COVID-19 Vaccination in Patients With Malignancy; A Systematic Review and Meta-Analysis of the Efficacy and Safety.

Background: Data on the efficacy and safety of COVID-19 vaccines in patients with malignancy are immature. In this paper, we assessed the literature involving the use of COVID-19 vaccines in cancer patients and reported the seroconversion rates as the main outcome and severity of COVID-19 infection and side effects following COVID-19 vaccination as the secondary outcomes. Methods: A systematic review with meta-analysis was performed. Searches were conducted in electronic websites, databases, and journals, including Scopus, PubMed, Embase, and Web of Science from January 01, 2019, to November 30, 2021. Studies reporting data on the safety and efficacy of COVID vaccine in cancer patients using any human samples were included. The risk of bias was assessed using the NEWCASTLE-OTTAWA scale in the included studies. Results: A total of 724 articles were identified from databases, out of which 201 articles were duplicates and were discarded. Subsequently, 454 articles were excluded through initial screening of the titles and abstracts. Moreover, 41 studies did not report the precise seroconversion rate either based on the type of cancer or after injection of a second dose of COVID vaccine. Finally, 28 articles met all the inclusion criteria and were included in this systematic review. The overall seroconversion rates after receiving a second dose of COVID-19 vaccine, based on type of cancer were 88% (95% CI, 81%-92%) and 70% (95% CI, 60%-79%) in patients with solid tumors and hematologic malignancies, respectively. Conclusion: Overall, we conclude that vaccination against COVID-19 in patients with active malignancies using activated and inactivated vaccines is a safe and tolerable procedure that is also accompanied by a high efficacy.

Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Central Register of Controlled Trials, COVID-19 Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies. STUDY SELECTION: Prospective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants. METHODS: A frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed. RESULTS: 82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I2=80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I2=89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I2=89%; 0.29, 0.11 to 0.58, I2=97%), and solid cancers (0.55, 0.46 to 0.65, I2=78%; 0.44, 0.36 to 0.53, I2=84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I2=0%; 0.06, 0.04 to 0.08, I2=0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I2=92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I2=88%; 0.62, 0.54 to 0.70, I2=90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I2=92%; 0.77, 0.66 to 0.85, I2=93%), and solid cancers (0.90, 0.88 to 0.93, I2=51%; 0.89, 0.86 to 0.91, I2=49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I2=0%; 0.97, 0.83 to 1.00, I2=89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines. CONCLUSION: Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021272088.

Importance of the second SARS-CoV-2 vaccination dose for achieving serological response in patients with rheumatoid arthritis and seronegative spondyloarthritis.

OBJECTIVES: To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response. METHODS: We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response. RESULTS: Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC. CONCLUSIONS: Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.

COVID-19 Vaccine Response in People with Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to investigate the effect of disease modifying therapies on immune response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines in people with multiple sclerosis (MS). METHODS: Four hundred seventy-three people with MS provided one or more dried blood spot samples. Information about coronavirus disease 2019 (COVID-19) and vaccine history, medical, and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV-2. Antibody titers were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following the SARS-CoV-2 vaccine according to disease modifying therapy. We used regression modeling to explore the effect of vaccine timing, treatment duration, age, vaccine type, and lymphocyte count on vaccine response. RESULTS: Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio = 0.03, 95% confidence interval [CI] = 0.01-0.06, p < 0.001) and fingolimod (odds ratio = 0.04; 95% CI = 0.01-0.12) were associated with lower seroconversion following the SARS-CoV-2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly associated with the response to the vaccination. The vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Preliminary data on cellular T-cell immunity showed 40% of seronegative subjects had measurable anti-SARS-CoV-2 T cell responses. INTERPRETATION: Some disease modifying therapies convey risk of attenuated serological response to SARS-CoV-2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. ANN NEUROL 20219999:n/a-n/a.

Anti-HBc IgG Levels: A Predictor of HBsAg Seroclearance in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue-Induced HBeAg Seroclearance.

