Current and Emerging Therapeutic Strategies for Chronic Hepatitis B Virus Infection: A Review

The main objective in treating chronic hepatitis B (CHB) is to achieve sustained suppression of HBV DNA in order to slow or prevent the progression of liver disease. Interferon-alpha or nucleoside analog therapy aims to reduce HBV DNA levels to below 105 copies/mL in HBeAg-positive cases, and even lower in HBeAg-negative cases. HBeAg seroconversion and HBsAg loss are important markers of treatment success, though HBsAg loss remains infrequent. Interferon-based therapies have shown higher rates of HBsAg seroconversion compared to nucleoside analogs, which is likely due to their differing mechanisms of action. Treatment selection is based on patient-specific factors, including baseline HBV DNA and ALT levels, liver histology, and the patient’s ability to tolerate side effects. Global guidelines recommend initiating therapy for patients with elevated ALT and HBV DNA levels greater than 20,000 IU/mL, along with ongoing monitoring for resistance and treatment adherence. Recent advancements in antiviral agents, such as tenofovir and entecavir, have improved efficacy and reduced resistance compared to older treatments like lamivudine. Special considerations are necessary for populations such as pregnant women, individuals with cirrhosis, and those co-infected with HIV or HCV. While combination therapies may offer potential benefits, their optimal use still requires further research. Long-term monitoring is essential for achieving durable responses and improving outcomes in the management of CHB.

Introduction

Chronic infection with the Hepatitis B Virus (HBV) remains a significant global health issue, impacting more than 250 million people worldwide. This persistent infection is a primary contributor to the development of serious liver diseases, such as cirrhosis and hepatocellular carcinoma (HCC). Despite existing preventive measures like vaccinations, many patients with chronic HBV require ongoing medical management due to the virus’s persistent nature. The lack of a complete cure further emphasizes the need for effective therapeutic strategies [1].

Current treatments primarily focus on suppressing viral replication through nucleos(t)ide analogs (NAs) and modulating immune responses using interferon therapy. While these treatments help reduce disease progression and liver damage, they often require long-term administration and may not fully eradicate the virus. Additionally, challenges such as drug resistance, limited immune control, and adverse side effects highlight the need for continued research and innovation in treatment approaches [2].

Emerging therapies aim to overcome these limitations by targeting novel pathways for viral suppression and immune restoration. These include direct-acting antiviral agents, immune modulators, and combination therapies designed to improve efficacy and reduce the burden of treatment [3]. This review explores both current treatments and potential advancements that could shape future management strategies for chronic HBV, offering hope for improved patient outcomes and the possibility of a functional cure.

Understanding Virologic Outcomes: Essential Definitions and Criteria for Response Evaluation

The primary objective in managing chronic Hepatitis B (HBV) is the long-term suppression of HBV DNA to slow the progression of liver disease. This goal can be achieved through the use of interferon alpha or nucleoside analog therapies. For patients with HBeAg-positive chronic hepatitis B, effective suppression of HBV DNA is typically defined as a viral load below 10⁵ copies/mL (or less than 20,000 IU/mL). In contrast, lower thresholds are usually applied for those with HBeAg-negative hepatitis [4]. While specific response criteria may differ, achieving sustained HBV DNA suppression following treatment completion remains a critical clinical objective [5] (Table I). Furthermore, HBeAg seroconversion, characterized by the loss of HBeAg and the appearance of anti-HBe antibodies, is an important marker that can guide the duration of nucleoside analog therapy.

Table I. Advantages and Disadvantages of Currently Available Antiviral Agents

Parameter	Definition
Virologic response	A reduction in serum HBV DNA levels to less than 105 copies/mL (<20,000 IU/mL) in HBeAg-positive individuals and below 104 copies/mL (<2,000 IU/mL) in HBeAg-negative individuals. This may include the loss of HBeAg, with or without the subsequent appearance of anti-HBe.
Biochemical response	The normalization of serum alanine aminotransferase (ALT) levels. Suppression of HBV DNA levels to between 104 and 105 copies/mL, with or without the loss of HBeAg, alongside normalized ALT levels.
On-treatment response	Initial improvements in virologic and biochemical markers that necessitate ongoing therapy.
Maintained response	Sustained virologic and biochemical improvements observed for 6 to 12 months after stopping therapy.
Durable response	Long-term virologic and biochemical stability following the cessation of treatment.

