HCC risk in patients who are HBeAg-positive and have chronic hepatitis B under long-term nucleos(t)ide analogue therapy: New insights from Asia
Authors: George Papatherodoridis, Pietro Lampertico
Journal: Hepatology (2024)

Patients who are HBeAg-positive with chronic HBV infection are classified into cases with chronic hepatitis B (CHB), who have high HBV DNA and elevated alanine aminotransferase (ALT) levels and are universally recommended to be treated, and into cases with only infection (previously "immunotolerant phase"), who have high HBV DNA and persistently normal ALT levels.1–3 Given the low risk of liver disease progression and the poor response to the existing anti-HBV agents, current guidelines do not recommend treatment in all patients who are HBeAg-positive with chronic HBV infection but close monitoring with serial ALT and HBV DNA measurements every 3–6 months.1–3 In particular, the existing data show that nucleos(t)ide analogue (NA) therapy can achieve the inhibition of HBV replication in up to 60% of such patients, while the probability of HBeAg to anti-HBe seroconversion is extremely low (<5% after 4 y)4 and thus very prolonged, perhaps indefinite, therapy will be required, if treatment is initiated.5 Considering that patients who are HBeAg-positive with chronic HBV infection are usually quite young, the benefit of inhibition of HBV replication is balanced against the potential adverse events, concerns about possible pregnancy, the possibility of spontaneous HBeAg seroconversion, and the cost of long-term NA therapy.5 On the other hand, there are obvious concerns about not treating patients with chronic HBV with high viral load (HVL), especially since advanced liver histological lesions have been reported in a proportion of such patients and the continued HBV replication has been suggested to potentially increase the risk of liver disease progression and HCC.6,7 Since older age is a critical factor increasing the risk of both advanced liver lesions and HCC,6 current guidelines from Europe and the United States recommend treatment initiation in all patients who are HBeAg-positive older than 30–40 years and Asian guidelines recommend liver biopsy in patients who are HBeAg-positive older than 35 years, whereas liver biopsy or alternative assessment of the severity of liver histological lesions is recommended in all cases who do not fulfill treatment indications by HBV DNA/ALT and/or age criteria. Additional parameters like a positive family history of cirrhosis or HCC may also drive treatment decisions.1–3 The paper from Choi et al8 investigated further the important association between HBV DNA levels and HCC risk in HBeAg-positive CHB. The most interesting finding of this study, which included adult patients without cirrhosis with HBeAg-positive CHB treated with long-term NA therapy, was that baseline viremia levels were associated with the HCC risk despite NA therapy, but the association was not linear. In particular, patients with the highest viral load (HBV DNA ≥8 log10 IU/mL) before treatment had the lowest long-term HCC risk; in the multivariable analysis with adjustment for age, gender, platelets, and ALT levels, HRs for HCC development were 6.2, 8.0, and 4.0 in cases with pretreatment HBV DNA 5–<6, 6–<7, and 7–<8 log10, respectively, compared to cases with HBV DNA ≥8 log10. However, the yearly absolute risk, that is, incidence rate per 100 person-years, was low, ranging between 0.48 and 1.38 in patients with pretreatment HBV DNA 5–<8 log10 compared to 0.10 in patients with HBV DNA ≥8 log10. Interestingly, as shown in Figure 2, the slope of the cumulative HCC incidence did not change substantially during the first 5–6 years in any subgroup, questioning a preventive effect of long-term NA therapy on HCC development in such patients. The study has significant strengths. It involves a large multicenter cohort from 3 Asian countries (Korea, Hong Kong, and Taiwan) including >7500 treated adult patients with HBeAg-positive CHB. Thus, the study population is quite homogeneous including only Asian patients who are HBeAg-positive, treatment-naive without cirrhosis, and mostly with elevated ALT, who were all treated with a high genetic barrier NA such as entecavir and tenofovir disoproxil fumarate. In the effort to overcome the limitations of a retrospective cohort study and the potential hidden confounding factors, appropriate statistical methodology was applied including not only multivariable models but also propensity score weighting and matching and several sensitivity analyses aiming to strengthen the validity of the findings. On the other hand, results and data interpretation from any study must be carefully assessed before their generalization may be widely accepted and potentially affect the clinical practice. In general, in retrospective cohort studies, the probability of bias and confounders can never be eliminated regardless of the robustness of statistical methods. In addition, in the present study, the number of patients at risk after 5–6 years seems to be limited for a robust analysis of a rare event such as HCC in this setting (0.6% overall annual HCC incidence), whereas several HCC risk factors, such as fibrosis severity, family history of HCC, or comorbidities as well as on-therapy ALT and HBV DNA responses, were not taken into consideration.9 Moreover, although patients were considered to be noncirrhotic, the presence of cirrhosis cannot be definitely excluded by