Differential Relapse Patterns After Discontinuation of Entecavir vs Tenofovir Disoproxil Fumarate in Chronic Hepatitis B.

BACKGROUND AND AIMS: Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy. METHODS: This study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods. RESULTS: During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups. CONCLUSIONS: TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.

Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).

BACKGROUND & AIMS: Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). METHODS: This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. RESULTS: Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. CONCLUSIONS: The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.

Incidence of Hepatic Decompensation After Nucleos(t)ide Analog Withdrawal: Results From a Large, International, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study).

INTRODUCTION: Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares. METHODS: This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n = 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ≥12 months before cessation (n = 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment. RESULTS: Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001). DISCUSSION: Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome.

Sorted B cell transcriptomes point towards actively regulated B cell responses during ongoing chronic hepatitis B infections.

The natural course of chronic hepatitis B virus (HBV) infections follows distinct clinical disease phases, characterized by fluctuating levels of serum HBV DNA and ALT. The immune cells and their features that govern these clinical disease transitions remain unknown. In the current study, we performed RNA sequencing on purified B cells from blood (n = 42) and liver (n = 10) of healthy controls and chronic HBV patients. We found distinct gene expression profiles between healthy controls and chronic HBV patients, as evidenced by 190 differentially expressed genes (DEG), but also between the clinical phenotypes of a chronic HBV infection (17-110 DEG between each phase). Numerous immune pathways, including the B cell receptor pathway were upregulated in liver B cells when compared to peripheral B cells. Further investigation of the detected DEG suggested an activation of B cells during HBeAg seroconversion and an active regulation of B cell signalling in the liver.

Impact of COVID-19 on the lives and psychosocial well-being of persons with epilepsy during the third trimester of the pandemic: Results from an international, online survey.

OBJECTIVE: To evaluate the impact of the coronavirus disease 2019 (COVID-19) measures on the lives and psychosocial well-being of persons with epilepsy (PWE) during the third trimester of the COVID-19 pandemic. METHODS: A structured questionnaire investigating different aspects of the lives and psychosocial well-being of PWE during the COVID-19 pandemic was developed. Persons with epilepsy were invited via social media to anonymously respond to a secure web-based online questionnaire (www.icpcovid.com). Responses were collected between July 26th and December 3rd, 2020. Hospital anxiety and depression scales (HADS) were used to screen respondents for depression (HADS-D) and anxiety (HADS-A). RESULTS: Responses of 407 PWE were included in the analysis; 304 (74.7%) respondents were female and 245 (60.2%) living in Europe, 157 (38.6%) in South America, and 5 (1.2%) in Canada. Seventy-six (18.7%) reported a decrease of income during the COVID-19 lockdown, and 122 (30.0%) experienced difficulties in obtaining anti-seizure medication (ASM), mostly (72/122, 59.0%) due to unavailability. Seizure frequency increased in 122 (30.0%); 295 (72.5%) screened positive for anxiety, and 159 (39.1%) for depression. Hundred eighty-eight (46.2%) reported reluctance to seek medical care; 27.3% believed that epilepsy was associated with an increased risk of COVID-19 disease. Forty-six (74.2%) of 62 PWE who were followed up by telephone or video consult were satisfied with this consult. Fifty-five respondents, most (89.1%) of whom were from Europe, had also participated in a previous survey during the early months of the pandemic. In this subgroup, although there was no difference in prevalence of a positive screening for depression or anxiety, mean scores on HADS-A and HADS-D increased from 6.65 ±â€¯3.99 to 7.27 ±â€¯4.01 (p = 0.418), and from 5.84 ±â€¯4.43 to 6.60 ±â€¯4.45 (p = 0.371), respectively. CONCLUSIONS: The COVID-19 pandemic continues to impact the psychosocial and somatic well-being of PWE. To minimize this impact, ensuring uninterrupted access to ASM is essential. Teleconsultations are valid alternatives for continued follow-up, but should include attention to psychosocial well-being. Persons with epilepsy should be more actively informed that epilepsy is not a risk factor for developing (more severe) COVID-19 disease.