Although HBsAg seroconversion is considered a more desirable outcome than simple HBV suppression, its occurrence with current antiviral therapies remains relatively infrequent, rendering it an unrealistic primary treatment goal. However, a systematic review of clinical trials assessing interferon alpha therapy suggests that treated patients have a higher rate of HBsAg seroconversion compared to those who remain untreated. A meta-analysis of 16 randomized controlled trials revealed that patients receiving interferon were six times more likely to experience HBsAg loss from the serum than those who did not receive treatment [6]. Long-term follow-up studies of HBeAg-positive patients treated with standard interferon alpha, with an average follow-up duration of 6.2 years (ranging from 1 to 11 years), indicated that 71% of those with sustained responses eventually became HBsAg negative [7].

In contrast, a one-year course of lamivudine or adefovir has not demonstrated a significant increase in HBsAg seroconversion rates compared to placebo. Moreover, the effect of extended therapy with these agents on HBsAg seroconversion remains unclear. The observation that interferon therapy leads to earlier HBsAg seroconversion compared to nucleoside analogs underscores key differences in their mechanisms of action. This finding suggests that combining both therapies may offer potential benefits [8].

Factors Influencing the Selection of Treatment

When selecting the most appropriate treatment for chronic hepatitis B, healthcare providers must take various factors into account. These include baseline serum ALT levels, HBV DNA concentrations, liver biopsy results, treatment costs, patient tolerance to potential side effects, age, other existing health conditions, and the feasibility of monitoring throughout the therapy. Given that both interferon and nucleoside analogs offer unique benefits and drawbacks, there is no single treatment that suits every patient [5] (Table II).

Table II. Representation of Advantages and Disadvantages of Hepatitis B Treatment Agents

Agent(s)	Advantages	Disadvantages
Peginterferon	- Treatment duration is limited - long-lasting responses after treatment ends - 5%–8% rate of HBsAg disappearance	- Requires injection - common side effects - high cost - less effective in patients with high viral load
Nucleos(t)ide analogs	- Taken orally - minimal side effects - strong inhibition of viral replication - more affordable than interferon	- Risk of developing drug resistance - long-term or indefinite therapy required - low rates of HBsAg disappearance - moderately costly for prolonged use

A key benefit of interferon therapy is its relatively short treatment duration, which can lead to lasting responses without the necessity for ongoing treatment. In contrast, nucleoside analogs often require extended use to sustain viral suppression.

Recommendations for Managing Hepatitis B

The AASLD, Asian-Pacific Association, and EASL have all created hepatitis treatment guidelines B [9], [10]. While these guidelines are largely consistent, they are periodically updated to reflect advancements in treatment. Variations among them often arise due to differences in the global availability of therapeutic options and delays in incorporating newly published data. Since these guidelines are based on scientific evidence, they do not currently endorse combination therapy involving multiple nucleoside analogs or the simultaneous use of interferon with a nucleoside analog, as clinical trials have not demonstrated significant additional benefits from such approaches. The guidelines continue to evolve as more data become available.

The guidelines provide consistent recommendations regarding treatment. Generally, therapy is advised for patients who demonstrate biochemical signs of liver damage and have serum HBV DNA levels above 20,000 IU/mL (approximately 100,000 copies/mL) [11]. Nucleoside analogs are specifically recommended for those with decompensated cirrhosis. Treatment is also commonly suggested for patients with serum ALT levels more than twice the upper normal limit [5] (Table III), although there is some debate among experts about the significance of particular ALT and HBV DNA thresholds [11]. This recommendation is supported by research indicating that patients with only mild ALT increases prior to treatment tend to have lower sustained virologic response rates, regardless of whether they are treated with interferon or nucleoside analogs [12].

Table III. Scientific Table Representation of Treatment Strategies for Chronic Hepatitis B

Treatment strategy	Serum ALT level	Serum HBV DNA level	HBeAg status	Notes
Observation; consider treatment if ALT increases	≤2 × ULN	>20,000 IU/mL	Positive	Current treatments have limited efficacy; continue monitoring and reconsider treatment if ALT levels rise.
Initial treatment options	>2 × ULN	>20,000 IU/mL	Positive	Lamivudine and telbivudine are less preferred due to resistance concerns. Treatment duration: pegylated interferon (48 weeks), nucleoside/nucleotide analogs (≥1 year).
Alternative options for non-responders or resistance	>2 × ULN	>20,000 IU/mL	Positive	Use tenofovir or entecavir for treatment. For lamivudine resistance, add adefovir/tenofovir or switch to emtricitabine-tenofovir/high-dose entecavir. For adefovir resistance, add lamivudine or switch to emtricitabine-tenofovir/entecavir.
Treatment endpoints	>2 × ULN	>20,000 IU/mL	Positive	Aim for sustained ALT normalization and undetectable HBV DNA by PCR.
Liver biopsy consideration for moderate/severe inflammation	1–2 × ULN	>2,000 IU/mL	Negative	Liver histology should be assessed to inform treatment decisions.
Observation	≤ULN	≤2,000 IU/mL	Negative	Closely monitor; initiate therapy if HBV DNA or ALT levels rise.
Compensated cirrhosis	Any	>2,000 IU/mL	Positive/negative	Treat with tenofovir or entecavir; avoid lamivudine and telbivudine.
Decompensated cirrhosis	—	Detectable	Positive/negative	Refer for liver transplantation and coordinate care with a transplant center. Preferred treatments include adefovir plus lamivudine/telbivudine, entecavir, or tenofovir.
Note. ALT: Alanine aminotransferase, ULN: Upper limit of normal, HBeAg: Hepatitis B e antigen, HBV DNA: Hepatitis B virus DNA.

