Asian consensus recommendations on optimizing the diagnosis and initiation of treatment of hepatitis B virus infection in resource‐limited settings

Asia has an intermediate‐to‐high prevalence of and high morbidity and mortality from hepatitis B virus (HBV) infection. Optimization of diagnosis and initiation of treatment is one of the crucial strategies for lowering disease burden in this region. Therefore, a panel of 24 experts from 10 Asian countries convened, and reviewed the literature, to develop consensus guidance on diagnosis and initiation of treatment of HBV infection in resource‐limited Asian settings. The panel proposed 11 recommendations related to diagnosis, pre‐treatment assessment, and indications of therapy of HBV infection, and management of HBV‐infected patients with co‐infections. In resource‐limited Asian settings, testing for hepatitis B surface antigen may be considered as the primary test for diagnosis of HBV infection. Pre‐treatment assessments should include tests for complete blood count, liver and renal function, hepatitis B e‐antigen (HBeAg), anti‐HBe, HBV DNA, co‐infection markers and assessment of severity of liver disease. Noninvasive tests such as AST‐to‐platelet ratio index, fibrosis score 4 or transient elastography may be used as alternatives to liver biopsy for assessing disease severity. Considering the high burden of HBV infection in Asia, the panel adopted an aggressive approach, and recommended initiation of antiviral therapy in all HBV‐infected, compensated or decompensated cirrhotic individuals with detectable HBV DNA levels, regardless of HBeAg status or alanine transaminase levels. The panel also developed a simple algorithm for guiding the initiation of treatment in noncirrhotic, HBV‐infected individuals. The recommendations proposed herein, may help guide clinicians, to optimize the diagnosis and improvise the treatment rates for HBV infection in Asia.     

Treatment of chronic hepatitis B virus infection: an Asia-Pacific perspective

Chronic hepatitis B infection is a serious health threat in the Asia–Pacific area. A consensus meeting on the treatment of chronic hepatitis B infection was conducted in Hong Kong, in August 1997. It was generally agreed that treatment of chronic hepatitis B infection should be based on the understanding of the natural history of chronic hepatitis B infection. To date, interferon α is the only Food and Drug Administration (FDA)-approved form of therapy for chronic hepatitis B infection. The overall response in Asian patients is unsatisfactory: approximately 15–20% will clear hepatitis B e antigen, but less than 5% will clear hepatitis B surface antigen. Newer immunomodulatory therapies are under trial. In contrast, nucleoside analogues, such as lamivudine (pending FDA approval) and famciclovir, have been shown to be potent suppressors of hepatitis B viral replication; however, their role as monotherapy in the treatment of chronic hepatitis B infection remains to be defined. Also, the issues of resistance to nucleoside analogues and withdrawal rebound need to be carefully studied. The future direction of therapy in chronic hepatitis B infection is probably a combination of nucleoside analogues or nucleoside analogues with immunomodulatory therapy.     

Challenge of managing hepatitis B virus and hepatitis C virus infections in resource-limited settings

The global burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and coinfection represents a major public health concern, particularly in resource-limited settings. Elimination of HCV by 2030 has become foreseeable, with effective direct-acting antiviral oral therapies and the availability of affordable generics in low-and-middle-income countries (LMICs). However, access to oral nucleos(t)ide therapy for HBV remains critical and is limited outside the existing global HIV program platforms despite affordable prices. Prevention of mother-to-child transmission of HBV through scaling up of birth dose implementation in LMICs is essential to achieve the 2030 elimination goal. Most individuals living with HBV and/or HCV in resource-limited settings are unaware of their infection, and with improved access to medications, the most significant barrier remains access to affordable diagnostics and preventive strategies. The coronavirus disease 2019 pandemic interrupted hepatitis elimination programs, albeit offered opportunities for improved diagnostic capacities and raised political awareness of the critical need for strengthening health care services and universal health coverage. This review underpins the HBV and HCV management challenges in resource-limited settings, highlighting the current status and suggested future elimination strategies in some of these countries. Global efforts should continue to improve awareness and political commitment. Financial resources should be secured to access and implement comprehensive strategies for diagnosis and linkage to care in resource-constrained settings to fulfill the 2030 elimination goal.     

