPRETATION A simple-to-use risk score that uses baseline clinical variables was developed and validated. The score accurately estimates the risk of developing HCC at 3, 5, and 10 years in patients with chronic hepatitis B. Clinicians can use this score to assess risk of HCC in patients with chronic hepatitis B and subsequently make evidence-based decisions about their clinical management. FUNDING The Academia Sinica; the National Health Research Institute, Taiwan; and Bristol-Myers Squibb.

Hepatitis B Reactivation in Patients With Previous Hepatitis B Virus Exposure Undergoing Rituximab-Containing Chemotherapy for Lymphoma: A Prospective Study

PURPOSE Patterns of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) -negative, antihepatitis B core antigen antibody (anti-HBc) -positive patients with lymphoma receiving rituximab-containing chemotherapy have not been well described. PATIENTS AND METHODS HBsAg-negative, anti-HBc-positive Chinese patients with undetectable serum HBV DNA (< 10 IU/mL), diagnosed with hematologic malignancies and receiving rituximab-containing chemotherapy, were prospectively monitored every 4 weeks for up to 2 years. Entecavir was started when HBV reactivation (defined as detectable HBV DNA) was encountered. RESULTS Among 260 patients receiving rituximab-containing chemotherapy, 63 patients (24.2%) who were HBsAg negative and anti-HBc positive underwent follow-up for a median of 70 weeks (range, 6 to 104 weeks). The 2-year cumulative rate of HBV reactivation was 41.5%, occurring at a median of 23 weeks (range, 4 to 100 weeks) after rituximab treatment. The median HBV DNA level at reactivation was 43 IU/mL (range, 14 to 920 IU/mL). A baseline undetectable antibody to HBsAg (anti-HBs; < 10 mIU/mL) was the only significant risk factor that was positively associated with HBV reactivation (hazard ratio, 3.51; 95% CI, 1.37 to 8.98; P = .009). Patients with negative baseline anti-HBs, compared with those with positive anti-HBs, had a significantly higher 2-year cumulative rate of HBV reactivation (68.3% v 34.4%; P = .012). At HBV reactivation, all patients had normal ALT, and all patients but one were HBsAg negative. Entecavir successfully controlled HBV reactivation in all patients. CONCLUSION A high rate of HBV reactivation was observed in HBsAg-negative, anti-HBc-positive patients undergoing rituximab-containing chemotherapy, with the risk of reactivation significantly higher in anti-HBs-negative patients. Periodic HBV DNA monitoring was an effective strategy in preventing HBV-related complications.

Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B

The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir. The NAs work mainly by inhibiting hepatitis B virus (HBV) DNA polymerase activity and thus suppress HBV replication. Oral NAs have become the mainstay of CHB treatment, mainly due to their profound viral suppressive effects and also due in part to the ease of single daily dosing and lack of significant side effects. One major drawback of NA therapy is the development of drug resistance mutations with long-term treatment. Lamivudine, the first oral NA approved for CHB patients, is associated with high rates of drug resistance, with resultant virological relapse and biochemical flare. Fortunately, newer and more potent NAs, such as entecavir and tenofovir, have very low resistance rates, with potent and durable viral suppression. This review is aimed at the current developments in NAs for CHB treatment, detailing the mechanisms of antiviral activity of the different agents, the efficacy of viral suppression, the achievement of treatment endpoints, the development of drug resistance and the optimal strategies for using these drugs.

Occult Hepatitis B Infection and HBV Replicative Activity in Patients with Cryptogenic Cause of Hepatocellular Carcinoma