All key guidelines emphasize the need to take liver histological results into account when determining treatment options. Therapy is typically prioritized for patients with moderate to severe hepatitis, though the precise grading or staging of liver histology is not yet considered a definitive factor in treatment selection.

Antiviral Agents

By 2009, seven antivirals were approved for hepatitis B, with pegylated interferon alpha-2a replacing standard interferon. Treatment should be personalized based on patient and virus characteristics [13].

Interferons

Interferon Alpha

Interferon alpha, approved in 1992 for chronic hepatitis B, is effective within 4–12 months and does not cause drug resistance. It enhances immune response, potentially reducing HBV cccDNA and leading to HBsAg loss in 5%–8% of patients. However, it has lower patient tolerance and less HBV DNA suppression compared to other treatments [14].

During interferon alpha therapy, ALT flares have been reported in some patients. Although these flares may be beneficial in achieving a virologic response, their occurrence is unpredictable and does not always correlate with antiviral effectiveness. Studies suggest that in patients with high viral loads, the intensity of an ALT flare may be an indicator of sustained virologic response, highlighting the importance of a strong cell-mediated immune response in controlling viral replication [14].

Pegylated Interferon Alpha

Pegylated interferon has been shown to be more effective than conventional interferon and is approved for use in more than 75 countries [15]. Clinical studies have tested weekly doses of 1.0 μg/kg for peginterferon alfa-2b and 180 μg for peginterferon alfa-2a [16]. However, it is still uncertain whether the improved efficacy is mainly attributed to a more significant reduction in viral replication or enhanced immunomodulatory effects.

The effectiveness of interferon treatment seems to be affected by the HBV genotype. A study from Taiwan found that patients with HBeAg-positive chronic hepatitis B and genotype B showed a better response to conventional interferon compared to those with genotype C [17]. Additionally, a large multicenter trial on peginterferon alfa-2b showed that HBeAg-positive patients with genotype A had higher rates of HBeAg loss (47%) compared to those with genotypes B, C, or D (44%, 28%, and 25%, respectively) [18].

A follow-up study conducted three years later found that patients with HBV genotypes A and B had the highest sustained virologic response rates (96% and 86%) and HBsAg clearance rates (58% and 14%) [19]. In contrast, patients with genotype D showed response rates of 76% and 6%, respectively. These results support earlier research suggesting that HBeAg-positive patients with genotype A tend to have a more favorable response to interferon therapy compared to those with genotype D.

The relationship between HBV genotype and treatment response in HBeAg-negative patients remains uncertain. However, a systematic review of more than 500 patients treated with interferon revealed that genotype C had the highest sustained virologic and biochemical response rates, while genotype D had the lowest (50% and 21%, respectively) [20]. This genotype-specific response is particularly important when treating North American patients with chronic HBV, especially considering the increase in Asian HBV carriers with genotypes B and C in the region since the late 20th century.

Nucleoside and Nucleotide Analogs

Nucleoside and nucleotide analogs offer excellent oral bioavailability, a favorable safety profile, and antiviral efficacy comparable to interferon alfa-2b. They are particularly useful for patients with decompensated cirrhosis, as even low doses of interferon can exacerbate liver function and elevate the risk of infection [21].

These medications act by mimicking natural nucleosides during HBV DNA synthesis, thus inhibiting viral reverse transcriptase and DNA polymerase. However, since they only partially suppress viral replication, treatment usually needs to extend beyond a year for optimal results. Prolonged monotherapy, though, raises the risk of developing drug resistance. Fig. 1 highlights common mutations in HBV nucleotides associated with resistance and potential cross-resistance. Additional limitations of nucleos(t)ide analogs include challenges in eliminating HBV cccDNA and a relatively low rate of HBsAg clearance after one year of treatment, unlike interferon. These difficulties may be related to the absence of direct immunomodulatory effects on the HBV response [5]. After stopping nucleoside analog therapy, ALT flares have been observed in about 25% of cases.

