Evidence for Benefits of Early Treatment Initiation for Chronic Hepatitis B

Abstract

Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Antiviral treatment reduces the risk of HCC and mortality; nonetheless, globally in 2019, only 2.2% of CHB patients received treatment. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage. This contrasts with hepatitis C or HIV where early treatment is recommended in all infected patients, regardless of end-organ damage. This narrative review aims to provide an overview of data on the early initiation of antiviral treatment and its related potential economic impact. Literature searches were performed using PubMed and abstracts from international liver congresses (2019-2021). Data on risk of disease progression and HCC and the impact of antiviral treatment in currently ineligible patients were summarized. Cost-effectiveness data on early antiviral treatment initiation were also collated. Accumulating molecular, clinical, and economic data suggest that early initiation of antiviral treatment could save many lives through HCC prevention in a highly cost-effective manner. In light of these data, we consider several alternative expanded treatment strategies that might further a simplified 'treatment as prevention' approach.

Keywords: cirrhosis; hepatitis B; hepatocellular carcinoma; liver fibrosis; viral hepatitis.

Figure 1

HCC pathogenesis. These schematics summarize some of the key HCC pathogenesis mechanisms in CHB patients (A) and in which CHB disease phases these have been detected (B). (A) HBV infects normal liver hepatocytes and can lead to CHB infection. During HBV infection, chronic hepatitis can develop, leading to cirrhosis and HCC in some patients. Approximately 20% of HBV-associated HCC cases develop in the absence of cirrhosis. HCC pathogenesis mechanisms can be direct or indirect. Direct HCC pathogenesis mechanisms are mediated by HBV and include HBV DNA integration into the host genome and the expression of HBV-encoded oncogenic protein. HBV DNA integration causes changes to the host genome via insertional mutagenesis, promoting genomic instability, and can lead to the expression of mutant HBV proteins. Indirect HCC mechanisms are mediated by the host immune system attacking HBV-infected hepatocytes. This leads to chronic necroinflammation, liver regeneration, and fibrosis, which cause genetic and epigenetic changes within hepatocytes. (B) Several studies have shown that HBV DNA integration into the host genome can be detected in liver samples from CHB patients across disease phases. Immune activity against HBV can also be detected in CHB patients across disease phases, as can necroinflammation and fibrosis in some patients. CHB, chronic hepatitis B; HBeAg, hepatitis B envelope antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

Figure 2

Association between the baseline HBV DNA levels and HCC risk in untreated and NA-treated non-cirrhotic adult patients with CHB. (A). In untreated HBeAg-positive and -negative, non-cirrhotic, adult CHB patients with persistently normal ALT levels (n = 6949), HCC risk was the highest with baseline levels of approximately 6 log₁₀ IU/mL. (B). In untreated HBeAg-positive, non-cirrhotic, adult CHB patients with persistently normal ALT levels (n = 2081), HCC risk was the highest with baseline HBV DNA levels of approximately 6 log₁₀ IU/mL. (C). In HBeAg-positive, non-cirrhotic, adult CHB patients treated with ETV or TDF (n = 2073), the on-treatment HCC incidence rate increased incrementally with decreasing baseline HBV DNA levels ≥5 log₁₀ IU/mL. (D). Compared with untreated HBeAg-positive, non-cirrhotic adult CHB patients with normal ALT levels (n = 2643), NA treatment in HBeAg-positive, non-cirrhotic, adult CHB patients (n = 2073) reduced the HCC incidence in patients with moderate baseline viral load (5.00–7.99 log₁₀ IU/mL), but the HCC risk did not decrease to the same extent in patients with a high baseline viral load (≥8.0 log₁₀ IU/mL). ALT, alanine aminotransferase; CHB, chronic hepatitis B; CI, confidence interval; ETV, entecavir; HBeAg, hepatitis B envelope antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio; NA, nucleos(t)ide analog; TDF, tenofovir disoproxil fumarate. All panels in this figure were made by Y-S Lim based on data in Kim G-A et al. Aliment Pharmacol Ther. 2020;51:1169–1179 (panels A and B) and Choi W-M et al. J Clin Invest. 2022;132:e154833 (panels C and D).

Figure 3

Impact of NA treatment on CHB clinical parameters in patients currently ineligible for antiviral treatment. This schematic summarizes the studies of NA treatment in CHB patients currently ineligible for antiviral treatment including those in the HBeAg-positive chronic infection/immune-tolerant disease phase. Patient numbers are shown in brackets in the first column. Patient baseline characteristics (HBeAg status and HBV DNA and ALT level) are shown in the second column. NA treatment and duration are shown in the third column. Key efficacy and safety results are shown in the fourth column. AE, adverse event; ALT, alanine aminotransferase; CHB, chronic hepatitis B; EHLI, evident histological liver injury; ETV, entecavir; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, nucleos(t)ide analog; TDF, tenofovir disoproxil; TEAE, treatment-emergent adverse event [64,66,67,68,69].

Figure 4

Potential expanded HBV treatment strategies. This figure summarizes the categories of CHB patients who would be eligible for antiviral treatment initiation under the proposed alternative treatment strategies. The Chinese guidelines [75], East Asian expert opinion [61], U.S. treatment algorithm [84] and U.S. expert panel [85] recommend initiation of antiviral treatment in more CHB patients compared with the current EASL, APASL, or AASLD guidelines, but include different patient subpopulations. The test-and-treat-all strategy would initiate antiviral treatment in all HBsAg-positive patients. The ‘opt-out’ strategy would initiate antiviral treatment in all cirrhotic patients and non-cirrhotic adult patients with HBV DNA ≥2000 IU/mL regardless of HBeAg and ALT status. AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; APASL, Asian Pacific Association for the Study of the Liver; CHB, chronic hepatitis B; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.