Current status of drug therapy for chronic hepatitis B

Abstract

In this editorial, we comment on the article by Meng et al. Chronic hepatitis B (CHB) is a significant global health problem, particularly in developing countries. Hepatitis B virus (HBV) infection is one of the most important risk factors for cirrhosis and hepatocellular carcinoma. Prevention and treatment of HBV are key measures to reduce complications. At present, drug therapy can effectively control virus replication and slow disease progression, but completely eliminating the virus remains a challenge. Anti-HBV treatment is a long-term process, and there are many kinds of antiviral drugs with different mechanisms of action, it is essential to evaluate the safety and efficacy of these drugs to reduce side effects and improve patients’ compliance. We will summarize the current status of CHB drug treatment, hoping to provide a reference for the selection of clinical antiviral drugs.

Key Words: Chronic hepatitis B; Hepatitis B virus; Anti virus; Drug treatment; Therapy

Core Tip: Chronic hepatitis B poses a serious threat to human health, and drug treatment is the most important method. The purpose of treatment is to sustainably inhibit virus replication and even achieve clinical cure, prevent or slow down disease progression, and reduce the incidence of cirrhosis and hepatocellular carcinoma. The widely used drugs at present are interferon and nucleoside/nucleotide analogue. On the premise of ensuring the efficacy, increasing drug safety and reducing side effects is an important research direction of anti-hepatitis B virus treatment.

INTRODUCTION

Hepatitis B virus (HBV) belongs to the hepatotropic DNA virus family, with strong resistance and infectivity. When HBV is infected, virion first enters the liver cells, makes the virus relaxed circular DNA (rcDNA) invade the nucleus, under the action of various enzymes such as DNA polymerase, the gaps in rcDNA are repaired and converted into covalently closed circular DNA (cccDNA). Then, using cccDNA as a template, various mRNAs encoding different components are transcribed, and produces virion over and over. cccDNA is a key point in the HBV replication process and accompanies the entire process of HBV infection.

However, cccDNA has a long half-life and is stored in the cccDNA storage pool, which is difficult to clear completely. cccDNA is considered to be an important reason for persistent HBV infection, poor drug response and relapse after drug withdrawal, so eliminating cccDNA becomes the key to cure chronic hepatitis B (CHB)[1].

CHB is a chronic liver disease caused by persistent HBV infection, which can progress into cirrhosis and liver cancer, endangering the life safety of patients. In CHB patients, the cumulative incidence of cirrhosis over 5 years is about 10%-20%, and 2%-5% of cirrhosis progresses to liver cancer each year[2]. According to the World Health Organization, approximately 296 million people worldwide are living with CHB, with 4.5 million new infections each year, resulting in approximately 820000 deaths annually, mainly from complications such as cirrhosis and hepatocellular carcinoma (HCC). HBV infection is widely distributed around the world, with 80% of the infected patients coming from 21 countries in China, India, and Asia and Africa[3].

The genotype of HBV varies in different regions, with B and C being the main types in China. Different genotypes of HBV have different characteristics and prognosis. For example, patients with type B and type C CHB have a higher risk of mother-to-child transmission, type B is associated with HCC in young non cirrhotic patients, type C is associated with post hepatitis cirrhosis, and type C is more likely to progress to liver cancer than type B[4].

The main routes of HBV transmission include mother-to-child transmission, blood transmission, and sexual transmission. Prevention is the key to controlling the spread of HBV. Since 1982, HBV vaccine has been widely used, significantly reducing the infection rate of newborns and children, and reducing the incidence of HBV related cirrhosis and liver cancer at the source.

A study have shown that the incidence of liver cancer in HBV patients is 20-100 times higher than that in uninfected patients[5]. Therefore, the management of existing CHB patients is particularly important. In the absence of a complete cure for CHB, the management goal is mainly to reduce the risk of liver adverse events and improve the long-term prognosis of patients through active antiviral therapy[6].

DRUG THERAPY FOR CHB

From the perspective of the lifecycle and pathogenesis of HBV, theoretically, as long as any stage and pathogenic process of HBV replication can be blocked, disease progression can be slowed down or prevented. At present, anti HBV drugs in clinical practice include interferon (IFN) and nucleoside/nucleotide analogues (NAs) (Table 1).