Access to healthcare and prevalence of anxiety and depression in persons with epilepsy during the COVID-19 pandemic: A multicountry online survey.

OBJECTIVE: The objective of this study was to assess access to healthcare and to estimate the prevalence of depression and anxiety among persons with epilepsy (PWE) during the ongoing coronavirus disease 2019 (COVID-19) pandemic. METHODS: We conducted a multicountry online survey among PWE. Persons with epilepsy were invited to participate through various social media channels. The Hospital Anxiety and Depression Scale (HADS) and 9-item Patient Health Questionnaire (PHQ-9) scale were used to score anxiety and depression. Logistic regression modeling was used to investigate factors associated with anxiety and depression. RESULTS: Three hundred ninety-nine PWE were included (mean age: 38.22 ±â€¯12.09 years), the majority were female (80.2%) and living in high-income countries (83.2%). Two hundred three PWE reported symptoms of a cold since January 2020. Nine (25%) of the 36 PWE tested for COVID were positive. A total of 72 PWE (19.6%) reported problems to obtain antiseizure medication (ASM), which in 25% of cases was directly COVID-related. Of the 399 PWE, 201 (50.4%) screened positive for anxiety according to the HADS; 159 (39.8%) and 187 (46.9%) PWE screened positive for depression based on the HADS and PHQ-9 scale, respectively. Female gender and financial problems were associated with both depression and anxiety. A planned follow-up consultation with the treating physician was associated with a lower risk of depression, whereas difficulties to access ASM treatment increased the odds of depression. In 65/137 (47.4%) PWE with a planned follow-up visit with the treating physician, this consultation was canceled. CONCLUSIONS: Innovative approaches are needed to ensure continuity in access to ASM treatment. Healthcare workers should ensure continued follow-up, either through inperson or telehealth appointments, to timely identify symptoms of anxiety and depression and act accordingly.

Durability of Response After Hepatitis B Surface Antigen Seroclearance During Nucleos(t)ide Analogue Treatment in a Multiethnic Cohort of Chronic Hepatitis B Patients: Results After Treatment Cessation.

In 70 chronic hepatitis B patients with hepatitis B surface antigen seroclearance during nucleos(t)ide analogue therapy, response was sustained in all 54 patients who discontinued treatment. Clinically significant relapses as indicated by high hepatitis B virus DNA and ALT levels were not observed. Anti-HBs positivity may not be required to ensure sustained off-treatment response.

A first case of Mixta calida bacteremia and meningitis in a 5-week old child.

Mixta calida, previously known as Pantoea calida, was initially isolated from powdered infant milk in 2010. It falls within the Erwiniaceae family (class: Enterobacterales). While Mixta calida was traditionally regarded as non-pathogenic, we now present a case of Mixta calida bacteraemia and meningitis in a 5-week-old child, successfully treated with cefotaxime. This case, in contrast to prior reports with potential contamination issues, is the first to offer compelling evidence of Mixta calida's pathogenicity in humans.

A first case of Chimaeribacter species catheter-related bloodstream infection.

We present a case of a 80-year-old patient with a catheter-related bloodstream infection caused by Chimaeribacter species. The Chimaeribacter genus represents a novel genus within the Yersiniaceae family. To the best of our knowledge, as of today, nothing is known about the pathogenicity of Chimaeribacter species, nor about the appropriate antimicrobial management. In the present case, we demonstrate, for the first time, a potential clinical relevance of the Chimaeribacter species. Antimicrobial susceptibility data are presented.

Progression of the FIB-4 index among patients with chronic HCV infection and early liver disease.

