Progression of Untreated Minimally Active Chronic HBV Infection Compared to Inactive Infection

Nucleos(t)ide analogs (NUCs) are recommended when both are fulfilled in the absence of hepatocellular carcinoma (HCC) or cirrhosis; (1) elevated serum hepatitis B virus (HBV)-DNA (≥20,000 IU/mL for hepatitis B e antigen–positive chronic hepatitis B [CHB] or ≥2000 IU/mL for hepatitis B e antigen–negative CHB) and (2) serum alanine aminotransferase ≥2× upper limit of normal.1Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1811) Google Scholar Therefore, many patients still remain untreated. Such untreated patients have so called “minimally active CHB,” where serum HBV-DNA is persistently >2000 IU/mL and other parameters for NUCs are below the criteria.2Cho E.J. Kim S.E. Suk K.T. et al.Current status and strategies for hepatitis B control in Korea.Clin Mol Hepatol. 2017; 23: 205-211Crossref PubMed Scopus (75) Google Scholar There have been little data concerning their prognosis. Here, we aimed to evaluate prognosis of such untreated minimally active (UMA) group compared with an inactive carrier (IC) group. This is a single-center, retrospective study. The recruitment algorithm and criteria for NUCs are depicted in Figure 1A and B, respectively. At enrollment, liver stiffness (LS) was determined using transient elastography.3Kim G. Kim M.Y. Baik S.K. Transient elastography versus hepatic venous pressure gradient for diagnosing portal hypertension: a systematic review and meta-analysis.Clin Mol Hepatol. 2017; 23: 34-41Crossref PubMed Scopus (45) Google Scholar During follow-up, all patients received laboratory tests every 3–6 months and HCC surveillance every 6 months. Endpoints were development of HCC4Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6606) Google Scholar or cirrhotic complication event (CCE) including ascites, variceal hemorrhage, hepatic encephalopathy, cirrhosis-related death, or liver transplantation. When patients experienced multiple CCEs, we selected the first one for analysis. This study was approved by the institutional review board. Differences among continuous and categorical variables were examined with Student’s t test (or Mann-Whitney test) and chi-square test (or Fisher’s exact test). Cumulative risks were calculated using Kaplan-Meier method. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using Cox regression analysis. Propensity score (PS) was calculated through logistic regression, using age, sex, diabetes, and LS. Differences between 2 groups were balanced through inverse probability of treatment weighting (IPTW) and PS-matching analysis. All statistical analyses were conducted using the SAS software version 9.4 (SAS Institute, Cary, NC) and R version 3.4.1 (R Foundation for Statistical Computing, Vienna, Austria). Two-sided P values <.05 were considered to indicate statistical significance. Baseline characteristics are summarized in Supplementary Table 1. During follow-up (mean 75.1 and median 76.4 [interquartile range, 55.5–103.3] months), cumulative HCC risks in the UMA group were higher compared with the IC group (Figure 1C), with an adjusted HR of 4.138 (95% CI, 1.181–14.502; P = .026). Cumulative CCE risks in the UMA group were similar, compared with the IC group (Figure 1D), with an adjusted HR of 2.338 (95% CI, 0.551–9.924; P = .250). Baseline characteristics according to development of HCC or CCE are also described in Supplementary Table 2. Baseline characteristics after IPTW analysis are described in Supplementary Table 1. Cumulative HCC risks in the UMA group were higher compared with the IC group with, an HR of 3.509 (95% CI, 1.225–10.000; P = .019) (Figure 1E). Cumulative CCE risks in UMA group were similar, compared with the IC group, with an HR of 2.762 (95% CI, 0.951–8.000; P = .062) (Figure 1F). Baseline characteristics after PS-matching