Table 1 Characteristics of anti hepatitis B virus drugs.

Drug	Approve time (year)	Classification	Mechanism	Administration method	Metabolize	Major side effect	Drug resistance
LAM	1998	NRTI	Competitive binding to HBV DNA polymerase binding site[64]	Oral administration	Kidney	Less side effects, may lead to myopathy or even rhabdomyolysis[65]	Susceptible to drug resistance, especially YMDD mutation[68]
LDT	2008	NRTI	Competitive binding to HBV DNA polymerase binding site[78]	Oral administration	Kidney	Myopathy and peripheral neuropathy[74]	The rate of drug resistance in long-term treatment was high, and the common drug resistance mutations were rtM204I and rtL180M [79,85]
ADV	2002	NtRTI	Competitive binding of HBV DNA polymerase binding site and embedding into viral DNA strand[71]	Oral administration	Kidney	Renal function damage[75]	Compared to LAM, the risk of resistance is low[71]
ETV	2005	NRTI	Competitive binding to HBV DNA polymerase binding site[12,13]	Oral administration	Kidney	Less side effects, possible renal function damage[14]	Low resistance rate, but resistance to LAM-resistant HBV increased[16,20]
TDF	2008	NtRTI	Competitive binding of HBV DNA polymerase binding site and embedding into viral DNA strand[26]	Oral administration	Kidney	Bone and kidney injury[34]	Low risk of drug resistance
TAF	2016	NtRTI	Competitive binding to HBV DNA polymerase binding site[43]	Oral administration	Liver	Fewer bone and kidney side effects, but can lead to dyslipidemia[52]	Low risk of drug resistance
TMF	2021	NtRTI	Competitive binding to HBV DNA polymerase binding site[56]	Oral administration	Liver	Fewer bone and kidney side effects[58]	Low risk of drug resistance, and effective against multiple drug-resistant HBV
INF-α	1986	Standard interferon	Regulate the immune response and induce the synthesis of antiviral proteins in host cells[87]	Subcutaneous injection	Kidney	More side effects: Systemic adverse reactions	No drug resistance
Peg-IFN-α	2001	Long-acting Interferon	Regulate the immune response and induce the synthesis of antiviral proteins in host cells[87]	subcutaneous injection	Liver and kidney	Similar to INF-α	No drug resistance

NRTI: Nucleoside reverse transcriptase inhibitors, NtRTI: Nucleotide reverse transcriptase inhibitors; LAM: Lamivudine; ADV: Adefovir dipivoxil; ETV: Entecavir; LdT: Telbivudine; TDF: Tenofovir disoproxil fumarate; TAF: Tenofovir disoproxil fumarate; TMF: Tenofovir amibufenamide; IFN: Interferon; Peg-IFN-α: Polyethylene glycol interferon α; YMDD: Polymerase-tyrosine-methionine-aspartate; HBV: Hepatitis B virus.

Nucleoside/NAs

NAs are derivatives modified or substituted by chemical groups based on nucleoside/nucleotide. It’s a kind of competitive inhibitor of HBV polymerase/reverse transcriptase (RT), directly inhibiting the generation of HBV DNA and is the first choice for anti-HBV therapy. In the late 1990s, the first NAs, lamivudine (LAM), was used to treat CHB patients[7]. With the continuous development of medicine, adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (LdT), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) and tenofovir amibufenamide (TMF) have been approved for the treatment of CHB[8]. Recommended first-line NAs such as ETV, TDF and TAF have various advantages such as convenient oral administration, low cost, and high safety, and are widely used in clinical practice. NAs has good virological response, but due to the inability to clear cccDNA and poor hepatitis B surface antigen (HBSAg) seroconversion rate, it is difficult to reach the indications for drug discontinuation. Therefore, long-term medication may be required, and virological recurrence may occur once the drug is stopped[9-11].