On‐treatment monitoring of chronic hepatitis B virus infection: An Asian–Pacific perspective

Chronic infection with hepatitis B virus (HBV) is a major global health problem and an important cause of morbidity and mortality from sequelae of liver cirrhosis and hepatocellular carcinoma. In the past decades, better understanding of the natural history and immunopathogenesis of chronic HBV infection and of the development of many powerful antiviral agents has allowed us to improve therapeutic efficacy. Among these agents, nucleos(t)ide analogs are important and potent viral suppressors. However, when administered alone, they are not able to permanently eradicate HBV, and long‐term maintenance therapy is required for therapeutic efficacy. Additionally, prolonged treatment is frequently associated with the emergence of drug‐resistant HBV mutants. Before an ‘ideal’ drug(s), or drug combination, with optimal antiviral efficacy and negligible rates of drug resistance becomes available, the on‐treatment monitoring approach using serum HBV DNA level as a predictor for therapeutic efficacy and drug resistance is useful. However, most countries in the Asia–Pacific region have low income economies, insufficient medical care systems, and low awareness of the disease among the general population and government officers. The easy approach of the road‐map concept using an affordable drug to treat chronic HBV infection is more important in this region. There is already evidence that the long‐term outcomes of chronic HBV infection can be improved under well‐managed antiviral therapy. Profound and long‐lasting suppression of HBV replication, either maintained on‐therapy or sustained after stopping therapy, has been identified as the key determinant for achieving the goals of therapy, for reducing liver damage, and for preventing development of cirrhosis and/ or hepatocellular carcinoma.     

Pregnancy and chronic hepatitis B virus infection

The combination of chronic hepatitis B virus (HBV) infection and pregnancy presents unique management questions. Aspects of care that need to be considered include effects of hepatitis B on pregnancy, effects of pregnancy itself on the course of hepatitis B infection, treatment of hepatitis B during pregnancy and prevention of mother-to-infant transmission. Chronic HBV infection is usually mild in pregnant women, but may flare shortly after delivery. Effect of HBV infection on pregnancy outcomes are generally favorable, but may depend on severity of liver disease. Mother-to-infant transmission can be minimized by current immunoprophylaxis strategies, however, high levels of viremia in mothers may be a factor in the small but reproducible failure rate of current immunoprophylaxis strategies. Use of antivirals during pregnancy needs to be individualized. Careful planning and management of pregnancy must be done among patients with chronic HBV infection.     

慢性乙型病毒性肝炎治疗现状和展望

HBV感染是导致肝硬化和肝癌的主要原因,在过去20余年里,慢性乙型肝炎的治疗药物主要为干扰素和核苷(酸)类似物两大类,它们虽然能有效抑制病毒复制,但仍面临HBsAg清除率极低,安全停药难等问题,难以实现"临床治愈(或功能性治愈)"。新型的血清标志物的出现为指导临床如何安全停用抗病毒药物开辟了新的途径,同时,治疗慢性乙型肝炎的新型药物和生物制剂的崛起也给慢性乙型肝炎患者带来福音。     

Reactivation of hepatitis B virus during interferon‐free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co‐infection

Direct‐acting antiviral agents (DAA) for hepatitis C virus (HCV) are not effective for hepatitis B virus (HBV), which may be suggestive of reactivation of anti‐HBe hepatitis during interferon (IFN)‐free DAA therapy in HBV/HCV co‐infected patients with inactive HBV. A 69‐year‐old male patient was diagnosed with chronic hepatitis due to HBV/HCV co‐infection with serum levels of alanine aminotransferase (ALT) of 94 U/L, HCV RNA of 4.2 log IU/mL and HBV DNA of 2.5 log copies/mL. HCV was thought to be responsible for the hepatitis activity because of low level of HBV core‐related antigen (3.1 log U/mL). He was treated with combination therapy of daclatasvir and asunaprevir. Serum ALT gradually increased, and reached 237 U/L on day 43 in spite of undetectable HCV RNA. Serum HBV DNA was increasing to 7.0 log copies/mL at that time. The treatment was stopped due to suspicion of drug‐induced liver injury and/or HBV reactivation. Administration of entecavir reduced HBV DNA levels, followed by improvement in ALT levels. This report proposes that close monitoring of HBV DNA during the anti‐HCV DAA therapy and the commencement of anti‐HBV therapy with nucleoside analogs after the increase of HBV DNA should be considered in patients with HBV/HCV co‐infection.     

