Editor’s Note:
The World Health Organization (WHO) has set ambitious goals in its Action Plan for the Elimination of Viral Hepatitis: by 2030, the diagnosis rate for chronic hepatitis B (CHB) should reach 90%, the treatment rate for eligible patients should be 80%, new infections should decrease by 90%, and related deaths should decrease by 65%. However, recent data shows that in mainland China and Hong Kong, the diagnosis rates for CHB are only 19% and 27%, respectively, and the treatment rates are only 11% and 22%, respectively. Globally, the diagnosis and treatment rates for CHB are only 10% and 5%, respectively. Achieving WHO’s 2030 goal of eliminating viral hepatitis as a public health threat remains a daunting challenge. At the 13th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2023), Dr. Wai-Kay Seto from the University of Hong Kong, China, was invited to give a special report on the risks and benefits of long-term HBV treatment.
Increasing Detection Rates to Aid HBV Elimination Goals
In 2016, there were approximately 257 million individuals worldwide with chronic HBV infection, but only a small fraction received diagnosis and treatment. A systematic review and meta-analysis by Tan et al. in Singapore indicated that among all chronic hepatitis B patients, the proportion of patients with cirrhosis was as high as 9% (95% CI: 8%-10%), with the proportion of F3 stage liver fibrosis patients reaching 21% (95% CI: 19%-23%) in the Western Pacific region. According to the 2015 WHO guidelines, patients with cirrhosis, abnormal alanine aminotransferase (ALT) levels, HBV DNA levels exceeding 2000 IU/mL or 20000 IU/mL meet the criteria for antiviral therapy. The overall proportion of patients meeting the criteria for treatment among all patients was 19% (95% CI: 18%-20%), ranging from 12% (6%-18%) in community studies to 25% (19%-30%) in clinical center studies. In the Western Pacific region, the overall proportion of patients meeting the criteria for treatment ranged from 17% to 25%. However, this data is based on clinical data from a single time point and exhibits significant heterogeneity.
To achieve the goal of reducing CHB-related deaths by 65% by 2030, care for CHB patients requires a continuous process, including screening and testing, diagnosis and treatment of detected CHB patients, monitoring of disease progression risk, and management of complications. However, the HBV testing rate in the general population remains low, resulting in significant gaps and deficiencies in this aspect. Through innovative interventions using digital crowdsourcing, we provided 1-minute video promotional information to primary healthcare patients using smartphones. Compared to institution-based diagnostic and treatment models, this significantly increased HBV testing rates among patients (adjusted odds ratio of 1.79) and reduced HBV-related stigma.
The Importance of Long-Term Continuous Antiviral Treatment
The short-term goals of CHB treatment are virological response (HBV DNA clearance) and biochemical response (ALT normalization). With continued treatment, the proportion of patients achieving HBeAg seroconversion or serological conversion, as well as histological improvement, increases. Some patients may achieve HBsAg clearance and regression of liver fibrosis. The long-term goal of treatment is to reduce the risk of cirrhosis and hepatocellular carcinoma (HCC) and decrease the need for liver transplantation and mortality.
Nucleos(t)ide analogs (NAs) such as entecavir (ETV), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF) are convenient for oral administration, have excellent safety profiles, and very low resistance rates, making them suitable for long-term CHB treatment.
For patients aged >60 years, those with musculoskeletal diseases (long-term use of steroids or other drugs affecting bone density, a history of brittle bone fractures, osteoporosis), or those with kidney dysfunction (estimated glomerular filtration rate [eGFR] <60 ml·min-1·1.73 m-2, albuminuria >30 mg/24 h or positive urine protein, blood phosphate <2.5 mg/dl, hemodialysis), ETV or TAF should be preferred over TDF. For pregnant women or those planning pregnancy in the near future, or patients with concurrent HIV infection, TDF should be the preferred treatment over ETV or TAF. Breastfeeding is not a contraindication for antiviral therapy.
The efficacy of TAF in treating CHB is similar to that of TDF but with significantly improved kidney and bone safety. After 2 years of treatment, the decrease in bone density in the hip and lumbar spine in the TAF treatment group was significantly smaller than in the TDF treatment group (average change of -0.33% vs. -2.51% and -0.75% vs. -2.57%, respectively, p < 0.001). The median decrease in eGFR in the TAF treatment group was also significantly smaller than in the TDF treatment group patients (-1.2 mg/dl vs. -4.8 mg/dl, p < 0.001).
