Revisiting the natural history of chronic hepatitis B infection

Despite the successful implementation of hepatitis B vaccination campaigns in many countries, hepatitis B remains a challenging issue of global public health. It has been recently estimated that 257 million individuals have chronic HBV infections. Around 20%–40% of patients with chronic hepatitis B (CHB) suffer from persistent or intermittent hepatic necroinflammation, leading to cirrhosis, hepatic failure, or HCC.1 Understanding the natural history of CHB is essential for the timely treatment of patients at risk to prevent long-term adverse outcomes. Prior research has delineated distinct phases during the natural history of CHB, but the disease course varies significantly among individuals, likely due to complex interplays between the virus and the host’s immune system. CLASSICAL VIEW OF THE NATURAL HISTORY OF CHB The chronicity rate following acute HBV infection varies depending on the age of acquisition of infection. It ranges from 90% in cases of infection at the perinatal or infancy period, 20%–30% in children under 5 years old, to less than 5% in immunocompetent adults. In high endemic areas, such as the Asia-Pacific region, the majority of patients with CHB contract HBV either at birth or during early childhood.2 HBV replication capacity, reflected by the serum HBV DNA level, is the driving force for disease progression.3 Traditionally, the natural history of CHB resulting from infection in early life can be categorized into 4 distinct phases based on HBeAg status, alanine transaminase (ALT) levels, HBV DNA levels, and histological findings: immune-tolerance, immune-clearance, inactive carrier, and reactivation phases (Figure 1).4FIGURE 1: The classical view of the natural history of CHB acquired perinatally or in childhood. Abbreviation: ALT, alanine transaminase; CHB, chronic hepatitis B.The initial immune-tolerance phase is distinguished by highly elevated levels of serum HBV DNA (> 108 IU/mL), the presence of serum HBeAg, normal ALT levels, and minimal or absent necroinflammation on liver histology. The duration of the immune-tolerance phase varies and often persists for 1 or 2 decades. The transition from the immune-tolerance phase to the immune-clearance phase is marked by an increase in ALT levels and a gradual decrease in serum HBV DNA levels. After the immune-clearance phase, the majority of patients will eventually undergo HBeAg seroconversion, marked by the disappearance of HBeAg and the emergence of anti-HBe antibodies. Subsequent to HBeAg seroconversion, around 70%–80% of patients enter an inactive carrier phase characterized by sustained normalization of ALT, low serum HBV DNA (< 2000 IU/mL), and minimal or absent hepatic necroinflammation. A small proportion of HBeAg seroconverters will eventually undergo spontaneous HBsAg seroclearance, indicating the resolution of CHB and typically resulting in an excellent clinical outcome, provided there is no preexisting cirrhosis. However, ~5% of patients undergoing HBeAg seroconversion experience HBeAg reversion. Moreover, 10%–20% of individuals, despite maintaining HBeAg negativity, face hepatitis reactivation with serum HBV DNA levels surpassing 2000 IU/mL, known as HBeAg-negative hepatitis, and are at an increased risk of HBV complications if left untreated. In Western countries, such as in Europe or North America, HBsAg carriers acquire HBV infection postnatally and horizontally. Patients with CHB with horizontal transmission have a shorter phase of immune tolerance, and the HBeAg seroconversion rate is higher. In contrast, patients with CHB with vertical transmission exhibit a longer immune-tolerance phase and low HBeAg seroconversion rate in children.5 Recently, the term “immune tolerance” has been challenged because the immune response to HBV is often detected in the so-called “immune-tolerance” phase. Moreover, based on either the presence or absence of active hepatitis (defined as raised or normal ALT), new nomenclature has been suggested to rename 4 disease phases as HBeAg-positive chronic HBV infection, HBeAg-positive CHB, HBeAg-negative chronic HBV infection, and HBeAg-negative CHB to replace conventional terminology, immune tolerance, immune active, inactive carrier and reactivation, respectively, although this terminology change has not yet been universally accepted.6 NEW QUANTITATIVE BIOMARKERS IN THE NATURAL HISTORY OF CHB Uncovering the natural history of CHB has provided great assistance for its management. Current clinical guidelines suggest antiviral treatment should be initiated for patients with prolonged hepatitis activity, primarily for those in the immune-clearance and reactivation phases. However, clear-cut differentiation of disease phases is not always unambiguous, and some patients may fall into the gray zones. Thus, additional novel biomarkers in conjunction with conventional factors for CHB may help distinguish the disease phases and predict the clinical outcomes more precisely. Three new quantitative viral biomarkers, namely, quantitative levels of serum HBsAg, hepatitis B core-related antigen (HBcrAg), and HBV RNA, have been examined for this purpose. Quantitative HBsAg levels Research using quantitative measurement of HBsAg has discovered that HBsAg levels evolve along the course of CHB. HBsAg level peaks in the immune-tolerance phase and is the lowest in inactive carriers. However, HBsAg level rebounds upon HBV reactivation in patients with HBeAg-negative hepatitis B. Previous studies have shown that the median HBsAg levels in Chinese patients with CHB (mainly genotype B and C) were 4.53, 4.03, 3.35, and 2.86 log IU/mL,7 and those in Caucasians (mainly