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).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Serum hepatitis B virus (HBV) RNA may reflect intrahepatic HBV replication. Novel anti‐viral drugs have shown potent HBV RNA decline without concomitant hepatitis B surface antigen ...(HBsAg) decrease. How this relates to off‐treatment response is yet unclear.
Aim
To study the degree of on‐treatment viral antigen decline among patients with pronounced HBV RNA decrease in relation to off‐treatment sustained response and HBsAg loss.
Methods
HBV RNA, HBsAg and hepatitis B core‐related antigen (HBcrAg) were quantified in patients with chronic hepatitis B who participated in two randomised controlled trials of peginterferon‐based therapy. Sustained response (HBV DNA <2000 IU/mL) and/or HBsAg loss were assessed in patients with and without on‐treatment HBV RNA response (either >2 log HBV RNA decline or >1 log decline resulting in an undetectable value at on‐treatment week 24), stratified by concomitant HBsAg decline (<0.5/0.5‐1/>1 log).
Results
We enrolled 279 patients; 176 were hepatitis B e antigen (HBeAg)‐positive, and 103 were HBeAg‐negative. Sustained response was achieved in 20.4% of patients. At on‐treatment week 24, HBV RNA response was associated with higher sustained response rates (27.4% vs 13.0% in non‐responders, P = 0.004). However, among patients with an HBV RNA response (n = 135), 56.4% did not experience >0.5 log HBsAg decline. Among HBV RNA responders, sustained response was achieved in 47.6% of those with >1 log HBsAg decline (n = 20/42), vs 16.0% with <0.5 log decline (n = 12/75, P = 0.001). Similar results were obtained with HBcrAg and when response was defined as HBsAg loss.
Conclusions
In this cohort, many patients with HBV RNA response during peginterferon‐based treatment did not experience HBsAg and/or HBcrAg decline. The absence of concomitant decline in these viral antigens was associated with low rates of treatment response and HBsAg loss. Future trials should therefore consider kinetics of combined biomarkers to assess anti‐viral efficacy.
Trial registration, ClinicalTrials.gov: NCT00114361, NCT00146705.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Serum Hepatitis B core‐related antigen (HBcrAg) level moderately correlates with cccDNA. We examined whether HBcrAg can add value in monitoring the effect of peginterferon (PEG‐IFN) therapy for ...HBeAg‐negative chronic hepatitis B (CHB) infection. Thus, serum HBcrAg level was measured in 133 HBeAg‐negative, mainly Caucasian CHB patients, treated with 48 weeks of PEG‐IFN alfa‐2a. We assessed its association with response (ALT normalization & HBV DNA < 2000 IU/mL) at week 72. HBcrAg level strongly correlated with HBV DNA level (r = 0.8, P < 0.001) and weakly with qHBsAg and ALT (both r = 0.2, P = 0.01). At week 48, mean HBcrAg decline was −3.3 log U/mL. Baseline levels were comparable for patients with and without response at week 72 (5.0 vs 4.9 log U/mL, P = 0.59). HBcrAg decline at week 72 differed between patients with and without response (−2.4 vs −1.0 log U/mL, P = 0.001), but no cut‐off could be determined. The pattern of decline in responders resembled that of HBV DNA, but HBcrAg decline was weaker (HBcrAg −2.5 log U/mL; HBV DNA: −4.0 log IU/mL, P < 0.001). For early identification of nonresponse, diagnostic accuracy of HBV DNA and qHBsAg decline at week 12 (AUC 0.742, CI‐95% 0.0.629‐0.855, P < 0.001) did not improve by adding HBcrAg decline (AUC 0.747, CI‐95% 0.629‐0.855 P < 0.001), nor by replacing HBV DNA decline by HBcrAg decline (AUC 0.754, CI‐95% 0.641‐0.867, P < 0.001). In conclusion, in Caucasian patients with HBeAg‐negative CHB, decline of HBcrAg during PEG‐IFN treatment was stronger in patients with treatment response. However, HBcrAg was not superior to HBV DNA and qHBsAg in predicting response during PEG‐IFN treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
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 <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 < .001) and a weak correlation with HBsAg (.25). At week 12, HBV-RNA was significantly lower among patients with lower HBsAg (<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-Pegylated Interferon (HBV-RNA) declined early during PEG-IFN treatment among patients achieved response and HBsAg loss. Serum HBV-RNA is a potential negative predictor of clinical response at week 12 of therapy. HBV-RNA may increase response rates to PEG-IFN treatment in HBeAg-negative patients.
We studied whether 48 weeks of PEG-IFN alfa-2a add-on increases HBsAg-decline and clearance in HBeAg-negative patients on long-term nucleo(s)tide analogue (NA) therapy. In this ...investigator-initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg-negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG-IFN alfa-2a add-on (180 μg per week) or continued NA-monotherapy with subsequent follow-up to Week 72. Endpoints were HBsAg decline (≥1 log
IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified-intention-to-treat analysis, 58 patients received PEG-IFN add-on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log
in the add-on arm versus none on NA-monotherapy (p < .001), and HBsAg clearance was observed in 6 (10%) PEG-IFN add-on patients versus 0% NA-monotherapy (p = .01). HBVRNA was only detected in 2% after PEG-IFN treatment versus 19% in NA-monotherapy (p = .002) at Week 48. PEG-IFN add-on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG-IFN add-on, whereas an HBsAg level > 200 IU/mL at on-treatment Week 12 was highly predictive of non-response (NPV = 100%). Addition of PEG-IFN to long-term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg-negative patients on long-term NA. On-treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG-IFN add-on and could be used as a potential stopping-rule for PEG-IFN therapy. Our findings support further exploration of immune modulation add-on to antiviral therapy, preferably using response-guided strategies, to increase functional cure rates in patients with CHB.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Various treatment combinations of peginterferon (PEG‐IFN) and nucleos(t)ide analogues have been evaluated for chronic hepatitis B (CHB), but the optimal regimen remains unclear.