First-line NAs

ETV: ETV is a guanine nucleoside analogue, which can be converted into ETV triphosphate by phosphokinase, and then competitively binds to the HBV DNA polymerase site, effectively inhibiting virus replication, and improving liver inflammation and fibrosis[12,13]. ETV is excreted through the kidney and may cause renal dysfunction with prolonged administration[14]. A study showed that the cumulative rates of HBV DNA seroconversion in patients receiving ETV monotherapy of 1-year and 5-year were 82.9% and 97.1%, respectively, reflecting the high virological response of ETV, but the serological conversion ability to hepatitis B e antigen (HBeAg) and HBsAg was poorer than that of IFNs[12]. A study from Korea showed a cumulative HBeAg serological clearance of 40.2% over 5 years in HBeAg-positive patients using ETV[15]. Another study from Japan showed that the cumulative HBeAg and HBsAg serological clearance rates for 5 years were 37% and 2.5%, respectively[16].

Although the long-term prognosis of ETV treatment in most CHB patients can be improved, there are some patients with HBV DNA remains at detectable levels and shows poor response. A study reported a 48-week cumulative virological response rate of 89.4% was found in patients treated with ETV at initial treatment[17]. Continuous poor response not only fails to prevent disease progression, but is a potential risk factor for cirrhosis and liver cancer. Patients with persistent hypoviremia have a 1.98 times higher risk of developing HCC than patients with persistent virological response[18,19]. Poor response often interacts with drug resistance. Long-term low-level replication of HBV DNA is a high risk factor for drug resistance, and drug resistance reduces the drug sensitivity of HBV to NAs. Long term treatment may also cause genetic mutations leading to drug resistance, often occurring in the RT region of the HBV polymerase gene. A study has shown that the 10-year cumulative resistance rate of patients using ETV is 1.1%, while the 5-year cumulative resistance rate of patients with previous LAM resistance to ETV can reach 51%[16,20]. A study has shown that the higher the HBV DNA, the longer it takes to achieve complete virological response (CVR) during treatment, and the more likely lead to poor response[21]. When there is a poor virological response, relevant drug resistance tests can be performed to change the treatment strategy timely to avoid virological rebound. European Association for the Study of the Liver (EASL) proposed that for patients with poor response, if HBV DNA showed a downward trend after 48 weeks of treatment, the original strategy could be continued, otherwise, the drug should be changed[22].

American Association for the Study of Liver Disease (AASLD) proposed to continue the original strategy for hypoviremia[23]. Yim et al[24] divided CHB patients who could still detect HBV DNA after more than 48 weeks of ETV treatment into the original treatment group and the conversion to TDF group, and found that the 48-week CVR rate in the TDF group was significantly higher than that in the ETV group, and the HBV DNA decline was more obvious in the TDF group. A study found that after 24 weeks of TAF treatment, 75% of CHB patients with poor response (including 14 ETV treated patients) achieved HBV DNA negative conversion[25].

TDF: TDF is a monophosphate adenosine analogue. As the lipid precursor of tenofovir (TFV), it is rapidly hydrolyzed into TFV by non-specific carboxylesterase after entering plasma, then TFV is phosphorylated into the active product TFV diphosphate (TFV-DP) by cell kinase in hepatocytes. TFV-DP competes with the HBV DNA polymerase site to bind to the viral DNA strand, making the HBV DNA strand unable to be extended[26], thereby reducing the serum HBV-DNA load in the serum and promoting the negative transformation of HBV-DNA. A 7-year TDF treatment data showed that 99.3% of patients had HBV DNA negative conversion, and 54.5% of patients achieved HBeAg negative conversion[27]. It has been reported that 51% of patients treated with TDF for over 5 years experienced liver histological improvement and fibrosis regression[28]. Long-term follow-up has shown that TDF reduces the cumulative probability of liver decompensation, HCC, death, and liver transplantation[29]. The meta-analysis by Zuo et al[30] suggested that the virological response of the TDF group was superior to that of the ETV group in patients with initial CHB treatment. Chen et al[31] found that TDF had a stronger ability to inhibit HBV in the early stages of treatment, but no statistically significant difference was found between the two drugs at 144 weeks. In a national historical cohort study in Korea, a total of 24156 CHB patients who used ETV and TDF respectively were retrieved. The final results showed that the annual incidence rate of HCC in the TDF group (0.64 per 100 person years) was significantly lower than that in the ETV group (1.06 per 100 person years)[32].

TDF is one of the replacement drugs for ETV resistance. Mak et al[33] found that when TDF and ETV were used to treat CHB patients with hyperviremia, the incidence of acute kidney injury was higher in the TDF group.