BACKGROUND/AIMS: We investigated the efficiency of the indirect ratio of anti-HBc IgG at predicting HBsAg seroclearance in patients with nucleos(t)ide analogue (NA)-induced HBeAg seroclearance. METHODS: We performed a retrospective study that included 366 chronic hepatitis B patients (March 2007 to December 2016) at a single tertiary hospital. These patients were HBsAg seropositive, and experienced NA-induced HBeAg seroclearance. The indirect ratio of light absorbance of anti-HBc IgG levels were measured with chemiluminescent microparticle immunoassay using the Architect Anti-HBc assay (Abbott Laboratories, IL, USA) as a qualitative method prior to antiviral therapy. We calculated the cumulative incidences of HBsAg seroclearance based on the anti-HBc IgG levels. RESULTS: After a 10-year follow-up, 48 patients experienced HBsAg seroclearance (13.1%). Thirty-three of 179 patients who had an indirect ratio of light absorbance of anti-HBc IgG < 11 RLU (relative light unit) showed HBsAg seroclearance (18.4%); 15 of 187 patients who had an indirect ratio of light absorbance of anti-HBc IgG ≥ 11 RLU showed HBsAg seroclerance (8.0%) (p = 0.003). In multivariate analysis, age, and ALT at the time of HBeAg seroclearance were predictors of HBsAg seroclearance. Especially, the relative risk of HBsAg seroclearance in patients with baseline anti-HBc IgG levels < 11 RLU was 2.213 (95% CI, 1.220-4.014), compared to that in patients with higher levels of anti-HBc IgG at baseline (p = 0.009). CONCLUSION: Using an indirect method for anti-HBc IgG levels, baseline anti-HBc IgG levels (< 11RLU), age (≥ 50 years), and ALT (≥ 40 IU/L) might be associated with HBsAg seroclearance in patients with NA-induced HBeAg seroclearance.

Effect of Different Disease-Modifying Therapies on Humoral Response to BNT162b2 Vaccine in Sardinian Multiple Sclerosis Patients.

Objectives: Vaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients. Methods: We obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially influencing humoral immunity from COVID-19 vaccine. Results: MS patients treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared to untreated patients. We did not observe a statistically significant difference in response between patients treated with the other drugs (dimethyl fumarate, interferon, alemtuzumab and glatiramer acetate) and untreated patients. In addition, older age, male sex and active smoking were significantly associated with lower antibody titers against SARS-CoV-2. MS patients previously infected with SARS-CoV-2 had significantly higher humoral responses to vaccine than uninfected patients. Conclusion: Humoral response to BNT162b2 is significantly influenced by the specific DMTs followed by patients, as well as by other factors such as previous SARS-CoV-2 infection, age, sex, and smoking status. These results are important to inform targeted strategies to prevent clinically relevant COVID-19 in MS patients.

Effects of dyslipidemia on E antigen seroconversion of patients with chronic hepatitis B treated by nucleoside (acid) analogs.

BACKGROUND: The prevalence of dyslipidemia in China is increasing annually. Current studies suggest that dyslipidemia affects the antiviral efficacy of hepatitis C virus (HCV) therapies, while recent studies suggest that serum lipids influence the response rates of chronic hepatitis B (CHB) patients receiving PEGylated interferon-alpha (Peg IFN-α) treatment. However, the role of dyslipidemia in the efficacy of nucleoside (acid) analogues (NAs) in CHB patients remains unclear. METHODS: From January 2010 to December 2013, data from 179 treatment-naive patients with CHB who were hepatitis B e antigen (HBeAg)-positive and had visited the first affiliated hospital of Wenzhou Medical University were assessed. Of these patients, 68 were assigned to the dyslipidemia group (diagnosed with CHB complicated with dyslipidemia) and 111 to the normolipidemic group. The following 3 treatment strategies were performed for all CHB patients over a 5-year period: lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy, telbivudine (LdT) monotherapy, and entecavir (ETV) monotherapy. Serum assessments, blood biochemistry, HBV serological markers, HBV DNA before treatment and HBeAg serological conversion and virological responses at different timepoints after treatment were compared between the two groups. Measurement data were compared by τ tests and enumeration data by χ2 tests. Correlation analysis was performed using binary logistic regression analysis. RESULTS: The rates of HBeAg seroconversion in the dyslipidemia group at years 1, 2, 3, and 4 were 10.3, 13.2, 17.6, and 22.1%, respectively, which were not significantly lower than those of the normolipidemic group (11.7, 16.2, 18.0 and 33.3%; χ2 = 0.085, 0.293, 0.004, and 2.601, respectively; Ρ > 0.05). However, the rates of HBeAg seroconversion in the dyslipidemia group were significantly lower than those in the normolipidemic group at year 5 (27.9% vs. 43.2%, χ2 = 4.216, Ρ < 0.05). Univariate logistic regression analysis revealed significant differences in group, gender, PTA, ALT, AST, CR, and LDL-C between groups with and without seroconversion. Multivariate regression analysis demonstrated that dyslipidemia (OR = 1.993, Ρ = 0.038) and male gender (OR = 2.317, Ρ = 0.029) were risk factors associated with HBeAg seroconversion. CONCLUSIONS: During antiviral therapy, dyslipidemia affects HBeAg seroconversion in CHB patients treated with NAs, but does not affect the virological response.

Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP-Based Therapy.

Therapy with nucleic acid polymers (NAPs), tenofovir disoproxil fumarate (TDF), and pegylated interferon (pegIFN) achieve high rates of HBsAg loss/seroconversion and functional cure in chronic hepatitis B virus (HBV) infection. The role of hepatitis B surface antigen (HBsAg) seroconversion and inactivation of covalently closed circular DNA (cccDNA) in establishing functional cure were examined. Archived serum from the REP 401 study was analyzed using the Abbott ARCHITECT HBsAg NEXT assay (Chicago, IL), Abbott research use-only assays for HBsAg immune complexes (HBsAg ICs), circulating HBV RNA, and the Fujirebio assay for hepatitis B core-related antigen (HBcrAg; Malvern, PA). HBsAg became < 0.005 IU/mL in 23 participants during NAP exposure, which persisted in all participants with functional cure. HBsAg IC declined during lead-in TDF monotherapy and correlated with minor declines in HBsAg. Following the addition of NAPs and pegIFN, minor HBsAg IC increases (n = 13) or flares (n = 2) during therapy were not correlated with HBsAg decline, hepatitis B surface antibody (anti-HBs) titers, or alanine aminotransferase. HBsAg IC universally declined during follow-up in participants with virologic control or functional cure. Universal declines in HBV RNA and HBcrAg during TDF monotherapy continued with NAP + pegIFN regardless of therapeutic outcome. At the end of therapy, HBV RNA was undetectable in only 5 of 14 participants with functional cure but became undetectable after removal of therapy in all participants with functional cure. Undetectable HBV RNA at the end of therapy in 5 participants was followed by relapse to virologic control or viral rebound. Conclusion: Anti-HBs-independent mechanisms contribute to HBsAg clearance during NAP therapy. Inactivation of cccDNA does not predict functional cure following NAP-based therapy; however, functional cure is accompanied by persistent inactivation of cccDNA. Persistent HBsAg loss with functional cure may also reflect reduction/clearance of integrated HBV DNA. Clinicaltrials.org number NCT02565719.

The times they are a-changing - A refined proposal for finite HBV nucleos(t)ide analogue therapy.

Although discontinuation of nucleos(t)ide analogue (NA) treatment before HBsAg loss is part of all current HBV treatment guidelines for HBeAg-positive patients who achieve HBeAg seroconversion, a treatment endpoint known to be associated with silencing of HBV transcriptional activity and restoration of HBV-specific immune control, whether it is even appropriate to consider NA discontinuation before HBsAg loss in the HBeAg-negative phase remains highly controversial. Despite the growing evidence that a relevant, albeit small, proportion of patients with HBeAg-negative disease can be cured by stopping NA treatment, the fear of discontinuation-associated relapse and the uncertainty of how to predict off-therapy response and monitor patients after discontinuation have generated scepticism and subsequently led to low implementation of this concept in the clinic. In this article, we propose a concept in which NA discontinuation-associated relapse is an integral part of the stop-to-cure approach and ultimately the trigger for achieving HBsAg loss. However, the relapse in this sense becomes functionally effective only if HBV-specific immune reinvigoration and silencing of HBV transcriptional activity have been achieved during the NA treatment period. The probability of functional cure and the severity of post-discontinuation flares depend on the underlying baseline transcriptional activity of HBV when NA therapy was started, as well as the duration of NA treatment, both factors that should be considered as we move towards individualised approaches to HBV cure.

Changes of cytokine levels and T cell surface molecules in patients with chronic hepatitis B and the association with functional cure.