NAs are Typically Not Discontinued
In a multicenter prospective study that we published in 2015, Asian HBeAg-negative chronic hepatitis B (CHB) patients who met the discontinuation criteria according to the Asian Pacific Association for the Study of the Liver (APASL) guidelines were included. These patients had been treated with entecavir (ETV) for ≥2 years, achieved undetectable HBV DNA levels on ≥3 occasions with a 6-month interval between each test. When they discontinued treatment for 24 weeks and 48 weeks, the virological relapse rates were 74.2% and 91.4%, respectively. Therefore, the risk of virological relapse after discontinuing nucleos(t)ide analog (NA) therapy in patients with chronic hepatitis B is very high. Long-term treatment should be maintained, and discontinuation should not be considered unless there is evidence of HBsAg clearance and no signs of cirrhosis.
Emphasizing Safety Concerns After Discontinuation
Patients with chronic hepatitis B require long-term treatment, but it is not necessarily lifelong. Some patients may still achieve successful treatment discontinuation with a low risk of relapse, guided by markers such as quantitative HBsAg levels. Our team’s research indicates that in non-cirrhotic patients with chronic hepatitis B, if they achieve undetectable HBV RNA and HBsAg levels < 10 IU/mL at the end of treatment, the cumulative relapse rate after discontinuing entecavir (ETV) for 48 weeks is less than 10% (9.2%). An international multicenter, multi-ethnic cohort study by Hirode et al. suggests that if patients have HBsAg levels < 10 IU/mL at the end of treatment, Asian and Caucasian patients can achieve HBsAg clearance rates of around 80% after discontinuing nucleos(t)ide analog (NA) therapy for 48 weeks. Therefore, for some patients, persistent responses can be maintained after discontinuing NA therapy.
A meta-analysis conducted by Hall et al. indicated that in HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogs (NA) and were followed up for 1-3 years, the cumulative HBsAg clearance rate was only around 4%. Some studies have reported higher HBsAg clearance rates in Western patient populations after discontinuing NA therapy (12%-21%). The aforementioned meta-analysis by Hall et al. showed that after NA discontinuation, the proportion of patients experiencing liver decompensation, liver-related deaths, liver transplantation, or HCC was only 0.5%.
However, data from cohort studies may not directly translate to real-world clinical practice. A real-world study conducted by Hsu et al. indicated that after discontinuation of NA therapy, the annual incidence rate of severe acute exacerbation (SAE) was 1.14% (95% CI: 0.81%-1.57%), with SAE rates of 1.84% (95% CI: 1.20%-2.70%) within 2 years and 0.63% (95% CI: 0.32%-1.10%) beyond 2 years. Following the occurrence of SAE, the most concerning aspect was the increased risk of progressing to acute-on-chronic liver failure (ACLF) and death (18.4% and 7.9%, respectively).
The recommendations regarding discontinuation of nucleos(t)ide analogs (NA) for the treatment of HBeAg-negative chronic hepatitis B patients vary among major guidelines:
1. EASL 2017 Guidelines :
– EASL recommends that in HBeAg-negative patients without cirrhosis who have achieved long-term virological suppression (≥3 years) with NA therapy, NA discontinuation can be considered if close monitoring can be ensured after discontinuation.
2. AASLD 2018 Guidelines :
– AASLD advises that when deciding to discontinue NA therapy in non-cirrhotic HBeAg-negative adults, careful consideration should be given to the risks and benefits of health outcomes. This includes considering the risks of virological relapse, liver decompensation, HCC, and death. Factors such as the burden of ongoing antiviral therapy, economic concerns related to medication costs and long-term monitoring, compliance, potential for resistance, and treatment interruption should also be considered. Patient and provider preferences are important in this decision-making process.
3. APASL 2015 Guidelines :
– APASL recommends that non-cirrhotic HBeAg-negative patients should be treated for at least 2 years and should achieve undetectable HBV DNA for three consecutive tests with six months between each test before considering NA discontinuation.
In summary, the EASL guidelines suggest considering NA discontinuation in non-cirrhotic HBeAg-negative patients with long-term virological suppression, while the AASLD guidelines emphasize the need to carefully weigh the risks and benefits, taking into account various factors, before discontinuing NA therapy. The APASL guidelines recommend a minimum duration of treatment and specific virological criteria before considering NA discontinuation. The decision to discontinue NA therapy should be made on an individualized basis, considering the patient’s specific clinical situation and preferences.