We aimed to investigate the incidence of occult hepatitis B infection (OBI) in patients with “cryptogenic” hepatocellular carcinoma (HCC) and to study the HBV replicative activity in these patients. Tumorous and adjacent nontumorous liver tissues were obtained from 33 cryptogenic HCC patients and 28 HCC patients with identifiable causes (13 with chronic hepatitis B [CHB], six with chronic hepatitis C, and nine alcohol‐related). OBI was identified by nested polymerase chain reaction (PCR). Intrahepatic HBV DNA, covalently closed circular DNA (cccDNA), and pregenomic RNA (pgRNA) were quantified by real‐time PCR and reverse‐transcription PCR (RT‐PCR), respectively. OBI was identified in 24 (73%) cryptogenic HCC patients, one (17%) HCC patient with HCV, and five (56%) patients with alcohol‐related HCC. In HCC patients with OBI, HBV DNA were detected in ≥2 HBV genomic regions more often in nontumorous tissues than in tumorous tissues (90% versus 57%, respectively; P = 0.007). Cryptogenic HCC patients with OBI had lower intrahepatic total HBV DNA levels than HCC patients with CHB (median: 0.010 versus 3.19 copies/cell, respectively; P < 0.0001). Only six (26%) cryptogenic HCC patients with OBI had detectable cccDNA (median: <0.0002 copies/cell), which was significantly lower than that of the CHB patients (median: 0.005 copies/cell; P < 0.0001). HBV pgRNA were detectable in 12 (52%) cryptogenic HCC patients with OBI (median: 0.0001 copies/cell), which was significantly lower than that of the CHB patients (median: 2.90 copies/cell; P < 0.001). Conclusion: 73% of patients with apparently unidentifiable causes for HCC were HBV‐related. The detection rate was higher in nontumorous tissues than tumorous tissues. The low intrahepatic HBV DNA and pgRNA levels indicated that persistent viral replication and possibly HBV integration are the likely causes of HCC in OBI patients. (HEPATOLOGY 2011;)

Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study

Background and objective The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) and the role of hepatitis B surface antigen (HBsAg) levels in predicting off-treatment durability has not been well investigated. Methods Following Asia-Pacific Association for the Study of the Liver guidelines, entecavir was stopped in Asian HBeAg negative patients treated for ≥2 years with undetectable HBV DNA levels on ≥3 separate occasions 6 months apart before treatment cessation. HBsAg and HBV DNA levels were prospectively monitored every 6–12 weeks for 48 weeks. Entecavir was restarted if there was virologic relapse (defined as HBV DNA >2000 IU/mL). Result 184 patients (mean age 53.9 years, 67.9% male) were recruited. The cumulative rate of virologic relapse at 24 and 48 weeks was 74.2% and 91.4%, respectively. The median HBV DNA level at virologic relapse was 11 000 (range 2115 to >1.98×108) IU/mL. 42 (25.8%) patients had elevated alanine aminotransferase (median level 97 U/L, range 37–1058 U/L) during virologic relapse. Mean rate of off-treatment HBsAg decline was 0.018 (±0.456) log IU/mL/year. No patients cleared HBsAg. There was no correlation between off-treatment serial HBsAg and HBV DNA levels (r=−0.026, p=0.541). HBsAg levels at the time of entecavir commencement, entecavir cessation and the subsequent rate of HBsAg reduction were not associated with virologic relapse (all p>0.05). Conclusions Entecavir cessation in Asian HBeAg negative CHB resulted in high rates of virologic relapse, suggesting nucleos(t)ide analogue therapy should be continued indefinitely until the recognised treatment endpoint of HBsAg seroclearance.

Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency.

BACKGROUND & AIMS Few studies have investigated the effects of different nucleos(t)ide analogues against hepatitis B virus (HBV) on levels of covalently closed circular DNA (cccDNA) and hepatitis B surface antigen (HBsAg) in patients. We measured the magnitude of reduction of cccDNA and HBsAg by nucleos(t)ide analogue therapy and assessed the correlation between their reductions. METHODS We recruited 124 patients who were treated with 1 of the 5 nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine, or clevudine). All patients had undergone liver biopsy when treatment began (baseline) and 1 year later. The cccDNA and HBsAg levels were measured by real-time polymerase chain reaction and the Elecsys II HBsAg Assay, respectively. RESULTS After 1 year of treatment, HBV in 7 patients had become resistant to the nucleos(t)ide analogue. The remaining 117 patients had an average reduction of approximately 0.2 log10 IU/mL in HBsAg, 5 log10 IU/mL in serum level of HBV DNA, 2 log10 copies/cell in intrahepatic total HBV DNA, and 1 log10 copies/cell in cccDNA. Although 88 of 117 patients (75%) had undetectable serum levels of HBV DNA (<12 IU/mL), all had detectable levels of HBsAg, and only 5 (4%) had undetectable levels of cccDNA. On treatment with nucleos(t)ide analogues, patients with greater reductions in levels of cccDNA had greater reductions in HBsAg, but these reductions did not reach statistically significant correlations. CONCLUSIONS Although nucleos(t)ide analogues potently reduced serum levels of HBV DNA, the reduction of HBsAg and cccDNA was small. In short-term therapy, the magnitude of HBsAg reduction does not correlate with that of cccDNA reduction.

Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region.

