China CDC Weekly Recollection Control of Chronic Hepatitis B in China: Perspective of Diagnosis and Treatment Yu Wang1; Min Wang1; Guanhua Zhang1; Xiaojuan Ou1; Hong Ma1; Hong You1; Jidong Jia1,# In the last three decades, China has made and guide antiviral therapy. Recently, the clinical extraordinary effort and achieved great progress in the utility of some novel markers have been investigated in control of hepatitis B. Thanks to the adoption of patients with HBV infection. Quantitative HBsAg universal administering of HBV vaccinations for (qHBsAg) levels are correlated with intra-hepatic newborns since 1992, the prevalence of hepatitis B covalently closed circular DNA (cccDNA) and can surface antigen (HBsAg) in the population born after predict treatment response (9). Baseline anti-HBc 1992 decreased significantly resulting in a decline in quantification (qAnti-HBc) may serve as a useful the general population from 9.75% to about 6% (1). marker indicating ongoing host-immune activity In the last 10 years, under the support of national against HBV, with high levels of anti-HBc being used major scientific research grants, many multicenter, to predict the loss of hepatitis B envelope antigen randomized controlled trials (RCTs) have been (HBeAg) (10–12), the efficacy of antiviral therapy conducted, generating more and more clinical evidence (13–14), and the absence of HBV relapse after for antiviral therapy for chronic hepatitis B (CHB) (2). treatment cession (15). HBV core-related antigen From 2005 to 2019, 4 editions of “Guidelines on the (HBcrAg) is a novel serum marker measuring Prevention and Treatment of Chronic Hepatitis B” composite viral protein and considered to be a surrogate were jointly issued by 2 sister branches of the Chinese marker of intrahepatic HBV cccDNA. A decrease in Medical Association including the Chinese Society of HBcrAg is related to the loss of HBeAg and HBsAg Hepatology and Chinese Society of Infectious Diseases and the safe discontinuation of antivirus treatment. (3–6). Sustained effort on continued medical HBcrAg may also be helpful for predicting hepato cellular education based in the clinical guidelines have raised carcinoma (HCC) development. Serum pre-genomic the knowledge base of specialists and internists and RNA (pgRNA) transcribed from HBV cccDNA has a improved the standard of care for CHB (7). Recently, strong correlation with intrahepatic cccDNA and is the National Healthcare Secrurity Adminstration has conducted government negotiations to massively considered to be an indirect marker of reservoir size reduce the price of antiviral medicine. The (16–17). These novel serum markers provide useful improvement of the reimbursement policy together tools for better monitoring of disease progression and with increased patient accessibility and affordability for evaluation of the efficacy of antiviral therapy. antiviral therapy have increased the uptake of antiviral TE is a noninvasive tool with ease of operation, therapy and improved the clinical outcomes (8). As a good repeatability, and reasonable accuracy for result, considerable progress has been made in identifying liver fibrosis or early cirrhosis. A diagnosis and treatment, making it possible to control multicenter study validated the diagnostic performace hepatitis B in China. of TE measured by FibroScan to stage liver fibrosis in a cohort of 469 Chinese patients with CHB (18). Another device for TE measurement (FibroTouch) has IMPROVEMENTS IN DIAGNOSTIC also comfirmed its clinical utility in a single-center MODALITY prospective study including 435 chronic liver disease paitents including 237 CHB paitents (19). In recent years, new serological markers, transient To quantitatively measure the degree of liver fibrosis elastography (TE), and novel pathological criteria in in CHB patients, an automatic digital technique the diagnosis of CHB have been extensively investiaged qFbrosis has been investigated and shown promising and increasingly used in China. Conventional HBV results (20). In complementary to Ishak modified serological markers have been widely used in patients histology activity index (HAI) and Ishak fibrosis score, with CHB to establish the phases of HBV infection a new classification (Beijing Classification) has been 596 CCDC Weekly / Vol. 2 / No. 31 Chinese Center for Disease Control and Prevention China CDC Weekly proposed by Chinese investigators that further divides HBeAg Seroconversion in HBeAg-positive CHB fibrosis beyond stage 3 into predominantly progressive, Patients with Combination and Sequential Treatment indeterminate, and predominately regressive (P-I-R of PegIFN alfa-2a and ETV” (OSST) study, score) to assess the dynamic changes in fibrosis pre- “Switching to PegIFN a-2a in NUC treated CHB and