Fig. 1. The progression of drug resistance during antiviral treatment for hepatitis B follows a predictable sequence. Initially, HBV DNA levels in the serum decline during therapy, potentially becoming undetectable. However, prolonged drug pressure can lead to the emergence of compensatory mutations, allowing resistant HBV variants to replicate more efficiently. These resistant variants gradually dominate the viral population. Genotypic resistance is often identified weeks or months before clinical signs, such as virologic breakthrough, characterized by a rise in HBV DNA levels. This is typically followed by biochemical breakthrough, marked by elevated serum alanine aminotransferase (ALT) levels, and eventually, virologic rebound, with a significant increase in HBV DNA and further ALT elevations if treatment is not adjusted.

Lamivudine

The approval of lamivudine in 1998 represented a significant step forward in the treatment of hepatitis B. It is an effective inhibitor of viral replication, convenient to administer, and typically well-tolerated with few severe side effects. Clinical research has demonstrated that a year of lamivudine treatment leads to a significant reduction in viral replication and improvement in liver histology [22]. One study reported HBeAg loss and seroconversion rates of 32% and 17%, respectively, after one year of therapy [22]. Extending treatment to two years increased the HBeAg seroconversion rate from 17% at one year to 27% at two years [23], [24].

However, extended use of lamivudine beyond one year is associated with increasing resistance rates—38% by two years, escalating to 65% by the fifth year [22]. In patients co-infected with HIV, resistance rates are even higher, reaching 90% by the fourth year, partly due to lamivudine’s early inclusion in HAART regimens [25]. Resistance that persists beyond two years has been linked to reduced histologic improvement and more frequent hepatitis flare-ups. Consequently, lamivudine is no longer recommended as a first-line treatment. Fortunately, newer nucleos(t)ide analogs with much lower resistance rates are now available [25].

Adefovir Dipivoxil

Adefovir dipivoxil, a nucleotide analog derived from adenosine monophosphate, was approved in 2002 for the treatment of chronic hepatitis B, including both HBeAg-positive and HBeAg-negative cases. Its efficacy has been demonstrated in randomized trials conducted across the U.S., Europe, and Asia. After 48 weeks of treatment, patients experienced median reductions in serum HBV DNA of 3.52 log10 and 3.91 log10 copies/mL for HBeAg-positive and HBeAg-negative cases, respectively. Although the rates of HBeAg loss and seroconversion were lower compared to those achieved with 52 weeks of lamivudine, improvements in HBeAg seroconversion and undetectable HBV DNA levels were observed during the second year of therapy. HBV DNA suppression remained consistent across various viral genotypes [26].

Adefovir suppresses viral replication slightly less effectively than lamivudine, with a difference of about 0.5 to 1.0 log. However, the two drugs have distinct resistance profiles. Mutations in the HBV polymerase gene (A181V and N236T) that lead to adefovir resistance are observed in 3% of patients after two years, with resistance rates increasing over time. By three years, resistance reaches 6% to 8%, rising to 15% to 18% at four years and 20% to 29% by the fifth year. Laboratory studies show that HBV strains with the N236T mutation remain sensitive to lamivudine, entecavir, and telbivudine [26].

Adefovir is effective for treating patients with lamivudine-resistant HBV, irrespective of disease severity, liver transplantation status, or cirrhosis-related complications. However, HBV strains resistant to adefovir remain sensitive to lamivudine. The likelihood of developing resistance to adefovir is higher when lamivudine therapy is discontinued in patients already resistant to lamivudine, compared to those who continue lamivudine alongside adefovir. Therefore, many experts recommend maintaining lamivudine treatment while starting adefovir in patients with pre-existing lamivudine resistance, as early detection of resistance allows for a more rapid and effective virologic response.

Adefovir is also associated with a potential risk of nephrotoxicity, requiring dosage adjustments in patients with renal impairment or those at higher risk for kidney damage. Despite its continued use, about 30% of patients do not achieve complete viral suppression, particularly those with high baseline viral loads. As a result, more potent agents like entecavir and tenofovir are increasingly replacing adefovir as first-line therapies [27].

Entecavir

Entecavir, a nucleoside analog, inhibits HBV replication by targeting HBV DNA polymerase and blocking DNA strand synthesis. Approved by the FDA in 2005, it demonstrated superior efficacy compared to lamivudine, with no resistance observed after one year of treatment [28].