Preventive Antiviral Treatment During Pregnancy
For pregnant women with a high viral load (HBV DNA level ≥ 20,000 IU/mL), preventive antiviral treatment with TDF should be initiated in the late stages of pregnancy (after 24 weeks of gestation). This approach can further reduce the rate of HBV mother-to-child transmission. A study conducted by Pan et al. in 2016 demonstrated a significant reduction in HBV mother-to-child transmission rates in the TDF group compared to the control group, whether through intention-to-treat analysis or according to the protocol [5% vs. 18% (P=0.007) and 0% vs. 7% (P=0.01), respectively]. The strategy of preventive antiviral treatment for pregnant mothers during pregnancy, combined with timely administration of the hepatitis B vaccine to the newborns, is an effective measure to block HBV mother-to-child transmission and is considered cost-effective in the Western Pacific region.
Prophylactic Antiviral Treatment for Immunocompromised Patients
Immunocompromised patients who are HBsAg-negative but anti-HBc-positive and are undergoing treatment regimens that include potent immunosuppressive agents, such as rituximab (rituxan), or are receiving hematopoietic stem cell transplantation (HSCT), have a higher risk of HBV reactivation. Therefore, these patients require prophylactic antiviral treatment with nucleos(t)ide analogs (NAs). Research conducted by your team has shown that in HBsAg-negative, anti-HBc-positive patients undergoing rituximab treatment, the cumulative incidence of HBV reactivation at a 2-year follow-up was significantly higher compared to baseline anti-HBs-positive patients (68.3% vs. 34.4%, P=0.012). In HBsAg-negative, anti-HBc-positive patients who underwent HSCT and were under 50 years old without chronic graft-versus-host disease, the cumulative incidence of HBV reactivation was significantly lower at a 2-year follow-up compared to other patient groups (5.6% vs. 65.0%, P=0.004).
International guidelines recommend the following:
1. For all HBsAg-positive patients undergoing immunosuppressive therapy, they should receive prophylactic antiviral treatment with ETV, TDF, or TAF. After discontinuation of immunosuppression, antiviral treatment should be continued for at least 12 months (for rituximab-treated patients, antiviral treatment should be continued for at least 18 months).
2. HBsAg-negative, anti-HBc-positive patients who are undergoing rituximab treatment or HSCT and have a higher risk of HBV reactivation should receive prophylactic antiviral treatment with ETV, TDF, or TAF. After discontinuation of immunosuppression, antiviral treatment should be continued for at least 12 months (for rituximab-treated patients, antiviral treatment should be continued for at least 18 months).
3. Patients receiving treatment with lamivudine or adefovir have a lower risk of HBV reactivation and may not require prophylactic antiviral treatment. However, this recommendation has a weaker level of endorsement.
These guidelines aim to prevent HBV reactivation in immunocompromised patients, which can be a serious complication in such individuals.
Expanding Indications for Treating Chronic Hepatitis B: Balancing Benefits and Risks
Bold Strategy: Treating All Patients
Research by Wong et al. has shown that if criteria such as HBV DNA levels >20000 IU/mL with elevated ALT levels, HBV DNA levels >2000 IU/mL with elevated ALT levels, or HBV DNA levels >2000 IU/mL regardless of ALT elevation are used as indications for antiviral treatment, the proportion of patients meeting treatment criteria is 18.0%, 23.2%, and 33.9%, respectively. However, among chronic hepatitis B patients who do not meet established treatment standards, a significant proportion already has advanced liver fibrosis. Simplifying treatment criteria to include all patients with detectable HBV DNA for antiviral treatment can reduce the complexity of assessing treatment eligibility, increase treatment rates, and promote the goal of eliminating HBV. If 5 million people worldwide receive treatment, the cost per chronic hepatitis B patient using the active ingredient of ETV medication can be as low as $4 per year. Therefore, the strategy of treating all patients with detectable HBV DNA is feasible and contributes to achieving the goal of HBV elimination.
Expanding the Indications for Hepatitis B Treatment: Balancing Benefits and Risks
In Taiwan, the REVEAL-HBV study followed 20,069 inactive HBV carriers for an average of 13.1 years. These patients had a significantly higher cumulative risk of developing HCC compared to the control group, with an annual incidence rate of 0.06%. In a retrospective cohort study in South Korea involving 875 chronic hepatitis B patients treated with ETV, those with low-level viremia (HBV DNA levels <2000 IU/mL) and sustained virological response (HBV DNA consistently undetectable, <12 IU/mL) had a higher cumulative risk of HCC. This was particularly evident in patients with liver cirrhosis who had low-level viremia.
