Hepatitis B virus (HBV) RNA in serum is a novel biomarker for intrahepatic HBV replication and treatment response. For its proper use, it is essential to identify factors influencing serum HBV RNA level. Using a rapid amplification of complimentary DNA (cDNA) ends (RACE) PCR technique (lower limit of detection [LLD], 800 copies/mL [c/mL]), serum HBV RNA levels were measured in samples of 488 untreated individuals with chronic HBV infection who were eligible to treatment according to currently used recommendations. We explored the association of serum levels of HBV RNA with patient‐ and virus‐associated factors. HBV genotype distribution was 21/10/20/46/3% for A/B/C/D/other. Mean HBV RNA serum level was 5.9 (1.6) log10 c/mL (hepatitis B e antigen [HBeAg]‐positive chronic hepatitis B [CHB], 6.5 [1.2] log c/mL; HBeAg‐negative CHB, 4.1 [1.2] log c/mL; P < 0.001). By multivariable linear regression, factors associated with lower HBV RNA level were HBeAg negativity (β = –0.69; P < 0.001), HBV genotypes A (β = –0.13; P = 0.002), B (β = –0.07; P = 0.049), and C (β = –0.61; P < 0.001) in comparison to D, and presence of HBV basal core promoter mutation either alone (β = –0.14; P = 0.001) or in combination with precore mutation (β = –0.22; P < 0.001). Higher serum alanine aminotransferase (ALT) was associated with higher HBV RNA (β = 0.23; P < 0.001). HBV RNA correlated strongly with HBV DNA (HBeAg‐pos, r = 0.72; P < 0.001; HBeAg‐neg, r = 0.78; P < 0.001) and moderately with quantitative hepatitis B surface antigen (qHBsAg; HBeAg‐pos, r = 0.54; P < 0.001; HBeAg‐neg, r = 0.19; P = 0.04) and quantitative hepatitis B surface antigen (qHBeAg; r = 0.41; P < 0.001). Conclusion: In this multiethnic cohort of 488 untreated individuals with CHB, factors associated with serum HBV RNA level were HBeAg status, serum ALT, HBV genotype, and presence of basal core promotor mutations. For the future use of serum HBV RNA as a clinical marker, it seems mandatory to take these factors into consideration. (Hepatology 2018).

Quantification of MHBs, particularly LHBs represents a novel tool for the identification of the IC stage.

Ancient DNA traces the history of hepatitis B Hepatitis B virus (HBV) infections represent a worldwide human health concern. To study the history of this pathogen, Kocher et al . identified 137 human remains with detectable levels of virus dating between 400 and 10,000 years ago. Sequencing and analyses of these ancient viruses suggested a common ancestor between 12,000 and 20,000 years ago. There is no evidence indicating that HBV was present in the earliest humans as they spread out of Africa; however, HBV was likely present in human populations before farming. Furthermore, the virus was present in the Americas by about 9000 years ago, representing a lineage sister to the viral strains found in Eurasia that diverged about 20,000 years ago. —LMZ

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Background Hepatitis B virus RNA (HBV-RNA) is a novel serum biomarker that correlates with transcription of intrahepatic covalently closed circular (cccDNA), which is an important target for pegylated interferon (PEG-IFN) and novel therapies for functional cure. We studied HBV-RNA kinetics following PEG-IFN treatment and its potential role as a predictor to response in HBeAg-negative chronic hepatitis B (CHB) patients. Methods HBV-RNA levels were measured in 133 HBeAg-negative CHB patients treated in an international randomized controlled trial (PARC study). Patients received PEG-IFN α-2a for 48 weeks. HBV-RNA was measured from baseline through week 144. Response was defined as HBV-DNA &lt;2000 IU/mL and ALT normalization at week 72. Kinetics of HBV-RNA were compared with HBV-DNA, HBsAg, and HBcrAg. Results Mean HBV-RNA at baseline was 4.4 (standard deviation [SD] 1.2) log10 c/mL. At week 12, HBV-RNA declined by −1.6 (1.1) log10 c/mL. HBV-RNA showed a greater decline in responders compared to nonresponders early at week 12 (−2.0 [1.2] vs −1.5 [1.1] log10 c/mL, P = .04). HBV-RNA level above 1700 c/mL (3.2 log10 c/mL) had a negative predictive value of 91% at week 12 and 93% at week 24 (P = .01) for response. Overall, HBV-RNA showed a stronger correlation with HBV-DNA and HBcrAg (.82 and .80, P &lt; .001) and a weak correlation with HBsAg (.25). At week 12, HBV-RNA was significantly lower among patients with lower HBsAg (&lt;100 IU/mL) or HBsAg loss at week 144. Conclusions During PEG-IFN treatment for HBeAg-negative CHB, HBV-RNA showed a fast and significant decline that correlates with treatment response and HBsAg loss at long-term follow-up. Clinical Trials Registration NCT00114361

Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG‐IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg‐positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99‐01 study). Patients received 52 weeks PEG‐IFN monotherapy (n = 136) or PEG‐IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG‐IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG‐IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow‐up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P = .01; week 24:3.7 vs 4.9 log c/mL, P < .001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG‐IFN treatment. Early on‐treatment HBV RNA level may be used to predict nonresponse.

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