Entecavir is effective against both wild-type HBV and strains resistant to lamivudine. In phase 3 clinical trials, treatment-naïve HBeAg-positive and HBeAg-negative patients were given a 0.5 mg dose of entecavir, while those with lamivudine-resistant HBV received a 1 mg dose. In comparison to lamivudine and adefovir, entecavir showed greater antiviral effectiveness, achieving undetectable HBV DNA levels in 67% of treatment-naïve HBeAg-positive patients and 90% of HBeAg-negative patients after one year. Among HBeAg-positive patients who continued treatment for an additional year, 80% reached undetectable HBV DNA levels with entecavir, whereas only 37% of those on lamivudine achieved the same result.

Resistance to entecavir is rare in patients who have not previously received nucleoside analog treatment, with only about 1% developing resistance after five years of therapy. However, resistance is more common in patients with prior lamivudine resistance. In lamivudine-refractory patients, virologic rebound due to entecavir resistance was detected in 1% of cases after one year, rising to 9% after two years, with the risk increasing further with longer treatment duration [28].

Telbivudine

Telbivudine, an L-nucleoside analog of thymidine, is more potent than lamivudine in treating both HBeAg-positive and HBeAg-negative hepatitis B. In a trial involving 1,367 patients, telbivudine demonstrated superior virologic and biochemical responses compared to lamivudine [29], and patients who switched from adefovir to telbivudine showed significant reductions in serum HBV DNA [8].

Resistance developed in 5% and 25% of HBeAg-positive patients after one and two years, respectively, and in 2% and 11% of HBeAg-negative patients [30]. The best response rates were observed in patients with HBV DNA levels below 3 log10 copies/mL at week 24, with optimal results in those with undetectable HBV DNA by PCR. Resistance is associated with the M204I and L180M mutations, and telbivudine is not recommended for patients with lamivudine-resistant HBV. Despite its potency, telbivudine has higher resistance rates than entecavir and tenofovir, limiting its use. A study combining telbivudine with pegylated interferon was discontinued due to increased rates of myopathy and elevated creatine kinase levels [29].

Tenofovir Disoproxil Fumarate

Tenofovir, a 300-mg acyclic nucleotide analog, inhibits both HBV polymerase and HIV reverse transcriptase. Approved for HIV treatment in 2001 and for HBV in 2008, it demonstrates greater antiviral potency compared to adefovir, particularly in treatment-naïve patients and those with lamivudine-resistant HBV [31].

No cases of tenofovir resistance have been reported in either HBeAg-positive or HBeAg-negative patients after two years of treatment. However, preliminary data suggest that HBV resistant to adefovir may exhibit reduced sensitivity to tenofovir, though it remains unclear whether specific mutations in the HBV polymerase gene could lead to resistance in either treatment-naïve or adefovir-resistant patients [32].

Long-term use of tenofovir has been associated with bone loss and decreased bone mineral density, especially in individuals co-infected with HIV. Similar to adefovir, extended tenofovir therapy can result in renal tubular damage and Fanconi syndrome, particularly among older patients and those with preexisting kidney issues. Monitoring of serum creatinine levels is advised, and dose adjustments or discontinuation may be necessary if renal function declines. In HIV-infected individuals, concurrent use of ritonavir or didanosine has been linked to an increased risk of Fanconi syndrome [32].

Emtricitabine

Emtricitabine, a fluorinated cytosine analog, inhibits both HBV DNA polymerase and HIV reverse transcriptase. It is approved for the treatment of HIV-1 infection in the United States and other regions. In a phase 3, placebo-controlled trial involving previously untreated chronic HBV patients, a 48-week regimen of 200 mg daily emtricitabine resulted in a median reduction of 3 log10 copies/mL in serum HBV DNA and significant improvements in liver histology.

In patients co-infected with HBV and HIV, emtricitabine demonstrated HBV DNA suppression comparable to that observed in HBV monoinfected individuals. However, because emtricitabine shares structural similarities with lamivudine, it also carries the same mutation sites and resistance profile. The YMDD mutation was found in 9% to 13% of patients after 48 weeks of treatment and in 19% after 96 weeks. Due to its high resistance rates, emtricitabine is not typically considered a first-line option for the treatment of HBV monoinfection [33].

Clevudine

Clevudine, a pyrimidine analog, is an effective inhibitor of HBV replication both in vitro and in vivo. It has been studied in clinical trials involving animal models and humans, and has been approved for the treatment of hepatitis B in Korea based on 24-week clinical trials. One study showed that a 12-week regimen of clevudine resulted in a reduction of more than 4 log10 copies/mL in serum HBV DNA levels. However, after therapy was discontinued, HBV DNA levels generally returned to pretreatment levels in most cases [34].

