Virus Recurrence Research Articles

DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence, however, how the host innate immune system responds to cccDNA is still less known. Here, based on cccDNA-hepatic proteins interaction profiling, DNA sensor ATP-binding cassette subfamily F member 1 (ABCF1) is identified as a novel cccDNA-binding protein and host restriction factor for HBV replication. Mechanistically, ABCF1 recognizes cccDNA by KKx4 motif and forms phase-separated condensates by the poly-glutamine (PolyQ) region of the N-terminal intrinsically disordered low-complexity domain (LCD). Subsequently, ABCF1-cccDNA phase separation not only activates the type I/III interferon (IFN-I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. In turn, to sustain viral replication, HBV reduces ABCF1 expression by HBx-mediated ubiquitination and degradation of SRY-box transcription factor 4（SOX4）, leading to defects in SOX4-mediated upregulation of ABCF1 transcription. Taken together, the study shows that ABCF1 interacts with cccDNA to form phase separation that dually drives innate immune signaling and HBV transcriptional inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection.

Characterization of Herpesviridae Family Members, BK Virus, and Adenovirus in Children and Adolescents with Nephrotic Syndrome.

A prospective study was conducted to determine the genome identification of the viruses Epstein-Barr (EBV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6 type A and type B) and 7 (HHV-7), polyomavirus (BKV), and human adenovirus (HAdV) in plasma and urine samples of pediatric patients with NS. A total of 35 patients aged 1 to 18 years with NS and under immunosuppressant drugs participated in the study. Plasma and urine samples were collected at regular intervals during a median follow-up of 266 days (range 133-595), and DNA was analyzed to detect the selected DNA viruses. Eleven patients (31.4%) had active virus infections, and patterns were classified as coinfection, recurrent, and consecutive. Of these, six patients (54.5%) presented viral coinfection, six (54.5%) viral recurrence, and seven patients (63.3%) had viral consecutive infection. Ten of the eleven patients with active infection had a proteinuria relapse (91%) and eight (72.7%) were hospitalized (p = 0.0022). Active HCMV infection was the most frequent infection and was observed in six patients (54.5%), three of the eleven patients (27.2%) had suspected HCMV disease in the gastrointestinal tract, and one had HHV-7 coinfection. The frequency of other infections was: 9% for HHV-6, 45.5% for BKV, 27.3% for HHV-7, 18.2% for EBV, and 18.2% for HAdV. viral infections, especially HCMV, can be an important cause of morbidity and nephrotic syndrome relapse in children.

Efficacy of Newer Nucleos(t)ide Analogs After Hepatitis B Immunoglobulin Discontinuation Against Hepatitis B and D Recurrence in Liver Transplant Recipients.

The use of nucleos(t)ide analogs (NAs) with a high genetic barrier to resistance, namely entecavir and tenofovir, has improved the efficacy of antiviral prophylaxis against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, the optimal duration and dosage of hepatitis B immunoglobulin (HBIG) administration, particularly in patients transplanted for HBV and hepatitis D virus (HDV) coinfection, remains controversial. We evaluated 28 patients transplanted for HBV/HDV cirrhosis. After LT, each patient received a fixed scheme of low-dose HBIG plus NA for 6 mo post-LT and then continued with long-term NA prophylaxis (entecavir: 8, tenofovir: 20 patients). During 72 mo of follow-up, reappearance of hepatitis B surface antigen at low titers was observed in 1 (3.6%) patient at 33 mo after HBIG discontinuation, which became negative after a single dose of HBIG 1000 IU/L, whereas both serum HBV DNA and HDV RNA remained persistently undetectable and without any clinical or biochemical evidence of HBV/HDV recurrence. We showed for the first time the efficacy of a short, fixed scheme of low-dose HBIG plus NA followed by long-term NA monoprophylaxis against HBV/HDV recurrence after LT, although careful follow-up is needed after HBIG discontinuation, whereas further larger studies are needed to confirm these findings.

The Coexistence of Cervical Intraepithelial Neoplasia (CIN3) and Adenocarcinoma In Situ (AIS) in LEEP Excisions Performed for CIN3.