post-antiviral therapy (21). Recently, one study patients ” (NEW SWITCH) study, Endeavor Study, using the Beijing classification found that liver fibrosis and Anchor study, Chinese researchers proposed a progression was associated with low serum HBV DNA roadmap for NA-Peg-IFN sequential therapy. In level (20–200 IU/mL) at week 78 of nucleoside particular, in patients who achieved undectable HBV, (nucleotide) analogue (NA) therapy, indicating that the loss of HBeAg, and a low level of HBsAg (<1,500 switching to or adding a more potent antiviral agent IU/mL) under NA therapy, adding or swiching to Peg- would benefit these patients (22). IFN could yield a relatively higher rate of HBsAg loss ((and a low level of HBsAg (<1,500 IU/mL) under NA IMPROVEMENT IN CLINICAL STUDIES therapy, adding or swiching to Peg-IFN could yield a OF ANTIVIRAL THERAPY relatively higher rate of HBsAg loss (33–39). Furthermore, a prospective cohort study from China showed that Peg-IFNα-2a-based therapy could reach In the last decade, both the number and quality of high rates of HBsAg clearance (29.8% and 44.7% at clinical studies on treatment of HBV has dramatically week 48 and 96, respectively) and seroconversion improved (2). A large number of studies conducted by (20.2% and 38.3% at week 48 and 96, respectively) Chinese hepatologists showed that NA treatment can in patients diagnosed as inactive HBsAg carrier strongly suppress virus replication, improve liver status (40). histology, reduce the risk of complications and HCC progression, and reduce liver related all-cause mortality (23–27). An observational study showed that entecavir UPDATE OF GUIDELINES AND OF (ETV) monotherapy is associated with less virological EDUCATION ACTIVITY breakthroughs and potentially higher HBV-DNA suppression than de novo combinationof lamivudine The guidelines on the Prevention and Treatment for (LAM) and adefovirdipivoxil (ADV) during 3 years of Chronic Hepatitis B were first jointly published by the treatment for naïve HBV-related compensated liver Chinese Society of Hepatology and Chinese Society of cirrhosis (28). Another real world study also Infectious Diseases in 2005, and updated in 2010, demonstrated that ETV was efficacious and well tolerated 2015, and 2019. The 2019 version of the guidelines through 48 weeks of treatment in a heterogeneous has two important changes (3). First, antiviral therapy Chinese CHB population (29). A nationwide observational is recommended if aminotransferase (ALT) is higher study showed that more than 50% of patients with than 1 times instead of 2 times of the upper limit of CHB in Tier-2 city hospitals in China initially received normal levels (ULN, 40 IU/L for both men and ETV therapy, which not surprisingly was more women) for those with evidence of cirrhosis, effective than LAM-based treatments and associated intermediate degree of necroinflammation/fibrosis on with lower rate of treatment modification (30). non-invasive modality or on liver histology, older than Effective viral suppression is necessary to reduce 30 years, or family history of HCC/cirrhosis. This HCC development in cirrhotic patients (31). expansion of treatment indications will convey the Tenofovir disoproxil fumarate (TDF) and ETV are benefit to antiviral therapy for larger populations, first-line therapies, and in recent years, controversy thereby reducing the risk of disease progression. exists on which one is superior to reduce the risk of Secondly, ETV, TDF, tenofoviralafenamide (TAF), HCC development. A meta-analysis was performed by and Peg-IFNαare recommended as the first-line Chinese researchers to clarify this issue with critical choice for treatment of naïve patients, which is in line clinical and methodological considerations, showing with recommendations from the World Health that disparities in follow-up duration may be a key Organization (WHO), American Association for the factor to influence the results (32). Study of Liver Diseases (AASLD), Asian Pacific Combination or sequential strategies based on the Association for the Study of the Liver (APASL) and potent antiviral effect of NA and immune modulation European Association for the Study of the of interferons (IFN) have been estenstively explored in Liver (EASL); however, LAM, telbivudine (LdT), and China. Based on evidence from the “Optimising ADV are not recommended. Chinese Center for Disease Control and Prevention CCDC Weekly / Vol. 2 / No. 31 597 China CDC Weekly With the update of the guidelines, educational increased from 13.5% in 2003 to 79.7% in 2016 (42), activities, and training programs were conducted to and the proportions in cirrhotic paitents increased improve the standard of care (SOC) for CHB in from 41.9% in 2010 to 92.8% in 2019 (43). China, especially in health