Should Society Guidelines Move Towards More Permissive Therapy for Chronic Hepatitis B Virus Infections?

Vol. 28, Issue 1 (September 2023)

	Manavi Bhagwat, MD Resident Physician, Internal Medicine Rush University Medical Center Chicago, Illinois, USA
	Zoë Post, MD Fellow Physician, Gastroenterology & Hepatology Rush University Medical Center Chicago, Illinois, USA
	Nancy S. Reau, MD Professor, Department of Internal Medicine, Division of Digestive Diseases and Nutrition Rush University Medical Center Chicago, Illinois, USA

Chronic infection with hepatitis B virus (HBV) is associated with high morbidity and mortality worldwide through progression to hepatocellular carcinoma (HCC) and cirrhosis. As of 2019, it was estimated that 316 million people globally have chronic HBV infection.¹ HBV is an important cause of HCC; over 50% of HCC cases worldwide are attributable to the virus. The global burden of HBV infection is unevenly prevalent throughout the world. The Asian continent has prevalence rates estimated as high as 4%, while disease rates are under 1% in North America.² Due to the high burden of disease caused by HBV, the World Health Organization (WHO) published a global health sector strategy in 2016 calling for HBV elimination that aimed for a 95% reduction in new cases and 65% reduction in deaths by 2030. This review aims to compare expert guidelines published in the last five years considering newer research that suggests use of more permissive therapy.

The natural course of HBV infection is categorized by five major phases (Table 1), and the stage of infection guides treatment recommendations.

Table 1. Clinical and Pathological Characteristics of Stages of Hepatitis B Infections

Phase I	HBeAg positive (HBeAg+) chronic HBV infection	Also referred to as “immune tolerant” phase. Patients initially have high levels of HBV DNA in their serum and can infect others but are not yet showing signs of hepatic inflammation.
Phase II	HBeAg+ chronic hepatitis	Over time, immune response to infected hepatocytes increases, resulting in hepatic inflammation and fibrosis. Patients can still infect others.
Phase III	HBeAg negative (HBeAg-) chronic HBV infection	Over time, there is less active inflammation and more fibrosis in hepatocytes. As a result of the immune response, patients lose the ability to infect others.
Phase IV	HBeAg-chronic hepatitis	Patients cannot infect others but have progressive levels of liver inflammation that can lead to HCC and/or cirrhosis.
Phase V	HBsAg negative (HBsAg-) phase	A group of patients exhibit loss of HBsAg, resulting in a greatly decreased risk of progression to cirrhosis and HCC. This is also called a “functional cure.”
HBeAg: Hepatitis B Envelope Antigen; HBsAg: Hepatitis B surface antigen

 

Table 2. Clinical and Pathological Differences in Hepatitis B Phases

Phase	HBeAg+	HBeAg-	HBsAg-
	Chronic infection	Chronic hepatitis	Chronic infection	Chronic hepatitis	Occult infection
Hepatic Necroinflammation	-/+	++/+++	+	++/+++	+
Hepatic Fibrosis	none/minimal	variable	present	variable	variable
HBV DNA	++++	+++	++	+	+
ALT	normal	+++	normal	+	variable
HBsAg	+	+	+	+	-
HBeAg	+	+	-	-	-
Anti-HBeAg	-	-	+	+	+
Anti-HBsAg	-	-	-	-	+

 

The goal of treating chronic HBV is to improve clinical outcomes in patients, including preventing progression of chronic hepatic inflammation to cirrhosis, reducing risk of HCC, and improving rates of survival. The Reveal-HBV study demonstrated that increased HBV DNA portends increased risk of disease progression to HCC and cirrhosis, even at levels as low as 1,000 IU/mL to 10,000 IU/mL.³ In fact, newer data show that the patients with greatest risk of HCC may be those with moderate serum levels of HBV DNA (1,000,000 IU/mL).⁴ Treatment has traditionally been limited to patients with chronic hepatitis, or those patients with increased liver enzymes and viremia about a threshold of 2,000 IU/mL. However, in the last five years, several national and regional expert societies have updated guidelines with more permissive criteria to determine which patients are eligible for treatment. Regarding treatment options, the consensus is to recommend the use of a nucleoside analogue with high barrier to resistance, making entecavir (ETV), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF) first line oral therapies. Well-chosen patients may still consider pegylated interferon alpha, the only finite therapy for HBV, though efficacy is low.

One aspect of variation between published guidelines lies in the definitions of the phases of HBV infections. National associations vary in their limits for treatment of HBV DNA, vary in the definition of abnormal liver enzymes, and inconsistently include age and other factors as indications for treatment (Table 3). Some guidelines use additional standards in defining phases of infection, like quantitative HBsAg measurement. Finally, some publications do not define phases at all. For that reason, differentiating which patients should be treated instead of monitored closely is a special challenge.