are described in Supplementary Table 1. Likewise, UMA group was at a higher risk of HCC, with an HR of 9.901 (95% CI, 1.239–76.923; P = .031), but at a similar risk of CCE, with an HR of 1.060 (95% CI, 0.319–3.521; P = .923) compared with the IC group. The UMA group consistently retained higher cumulative HCC risk than the IC group. Persistent HBV-DNA integration into hepatocytes in the UMA group leads to genomic alterations or chromosomal instability, accelerating carcinogenesis, even before highly active necroinflammation status or advanced fibrosis or cirrhosis develop.5Seto W.K. Lo Y.R. Pawlotsky J.M. et al.Chronic hepatitis B virus infection.Lancet. 2018; 392: 2313-2324Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar Regarding CCE risk, there was no difference between 2 groups. This discrepancy is probably because HCC occurs through direct oncogenic pathway as well as indirect pathway by necro-inflammation and fibrosis. However, as this result might be underpowered due to small event number, further studies are required. Our study has several strengths. To date, this is the first study to compare prognosis between UMA group and IC group in the current era of potent NUCs. Next, we adjusted for imbalances in fibrotic burden between two groups as much as possible, using quantitative LS value, which allowed the more refined assessments of fibrotic burden and prognosis Our study has limitations. First, upper limit of normal of serum alanine aminotransferase in this study may be relatively high especially for women, so some patients should have been treated with NUCs according to the guideline.1Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1811) Google Scholar Second, as carcinogenesis is complicated by many other factors like family history, smoking, or other comorbidities, which were not incorporated into our analyses, further epidemiological studies are required. Third, as liver biopsy was not routinely performed, we cannot assess real liver injury by HBV in terms of necroinflammation or fibrosis.6Lo R.C. Kim H. Histopathological evaluation of liver fibrosis and cirrhosis regression.Clin Mol Hepatol. 2017; 23: 302-307Crossref PubMed Scopus (66) Google Scholar Furthermore, 1.9% of the study population had LS ≥13 kPa. They may have “subclinical cirrhosis” as defined by LS ≥13 kPa without any clinical evidence of cirrhosis.7Kim M.N. Kim S.U. Kim B.K. et al.Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis.Hepatology. 2015; 61: 1851-1859Crossref PubMed Scopus (98) Google Scholar So, the possibility of overestimation in HCC or CCE risks, even though small, may exist. Finally, serum quantitative hepatitis B surface antigen, the useful biomarker associated with HCC risk,8Tseng T.C. Liu C.J. Yang H.C. et al.High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load.Gastroenterology. 2012; 142 (quiz e1113–144): 1140-1149-e3Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar was not incorporated in our analyses, owing to limited reimbursements. In conclusion, our result may be a corner stone justifying future clinical trials concerning the benefit of earlier NUCs in the UMA group. Supplementary Table 1Comparison of Baseline Characteristics Between the UMA Group and IC Group Before and After AdjustmentVariablesBefore adjustmentUMA group (n=152)IC group (n = 621)P valueAge, y54.3 ± 10.558.2 ± 11.2<.001Male gender, no. (%)81 (53.5)345 (55.6).615Diabetes, no. (%)16 (10.5)62 (10.0).842Body mass index, kg/m223.5 ± 3.523.5 ± 2.9.871Positive HBeAg, no. (%)39 (25.7)0 (0)<.001HBV-DNA, log10 IU/mL4.67 ± 0.602.30 ± 0.33<.001Platelet count, ×103/uL203.5 ± 61.2206.5 ± 54.9.598ALT, U/mL55.8 ± 8.120.9 ± 7.4<.001Total bilirubin, mg/dL0.80 ± 0.330.81 ± 0.35.736LS value, kPa6.9 ± 4.65.6 ± 2.0<.001VariablesAdjustment by IPTW analysisUMA groupIC groupP valueAge, y56.7 ± 0.957.4 ± 0.5.474Male