A sample of 414 women underwent LEEP for CIN3. The study sample consisted of 370 women with a CIN3 lesion alone and 44 women with a CIN3 lesion coexisting with AIS or adenocarcinoma. We studied the individual HR HPV genotypes and their frequency in the two groups under study. Furthermore, the therapeutic results and follow-ups for the population were studied on the entire study sample. In patients with a single CIN3 lesion, 11 high-risk genotypes were detected; in patients with CIN3 associated with AIS or AC, only 4 different genotypes were detected (16, 18, 45, 33). Overall, the frequency of HPV 18 was significantly higher in CIN3 coexisting with AIS compared to solitary CIN3 lesions, χ2 = 27.73 (p < 0.001), while the frequency of other high-risk genotypes was significantly higher in patients with a single CIN3 than in patients with CIN3 coexisting with AIS. In our study population, mixed lesions (CIN3 coexisting with AIS), unlike their squamous counterparts (single CIN3 lesions), were characterized by skip lesions, which demonstrate more aggressive behavior and a higher rate of viral persistence and recurrence. A relatively high rate (10.7%) of AIS-AC was found in women treated for CIN3. Our study confirms the multifocal biological nature of the CIN3 lesion coexisting with AIS compared to the single CIN3 lesion. All this justifies the different treatments to which CIN3 lesions coexisting with AIS are addressed; in fact, the latter are treated with hysterectomy, while CIN3 is treated with conization alone.

Entecavir versus tenofovir for prevention of hepatitis B virus-associated hepatocellular carcinoma after curative resection: study protocol for a randomized, open-label trial

BackgroundEntecavir and tenofovir disoproxil fumarate (TDF) are standard first-line treatments to prevent viral reactivation and hepatocellular carcinoma (HCC) in individuals chronically infected with the hepatitis B virus (HBV), but the long-term efficacy of the two drugs remains controversial. Also unclear is whether the drugs are effective at preventing viral reactivation or HCC recurrence after hepatectomy to treat HBV-associated HCC. This trial will compare recurrence-free survival, overall survival, viral indicators and adverse events in the long term between patients with HBV-associated HCC who receive entecavir or TDF after curative resection.MethodsThis study is a randomized, open-label trial. A total of 240 participants will be randomized 1:1 into groups receiving TDF or entecavir monotherapy. The two groups will be compared in terms of recurrence-free and overall survival at 1, 3, and 5 years after surgery; adverse events; virological response; rate of alanine transaminase normalization; and seroreactivity at 24 and 48 weeks after surgery.DiscussionThis study will compare long-term survival between patients with HBV-associated HCC who receive TDF or entecavir monotherapy. Numerous outcomes related to prognosis will be analyzed and compared in this study.Trial registrationClinicalTrials.gov NCT02650271. Registered on January 7, 2016.

Recurrence Rate of Early Hepatitis C Virus Infection After Renal Transplantation Following Successful Treatment of Patients on Dialysis With Direct-Acting Antiviral Agents.

Recurrence of hepatitis C virus after organ transplant has dreadful complications. An excellent response has been shown with direct-acting antiviral agents in transplant recipients. Although a sustained virological response is considered as the virological cure, it requires patients to be on dialysis for 3 months more before undergoing renal transplant, thus increasing the risk of hepatitis C virus reinfection and associated complications. We aimed to determine hepatitis C virus recurrence in renal transplant recipients who had achieved endof-treatment response before transplant. Per our institutional dialysis protocol, patients who do not achieve rapid virological response are treated with 6 months of direct-acting antiviral agents. All patients who achieve end-of-treatment response are then referred for renal transplant. Our study included kidney transplant recipients who were treated with directacting antiviral agents and had a hepatitis C virus polymerase chain reaction test 3 months after renal transplant. We obtained demographic and clinical data of patients and used SPSS version 20.0 for statistical analyses. Our study included 48 transplant recipients; most were males (81.1%) with mean age of 28.7 ± 9.4 years. All patients received sofosbuvir, daclatasvir, and ribavirin combination before transplant. Most patients (70%) received treatment for 3 months. The polymerase chain reaction test for hepatitis C virus was conducted after a mean of 8.3 ± 3.3 months posttransplant. Laboratory parameters showed total bilirubin of 3.6 ± 17.5 mg/day, alanine aminotransferase of 51.5 ± 80.2 IU/L, and gammaglutamyltransferase of 133.9 ± 220 IU/L. Two recipients (4.2%) had posttransplant recurrence of hepatitis C virus infection. To our knowledge, this study is the first to document excellent response of direct-acting antivirals in renal transplant recipients who had been referred early for transplant. Thus, dialysis patients can undergo transplant after achieving end-oftreatment response.