Hepatocellular carcinoma (HCC) is the predominant primary liver cancer in many countries and is the third most common cause of cancer-related death in the Asia-Pacific region. The incidence of HCC is higher in men and in those over 40 years old. In the Asia-Pacific region, chronic hepatitis B virus and hepatitis C virus infections are the main etiological agents; in particular, chronic hepatitis B infection (CHB) is still the major cause in all Asia-Pacific countries except for Japan. Over the past two decades, the incidence of HCC has remained stable in countries in the region except for Singapore and Hong Kong, where the incidence for both sexes is currently decreasing. Chronic hepatitis C infection (CHC) is an important cause of HCC in Japan, representing 70% of HCCs. Over the past several decades, the prevalence of CHC has been increasing in many Asia-Pacific countries, including Australia, New Zealand, and India. Despite advancements in treatment, HCC is still an important health problem because of the associated substantial mortality. An effective surveillance program could offer early diagnosis and hence better treatment options. Antiviral treatment for both CHB and CHC is effective in reducing the incidence of HCC.

Oral Nucleoside/Nucleotide Analogs Without Hepatitis B Immune Globulin After Liver Transplantation for Hepatitis B

OBJECTIVES:The long-term outcomes of oral antiviral therapy without hepatitis B immune globulin (HBIG) in prevention of reinfection with hepatitis B after liver transplantation are not known. We aimed to determine the long-term outcomes from a large population of chronic hepatitis B (CHB) liver transplant recipients using oral antiviral therapy alone.METHODS:A total of 362 consecutive CHB patients transplanted from January 2003 to May 2011 were included. None of the patients received HBIG. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up.RESULTS:Of the 362 patients, 176 (49%), 142 (39%), and 44 (12%) were on lamivudine (LAM), entecavir (ETV), and combination therapy (predominantly LAM+adefovir), respectively, at the time of transplant. The median follow-up length was 53 months. The rate of hepatitis B surface antigen seronegativity and hepatitis B virus (HBV) DNA suppression to undetectable levels at 8 years was 88 and 98%, respectively. The virological relapse rates (>1 log increase IU/ml) at 1, 3, 5, and 8 years was 5, 10, 13 and 16%, respectively. The virological relapse rate at 3 years for LAM, ETV, and combination group was 17, 0, and 7%, respectively (P<0.001). Forty-two patients had virological relapse, of which 36 had YMDD mutation (31 in the LAM group and 5 in the combination group). The overall 8-year survival was 83%, with no difference between the three treatment groups (P=0.94). No mortality from HBV recurrence occurred in the 362 patients.CONCLUSIONS:Oral nucleoside/nucleotide analogs without HBIG are effective in preventing graft loss secondary to hepatitis B recurrence after liver transplantation. However, new agents with a high barrier to resistance should be used to minimize drug resistance and to prevent virological rebound.