TDF has a short half-life in plasma, and most of the TDF in plasma needs to be excreted through the kidney, increasing the burden on the kidney. Therefore, although TDF antiviral therapy is effective, the risk of kidney and bone damage increases with the patient's age after long-term use of TDF[34]. Multiple studies have shown that TDF can reduce blood lipid[35,36]. Studies have found that TDF up-regulates the expression of CD36 through PPAR-α activation, thereby regulating lipid metabolism[37]. CD36 is a member of the B-class scavenger receptor family, which can effectively bind to low-density lipoprotein and transport it, playing a lipid-lowering role. In a 48-week double-blind phase 3 study, the efficacy of TDF and ADV was compared. The results showed that the HBV DNA seroconversion rates of HBeAg positive and HBeAg negative patients in the TDF group were 75% and 93%, respectively, which were significantly higher than those in the ADV group (13% and 63%)[38]. Extended follow-up showed that after 4 years of treatment with TDF, 96% of HBeAg positive patients and 99% of HBeAg negative patients had HBV DNA negative conversion at the endpoint. Among HBeAg positive patients, 29% experienced HBeAg seroconversion[39,40].

TAF: As a novel nucleotide RT inhibitor, TAF is a precursor drug of TFV. Through protide technology, TAF adds a phosphoramidite structure on the basis of the structure of TFV, which better shields the active ingredient TFV, reduces the molecular polarity, improves the lipophilicity, and enhances membrane permeability. TAF can not only enter hepatocytes through passive diffusion, but also be efficiently and actively taken up by hepatocytes through liver uptake transfer proteins (OATP1B1 and OATP1B3)[41]. Studies have shown that TAF can reduce liver fibrosis both in vivo and in vitro by upregulating NS5ATP9, downregulating TGF β 1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways[42]. The mechanism of action of TAF is similar to TDF[43], but it has better stability, longer half-life, and can remain mostly intact when penetrating virus-infected cells. Therefore, the same efficacy can be achieved with less than 1/10 dose of TDF. Most of TAF is hydrolyzed into TFV in hepatocytes, which is mainly metabolized by liver and can target hepatocytes, thus reducing bone and kidney toxicity[22,44]. Studies have shown that renal function can be improved after TDF conversion to TAF treatment[45,46]. AASLD[23] and EASL[22] recommend the use of TAF in the elderly, patients with kidney damage and bone disease. Two multi-center, randomized, double-blind controlled studies demonstrated the efficacy and safety of TAF[47,48]. The two studies randomly divided target CHB patients into TAF group (25 mg/day) and TDF group (300 mg/day) in a 2:1 ratio. The results showed that the efficacy of TAF treatment for 48 weeks was not inferior to TDF, and TAF had a better ALT normalization rate than TDF. Patients treated with TAF had significantly lower bone density damage than those treated with TDF, and improved renal safety. At week 96, it was found that neither TAF nor TDF patients showed drug resistance[49]. According to the latest updated data, TAF has antiviral effects that are not inferior to TDF and better bone and kidney safety. However, multiple studies have shown that converting TDF to TAF is associated with increased body weight[35,50,51]. A large cohort study conducted by Surial et al[52] in Switzerland showed an average weight gain of 1.7 kg after switching to TAF for 18 months. At the same time, researchers have found that TAF can cause dyslipidemia, but the mechanism of TAF affecting blood lipids is still unclear[51,53,54]. A study have shown that statin use in patients with CHB can reduce the cumulative incidence of cirrhosis and decompensated cirrhosis. Therefore, for patients with CHB who gain weight and increase blood lipids during the application of TAF, statin therapy can be combined[55].