In some cases, a 3-log10 reduction in HBV DNA levels persisted for six months after a 24-week treatment course, suggesting a different viral rebound pattern compared to other nucleoside analogs. This prolonged effect may be related to clevudine’s suppression of HBV cccDNA, which is generally resistant to other oral antiviral therapies. However, data on the long-term safety and efficacy of clevudine remain limited. In 2009, clinical trials were discontinued following reports of myopathy in patients treated for more than 24 weeks [35].

Combination Therapy: Nucleoside and Nucleotide Agents

The combination tablet of tenofovir (300 mg) and emtricitabine (200 mg) has received FDA approval for HIV treatment. While not approved for hepatitis B, this combination may be helpful for patients with resistance to multiple HBV therapies. Tenofovir is effective against resistant HBV strains, and emtricitabine can target tenofovir-resistant strains. This combination therapy is sometimes used as a first-line option for HBV monoinfection in patients with advanced cirrhosis, where resistance concerns are more prominent. Additionally, the dual-agent formulation may enhance patient adherence and reduce overall treatment costs when compared to prescribing two separate nucleoside analogs [36].

Viral Resistance to Nucleoside and Nucleotide Analogues

Except for tenofovir, all nucleos(t)ide analogs are prone to causing drug resistance when used as monotherapy. Genotypic resistance, identified through assays such as InnoLipa, arises from nucleotide substitutions in the HBV polymerase gene and requires at least 10% of the viral population to be resistant. Resistance testing should be conducted before discontinuing treatment to prevent the emergence of undetectable resistant strains. Phenotypic resistance is assessed in laboratory settings by exposing HBV mutants to antiviral drugs to determine their susceptibility, though this method is primarily used for research purposes [37].

Monitoring and Managing Resistance

Clinical trials evaluating nucleos(t)ide analogs have shown that genotypic resistance can emerge weeks to months before a virologic breakthrough occurs. A virologic breakthrough is defined as an increase in serum HBV DNA levels by more than 1-log10 (10-fold) from their lowest recorded level [5] (Fig. 1). If treatment continues without modification, virologic rebound can occur, characterized by HBV DNA levels exceeding 100,000 copies/mL (or 20,000 IU/mL) along with rising ALT levels [5] (Fig. 1). Once resistance is confirmed, it is recommended that an alternative antiviral that does not have cross-resistance to the initial drug be introduced. Many experts suggest adding a second nucleos(t)ide analog rather than switching to another monotherapy, as this strategy helps reduce the risk of multidrug-resistant HBV [37].

Regular Testing for Virologic Breakthrough

Patients undergoing nucleos(t)ide analog therapy should be monitored every three months for serum HBV DNA levels. If a reduction of at least 1-log10 is not observed after three months, primary treatment failure is diagnosed, and a switch to a more potent antiviral is required. A critical evaluation also occurs at week 24 [38].

The GLOBE trial, which compared lamivudine and telbivudine, showed that patients with detectable HBV DNA at 24 weeks had an increased risk of developing resistance. The likelihood of treatment failure was closely tied to HBV DNA levels at this point. In clinical practice, patients with high baseline viral loads may still have HBV DNA levels above 10,000 copies/mL at week 24, even when using potent antivirals.

• If the patient is on a nucleos(t)ide analog with a high genetic barrier to resistance, such as entecavir or tenofovir, continued treatment is generally appropriate, as further viral suppression is expected.

• If the patient is on a drug with a high resistance potential, like lamivudine, or one with lower antiviral potency, like adefovir, switching to a more effective agent is advised [39].

Treatment should ideally begin with high-potency nucleos(t)ide analogs, such as entecavir or tenofovir, as they rapidly suppress HBV DNA and reduce the risk of resistance.

Addressing Virologic Breakthrough and Multidrug Resistance

If a virologic breakthrough occurs, adherence to the treatment regimen should first be assessed. If non-adherence is ruled out, genotypic resistance testing should be performed. If resistance is detected, switching to a nucleos(t)ide analog without cross-resistance is recommended. Clinical experience suggests that adding a second drug is often more effective than sequential monotherapy, as the latter can contribute to multidrug-resistant HBV.

Once multidrug resistance develops, treatment options become significantly limited, as combination therapy is unlikely to be effective in such cases. This highlights the importance of choosing potent first-line antivirals and monitoring HBV DNA levels closely to prevent resistance from emerging [40].