Most of the guideline variation, however, stems from differences in treatment approaches for chronic infection. Earlier guidelines recommend a more conservative approach to treatment in HBeAg positive chronic infection (previously called the immune tolerant phase).^{5, 6, 7, 8} Previous literature had suggested that in this phase of infection, patients, especially younger and healthier ones, did not mount a robust immune response to HBV and thus were not undergoing hepatic necroinflammation that eventually causes progression to HCC and cirrhosis. Additionally, patients in the HBeAg positive chronic infection phase could possibly undergo spontaneous seroconversion of HBsAg without any need for treatment, which is known to be associated with a favorable prognosis and can occur at rates as high as 40% over 25 years.⁹ Available antiviral treatment has low efficacy in accelerating rates of HBsAg seroclearance in patients with HBeAg positive chronic infection, and there is a high rate of viral relapse once treatments are stopped, indicating necessity of long-term treatment.¹⁰ To complicate factors, many studies that evaluate treatment and seroconversion rates contain inadequate sample sizes of patients with true HBeAg positive chronic infection, so accurate evidence is limited.¹¹ Additionally, since the presence of HbeAg is implicated in the development of fibrosis and HCC the loss of this antigen was thought to be associated with lower cancer risk.¹²

Newer research highlights the risks of a conservative approach. The development of fibrosis, previously thought to be mainly associated with HBeAg positive chronic hepatitis, is now being shown to be present in all stages.¹³ The risk of fibrosis development increases with length of chronic infection and with age.¹⁴ Emerging research shows that treatment of HBeAg positive chronic infection may delay the progression of fibrosis.¹⁵ Integration of HBV into the host genome has been found to occur with viral replication, even in HBeAg negative infection. Viral suppression through pharmaceutical treatment can disrupt cycles of viral replication, resulting in decreased integration. Unsurprisingly given this newer data, recent outcomes research is showing that patients in HBeAg positive chronic infection and chronic hepatitis have comparable rates of mortality and HCC.¹⁶ Inconsistent expert recommendations will lead to under treatment, while simple guidelines will help facilitate a decrease in morbidity from HBV.

Table 3. Differences in definitions and treatment recommendations for chronic infection

Group	Year	HBeAg+ chronic infection definition	Populations in which HBeAg+ individuals should be treated	HBeAg- chronic infection definition	Populations in which HBeAg- individuals should be treated
AASLD 17	2018	HBV DNA:  Very high (typically > 1,000,000 IU/mL)   Liver enzymes: Normal or minimally elevated ALT and/or AST*   Histological findings:  no fibrosis and minimal necroinflammation   *ULN defined by AASLD to be ALT of 35 IU/L for male patients and 25 IU/L for female patients	HBV DNA: >20,000 IU/mL   Liver Enzymes: ALT ≥2× ULN   Histological findings: evidence of significant histologic disease	HBV DNA: Often normal   Liver enzymes: Normal or elevated ALT and/or AST levels   Histological findings: chronic hepatitis with variable necroinflammation and/or fibrosis	HBV DNA:  ≥2,000 IU/mL   Liver enzymes: ALT ≥ 2x ULN
CASLD 5	2018	HBV DNA: often > 10,000,000 IU/mL   Liver enzymes: ALT normal*   Histological findings: normal   *ULN defined as <30 IU/L for male patients and < 19 IU/L in female patients	None	HBV DNA: often <2,000 IU/mL, sometimes >2,000 IU/mL   Histological findings: Normal or mildly abnormal non-invasive fibrosis assay	None
INASL 6	2018	HBV DNA: >20,000 IU/mL   Liver enzymes: ALT < 40 IU/L or 40-80 IU/L with minimal histological findings   Histological findings: minimal inflammation and fibrosis	Age: >30 years   Other considerations: Extra-hepatic manifestations of HBV, family history of HCC or cirrhosis with HBV >2,000 IU/mL	HBV DNA: <2,000 IU/mL or 2,000 to 20,000 IU/mL with histological findings of minimal necroinflammation and fibrosis	None
BSH 8	2020	Not defined	Age >30 years   Other considerations: Family history of HCC or cirrhosis, extrahepatic manifestations of HBV	Not defined	None
JSH 18	2020	HBV DNA: Not defined   Liver enzymes: ALT within ULN*   Histological findings: few abnormal findings     *ULN defined by JSH as ≤30 IU/L	HBV DNA: ≥2,000 IU/mL   AND   Liver enzymes: ALT ≥ 31 U/L   Other considerations: Clinical decompensation	HBV DNA: <2000 IU/mL   Liver enzymes: Persistently normal ALT levels	None
CSH 19	2021	HBV DNA: > 20,000,000 IU/mL   Liver enzymes: ALT with persistent or recurrent increase from normal limits*   Histological findings: Obvious necroinflammation, or fibrosis, or both   Other considerations: HBsAg >10,000 IU/mL         *ULN not defined by CSH	Histological findings: Liver biopsy with G ≥2, or S ≥2, or both   Other considerations: Age > 30 years old and any of the following: -Family history of HBV-related cirrhosis or liver cancer -Histological findings of obvious liver inflammation or fibrosis in those with persistently normal ALT levels - HBV-related extrahepatic manifestations	HBV DNA:  <2,000 IU/mL   Liver enzymes: ALT within ULN*   Histological findings: Liver biopsy with histological activity index score <4   Other considerations: HBsAg <1,000 IU/mL	Histological findings: Liver biopsy with G ≥2, or S ≥2, or both   Other considerations: Age >30 years and any of the following: -Family history of HBV-related cirrhosis or liver cancer -Histological findings of obvious liver inflammation or fibrosis in those with persistently normal ALT levels - HBV-related extrahepatic manifestations
KASL 20	2022	HBV DNA: Generally >10,000,000 IU/mL   Liver enzymes: Persistently normal ALT*   Histological findings: Minimal or absence of hepatic necroinflammation   *ULN defined as ALT of 34 IU/L for male patients and 30 IU/L for female patients	HBV DNA: ≥20,000 IU/mL    Other considerations: Clinical decompensation	HBV DNA: <2,000 IU/mL   Liver enzymes: Persistently normal ALT   Histological findings:  Minimal or absence of hepatic necroinflammation	HBV DNA: ≥2,000 IU/mL   Liver enzymes: ALT level ≥2x ULN   Other considerations: Clinical decompensation
US Expert Opinion 21	2022	HBV DNA: usually 10,000,000 IU/mL   Liver enzymes: ALT <ULN*                         *ULN not defined by this Opinion	HBV DNA: >2,000 IU/mL AND elevated ALT   Other considerations: HBV DNA>2,000 IU/mL and ALT within ULN* - consider risk factors for developing HCC, age, lifestyle, and desire to undergo treatment	Not defined	HBV DNA: >2,000 IU/mL AND elevated ALT   Other considerations: HBV DNA>2,000 IU/mL and normal ALT - treat if fibrosis present
AASLD: American Association for the Study of Liver Diseases; CASLD: Canadian Association for Study of Liver Disease; INASL: Indian National Association for Study of the Liver; BSH: Brazilian Society of Hepatology; JSH: Japan Society of Hepatology; CSH: Chinese Society of Hepatology; KASL: Korean Association for the Study of the Liver; US: United States; ULN: Upper limit of normal; ALT: alanine transaminase