...Aims
To study whether PEG‐IFN add‐on increases response compared to entecavir (ETV) monotherapy, and whether the duration of ETV pretreatment influences response.
Methods
Response was evaluated in HBeAg positive patients previously treated in two randomized controlled trials. Patients received ETV pretreatment for at least 24 weeks and were then allocated to 24‐48 weeks of ETV+PEG‐IFN add‐on, or continued ETV monotherapy. Response was defined as HBeAg loss combined with HBV DNA <200 IU/mL 48 weeks after discontinuing PEG‐IFN.
Results
Of 234 patients, 118 were assigned PEG‐IFN add‐on and 116 continued ETV monotherapy. Response was observed in 38/118 (33%) patients treated with add‐on therapy and in 23/116 (20%) with monotherapy (P = 0.03). The highest response to add‐on therapy compared to monotherapy was observed in PEG‐IFN naive patients with HBsAg levels below 4000 IU/mL and HBV DNA levels below 50 IU/mL at randomization (70% vs 34%; P = 0.01). Above the cut‐off levels, response was low and not significantly different between treatment groups. Duration of ETV pretreatment was associated with HBsAg and HBV DNA levels (both P < 0.005), but not with response (P = 0.82).
Conclusions
PEG‐IFN add‐on to ETV therapy was associated with higher response compared to ETV monotherapy in patients with HBeAg positive CHB. Response doubled in PEG‐IFN naive patients with HBsAg below 4000 IU/mL and HBV DNA below 50 IU/mL, and therefore identifies them as the best candidates for PEG‐IFN add‐on (Identifiers: NCT00877760, NCT01532843).
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Achieving hepatitis B e antigen (HBeAg) seroconversion is a satisfactory endpoint during antiviral treatment for chronic hepatitis B (CHB). This study aimed to develop and validate a novel scoring ...system to predict HBeAg seroconversion during entecavir (ETV) treatment. A total of 526 patients with HBeAg‐positive CHB treated with ETV for at least 1 year were randomly assigned to the training and validation cohorts. Baseline parameters including hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and alanine aminotransferase level were quantified. Patients who achieved HBeAg seroconversion were compared with those without HBeAg seroconversion. A prediction model was established to predict HBeAg seroconversion during ETV treatment. After a median follow up of 2.67 years, 93 (36.0%) and 87 (32.5%) patients in the training and validation cohorts developed HBeAg seroconversion. A prediction score composed of age, HBsAg and HBcAb quantification was derived. Areas under receiver operating characteristic curve at 5 years of this prediction score were 0.70 and 0.72 in the training and validation cohorts. By using the dual cutoff values of 0.28 and 0.58, the model was endowed with high sensitivity and specificity to exclude or identify patients developing HBeAg seroconversion (90.3% sensitivity and 90.2% specificity in the training cohort as well as 92.8% sensitivity and 84.4% specificity in the validation cohort, respectively). A novel prediction score that uses baseline clinical variables was developed and validated. The score accurately estimates the probabilities of developing HBeAg seroconversion at 5‐years ETV therapy in patients with CHB.
Highlights
HBeAg seroconversion is a satisfactory endpoint for the treatment ofHBeAg‐positive CHB patients.
In the study, we established a novel score model which was composed ofHBcAb and two routinely available clinical and laboratory parameters (age andHBsAg).
Our results demonstrated the model was not only good in terms ofaccuracy and sensitivity to predict 5‐year probability of HBeAg seroconversion,but also simpler. Importantly, this model performed equally well in cirrhotic andnon‐cirrhotic patients.
The probability of HBeAg seroconversion in individual patients treated withETV could be accurately calculated by this novel model.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Chronic infection with Hepatitis B virus (HBV) is a major risk factor for the development of advanced liver disease including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The relative ...contribution of virological factors to disease progression has not been fully defined and tools aiding the deconvolution of complex patient virus profiles is an unmet clinical need. Variable viral mutant signatures develop within individual patients due to the low-fidelity replication of the viral polymerase creating 'quasispecies' populations. Here we present the first comprehensive survey of the diversity of HBV quasispecies through ultra-deep sequencing of the complete HBV genome across two distinct European and Asian patient populations. Seroconversion to the HBV e antigen (HBeAg) represents a critical clinical waymark in infected individuals. Using a machine learning approach, a model was developed to determine the viral variants that accurately classify HBeAg status. Serial surveys of patient quasispecies populations and advanced analytics will facilitate clinical decision support for chronic HBV infection and direct therapeutic strategies through improved patient stratification.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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