Beyond survival: unraveling the dynamics of Ebola virus resurgence in Sub-Saharan Africa and the remarkable journey of survivors

Ebola virus disease (EVD) remains a significant public health threat, with sporadic outbreaks occurring in Sub-Saharan Africa. Survivors of EVD may experience various post-infection symptoms, collectively known as post-Ebola virus syndrome (PES), which include chronic arthralgia, uveitis, headache, and psychosocial stressors. In this review, we discuss the persistence of Ebola virus in survivors and its possible role in the reemergence of current outbreaks. We highlight that waning immunity of survivors enhances viral persistence and may lead to viral reactivation and recurrence of disease in previously affected tissues. The delicate equilibrium between diminished immune cell surveillance and limited viral replication may lead to enduring chronic inflammation. Our systematic review, based on an extensive survivor cohort, underscores the importance of continued research and preparedness efforts to combat future outbreaks through adequate surveillance and timely public health interventions. This review serves as a comprehensive guide to understanding the complexities of EVD survivorship, the challenges of PES, and the strategies to mitigate its impact.

Fourth-year Results of HBeAg Negative Chronic Hepatitis B Patients Discontinuing Nucleos(t)ide Analogue Therapy

Objective: There is not a definitive virological treatment for chronic hepatitis B . Withdrawal of nucleos(t)ide analogue (NA) therapy frequently results in viral recurrence, necessitating lifetime treatment. We aimed to look into the results of discontinuation of nucleos(t)ide analogue therapy in HBeAg negative patients. Methods: Treatment of HBeAg-negative patients without cirrhosis who had suppressed HBV DNA for a mean of ≥7 years and underwent nucleos(t)ide analogue therapy for a mean of ≥7 years were stopped according to the EASL guideline stopping rule. Standard laboratory tests, such as HBV DNA viral load, HBsAg, alanine aminotransferase, and adverse events, were monitored for more than four years during therapy and afterwards. Results: HBsAg loss was not observed in any of the patients during the four-year follow-up period. After the first 12 weeks, HBV-DNA was detected in all patients whose nucleos(t)ide analogue treatment was discontinued. The percentage of patients with HBV DNA &gt;2000 IU/mL was 70% at 6 months, 74% at 12 months, 78% at 24 months, and 79.7% at 36 months, HBV DNA &gt;2000 IU/mL was not detected in remaining patients over a four-year period. In the first year, 26% (n=18) of patients were started treatment for relapse, 46% (n=32) in the second year, 49% (n=34) in the third year, and 55% (n=38) in the fourth year. 45% (n=31) of the patients were still being followed without treatment at the end of the fourth year. Conclusion: Although the follow-up of hepatitis B e antigen-negative CHB patients on NA therapy was longer than in the literature, our recurrence rates were similar to other studies, and no patient lost HBsAg. The most significant benefit was that we were able to follow half of the patients without therapy for more than four years, eliminating the need for the patients to use drugs.

Role of NRF2 and reactive aldehydes in acute cellular rejection in liver transplant recipients

ObjectiveTo evaluate the level of oxidative stress and antioxidative response in the transplanted liver and its role in acute cellular rejection (ACR). Particular attention was paid to ACR diagnosis in patients with hepatitis C (HCV), as histopathological features of ACR and viral disease recurrence overlap. MethodsThis retrospective study included 40 liver transplant patients who underwent liver transplantation with two consecutive liver biopsies performed during one hospitalization period: 1.) initial biopsy of the donor liver (before implantation) and 2.) indication biopsy (after suspected ACR). Based on the etiology, patients were divided into two groups: 22 patients with alcoholic liver cirrhosis (EtOH group) and 18 patients with hepatitis C cirrhosis (HCV group). We analyzed the presence of acrolein, HNE (4-hydroxynonenal), and the major antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) in both biopsies. ResultsThe presence of acrolein and HNE in both biopsies indicates increased oxidative stress, while the decrease in these aldehydes in the indication biopsies indicates a decrease in oxidative stress over time, reflecting liver graft recovery. The absence of NRF2 in both biopsies reflects significantly reduced antioxidant protection in patients undergoing liver transplantation. ConclusionThe results support the role of oxidative stress in the pathogenesis of ACR. The presence of acrolein and the absence of HNE in the indication biopsy in patients with ACR could contribute to the diagnosis of ACR in clinical practice when functional antibodies are tested in the clinical setting.