TMF: TMF is a novel nucleotide RT inhibitor, with a mechanism of action similar to TDF. By optimizing the structure, the addition of a methyl group to the amidation group of TAF increases the lipophilicity of TMF, accelerates the rate of transmembrane transmission, and improves the plasma stability of the drug. It is metabolized by the liver and has lower bone and kidney adverse reactions[56,57]. A multicenter randomized clinical trial from China compared the efficacy of TMF and TDF after 48 weeks of treatment, and found that TMF exhibited similar antiviral effects as TDF and had lower bone toxicity[58]. The data updated by the researchers at week 96 confirmed this conclusion again[59]. Li et al[60] compared the virological response rates of TMF and TAF treatment for 24 weeks, and the results showed that TMF had a higher viral response rate (92% vs 74%) in the treatment naive group, while TMF and TAF had similar effects in the treatment experienced (TE) group. Zhang et al[61] compared the efficacy and safety of TMF and TAF in the treatment of CHB in a retrospective study involving 90 patients. After 48 weeks of treatment, they found no significant differences in virological response rates and HBeAg/HBsAg serological clearance rates (both P value = 1.000). Peng et al[62] recently published a study in the World Journal of Gastroenterology comparing the efficacy of TMF and TAF at 24 and 48 weeks, and found that the viral response rates were similar (24 weeks: 53.57% vs 48.31%, P value > 0.05; 48 weeks: 78.65% vs 78.57%, P value > 0.05). ALT normalization and renal safety in the TMF group were similar to those in the TAF group. However, since the study included non-alcoholic fatty liver disease (NAFLD) patients, we agree with Meng et al's viewpoint[63] that in order to make the results more rigorous, subgroup analysis should be conducted on patients with and without NAFLD.

Non-first-line NAs

LAM: LAM was approved by the Food and Drug Administration (FDA) in 1998 for the treatment of CHB and was the first NAs approved. Belonging to the cytosine nucleoside class of drugs, it is converted into active lamivudine triphosphate in cells and acts by competing with the natural substrate of polymerase, which can quickly and effectively inhibit HBV replication[64]. LAM has fewer side effects, but may lead to myopathy or even rhabdomyolysis[65]. Studies have shown that oral administration of LAM 100 mg once a day can significantly inhibit HBV DNA levels. The seroconversion rate of HBeAg increases with prolonged treatment time[66]. For CHB patients with significant liver fibrosis and compensatory cirrhosis, LAM treatment for 3 years can delay disease progression, reduce liver decompensation and the incidence of HCC[67]. The main reason limiting its use is the occurrence of drug resistance. HBV DNA polymerase tyrosine methionine aspartate (YMDD) mutation. However, long-term treatment can cause HBV DNA polymerase tyrosine-methionine-aspartate-aspartate (YMDD) mutation, with a higher incidence of drug resistance. It has been reported that after 5 years of treatment, the drug resistance rate of LAM is as high as 51%, and the drug resistance rate increases with the extension of antiviral treatment time[20,68]. The weakening of antiviral effect and virus rebound can further aggravate liver disease, and liver failure or even death may occur in severe cases[69]. LAM alone has not been used as a first-line treatment for decompensated cirrhosis. For patients with LAM resistance, it is not recommended to switch to ETV because of the high possibility of subsequent drug resistance[70].

ADV: ADV was approved by the FDA for the treatment of HBV in 2002. ADV is an acyclic purine nucleoside analogue that is phosphorylated into the active diphosphate ADV through cellular kinase action in vivo. It competes with deoxyadenosine triphosphate substrates to inhibit the activity of HBV DNA polymerase or RT, terminate viral DNA strand extension, and thus inhibit viral replication. The mechanism of action of ADV and LAM is different. ADV is effective against both wild type and LAM resistant HBV. Therefore, ADV is also a remedy drug for LAM resistance, and the incidence of drug resistance is lower than LAM[71]. The combination of ADV and LAM can effectively inhibit HBV DNA in LAM resistant CHB, and the incidence of ADV resistance is lower in combination patients[72]. Studies have shown that when ADV is resistant, TFV can be used as a salvage treatment for ADV resistant patients[73,74]. The main metabolic pathway of ADV is completed through renal excretion, which causes significant damage to the kidneys and often leads to reduced renal function[75]. After 5 years of treatment with ADV, 3% of patients showed an increase in serum creatinine exceeding 0.5 mg/dL, but it was reversible[76,77].