genotypes A and D) were 5.08, 4.38, 3.84, and 3.35 log IU/mL, in immune-tolerance, immune-clearance, reactivation, and inactive carrier phases, respectively.8 Studies have demonstrated that a combination of HBsAg levels (< 1000 IU/mL) and HBV DNA levels (≤ 2000 IU/mL) can effectively identify inactive carriers of genotype D with 94.3% diagnostic accuracy and 87.9% positive predictive value (PPV).9 Likewise, these criteria can be applied to detect inactive carriers among individuals infected with genotypes B and C, achieving a diagnostic accuracy of 78% and a PPV of 83%.10 Additionally, studies in a Taiwanese hospital-based cohort (mainly genotype B or C) have indicated that among individuals with low viremia (< 2000 IU/mL), the HBsAg level correlates with the risk of disease progression, including hepatitis flares, HBeAg-negative hepatitis, liver cirrhosis, and HCC. In patients with low viremia, an HBsAg level below < 1000 IU/mL can act as an indicator of minimal risk for HCC.11 Quantitative HBcrAg levels HBcrAg serves as a composite marker, detecting combinatorial reactivity against HBcAg, HBeAg, and a 22-kDa pre-core protein without the C-terminal arginine-rich domain (p22cr). Research has established a robust correlation between HBcrAg levels and both serum HBV DNA levels and intrahepatic HBV DNA levels, particularly in patients who are HBeAg-positive. Cohort studies across Asian and European populations have unveiled dynamic fluctuations in HBcrAg levels throughout the natural course of CHB.12 HBcrAg levels peak during the immune-tolerance phase, then gradually decrease during the immune-clearance phase, followed by a decline in HBeAg-negative hepatitis and a further decrease in the HBeAg-negative inactive carrier phase. Notably, individuals undergoing HBsAg seroclearance display the lowest HBcrAg levels. Research from China and Japan has associated lower HBcrAg levels with early spontaneous HBeAg seroconversion. Furthermore, the combination of HBcrAg ≤ 3 log U/mL and HBV DNA ≤ 2000 IU/mL has demonstrated promising predictive capability for identifying an inactive carrier state.13 Additionally, HBcrAg has been correlated with heightened risks of liver inflammation, advanced fibrosis, and HCC. In a hospital-based study involving 2666 Taiwanese HBsAg carriers (genotype B or C), HBcrAg is a risk factor for HCC. Further subgroup analysis, specifically targeting patients who are HBeAg-negative with normal ALT and intermediate viral load (serum HBV DNA: 2000–19,999 IU/mL), revealed a notably increased risk of HCC (HR: 6.29) in individuals exhibiting high levels of HBcrAg (≥ 10 KU/mL).14 Serum HBV RNA levels Accumulating evidence has revealed the presence of HBV RNA in serum. The primary form of serum HBV RNA is likely the pregenomic RNA found in secreted virions. This RNA in serum mirrors the transcriptional activity of cccDNA and thus serves as a surrogate biomarker for it.15 Studies have demonstrated a strong correlation between serum HBV RNA and other markers, such as serum HBV DNA and HBcrAg, as well as intrahepatic cccDNA, particularly in naïve HBV carriers. The level of HBV RNA fluctuates across different phases of chronic hepatitis B (CHB), resembling the pattern observed with HBcrAg. Specifically, serum HBV RNA levels peak during the immune-tolerance phase, decrease during the immune-clearance phase, and further decline in inactive carriers. A study on 378 treatment-naïve Chinese patients with CHB showed the serum HBV RNA levels were 7.87, 6.67, 5.31, and 2.00 log copies/mL in immune-tolerance, immune-clearance, reactivation, and inactive carrier phases, respectively.16 It also revealed higher diagnostic accuracy in employing serum HBV RNA with cutoff of 2.11 Log copies/mL, compared to a combination of serum HBV DNA (cutoff > 3.39 Log copies/mL) and HBsAg (cutoff > 2.74 Log IU/mL) for differentiating between the “HBeAg-negative immune reactive” phase and the inactive carriers. However, the role of serum HBV RNA in the long-term outcomes of CHB remains to be further explored. It is worth noting that the implementation of serum HBV RNA measurement in clinical practice still encounters several challenges, such as characterizing the molecular nature of serum HBV RNA and standardizing its quantification methodology. REVISIT OF HBV NATURAL HISTORY BY INTEGRATING NEW BIOMARKERS Given the significant variability in the natural history of CHB among infected individuals, accurately determining the disease phases of a given patient poses a challenge. However, with the development of new viral biomarkers, refining the definition of each clinical phase becomes feasible. By combining several virological and serological markers, we can characterize the clinical phases of CHB in a more precise and sophisticated manner. Consequently, the natural history of CHB can be reassessed by integrating these new quantitative markers, including serum levels of HBV DNA, HBsAg, HBcrAg, and HBV RNA, as illustrated in Figure 2. Additionally, combining multiple quantitative markers may further aid in identifying subpopulation groups at risk of disease progression. In summary, the incorporation of all these factors into current clinical guidelines may help optimize the management of CHB. Nevertheless, the role of combining these markers in predicting the long-term clinical outcomes of CHB, including the risk of liver cirrhosis and HCC, should be thoroughly investigated in a larger prospective cohort comprising patients with different HBV genotype infections from various parts of the world.FIGURE 2: Revisiting the natural history of CHB by integrating new quantitative viral markers. Abbreviation: ALT, alanine transaminase; CHB, chronic hepatitis B.