the diagnostic approach used in the present study, while the potential effect of on-therapy changes of fibrosis severity was not evaluated. Finally, the potential effect of the type of NA (entecavir vs. tenofovir disoproxil fumarate) on the incidence of HCC, as has been suggested by several Asian studies,10 was not analyzed. The authors reach 3 main conclusions. First, "HVL at baseline was associated with the lowest HCC risk," which was in agreement with the results of another recent similar single-center study from the same leading Korean group.11 Given that patients with HVL compared to low viral load (HBV DNA 5–<8 log10) had favorable characteristics of well-known strong HCC risk factors like younger age and higher platelet counts, the authors tried to adjust for these differences by various statistical approaches. The significant association between HBV viremia level and the HCC risk was maintained in all subgroups of age ≥40 years, but not in the most interesting and controversial subgroup of younger patients (<40 y old), although a type II error cannot be excluded because of the low number of HCCs in the latter subgroup. Second, "even with prolonged antiviral treatment, the accumulation of the risk of HCC, indirectly indicated by the declining HBV viral load, cannot be entirely reversed." Many studies and systematic reviews have already demonstrated that the overall risk of HCC in CHB can be reduced but cannot be eliminated during effective long-term NA therapy.12 However, whether such a reduction of HCC risk applies to all patients with CHB or to patients with CHB with advanced fibrosis or cirrhosis has not been clarified.9,12 In a long-term study of the PAGE-B cohort including entecavir/tenofovir disoproxil fumarate-treated Caucasian patients with CHB, the HCC incidence was found to significantly decline after year 5 only in patients with pretreatment cirrhosis and to remain stably low in patients without pretreatment cirrhosis.12 The authors speculated that "HCC risk that accumulates while waiting for ALT levels to rise is never fully reversible," but there are no data supporting that the HCC is reversible even if treatment starts early. Thus, the present findings cannot reliably support that starting NA therapy at a younger age and possibly HVL of the patients who were treated later having HBV DNA <8 log10 would have resulted in lower HCC incidence rates at the same age periods. Third, "early initiation of antiviral treatment when patients have high HBV viral load may need to be considered to maintain the lowest risk of HCC in adult patients with HBeAg-positive without cirrhosis and with CHB." This conclusion is valid for this study patient population, but it can be considered to be misleading if it is generalized to all patients who are HBeAg-positive with HVL. There is no question that all patients with HBeAg-positive CHB, like the patients of this study who fulfilled the existing treatment indications (HBV DNA >20,000 IU/mL and ALT≥2× upper limit of normal or significant liver histological lesions), should be immediately treated. The unanswered question, however, is whether treatment should be initiated in patients with HBeAg-positive chronic HBV infection who have, by definition, HVL but normal ALT. Since the median age in the present study was 44 years overall and 40 years in patients with HVL, the application of these findings for treatment initiation in patients who are HBeAg-positive with HVL would involve mostly patients with such characteristics living in Asian countries, who are currently recommended to undergo liver biopsy if they are older than 35 years and do not fulfill typical treatment indications.3 In contrast, according to Western guidelines, patients who are HBeAg-positive living in Western countries are currently recommended to be treated regardless of ALT levels if they are older than 30–40 years.1,2 On the other hand, the present data cannot support the initiation of NA therapy in young patients (<30 y old) who are HBeAg-positive with persistently normal ALT who are not currently recommended to be treated by any guideline.1–3 In conclusion, we still do not have a definite answer about the optimal treatment indications for all patients who are HBeAg-positive, and the study by Choi et al8 cannot provide all the answers. However, despite the limitations of the existing studies, increasing indirect data support the initiation of NA therapy in all patients who are HBeAg-positive above a certain age, most probably>30 years, as already recommended by European guidelines.1 Recently, Chinese guidelines extended the treatment indications for patients who are HBeAg-positive further, even in cases younger than 30 years old with minimal biochemical activity, no clinical evidence of active liver disease, and minimal risk of progression to cirrhosis/HCC if left untreated.13 On the other hand, given the mode of action of the available NAs, the main goal of therapy is to improve survival and quality of life by reducing liver-related complications, and thereby the top priority should be to treat patients with diagnosed or high probability for HBV-related liver disease as the vast majority of complications will occur in these patients. Thus, waiting for newer agents that may offer acceptable chances for functional cure with a short-term finite treatment strategy, any expansion of treatment indications with the current agents should carefully weigh the pros and cons of such a strategy.