gender, no. (%)81 (54.1)345 (55.2).816Diabetes, no. (%)16 (9.6)62 (9.9).916Body mass index, kg/m223.3 ± 0.323.6 ± 0.2.395Platelet count, ×103/uL204.3 ± 6.0207.4 ± 2.3.627HBV-DNA, log10 IU/mL4.57 ± 0.082.31 ± 0.04<.001ALT, U/mL47.3 ± 9.721.0 ± 0.3.007Total bilirubin, mg/dL0.89 ± 0.070.80 ± 0.01.21LS value, kPa5.9 ± 0.25.8 ± 0.1.716VariablesAdjustment by PS-matching analysis at 1:2 ratioUMA group (n = 135)IC group (n = 270)P valueAge, y55.1 ± 10.155.9 ± 10.0.358Male gender, no. (%)74 (54.8)138 (51.1).898Diabetes, no. (%)13 (9.6)23 (8.5).835Body mass index, kg/m223.1 ± 3.123.3 ± 2.7.526HBV-DNA, log10 IU/mL4.61 ± 0.592.39 ± 0.31<.001Platelet count, ×103/uL201.9 ± 59.4206.4 ± 57.0.54ALT, U/mL42.6 ± 19.420.68 ± 7.55.012Total bilirubin, mg/dL0.79 ± 0.320.81 ± 0.38.858LS value, kPa5.9 ± 2.06.0 ± 2.2.509NOTE. Data are expressed as mean ± standard deviation or, no. (%).ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IPTW, inverse probability of treatment weighting; LS, liver stiffness; PS, propensity score. Open table in a new tab Supplementary Table 2Comparison of Baseline Characteristics According to Development of HCC or CCEHCCVariablesPatients with HCC (n = 12)Patients without HCC (n = 773)P valueAge, y63.9 ± 9.457.3 ± 11.1.408Male gender, no. (%)11 (91.7)415 (53.7).015Diabetes, no. (%)3 (25.0)75 (9.7).112Body mass index, kg/m223.2 ± 2.623.6 ± 3.0.426Proportion of the UMA group, no. (%)6 (50.0)146 (18.9).017HBV-DNA, log10 IU/mL3.4 ± 1.62.8 ± 1.3.446HBeAg positive, no. (%)2 (16.7)37 (4.8).119Platelet count, ×103/uL161.0 ± 50.5206.8 ± 55.7.573ALT, U/mL34.8 ± 7.627.6 ± 8.5.705Total bilirubin, mg/dL1.0 ± 0.41.0 ± 0.1.995LS value, kPa7.6 ± 2.45.9 ± 2.7.701UMAgroup, no. (%)6 (50.0)146 (19.2).017CCEVariablesPatients with CCE (n = 11)Patients without CCE (n = 762)P valueAge, y71.2 ± 10.857.2 ± 11.0<.001Male gender, no. (%)8 (72.7)418 (54.9).362Diabetes, no. (%)5 (45.5)73 (9.6).003Body mass index, kg/m222.0 ± 2.623.5 ± 3.0.127Proportion of the UMA group, no. (%)4 (36.4)148 (19.4).241HBV-DNA, log10 IU/mL3.0 ± 1.52.8 ± 1.3.553HBeAg positive, no. (%)2 (18.2)37 (4.9).102Platelet count, ×103/uL170.0 ± 64.3206.6 ± 55.6.03ALT, U/mL34.4 ± 7.127.6 ± 8.4.704Total bilirubin, mg/dL0.7 ± 0.40.9 ± 1.1.672LS value, kPa8.5 ± 3.05.9 ± 2.7.002UMAgroup, no. (%)4 (36.4%)148 (19.4%).241NOTE. Data are expressed as mean ± standard deviation or, no. (%).ALT, alanine aminotransferase; CCE, cirrhotic complication event; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LS, liver stiffness. Open table in a new tab NOTE. Data are expressed as mean ± standard deviation or, no. (%). ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IPTW, inverse probability of treatment weighting; LS, liver stiffness; PS, propensity score. NOTE. Data are expressed as mean ± standard deviation or, no. (%). ALT, alanine aminotransferase; CCE, cirrhotic complication event; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LS, liver stiffness. The HBeAg-Negative “Gray Zone” Phase: A Frequent Condition With Different Outcomes in Western and Asian Patients?Clinical Gastroenterology and HepatologyVol. 18Issue 1PreviewOne of the main goals of antiviral therapy in hepatitis B virus (HBV)–infected patients is to prevent the progression to hepatic cirrhosis and reduce the risk of hepatocellular carcinoma (HCC). We have read with interest the paper by Lee et al1 dealing with a challenging therapeutic scenario in which patients do not fit within guideline recommendations for therapy. The authors defined untreated minimally active (UMA) patients as “untreated individuals with serum HBV-DNA persistently >2000 IU/mL and other parameters for nucleos(t)ide analogues administration below the criteria.” The main finding of their study was the increased risk of HCC in the UMA group compared with patients accurately classified as inactive carriers (ICs). Full-Text PDF