LdT: LdT is a L-nucleoside anti-HBV drug, which is an artificially synthesized deoxythymidine substance[78]. It can reduce the activity of HBV DNA polymerase. Once the 5'- adenosine produced by LdT metabolism participates in HBV DNA, it prevents the elongation of HBV DNA strands. The GLOBE study found that LdT has good virus clearance ability and excellent e antigen seroconversion rate[79], and LdT is approved by FDA for anti HBV treatment in pregnancy[80]. The use of LdT in pregnant women with HBV infection can inhibit the replication of HBV and significantly reduce the risk of mother-to-child transmission of HBV, with good safety. Multiple clinical studies have shown that LdT can improve renal function impairment during anti-HBV treatment[81,82]. Lee et al[83] believed that ADV combined with LDT was superior to ADV alone and ADV combined with other drugs in the protection of renal function. LdT can be used even in patients with high risk factors for renal impairment[84]. LdT is classified as a pregnancy category B drug by the FDA in the United States. In women with HBV infection during pregnancy, if there is active hepatitis, LdT is selected for treatment, and it has been found to be effective and safe for both the fetus and the mother[80]. The main disadvantage of LdT is its drug resistance. The second year drug resistance rates for HBeAg positive and HBeAg negative patients were 29% and 11%, respectively. The common drug-resistant mutations are rtM204I and rtL180M[79,85]. Effective treatments for LdT resistance include addition of ADV or change to TFV monotherapy[76]. During the treatment with LdT, special attention should be paid to muscle related adverse reactions, such as elevated levels of creatine kinase and myopathy. In a small number of patients, these muscle adverse reactions may lead to severe muscle weakness and pain, and even the need to stop treatment.

IFN (IFN-α/polyethylene glycol-IFN-α)

IFN-α is the earliest anti HBV drug. IFN is a type of cytokine that plays an important role in human immune defense, which is divided into common IFN-α and polyethylene glycol-IFN-α (Peg-IFN-α) according to the length of half-life. They have better HBeAg clearance rate than NAs[86]. IFN-α is a soluble glycoprotein secreted by infected and transformed cells, which has antiviral, anti-tumor, cell proliferation inhibiting, and immune regulating effects[87]. Peg-IFN-α is the product of pegylated IFN. Adding a large number of branched PEG molecules increases the molecular weight of IFN, reduces drug excretion, shields the antigenic determinants on the surface of IFN molecules, reduces the immunogenicity and clearance rate of IFN in the body, and the half-life can be extended to 40 hours[88]. IFN has dual effects of antiviral and immune regulation. On the one hand, it regulates T lymphocytes, NK cells, antigen-presenting cells, and promotes the secretion of cytokines such as IL-1 β, IL-6, tumor necrosis factor α (TNF-α), and IFN-γ, stimulating the host to produce anti HBV immune response[89,90]. On the other hand, it inhibits HBV replication by producing anti HBV proteins. NAs therapy does not directly target cccDNA[91]. The cccDNA persistently existing in the liver nucleus is the reason why HBV is difficult to cure[92]. IFN-α and TNF-α, as key factors produced by immune cells, can further promote inhibition of HBV replication and lead to instability of cccDNA[93]. IFN can also induce the degradation of cccDNA by promoting the expression of factors such as APOBEC3A and ISG20[94]. Peg-IFN-α can affect the epigenetic modifications of cccDNA, thereby inhibiting its transcription and reducing the replenishment of the cccDNA pool, indirectly leading to the depletion of the cccDNA pool[93]. After receiving PEG-IFN-α treatment, the cccDNA level of HBV in CHB patients was significantly reduced[95]. At present, multiple studies have shown that IFN-α has a good response to HBsAg clearance rate and HBeAg seroconversion rate[96]. The incidence of HCC in CHB patients treated with IFN-α is significantly lower than that in patients treated with NAs[97]. Long before Peg-IFN-α was widely used to treat HBV infection, Sun et al[98] found that the median survival of patients treated with IFN-α after HCC resection was significantly longer than that of the control group (63.8 months vs 38.8 months). Peg-IFN-α treatment can also achieve a higher HBsAg seroconversion rate and a lower incidence of HCC compared to NAs[99]. A Ultra-Long-term study observed that HBeAg positive CHB patients who had received IFN-α or Peg-IFN-α treatment had higher rates of HBeAg seroconversion and negative HBsAg conversion[100]. The 2012 EASL guidelines indicate that the best treatment for achieving seroconversion in HBeAg positive patients is Peg-IFN-α treatment. Several studies have shown that Peg-IFN-α can decrease serum HBsAg levels and continue to decrease during follow-up[101,102]. Despite the obvious advantages of IFN in the treatment of CHB, the use of IFN is limited by several disadvantages, such as high cost, the method of administration was subcutaneous injection, and the frequent and high incidence of side effects.