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

BACKGROUND The novel prodrug tenofovir alafenamide delivers the nucleotide reverse transcriptase inhibitor tenofovir to target cells more efficiently at a lower dose than tenofovir disoproxil fumarate, thereby reducing systemic exposure. We compared the efficacy and safety of the two drugs in patients with HBeAg-negative chronic hepatitis B virus (HBV) infection in a non-inferiority study. METHODS In this ongoing randomised, double-blind, phase 3, non-inferiority study in 105 centres in 17 countries, patients with HBeAg-negative chronic HBV were randomly assigned (2:1) by a computer-generated allocation sequence (block size six), stratified by plasma HBV DNA concentration and previous treatment status, to receive once-daily oral doses of tenofovir alafenamide 25 mg or tenofovir disoproxil fumarate 300 mg, each with matching placebo. Participants, investigators, and those assessing outcomes were masked to group assignment. Eligible patients were aged at least 18 years with HBeAg-negative chronic HBV infection (with plasma HBV DNA concentrations of >20 000 IU/mL), serum alanine aminotransferase concentrations of greater than 60 U/L in men or greater than 38 U/L in women and at no more than ten times the upper limit of normal, and estimated creatinine clearance of at least 50 mL/min (by the Cockcroft-Gault method). The primary efficacy endpoint was the proportion of patients who had HBV DNA less than 29 IU/mL at week 48 in those who received at least one dose of study drug; the study was powered to show non-inferiority with a 10% efficacy margin of tenofovir alafenamide compared with tenofovir disoproxil fumarate. Bone and renal safety, and key secondary safety endpoints were assessed sequentially. The study will be conducted for a total of 3 years as a double-blind comparison to assess the longer term response to treatment. This study is registered with ClinicalTrials.gov, number NCT01940341. FINDINGS Between Sept 12, 2013, and Oct 31, 2014, 426 patients were randomly assigned (285 assigned to tenofovir alafenamide and 141 assigned to tenofovir disoproxil fumarate; one patient assigned to tenofovir disoproxil fumarate did not receive the treatment. 268 (94%) of 285 patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48 versus 130 (93%) of 140 patients receiving tenofovir disoproxil fumarate (difference 1·8% [95% CI -3·6 to 7·2]; p=0·47), which demonstrates non-inferiority. Patients receiving tenofovir alafenamide had significantly smaller mean percentage declines in bone mineral density than those receiving tenofovir disoproxil fumarate (hip -0·29% [95% CI -0·55 to -0·03] vs -2·16% [-2·53 to -1·79], adjusted percentage difference 1·87% [95% CI 1·42 to 2·32; p<0·0001]; spine -0·88% [-1·22 to -0·54] vs -2·51% [-3·09 to -1·94], adjusted percentage difference 1·64% [95% CI 1·01 to 2·27]; p<0·0001). At week 48, mean change in serum creatinine was small in both groups (tenofovir alafenamide 0·01 mg/dL [95% CI 0·00 to 0·02] vs tenofovir disoproxil fumarate 0·02 mg/dL [0·00 to 0·04], adjusted percentage difference -0·01 mg/dL [95% CI -0·03 to 0·01]; p=0·32), but patients receiving tenofovir alafenamide had a smaller reduction in creatinine clearance (median change in estimated glomerular filtration rate -1·8 mL/min [IQR -7·8 to 6·0] vs -4·8 mL/min [-12·0 to 3·0]; p=0·004). Most adverse events were mild to moderate in severity in the two treatment groups. The most common adverse events overall were headache (tenofovir alafenamide 40 [14%] patients vs tenofovir disoproxil fumarate 14 [10%] patients), nasopharyngitis (30 [11%] vs 15 [11%]), and upper respiratory tract infection (35 [12%] vs ten [7%]). 14 (5%) patients receiving tenofovir alafenamide and nine (6%) patients receiving tenofovir disoproxil fumarate had serious adverse events, none of which was deemed by investigators to be related to study treatment; one patient in the tenofovir disoproxil fumarate group died, but this was not deemed to be related to study treatment. INTERPRETATION In patients with HBeAg-negative chronic HBV, the efficacy of tenofovir alafenamide was non-inferior to that of tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING Gilead Sciences.

A large case‐control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance

The kinetics of hepatitis B surface antigen (HBsAg) levels preceding spontaneous HBsAg seroclearance has not been fully investigated. The kinetics of HBsAg and hepatitis B virus (HBV) DNA of 203 treatment‐naïve, hepatitis B e antigen (HBeAg)‐negative patients with spontaneous HBsAg seroclearance were compared with 203 age‐ and sex‐matched HBeAg‐negative controls. Serum samples at 3 years, 2 years, 1 year, and 6 months before HBsAg seroclearance and at the time of HBsAg loss were tested. Median HBsAg levels at these respective time points before HBsAg seroclearance were 23.5, 3.51, 0.524, and 0.146 IU/mL. For all time points, patients with HBsAg seroclearance had significantly lower median HBsAg and HBV DNA levels, compared to those of the controls (all P < 0.001). Median HBsAg and HBV DNA levels declined significantly until HBsAg seroclearance (P < 0.001). Although median HBsAg levels also decreased significantly with time (P = 0.006) in controls, median HBV DNA levels remained similar (P = 0.414). Serum HBsAg levels, followed by HBsAg log reduction, were the best predictors of HBsAg seroclearance, with an area under the receiving operator characteristic (AUROC) of 0.833 (95% confidence interval [CI]: 0.792‐0.873) and 0.803 (95% CI: 0.755–0.849), respectively. The optimal cut‐off HBsAg level and HBsAg reduction to predict HBsAg seroclearance were <200 IU/mL (sensitivity, 84.2%; specificity, 73.4%) and 0.5 log IU/mL/year (sensitivity, 62.8%; specificity, 88.7%), respectively. For patients with HBsAg levels ≥200 IU/mL, an annual 0.5‐log reduction was highly predictive of subsequent HBsAg seroclearance (AUROC, 0.867; 95% CI: 0.778‐0.956). Conclusion: To conclude, serum HBsAg <200 IU/mL and 0.5‐log reduction in HBsAg were predictive of HBsAg seroclearance within 3 years of follow‐up. These parameters may serve as good indicators for the consideration of treatment duration and cessation for chronic hepatitis B. (HEPATOLOGY 2012;56:812–819)