Clinical and histological impact of previous hepatitis B virus infection in patients with chronic hepatitis C

Background: Recent reports suggest that hepatitis C virus (HCV) carriers with serological markers of prior hepatitis B virus (HBV) infection have more advanced liver fibrosis, irrespective of HBV‐DNA detection. Aims: We sought to assess the prevalence and impact of previous HBV infection in patients with HCV chronic infection. Methods: This cross‐sectional study included hepatitis B surface antigen‐ and human immunodeficiency virus‐negative subjects with positive HCV‐RNA. All patients had prior parenteral exposure as the probable source of HCV infection. Serum samples were tested for HBV‐DNA using a commercial assay. The METAVIR system was used for histological analysis. Results: One‐hundred and eleven patients were evaluated. Thirty‐one out of 111 patients (28%) tested positive for antihepatitis B core antigen (anti‐HBc). HBV‐DNA was not detected in any sample. Anti‐HBc‐positive patients showed higher histological grading, staging and a higher fibrosis progression rate. By multivariate analysis, anti‐HBc‐positivity was predictive of moderate to severe activity [odds ratio (OR)=3.532; P=0.032] and significant hepatic fibrosis (OR=3.364; P=0.017). After approximately 20 years of infection, advanced liver fibrosis (F3/F4) can be expected in 13% of anti‐HBc‐negative subjects who acquired HCV before the age of 30 and in 57% of those anti‐HBc‐positive patients who were infected by HCV after 30 years of age (P<0.001). Conclusion: Previous HBV infection is common among HCV carriers and may exert a negative impact on the natural history of HCV infection, independently of the presence of significant HBV replication.     

Forgotten,not neglected: viral hepatitis in resource‐limited settings,recall for action

In 2010, the World Health Assembly adopted a resolution calling for interventions for the prevention and control of chronic viral hepatitis. These infectious diseases mostly affect resource‐limited countries accounting for 80% of the world's population and facing numerous obstacles to contain the epidemic. At a time when morbidity and mortality of chronic liver disease have been considerably improved in wealthy countries by new innovative strategies and new potent antiviral drugs, it is now urgent to recall for concrete actions from stakeholders of global health policy to reduce the burden in resource‐limited countries.     

Roadmap to functional cure of chronic hepatitis B: An expert consensus

Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long‐term outcome, and is considered to be a ‘functional cure’ (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct‐acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg‐IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead‐in followed by Peg‐IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients.     

血清乙型肝炎病毒DNA定量在慢性乙型肝炎病毒感染的临床意义

目的:测定慢性HBV感染不同状态时血清HBV-DNA水平,阐明其在判断病情和指导治疗中的价值。方法:共90例慢性HBV感染患者接受研究,共中HBeAg阳性无症状携带者(ASC)15例,HBeAg阳性慢性肝炎(CHB)17例,HBeAg阴性CHB14例,HBeAg阴性ASC16例;另有28例HBeAg阳性CHB接受干扰素治疗。血清HBV-DNA浓度测定应用AG-9600Amplisensor荧光PCR定量系统,测定范围定为10~(3.00-9.50)copies/ml。结果:血清HBV-DNA在HBeAg阳性ASC病例最高,达10~(8.46±0.71)copies/ml,其次依次为HBeAg阳性CHB(10~(7.24±0.54) cooies/ml)、HBeAg阴性CHB(10~(6.04±0.69) copies/ml),HBeAg阴性ASC者最低,为10~(3.80±0.71)copies/ml。4组病例相互之间差异在统计学上均有显著意义(P<0.01)。28例BHeAg阳性CHB患者接受干扰素治疗,治疗结束时呈完全应答(CR)者13例,无应答(NR)15例。对13例CR患者继续随访6个月,其中4例血清ALT再升高(复燃)。血清HBV-DNA水平在治疗前,CR不伴ALT复燃组HBV-DNA为10~(3.44±0.43)copies/ml,明显低于CR伴ALT复燃组(10~(6.84±0.51))(P<0.01)和NR组(10~(7.18±0.66))(P<0.01)。结论:测定血清HBV-DNA水平有助于鉴别慢性HBV感染的不同状态;在HBeAg阳性CHB病例,干扰素治疗结束时,检测HBV-DNA水平对于判断疗效有指导价值,HBV-DNA低于104copies/ml往往能取得持久疗效。     

Long-term clinical impact of occult hepatitis B virus infection in chronic hepatitis B patients