High Risk of Significant Liver Fibrosis in the Gray Zone
A meta-analysis conducted by Chao et al., which included nine studies and a total of 830 chronic hepatitis B patients, found that in patients with consistently normal ALT levels (<40 IU/L), the proportion of those with F2 stage liver fibrosis was as high as 20.7%. Even when using new ALT normal value standards (males <30 IU/L, females <19 IU/L), the proportion of patients with normal ALT levels who had significant liver fibrosis remained high at 27.8%. Another study by Wong et al. indicated that in chronic hepatitis B patients with higher viral levels (HBV DNA levels >2000 IU/mL) and persistently normal ALT, the proportion with F2 stage liver fibrosis reached 28.1%. Risk factors for significant liver fibrosis included being male, having a higher BMI, and having concomitant diabetes.
Is It Worthwhile to Expand Treatment?
To weigh the benefits and risks of expanding NA treatment for chronic hepatitis B patients, the primary benefits include reducing the risk of liver disease progression and disease transmission. The drugs are cost-effective, safe, including during pregnancy, convenient with once-daily oral dosing, and can have psychological benefits. Risks primarily involve the potential for drug resistance, as well as the risk of drug toxicity and side effects. Some patients may experience stigma, and there are issues related to long-term medication adherence, the cost of producing and distributing drugs, limited benefits for treating patients, and the diversion of public health and individual healthcare resources.
Lim et al. conducted a modeling analysis to assess the impact of expanding hepatitis B treatment on the future disease burden and economy of South Korea. By 2035, the first scenario, which removes viral load restrictions for cirrhotic patients, could reduce 13,000 cases of HCC, save 11,800 lives, and cost $932 per Disability-Adjusted Life Year (DALY) saved. The second scenario, initiating treatment for non-cirrhotic patients at ALT levels of ULN, could reduce 26,700 cases of HCC, save 23,300 lives, and cost $1,367 per DALY saved. The final scenario, treating all patients with HBV DNA levels ≥2000 IU/mL, could reduce 43,300 cases of HCC, save 37,000 lives, and cost $2,583 per DALY saved. Compared to the baseline, all scenarios demonstrated a high cost-effectiveness.
In 2022, China updated its “Guidelines for the Prevention and Treatment of Chronic Hepatitis B,” recommending antiviral therapy for the majority of patients. The guidelines recommend antiviral therapy for the following scenarios:
1. For individuals who are HBV DNA positive, have continuously abnormal ALT levels (above the upper limit of normal, ULN), and have ruled out other causes, antiviral therapy is recommended.
2. For individuals who are HBV DNA positive, regardless of ALT levels, antiviral therapy is recommended if they meet any of the following conditions:
– Have cirrhosis of the liver or a family history of HCC.
– Are older than 30 years of age.
– Non-invasive indicators or liver histology suggest significant inflammation (G2) or fibrosis (F2).
– Exhibit extrahepatic manifestations related to HBV.
Zhang et al. used a Markov decision tree state-transition model to assess the cost-effectiveness of expanding antiviral treatment for chronic hepatitis B by simulating different ALT threshold values for treatment initiation (>40 U/L; >35 U/L for males, >25 U/L for females; >30 U/L for males, >19 U/L for females; treatment for all HBsAg-positive patients regardless of ALT levels). The results indicated that treating all HBsAg-positive patients is the optimal strategy in terms of cost-effectiveness for reducing HBV-related complications and deaths and saving Disability-Adjusted Life Years (DALYs). Therefore, expanding the treatment of chronic hepatitis B in China is cost-effective, and this strategy may have regional specificity.
Promoting a Shared Healthcare Model
In China, conducting HBV testing and follow-up in primary healthcare centers and referring chronic hepatitis B patients to specialized healthcare centers for antiviral treatment at the appropriate time has proven to be an effective and cost-effective shared healthcare model. This approach can improve detection rates and treatment rates, contributing to the goal of reducing chronic hepatitis B-related deaths by 65%.
Conclusion
In summary, nucleos(t)ide analogs (NAs) have good safety profiles and are crucial for improving the prognosis of chronic hepatitis B patients. Most patients require long-term treatment, and there is ongoing debate about treatment cessation. Pregnant women with higher viral loads, individuals previously infected who are receiving immunosuppressive therapy, and even those with low-level viremia or in the gray zone are at risk of liver disease progression. Expanding antiviral treatment for chronic hepatitis B is cost-effective, and the shared healthcare model has proven effective in China.