Repeated Hepatitis C Virus Recurrence in a Patient With a Prognosis of Ultimate Spontaneous Clearance: Relapse or Reinfection?

Departments of 1Infectious Diseases 2Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China Supported by Beijing public welfare foundation project for medical and health care (YWJKJJHKYJJ⁃Q2101) of Y. Wen in the First Affiliated Hospital of China Medical University. The remaining authors have no conflicts of interest to declare. Di Dai and Ying Wen have contributed equally.

Investigation of novel HCV therapies: Boscia angustifalia &Boscia senegalensis extracts loaded on galactosylated chitosan nanoparticles synthesized by eco-friendly method for HCV treatment

Hepatitis C virus (HCV) is a major causative agent of chronic liver diseases including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Treatment of HCV has evolved from early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C after receiving therapy with direct-acting antivirals (DAA) with a 0.5 % chance of the hepatitis C virus recurrence, similar to other chronic viral infections. So, retreatment options following treatment failure have become crucial issues. Hence, this study aims to investigate a new promising therapy for HCV. In the field of nanomedicine, chitosan nanoparticles are well-known delivery systems that are frequently used as polymeric carriers. Galactosylated chitosan nanoparticles have been widely applied in HCV treatment. In this study, we have modified galactosylation by an eco-friendly method using l-ascorbic instead of hazardous reagents and we have loaded it with newly tested two Boscia extracts each in three different concentrations. The synthesized chitosan nanoparticles showed two dispersion peaks, at 196 ± 29 nm and 1.33 ± 0.36 μm, with a zeta potential of +3.3 ± 0.4mV with high stability in a range of 40.7 mV. The percentage of encapsulation of Boscia angustifalia extract was found to be 46.58 ± 1.33 % and for Boscia senegalensis extract was 9.77 ± 0.33 %. The release of Boscia angustifalia extract from the nanoparticles was about 40 % in acidic media after 180 min and about 60 % in normal pH. However, the release of Boscia senegalensis extract was 20 % in acidic media and 56 % in normal media after 24 h. Testing of these two newly developed composites against HCV was carried out using an in vitro system for the production of hepatitis C virus (HCV) which was established by infection of human hepatoma cells. Evidence for persistent virus production was monitored by the ELISA technique using an anti-HCV-specific antibody. Results obtained showed that all samples had an anti-HCV activity that increased by increasing concentration, and Boscia angustifalia had remarkable anti-HCV activity compared to Boscia senegalensis.

T-cell specific antibody induction versus corticosteroid induction immunosuppression for liver transplant recipients: a meta-analysis

Corticosteroids remain the mainstay of immunosuppression for liver transplant recipients despite several serious complications including infection, hepatitis C virus (HCV) recurrence, diabetes mellitus (DM), and hypertension. We attempted to compare the safety and efficacy of T-cell specific antibody induction with complete corticosteroid avoidance. We searched MEDLINE, EMBASE, and Cochrane central library. Randomized controlled trials comparing T-cell specific antibody induction with corticosteroid induction immunosuppression were included. Our primary outcome was the incidence of biopsy-proven acute rejection. Eleven trials involving 1683 patients were included. The incidence of acute rejection was not significantly different between the antibody and steroid induction groups (risk ratio [RR] 0.85, 95% confidence interval [CI] 0.72, 1.01, P = 0.06, I2 = 0%). However, T-cell specific antibody induction significantly reduced the risk of cytomegalovirus infection (RR 0.48, 95% CI 0.33, 0.70, P = 0.0002, I2 = 3%), HCV recurrence (RR 0.89, 95% CI 0.80, 0.99, P = 0.03, I2 = 0%), DM (RR 0.41, 95% CI 0.32, 0.54, P < 0.0001, I2 = 0%) and hypertension (RR 0.71, 95% CI 0.55, 0.90, P = 0.005, I2 = 35%). Trial sequential analysis for acute rejection showed that the cumulative z-curve did not cross the Trial sequential boundary and the required information size was not reached. T-cell specific antibody induction compared to corticosteroid induction seems to significantly reduce opportunistic infections including cytomegalovirus infection and HCV recurrence and metabolic complications including DM and hypertension. However, given the insufficient study power, low quality of evidence, and heterogeneous immunosuppressive regimens, our results should be cautiously appreciated.