 

Discussion:

The goals for treatment of HBV are to promote seroclearance and decrease disease progression to HCC and cirrhosis. Emerging research shows that the chronic infection phases are not benign; rather, chronic infection is implicated in the development of catastrophic complications of HCC and cirrhosis. Patients with cirrhosis and viral replication, especially in the HBeAg positive chronic infection phase, could benefit from treatment. Treatment is of utmost importance in patients with older age, family history of HCC and cirrhosis, and extrahepatic manifestations of HBV. However, more permissive therapy is challenging due to imperfect efficacy and the need for long term therapy, which could result in higher costs over time.

Guidelines for the management of chronic HBV published in the last five years are greatly varied. There are inconsistencies in definitions of HBV infection phases, patient populations indicated for treatment, and timing of treatment. There is also variation in defining the normal limit of ALT. Some recent guidelines recommend more permissive indications for HBV antiviral treatment initiation, using recent evidence that early HBV chronic infection can still contribute to morbidity and mortality. However, it is worth noting that guidelines formed by expert opinion are not as limited by the need for high quality data to support recommendations. Regional differences are also evident as more permissive guidelines are found in Asian countries that have higher rates of endemic HBV. However, the expert opinion recently published in Clinical Gastroenterology and Hepatology for treatment recommendations in the United States²² has one of the most permissive guidelines, recommending treatment in all patients with HBV DNA >2,000 IU/mL and elevated ALT, and in certain cases patients with elevated HBV DNA and normal ALT (see Table 3), though it does not clearly define the upper limit of normal ALT. The importance of standardizing guidelines continues to increase as national borders become more fluid. Standardization would also allow better characterization of treatment eligibility and success rates in individuals.

The quest for functional cure would not only help clarify populations at risk and the impact of antiviral therapy but will also continue to modify for whom and when treatment should be considered. Developments in pharmacologic agents that increase treatment efficacy and maintenance of seroconversion would favor greater adoption of more permissive treatment guidelines. Specific treatment regimens that can optimize the delay of progression to fibrosis should also be comparatively studied. Finally, studies that evaluate treatment regimens for hepatitis B would benefit from a robust population of patients with HBeAg positive chronic infection. Guidelines published in the last five years are becoming more and more permissive based on pharmacological and epidemiological developments. Updated guidelines would help translate recent research into practice.

 

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