Combined Nucleoside or Nucleotide Analogue Therapy

Combination therapy with two or more nucleos(t)ide analogs has been proposed as a more effective treatment for HBV infection than monotherapy, supported by in vitro and woodchuck model studies. The goal is to delay drug resistance and achieve faster clinical stabilization, particularly for patients with decompensated cirrhosis or those needing a liver transplant. However, this approach has drawbacks, including higher costs, increased drug toxicity, and the potential for multidrug resistance, which may reduce long-term effectiveness [41].

Clinical Findings on Combination Therapy

Early clinical trials involving previously untreated HBeAg-positive chronic hepatitis B patients found that combining two nucleoside analogs (such as telbivudine and lamivudine) or a nucleoside analog with a nucleotide analog (such as lamivudine and adefovir) did not result in superior viral suppression in the first year compared to monotherapy. Potential reasons for this include competition for binding sites on HBV DNA polymerase or the phosphorylation enzymes necessary for drug activation, or the addition of a less potent drug that does not enhance the effect of a more potent one. However, a two-year study demonstrated that combining lamivudine and adefovir decreased the incidence of lamivudine resistance (15% vs. 43%) [41]. These findings, coupled with insights from HIV combination therapy, have led some experts to recommend combination therapy as a first-line approach to reduce the risk of resistance. Nonetheless, due to the low rates of resistance with newer nucleos(t)ide analogs, combination therapy may be more suitable for patients with high viral loads, obesity, or other factors that increase resistance risk [42].

Combination Interferon and Nucleoside Analog Treatment

The concept of combining interferon with a nucleoside analog for hepatitis B treatment stems from their complementary mechanisms of action, which could potentially boost antiviral efficacy. This combination may also shorten the duration of nucleoside analog therapy, thereby lowering the likelihood of developing viral resistance. To explore this approach, three large-scale multicenter studies examined the effects of pegylated interferon in combination with lamivudine for chronic hepatitis B patients.

In one study, HBeAg-positive patients were treated with peginterferon alfa-2b combined with either lamivudine or a placebo for one year. The combination therapy group experienced 44% HBeAg loss, compared to 29% in the peginterferon-only group. However, six months after treatment, response rates were similar (35% for combination therapy vs. 36% for peginterferon alone), which was likely due to the lower dosage of peginterferon (100 μg weekly for eight months, then reduced to 50 μg) [43]. Another study involving HBeAg-positive patients treated with peginterferon alfa-2a, either alone or with lamivudine, showed the greatest HBV DNA suppression in the combination therapy group. Despite this, the HBeAg seroconversion rates were similar between both interferon-containing groups, even six months after treatment [44].

A third trial focused on HBeAg-negative chronic hepatitis B patients using peginterferon alfa-2a also found that combination therapy led to more significant viral suppression, but it did not result in a higher sustained virologic response rate. However, lamivudine resistance was notably lower in patients receiving combination therapy than those treated with lamivudine alone.

These studies suggest that while pegylated interferon and lamivudine offer additive antiviral effects during treatment, they do not improve long-term response rates. Ongoing research is now investigating combinations of pegylated interferon with entecavir or tenofovir for longer treatment durations to enhance long-term therapeutic outcomes [16].

Antiviral Treatment in Special Populations

Pregnant Women

Nucleos(t)ide analog therapy during pregnancy may protect maternal health and reduce HBV transmission to newborns. Studies show that treating mothers with high HBV DNA levels in the last 4 to 12 weeks lowers the risk of infant infection when the HBV vaccine is administered at birth [45]. However, these studies have been small-scale, with design limitations and insufficient follow-up. Notably, when newborns receive a three-dose HBV vaccination along with a single dose of hepatitis B immune globulin (HBIG), the breakthrough infection rate is only about 5%. As a result, the use of antiviral therapy solely to prevent mother-to-child transmission remains controversial and is not currently a standard recommendation [45].

At present, no antiviral agents are officially approved for use during pregnancy, and their potential risks to fetal health remain a concern. The FDA classifies telbivudine and tenofovir as category B drugs, meaning they have not demonstrated embryologic toxicity in animal studies, but human data are insufficient. Tenofovir has been widely used in HIV-HBV co-infected pregnant women, providing some reassurance regarding its safety. Lamivudine is categorized as B for HIV-infected pregnant women, but as category C for those with HBV, reflecting potential risks observed in animal studies. However, its strong safety profile in treating HIV often leads to its use as a preferred option for managing hepatitis B during pregnancy [46].