BACKGROUND/AIMS: Long-term clinical outcomes of occult hepatitis B virus (HBV) infection were studied. METHODS: Fifteen chronic hepatitis B patients were monitored for a median of 4.4 years (range 0.9-15.3) after hepatitis B surface antigen (HBsAg) seroclearance. Serum HBV DNA was measured by real-time detection polymerase chain reaction. Thirteen patients underwent liver biopsies at the end of follow-up and liver histology was evaluated by Ishak score. Liver HBV DNA was also measured for 12 patients. RESULTS: At the end of follow-up, HBV viremia was absent in 13 (87%) patients, and antibody titers to hepatitis B core antigen showed an inverse correlation with time from HBsAg seroclearance (r=-0.554; P=0.0040). However, all patients retained liver HBV DNA and tested positive for the covalently closed circular HBV DNA replicative intermediate. The hepatic HBV DNA loads had no relation to liver histology. Paired biopsies from 11 patients disclosed that each necroinflammatory score significantly improved after HBsAg seroclearance. Amelioration of liver fibrosis was also evident in eight (73%) patients (P=0.0391 by signed rank test). CONCLUSIONS: A long-standing but strongly suppressed HBV infection may confer histological amelioration after HBsAg seroclearance.     

Role of occult hepatitis B virus infection in chronic hepatitis C

The development of sensitive assays to detect small amounts of hepatitis B virus(HBV) DNA has favored the identification of occult hepatitis B infection(OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV(HBs Ag) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody(antiHBc) in serum of HBs Ag-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C(CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma(HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.     

Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg‐positive chronic hepatitis B

Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG‐IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg‐positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99‐01 study). Patients received 52 weeks PEG‐IFN monotherapy (n = 136) or PEG‐IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG‐IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG‐IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow‐up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P = .01; week 24:3.7 vs 4.9 log c/mL, P < .001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG‐IFN treatment. Early on‐treatment HBV RNA level may be used to predict nonresponse.     

Histological improvement in patients with chronic hepatitis B virus infection treated with lamivudine

Abstract: Lamivudine is an oral nucleoside analogue with strong antiviral activity against hepatitis B virus (HBV). In previous clinical studies, a course of lamivudine for 4–12 weeks induced a profound decrease in HBV viraemia with excellent tolerance, but data on histology have not yet been reported. We studied the liver histology of 13 patients with stable chronic HBV infection treated with 25 mg, 100 mg or 300 mg lamivudine daily for 6 months. All patients became HBV-DNA negative during treatment. The paired biopsies taken at entry and during treatment were scored by two independent observers, using the components of the histology activity index (HAI) and fibrosis (modified Knodell). The items scored were piecemeal necrosis, focal necrosis, confluent necrosis, portal inflammation and fibrosis. Before treatment, the biopsies yielded a mean HAI of 4.4 (±0.8), which decreased to HAI 2.8 (±0.5) during treatment. An analysis of the individual components of the classification system showed a significant decrease in piecemeal necrosis from a pre-treatment 1.4 (±0.3) to 0.8 (±0.1) during treatment (p=0.02). Although a trend was found for the other components, it was not statistically significant, probably due to the number of pairs examined. In conclusion these results suggest that prolonged suppression of viral replication by lamivudine can improve liver histology. In contrast to previously published reports on α-interferon therapy, this study indicates that the improvement in liver histology with lamivudine is independent of HBe-seroconversion.     

Spontaneous remission of hepatitis B virus reactivation during direct‐acting antiviral agent‐based therapy for chronic hepatitis C

The administration of direct‐acting antiviral agents (DAAs) to treat hepatitis C virus (HCV) infection has been reported to cause hepatitis B virus (HBV) reactivation. However, the actual conditions of HBV reactivation and the ideal timing of medical intervention have not been fully evaluated. We report the cases of two female patients dually infected with HBV and HCV. Both patients were inactive HBV carriers. Although the serum HCV RNA levels promptly decreased after the initiation of DAA‐based therapy, the serum HBV DNA levels gradually increased during DAA‐based therapy, with the peak serum HBV DNA levels observed at 16 weeks after the initiation of DAA‐based therapy in both cases. Subsequently, we checked the serum HBV DNA levels closely every week several times. Fortunately, the serum HBV DNA levels gradually decreased without medical intervention. Neither case developed an alanine aminotransferase flare‐up. The HCV genotypes were 2a and 1b, and the DAA‐based therapies of Cases 1 and 2 were 12 weeks of sofosbuvir/ribavirin and ombitasvir/paritaprevir/ritonavir, respectively. The significance of our case reports is the demonstration of the existence of spontaneous remission of HBV reactivation that developed during DAA‐based therapy, the avoidance of intervention of nucleot(s)ide analogs by frequent monitoring of serum HBV DNA levels, and development of HBV reactivation regardless of the viral genotype or class of DAA. In conclusion, the close monitoring of serum HBV DNA levels during and after DAA‐based therapy is essential and medical intervention for HBV reactivation should be carefully considered on an individual basis.