This study aimed to examine changes in levels of cytokine and T cell surface molecules in chronic hepatitis B (CHB) patients receiving sequential interferon therapy following 1-year nucleos(t)ide analogs (NAs) treatment. Cytokine levels were measured in 30 patients, and T cell surface molecule expression was measured in 48 patients receiving sequential interferon therapy and 24 patients only receiving NA mono-therapy. An HBsAg titer of <0.05 IU/ml was defined as a "functional cure." In the cured group (HBsAg < 0.05 IU/ml), a decreasing probability was observed in IFN-γ (after Week 0), and IL-22 and IP-10 (after Week 12). In the non-cured group (HBsAg ≥ 0.05 IU/ml), a probability of slightly decreasing was observed for IFN-γ (after Week 12), and a probability of increasing IP-10 concentration (after Week 0) was observed. Generalized estimating equation (GEE) analyses showed significant differences in the levels of IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70 between the two groups. In GEE analysis, there were significant differences in expressions of CD45RO+ between the cured group and the non-cured group. The frequencies of T cells expressing Tim-3, CD62L, and CD152 were significantly lower in the sequential interferon therapy group than in the NA mono-therapy group. Changes in cytokine levels (IFN-γ, IP-10, IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70) and T cell surface molecules (CD45RO+ ) may predict HBsAg seroconversion in CHB patients receiving sequential interferon therapy. The period from Weeks 12 to 24 during sequential interferon therapy may be a critical time of immune status change.

Baseline serum exosome-derived miRNAs predict HBeAg seroconversion in chronic hepatitis B patients treated with peginterferon.

This study aimed to explore the value of baseline serum exosome-derived miRNAs for predicting HBeAg seroconversion in chronic hepatitis B (CHB) patients treated with peginterferon (Peg-IFN). A total of 120 treatment-naïve HBeAg-positive CHB patients who received Peg-IFN therapy (48 weeks) were enrolled. Next-generation sequencing was performed to screen the serum exosomal miRNAs that were associated with Peg-IFN treatment outcome, and qRT-PCR was used to validate them. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the predictive efficacy of biomarkers. Thirty-three patients (27.5%) achieved HBeAg seroconversion (response group), and 87 patients (72.5%) did not achieve HBeAg seroconversion (nonresponse group). In the identification cohort, 40 serum exosome-derived miRNAs were differentially expressed between the response group (four patients) and the nonresponse group (four patients). In the confirmation cohort, the expression levels of serum exosomal miR-194-5p (p < .001) and miR-22-3p (p < .001) were significantly downregulated in the response group (29 patients) compared to the nonresponse group (83 patients). Multivariate analysis identified baseline serum exosomal miR-194-5p, miR-22-3p, alanine aminotransferase (ALT), and HBV DNA as independent predictors of HBeAg seroconversion (all p < .05). The AUROCs of serum exosomal miRNAs (0.77 and 0.75 for miR-194-5p and miR-22-3p, respectively) were higher than that of ALT (0.70) and HBV DNA (0.69). The combination of exosomal miR-194-5p and miR-22-3p further improved the predictive performance with an AUROC of 0.82. Baseline serum exosomal miR-194-5p and miR-22-3p may serve as novel biomarkers to predict HBeAg seroconversion in CHB patients treated with Peg-IFN.

Meta-omics characteristics of intestinal microbiota associated to HBeAg seroconversion induced by oral antiviral therapy.

Tenofovir and entecavir are currently designated as the preferred oral antiviral drugs for chronic hepatitis B. However, only less than 40% of patients can achieve HBeAg seroconversion. We aim at investigating the role of intestinal microbiome in HBeAg seroconversion induced by oral antiviral therapy and describe multi-omics characteristics of HBeAg seroconversion associated intestinal flora. In this study, we prospectively collected fecal samples at baseline from the patients with HBeAg positive chronic hepatitis B who would have oral antiviral therapy. 16S rDNA sequencing and metabolomics were performed. We identified HBeAg seroconversion-related microbial signature and constructed prediction model for HBeAg seroconversion. Thirty-seven of these subjects achieved HBeAg seroconversion within 156 weeks after the initiation of oral antiviral therapy, while 41 subjects remained HBeAg positive even after over 156 weeks of therapy. A computational statistical and machine learning approach allowed us to identify a microbial signature for HBeAg seroconversion. Using random forest method, we further constructed a classifier based on the microbial signature, with area under curve being 0.749 for the test set. Patients who achieved HBeAg seroconversion tended to have lower abundance of certain fecal metabolites such as essential amino acids, and several dipeptides. By analyzing the fecal microbiota from the patients with and without HBeAg seroconversion, we showed intestinal microbiome play a critical role in HBeAg seroconversion induced by oral antiviral therapy. We also identified intestinal microbial signature that is associated with HBeAg seroconversion after oral antiviral therapy.

Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: During treatment of chronic HBV infections, loss or seroconversion of the HBV surface antigen (HBsAg) is considered a functional cure. HBsAg consists of the large (LHBs), middle (MHBs), and small surface protein (SHBs) and their relative proportions correlate strongly with disease stage. Our aim was to assess the association between HBsAg composition and functional cure during treatment. METHODS: A total of 83 patients were retrospectively analyzed. HBsAg loss was achieved by 17/64 patients during nucleos(t)ide analogue (NA) treatment and 3/19 patients following treatment with pegylated interferon-alfa2a (PEG-IFN) for 48 weeks. Sixty-three patients without HBsAg loss were matched as controls. LHBs, MHBs and SHBs were quantified in sera collected before and during treatment. RESULTS: Before treatment, median MHBs levels were significantly lower in patients with subsequent HBsAg loss than in those without (p = 0.005). During treatment, MHBs and LHBs proportions showed a fast decline in patients with HBsAg loss, but not in patients with HBV e antigen seroconversion only or patients without serologic response. MHBs became undetectable by month 6 of NA treatment in all patients with HBsAg loss, which occurred on average 12.8 ± 8.7 (0-52) months before loss of total HBsAg. Receiver-operating characteristic analyses revealed that the proportion of MHBs was the best early predictor of HBsAg loss before NA treatment (AUC = 0.726, p = 0.019). In patients achieving HBsAg loss with PEG-IFN, the proportions of MHBs and LHBs showed similar kinetics. CONCLUSION: Quantification of HBsAg proteins shows promise as a novel tool to predict early treatment response. These assessments may help optimize individual antiviral treatment, increasing the rates of functional cure in chronically HBV-infected patients. LAY SUMMARY: The hepatitis B surface antigen (HBsAg) is a key serum marker for viral replication. Loss of HBsAg is considered stable remission, which can be achieved with antiviral treatments. We have investigated whether the ratios of the different components of HBsAg, namely the large (LHBs) and medium (MHBs) HBsAg during different treatments are associated with the occurrence of HBsAg loss. We found that LHBs and MHBs decrease earlier than total HBsAg before HBsAg loss and we propose LHBs and MHBs as promising novel biomarker candidates for predicting cure of HBV infection.

Two-Dose Hepatitis B Vaccine (Heplisav-B) Results in Better Seroconversion Than Three-Dose Vaccine (Engerix-B) in Chronic Liver Disease.

BACKGROUND: The efficacy of the two-dose hepatitis B virus (HBV) vaccine (Heplisav-B®) in patients with chronic liver disease (CLD) is unknown. AIMS: To compare the immunogenicity achieved with Heplisav-B and the conventional three-dose vaccine (Engerix-B®) in patients with CLD, and to identify factors that predict seroconversion. METHODS: We retrospectively identified all adults who completed Heplisav-B or Engerix-B regimens from August 1, 2015, to January 31, 2019. Post-vaccination immunity was assessed by quantitative HBV surface antibody (HBsAb) measurement. RESULTS: We identified 166 patients (106 Engerix-B and 60 Heplisav-B) with chronic liver disease (mean age 59.0 ± 11.3 years, 52% male, 34% cirrhosis, mean MELD score of those with cirrhosis 10.1 ± 5.4) who had completed the vaccinations and had data available on post-vaccination HBsAb levels at least 2 months after completion of the vaccine regimen. Seroprotective HBsAb levels (> 10 mIU/ml) were achieved in 63% with Heplisav-B and in 45% with Engerix-B (p = 0.03). Univariable analysis showed that age (p = 0.01), insurance (p = 0.02), renal failure (p = 0.02), COPD (p = 0.05), and cirrhosis (p < 0.01) had a significant effect on achieving immunogenicity. On multivariable analysis, patients with cirrhosis (adjusted odds ratio [aOR]: 0.27, 95% CI 0.13-0.55), COPD (aOR: 0.06, 95% CI 0.01-0.56), or renal failure (aOR 0.36, 95% CI 0.14-0.93) had a lower likelihood of achieving immunity, and patients who received Heplisav-B® had a 2.7-fold greater likelihood of achieving immunity than those who received Engerix-B® (aOR: 2.74, 95% CI 1.31-5.71). CONCLUSION: The two-dose recombinant hepatitis B vaccine resulted in better seroconversion than the three-dose vaccine. Cirrhosis, COPD, and renal failure were associated with a lower likelihood of achieving immunogenicity.

Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study.

There has been no clear consensus on the optimal consolidation periods following HBeAg seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients. Our study aimed to prospectively compare relapse rates between 12 months' and 18 months' consolidation periods to see whether or not there is beneficial durability of tenofovir disoproxil fumarate (TDF) therapy with longer consolidation periods.We enrolled a total of 137 HBeAg-positive Asian CHB patients treated with TDF monotherapy. Forty-six patients achieved HBeAg SC. Then, they were randomly assigned to consolidation period of either 12 months (group A) or 18 months (group B). After stopping TDF therapy, all patients were followed up for 12 months.Thirteen patients (56.5%) relapsed in group A and 12 patients (52.2%) relapsed in group B after 12 months' follow-up (P = .958). Pretreatment HBsAg level is the only significant predictor for off-therapy recurrence by univariate analysis (P = .024). Baseline HBeAg >1000 S/CO in group B patients were significantly less likely to relapse than those of group A (P = .046). Baseline alanine aminotransferase (ALT) >133 U/L could significantly predict occurrence of HBeAg SC (P = .008; 95% CI: 0.545-0.763; AUC: 0.654).Overall, a prolonged consolidation period has no positive effect on TDF therapy on sustained viral suppression in HBeAg-positive Asian CHB patients. However, a prolonged consolidation period was beneficial to patients with high baseline semi-quantitative HBeAg levels in terms of off-treatment durability. Baseline ALT > 133 U/L could significantly predict the occurrence of HBeAg SC.

Hepatitis B surface antigen seroclearance: Immune mechanisms, clinical impact, importance for drug development.

HBsAg seroclearance occurs rarely in the natural history of chronic hepatitis B (CHB) infection and is associated with improved clinical outcomes. Many factors are associated with HBsAg seroconversion, including immune and viral factors. However, the immune mechanisms associated with HBsAg seroclearance are still difficult to elucidate. HBsAg seroclearance is the ideal aim of HBV treatment. Unfortunately, this goal is rarely achieved with current treatments. Understanding the mechanisms of HBsAg loss appears to be important for the development of curative HBV treatments. While studies from animal models give insights into the potential immune mechanisms and interactions occurring between the immune system and HBsAg, they do not recapitulate all features of CHB in humans and are subject to variability due to their complexity. In this article, we review recent studies on these immune factors, focusing on their influence on CHB progression and HBsAg seroconversion. These data provide new insights for the development of therapeutic approaches to partially restore the anti-HBV immune response. Targeting HBsAg will ideally relieve the immunosuppressive effects on the immune system and help to restore anti-HBV immune responses.

Long-Term Effects of Tenofovir on Liver Histopathology in Patients with Chronic Viral Hepatitis B Infection.

OBJECTIVE: The aim of this study to evaluate histopathological improvement and virological, serological and biochemical response rates in patients with chronic hepatitis B (CHB) who were treated with tenofovir disoproxil fumarate (TDF). MATERIAL AND METHOD: A total of 91 nucleosid(t)e-naive CHB patients who received TDF were evaluated. Virological, serological and biochemical test results were assessed at baseline and every 12 weeks. Liver biopsy specimens were assessed according to the modified Ishak scoring. RESULTS: The study was conducted on 52 patients. The mean age was 40±10 years and 40.4% were female. The mean follow-up period was 33±11 months. HBsAg seroclearance occurred in none of the patients. The serum level of HBV-DNA became undetectable in 94.2% of the patients. Mean histological activity index at baseline and on-treatment were 8.2±2.3 and 6.2±2.0 and the mean fibrosis scores were 2.65±1.3 and 2.33±1.1, respectively. CONCLUSION: We determined that TDF therapy provided remarkably good HBV DNA suppression and biochemical response rates, but low seroconversion. Improvement of liver necroinflammation was detected, but no significant change observed in fibrosis.