Vitamin D serum level in participants with positive history of recurrent herpes labialis

AimVitamin D plays an important role in immune system regulation, also its deficiency is assumed to affect the patients’ predisposition to viral diseases such as recurrent herpes labialis. In this cross-sectional study, we tried to compare the mean serum level of vitamin D in participants with a positive history of recurrent herpes labial lesions and healthy controls.Materials and methodsThe vitamin D serum level of 43 participants with a positive history of recurrent herpes labial lesions who were referred to the Motahhari laboratory in Shiraz during 2020–2022, was compared with 42 healthy controls. It was assessed by an Elisa kit. An Independent T-test was used to compare the vitamin D serum level between two genders. In order to assess the mean age value and gender distribution, an independent T-test and Pearson Chi-Square were used, respectively for the two groups. The serum vitamin D level was compared between both control and test groups.ResultsThere was no significant difference between vitamin D mean serum levels in the two evaluated groups (p.value = 0.72). Although the age (p.value = 0.09) and recurrence (p.value = 0.13) of herpes labialis had no statistically significant relation to the vitamin D serum level, the healing duration of herpes labialis was inversely related (p.value = 0.01). Lower-level of serum vitamin D were accompanied by a longer healing duration of the lesions.ConclusionAlthough the vitamin D serum level of participants with a history of recurrent herpes labialis had no relation with age and herpes virus recurrence frequency, a longer healing duration of lesions had been reported in patients with lower serum levels of vitamin D.

Successful use of interferon alfa-2a for persistent parvovirus B19 infection.

Human infection with parvovirus B19 causes a range of clinical manifestations, including benign erythema infectiosum in children, arthralgias in adults, aplastic crisis in patients with bone marrow failure, and potentially fatal congenital hydrops fetalis. Persistent parvovirus B19 infection is a rare disease presentation mostly seen in adult women or immunocompromised individuals. Treatment options include corticosteroids and intravenous immunoglobulin; however, viral clearance is difficult to obtain and rarely maintained. In this Grand Round, we report the case of a 43-year-old man with persistent parvovirus B19 infection and anaemia, who was refractory to standard treatment regimens, and whom we successfully treated with pegylated interferon alfa-2a. Initial treatment led to viral clearance and remission of anaemia, although secondary recurrence of virus required treatment extension. Despite extensive genetic and immunological evaluations, no underlying primary or secondary immunodeficiency was identified in the patient. We propose interferon alfa-2a as a treatment option for persistent parvovirus B19 infection and advocate long-term follow-up of patients and potentially repeated treatment.

Successful clinical and virological outcomes of liver transplantation for HDV/HBV-related disease after long-term discontinuation of hepatitis B immunoglobulins.

Indefinite, long-term administration of hepatitis B immunoglobulins (HBIg), together with a third generation nucleos(t)ide analog (NA), is the currently recommended prophylactic strategy to prevent viral recurrence after liver transplantation (LT) for Hepatitis Delta virus (HDV)/Hepatitis B virus (HBV)-related disease. We retrospectively analyzed the safety and long-term clinical and virological outcomes of a consecutive cohort of 16 patients (10 males, median age 64.5, range 41-75) transplanted for HDV/HBV-related cirrhosis at our Institution, who discontinued HBIg after a median of 24.5months (range 15-116) after transplant. All patients continued prophylaxis with same NA used before LT. Recurrence of HDV/HBV infection was defined as reappearance of serum HDV-RNA with detectable serum HBsAg and/or HBV-DNA. The median follow-up after LT was 138months (range 73-316) and 110months (range 52-200) after HBIg withdrawal. All patients were HBsAg-positive, HBV-DNA negative, and anti-HDV positive at the time of LT and without coinfections with HCV or HIV. Patients were followed with biochemical and virological tests every 3-6months after HBIg withdrawal. No recurrences of HDV/HBV infection or disease were observed during monoprophylaxis with NA. In addition, eight patients (50%) spontaneously developed anti-HBs titers above 10IU/L at a median of 74months (range 58-140) following HBIG discontinuation. HBIg withdrawal after LT is a safe and efficacious strategy in patients transplanted for HDV/HBV disease and is frequently associated with the spontaneous development of serological immunity against HBV. These data call for a revision of current prophylactic recommendations in this setting.