Women of childbearing age should avoid pregnancy while on nucleos(t)ide analog therapy. If pregnancy occurs, the risks of drug discontinuation, such as ALT flare-ups, must be weighed against potential risks to the fetus. Tenofovir is typically avoided in HIV-infected patients due to concerns about its impact on bone mineral density and fetal bone development [47].

The Antiretroviral Pregnancy Registry in the U.S. has monitored nearly 10,000 pregnancies since 1989, finding birth defect rates comparable to those in the general population. Interferon therapy is contraindicated during pregnancy due to its antiproliferative effects, and breastfeeding is generally not recommended for mothers on antiviral therapy during the infant’s first year [47].

Persons with Acute Hepatitis B

Because over 95% of individuals with acute hepatitis B achieve complete immunologic recovery, there are no definitive treatment recommendations. Some experts suggest nucleos(t)ide analog therapy for patients who remain HBeAg-positive beyond 10 to 12 weeks, as this increases the likelihood of chronic HBV carrier status.

The National Institutes of Health (NIH) recommends antiviral treatment for acute viral hepatitis with an INR above 1.5 or severe jaundice lasting over four weeks [48]. AASLD guidelines also support antiviral therapy for fulminant hepatitis B, given the safety of nucleos(t)ide analogs and the potential need for liver transplantation [49].

Persons with Cirrhosis

Nucleos(t)ide analog therapy is both safe and effective for patients with cirrhosis, leading to significantly improved outcomes, especially in those with advanced liver disease. In contrast, interferon is generally not recommended for cirrhotic patients, even those with mild decompensated cirrhosis, due to the risk of immune-mediated ALT flare-ups and the potential for further liver function deterioration. Additionally, there have been reports of serious infections in cirrhotic patients undergoing interferon therapy [50].

The AASLD guidelines recommend nucleos(t)ide analog therapy as the preferred treatment for HBV-related cirrhosis due to the risk of dose-limiting side effects and potential hepatic decompensation associated with interferon. However, some studies indicate that patients with stable, well-compensated cirrhosis may still benefit from interferon therapy, achieving higher virologic response rates compared to non-cirrhotic patients. Treatment decisions should be individualized, and interferon-treated cirrhotic patients should be closely monitored [10].

Persons with HIV-HBV Co-infection

With the advancements in HAART, liver disease has become a leading cause of death among individuals coinfected with HIV and HBV [51]. Treatment for hepatitis B should be considered for all HIV-HBV coinfected individuals who show signs of liver disease, regardless of their CD4 count.

• For patients not requiring HAART, HBV treatment should involve agents like adefovir or pegylated interferon, as these do not have activity against HIV.

• Entecavir is not recommended for patients not receiving HIV therapy, as it may reduce HIV RNA levels and potentially affect treatment outcomes.

• For patients with CD4 counts below 350/mm³, dual anti-HIV and anti-HBV therapy, such as emtricitabine and tenofovir or lamivudine and tenofovir, should be used to prevent resistance [52].

People with HBV-HCV Co-Infection

Patients coinfected with HBV and HCV often experience more severe liver damage and a higher risk of cirrhosis compared to those with a single viral infection. However, there is limited data on the optimal treatment strategy. Due to viral interference, one virus—typically HCV—tends to dominate, resulting in detectable HCV RNA but undetectable HBV DNA. Viremia can fluctuate, which necessitates close monitoring prior to treatment.

A trial involving 19 HBV-HCV co-infected patients found that 74% achieved a sustained virologic response after 48 weeks of pegylated interferon alpha and ribavirin, with two of five HBV DNA-positive patients clearing HBV [53]. However, HBV DNA re-emerged in four patients previously considered HBV-negative, highlighting the risk of HBV reactivation after HCV clearance.

While the optimal treatment for active HBV and HCV infections remains uncertain, some clinicians suggest combining a nucleos(t)ide analog with pegylated interferon alpha and ribavirin to target both viruses [53].

Conclusion

Effective management of chronic hepatitis B (CHB) focuses on sustained HBV DNA suppression to prevent liver disease progression. Modern therapies, including interferon-alpha and nucleoside analogs like tenofovir and entecavir, offer high efficacy, safety, and reduced resistance. Treatment decisions should be personalized, considering factors such as HBV DNA levels, ALT levels, and patient-specific conditions. Global guidelines emphasize early intervention, adherence, and resistance monitoring. Special populations, including pregnant women and those with co-infections, require tailored approaches. While combination and emerging therapies show promise, further research is needed to optimize their use. Long-term monitoring remains essential for achieving durable virologic suppression and improved outcomes.

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