Combination therapy

Multiple studies have shown that the 5-year cumulative incidence of liver cancer is 3.6%-11.4% in patients with HBV-DNA negative conversion[103,104], 2.58% in patients with HBeAg seroconversion[105], and only about 1% in patients with HBsAg clearance[106]. At present, serum clearance of HBsAg is regarded as the optimal endpoint for anti-HBV therapy, which can significantly reduce the risk of cirrhosis and liver cancer. Studies have shown that although patients receiving NAs therapy meet the criteria recommended by the AASLD guidelines for withdrawing from NAs therapy, the cumulative virological recurrence rates during the 1-year, 2-year, 3-year, and 4-year follow-up periods are 72.5%, 77.5%, 80.0%, and 82.5%, respectively[107]. Therefore, patients who meet the criteria for discontinuation of medication still need long-term follow-up after discontinuation. Due to the different mechanisms of IFN-α and NAs in treating HBV, multiple studies have shown that IFN-based therapy can achieve higher clinical cure rates and HBeAg serologic conversion rates compared to take NAs alone, including IFN monotherapy, combination therapy, and sequential therapy. IFN monotherapy is often used for HBeAg negative patients with low viral load. A randomized controlled trial in Singapore found that CHB patients with oral NAs were treated with addition or switch to Peg-IFN-α for 48 weeks. The clinical cure rates of the control group, sequential group, and combination group were 0%, 7.8%, and 10.1%, respectively. Patients treated with Peg IFN - α had significantly higher clinical cure rates than those treated with NAs alone[108]. For patients who use ETV and other NAs to achieve virological suppression and have baseline HBsAg ≤ 1500 IU/mL, the probability of achieving HBsAg clearance after 1 year of continued NAs treatment is about 0%-3%. However, if they switch to limited course Peg-IFN-α treatment, 20% of patients can achieve HBsAg clearance after 1 year[109]. It has been reported that long-term Peg IFN - α treatment can achieve a negative HBeAg conversion rate of over 30% for HBeAg positive CHB, and for HBeAg negative CHB, NAs combined with Peg-IFN-α treatment for 48 weeks is more effective than NAs alone[6]. A randomized controlled trial included HBeAg-positive patients with consistent HBV-DNA loads. After 9-36 months of ETV treatment, the group receiving sequential combination therapy with PEG-IFN-α at 48 weeks had a higher proportion of patients with HBsAg levels < 10 IU/mL and a higher HBsAg seroconversion rate (15.9% vs 0%) compared to the group continuing ETV treatment[110]. Ahn et al[111] found that HBsAg clearance after 48 weeks of TDF combined with PEG-IFN-α was significantly higher than that of TDF alone (10.4% vs 3.5%) in patients receiving initial antiviral therapy. Overall, the combination therapy of NAs and Peg-IFN-α can achieve better therapeutic effects with shorter treatment time[95]. Li et al[112] found that patients who achieved clinical cure with IFN treatment continued to consolidate treatment for less than 12 weeks, 12-24 weeks, and more than 24 weeks. The sustained clinical cure rates of one year after discontinuation were 86.7%, 98.3%, and 91.2%, respectively. The anti HBs levels in the latter two groups were significantly higher than those in the former group, indicating that patients who have been clinically cured should continue to receive IFN consolidation therapy for 12-24 weeks to achieve a lasting clinical cure.

CONCLUSION

Vaccination and public health measures are crucial for preventing the spread of HBV. For patients already infected with HBV, NAs and IFN are the main choices for antiviral treatment of HBV. NAs first-line therapy has good viral suppression effect, many types of oral drugs can be selected. The side effects vary depending on the metabolic pathway, but overall, the side effects are relatively few. Good compliance, but limited efficacy and low possibility of cure. In contrast, IFN-based treatment can enhance the host's immune response, IFN-α has a good response to HBsAg clearance rate and HBeAg seroconversion rate, and has the potential to cure hepatitis B. However, it is expensive and has more side effects, such as fever and leukopenia. The combination of two kind of drugs can reduce resistance and improve clinical cure rates. In clinical practice, doctors should choose the most appropriate treatment plan based on the patient's specific condition, including virological characteristics, liver function status, and individual tolerance.