Early intrahepatic recurrence of HBV infection in liver transplant recipients despite antiviral prophylaxis

Background & AimsProphylaxis with nucleos(t)ide analogues (NUCs) and hepatitis B immunoglobulin (HBIG) has decreased the rate of HBV recurrence after orthotopic liver transplantation (OLT), but the duration of this prophylaxis remains debated. Our aim was to investigate the recurrence of both intrahepatic and serum HBV markers after OLT in patients receiving long-term NUC and HBIG prophylaxis. MethodsA total of 31 HBV-positive patients benefiting from OLT were prospectively enrolled in five French centres between 2012 and 2015. Tissue samples from the native liver, liver reperfusion biopsy, and 12-month post-OLT (M12) biopsy were collected. Intrahepatic HBV markers were quantified using Droplet Digital PCR. Serum hepatitis B core-related antigen (HBcrAg) and HBsAg were quantified using the Lumipulse platform. ResultsAmong the 31 patients, 26 were HBeAg negative and 28 had undetectable serum HBV DNA at OLT. All patients received HBIG and NUC after OLT, and serum HBV DNA was undetectable at M12. Of the 27 available native livers, 26 had detectable total HBV DNA (median, 0.045 copies/cell), 21 were positive for cccDNA (0.001 copies/cell), and 19 were positive for 3.5-kb HBV RNA (0.0004 copies/cell). Among the 14 sequential reperfusion and M12 biopsies, seven were positive for HBV markers on the reperfusion sampling, and six of them were also positive at M12. Of the 27 patients with available serum samples at M12, eight were positive for HBcrAg and five were positive for HBsAg by ultrasensitive quantification, although they were negative by conventional techniques. Overall, among the 17 patients having a matched biopsy and serum sample at M12, only one had undetectable HBV markers in both the liver and serum. ConclusionsOur results demonstrate a very early detection of viral genome in the graft and intrahepatic viral recurrence despite NUC and HBIG prophylaxis. Clinical Trials RegistrationThis study is registered at ClinicalTrials.gov (NCT02602847). Impact and ImplicationsIn this work, we show that, despite the recommended prophylaxis based on NUC and HBIG, HBV can infect the new liver very rapidly after transplantation. Twelve months after transplantation, the majority of patients had at least one HBV marker detected in either serum or the liver. Therefore, our results demonstrate early intrahepatic viral recurrence despite NUC and HBIG therapy and underline the importance of an optimal patient compliance to the antiviral prophylaxis to prevent viral rebound.

Entecavir Combined With Short-term Hepatitis B Immunoglobulin in Preventing Hepatitis B Virus Recurrence in Liver Transplant Recipients

The combination of nucleoside analogs and long-term hepatitis B immunoglobulin (HBIG) is considered to be the standard regimen for preventing hepatitis B virus (HBV) recurrence after liver transplant (LT). However, long-term use of HBIG causes many adverse effects. The aim of this study was to evaluate the effect of nucleoside analogs entecavir combined with short-term HBIG in preventing HBV recurrence after LT. This retrospective study assessed the effect a combination of entecavir and short-term HBIG in prophylaxis of HBV recurrence among 56 LT recipients who had undergone the procedure because of HBV-associated liver disease at our center between December 2017 and December 2021. All patients received entecavir treatment combined with HBIG for the prevention of hepatitis B recurrence, and HBIG treatment was withdrawn within 1 month. The patients were followed up to determine levels of hepatitis B surface antigen, antibody to hepatitis B surface antigen (HBsAb), and HBV-DNA and the recurrence rate of HBV. Only 1 patient appeared positive for hepatitis B surface antigen at 2 months post-LT. The overall HBV recurrence rate was 1.8%. The HBsAb titers of all patients gradually decreased over time, with a median of 376.6 IU/L at 1 month post-LT and a median of 13.47 IU/L at 12 months post-LT. During the follow-up period, the HBsAb titer of the preoperative HBV-DNA-positive patients remained at a lower level than that of HBV-DNA-negative patients. Entecavir combined with short-term HBIG can exert a good effect for the prevention of HBV reinfection post-LT.

A Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Tacrolimus and Corticosteroids in Combination With or Without Mycophenolate Mofetil in Liver Transplantation Recipients Infected With Hepatitis B Virus

Mycophenolate mofetil exhibits pharmacologic mechanisms different from calcineurin inhibitors. Therefore, the dose of calcineurin inhibitors can be reduced along with side effects for effective immunosuppression. We aimed to evaluate the efficacy and safety of tacrolimus and corticosteroid in combination with or without mycophenolate mofetil in living donor liver transplantation (LDLT) recipients infected with hepatitis B virus (HBV). A randomized, open-label, comparative, multicenter, phase IV study was conducted with 119 patients from January 2014 to September 2017. In the full analysis set population, 58 and 59 patients were included in the study group (triple-drug regimen: TacroBell+My-rept+corticosteroid) and the control group (dual-drug regimen: TacroBell+corticosteroid), respectively. In the per protocol set population, 49 and 42 patients were included in the study and control groups, respectively. In the full analysis set population, the incidence of biopsy-proven acute cellular rejection (rejection activity index score ≥4) was 3.4% in the study group; however, this finding was not observed in the control group (P = .468). Hepatitis B virus recurrence was observed in one patient in the control group. No cases of biopsy-proven acute cellular rejection and HBV recurrence were observed in the per protocol set population. The incidences of serious adverse events were 25.9% and 18.0% in the study and control groups, respectively; however, the difference between the groups was not statistically significant (P = .376). Although the study involved a small number of patients, the triple-drug regimen can be considered safe and effective for immunosuppression after living donor liver transplantation in patients infected with HBV.

High-potency nucleos(t)ide analogues alone or plus immunoglobulin for HBV prophylaxis after liver transplantation: a meta-analysis.

The optimum prophylactic regimen against hepatitis B virus (HBV) recurrence after liver transplantation (LT) in HBV-infected patients is uncertain but of great clinical relevance. New evidence suggests that hepatitis B immunoglobulin (HBIG)-free approach would become a reasonable choice in the era of high-potency nucleos(t)ide analogues (HPNAs). We aimed to provide robust estimates for long-term survival and HBV recurrence in patients receiving different HBV-prophylaxis strategies after LT. We did a systematic review and meta-analysis using both pseudo-individual patient data recovered from included studies (IPDMA) and conventional trial-level aggregate data meta-analysis (ADMA). Hazard ratios (HRs) were calculated using different Cox proportional hazard models accounting for inter-study heterogeneity. ADMA was conducted to pool outcomes at specific time points. A total of 16 studies involving 7897 patients and 41 studies involving 9435 were eligible for IPDMA and AMDA, respectively. Cumulative HBV recurrence rate and overall survival (OS) at 1, 3, 5 and 10years post-LT were 0.3%, 0.9%, 1.2%, 1.7% and 95.6%, 89%, 86.4%, 86.4% in the HPNAs (i.e., entecavir and tenofovir) + HBIG combination group vs. 0.6%, 0.6%, 1.2%, 1.7% and 94.5%, 86.8%, 84.8%, 81.2% in the HPNAs monotherapy group (HR 1.20, 95% CI 0.56-2.60, p = 0.64; HR 1.09, 95% CI 0.70-1.69, p = 0.72), respectively. The results were compatible with AMDA. A similar HBV recurrence and overall survival were found in patients who used HPNAs (mainly entecavir) monotherapy as in those who received a combination of HPNAs and HBIG. These findings address concerns regarding the safety and effectiveness of HPNAs monotherapy.

Impact of the use of anti-glaucoma medications on the risk of herpetic keratitis recurrence.

Numerous case reports have associated anti-glaucoma medications with recurrence of herpes simplex virus (HSV) and herpes zoster virus (HZV) keratitis. The aim of our study was to determine whether different anti-glaucoma agents are associated with recurrence of herpetic keratitis. This was a retrospective cohort study using health databases from a Canadian province from January 2001 to December 2012. A new cohort of users on topical prostaglandins (PGs), beta blockers (BBs), alpha-2 agonists (AAs) and carbonic anhydrase inhibitors (CAIs) was created. The date of the third anti-glaucoma drug dispensation within 90days was deemed the index date of the case. Herpetic keratitis events, as defined by an ICD-9/10 code for HSV or HZV keratitis, or the dispensation of an anti-viral medication by either an ophthalmologist or an optometrist, were examined prior to and following the index date. Risk ratios (RRs) were computed to compare the risk of HSV/HZV keratitis among the PG, BB, AA, and CAI groups individually and collectively while adjusting for age and sex. Among 19,986 users of glaucoma medications identified, there were 684 cases of HSV/HZV keratitis. There was no increased risk of HSV/HZV keratitis recurrence for any of the four glaucoma medications classes individually or collectively when adjusted for age and sex. There was also no increased risk for redeveloping either HSV keratitis only or HZV keratitis only amongst all anti-glaucoma users. There is no association between the use of topical ocular hypotensive therapies and HSV/HZV keratitis recurrence. Further studies are needed to confirm these findings.