BACKGROUND AND AIMS: Historical paired liver biopsy studies are likely to underestimate current progression of disease in patients with chronic hepatitis C virus (HCV) infection. We aimed to assess liver disease progression according to the non-invasive Fibrosis-4 (FIB-4) index in patients with chronic HCV and early disease. METHODS AND RESULTS: Patients diagnosed with chronic HCV and FIB-4 <3.25 from four international liver clinics were included in a retrospective cohort study. Follow-up ended at start of antiviral therapy resulting in sustained virological response, at time of liver transplantation or death. Primary outcome of advanced liver disease was defined as FIB-4 >3.25 during follow-up. Survival analyses were used to assess time to FIB-4 >3.25.In total, 4286 patients were followed for a median of 5.0 (IQR 1.7-9.4) years, during which 41 071 FIB-4 measurements were collected. At baseline, median age was 47 (IQR 39-55) years, 2529 (59.0%) were male, and 2787 (65.0%) patients had a FIB-4 <1.45. Advanced liver disease developed in 821 patients. Overall, 10-year cumulative incidence of advanced disease was 32.1% (95% CI 29.9% to 34.3%). Patients who developed advanced disease showed an exponential FIB-4 increase. Among patients with a presumed date of HCV infection, cumulative incidence of advanced disease increased 7.7-fold from 20 to 40 years as opposed to the first 20 years after HCV infection. CONCLUSIONS: The rate of advanced liver disease is high among chronic HCV-infected patients with early disease at time of diagnosis, among whom liver disease progression accelerated over time. These results emphasise the need to overcome any limitations with respect to diagnosing and treating all patients with chronic HCV across the globe.

Clinical management of chronic hepatitis B: A concise overview.

Worldwide, over 250 million people are chronically infected with the hepatitis B virus (HBV). Infected patients have an up to 100-fold increased risk for liver-related complications, including cirrhosis, hepatic decompensation and hepatocellular carcinoma. Nonetheless, the majority of the infections remains asymptomatic, stressing the importance of HBV screening and linkage to care. Excellent clinical outcomes are seen during nucleos(t)ide analogue (NA) therapy, which often is continued indefinitively due to a lack of functional cure. Increasing evidence suggests that NA discontinuation following long-term treatment induced viral suppression in patients without a functional cure may be a favourable option. Reliable biomarkers are, however, urgently needed to select the patients that would benefit from NA withdrawal. In addition, renewed and novel approaches to improve screening and linkage to care are other fundamental factors in the optimisation of the clinical management of chronic hepatitis B.

Humoral immunity in hepatitis B virus infection: Rehabilitating the B in HBV.

Insights into the immunopathogenesis of chronic HBV infections are fundamental in the quest for novel treatment approaches aimed at a functional cure. While much is known about the ineffective HBV-specific T-cell responses that characterise persistent HBV replication, B cells have been left largely understudied. However, an important role for humoral immunity during the natural history of HBV infections, as well as after functional cure, has been inadvertently revealed by the occurrence of HBV flares following B cell-depleting treatments. Herein, we review our current understanding of the role of the humoral immune response in chronic HBV, both at the level of HBV-specific antibody production and at the phenotypic and broader functional level of B cells. The recent development of fluorescently labelled HBV proteins has given us unprecedented insights into the phenotype and function of HBsAg- and HBcAg-specific B cells. This should fuel novel research into the mechanisms behind dysfunctional HBsAg-specific and fluctuating, possibly pathogenic, HBcAg-specific B-cell responses in chronic HBV. Finally, novel immunomodulatory treatments that partly target B cells are currently in clinical development, but a detailed assessment of their impact on HBV-specific B-cell responses is lacking. We plead for a rehabilitation of B-cell studies related to both the natural history of HBV and treatment development programmes.

Impact of COVID-19 on Healthcare Workers in Brazil between August and November 2020: A Cross-Sectional Survey.

During the COVID-19 pandemic, healthcare workers (HCW) have been subjected to greater workloads. We conducted a cross-sectional online survey to assess the impact of the COVID-19 pandemic on Brazilian HCW. Data were collected between 11 August and 1 November 2020. Of the 295 respondents, 95 (32.2%) were medical doctors, 82 (27.8%) administrative staff, 53 (18.0%) nurses, 27 (9.2%) laboratory staff, and 38 (12.9%) were other staff. COVID-19-related restructuring at the health facilities was reported by 207 (70.2%) respondents, and 69 (23.4%) had their tasks changed. Preventive measures were well respected when seeing suspected patients. Overall, 167 (56.6%) HCW screened positive for anxiety and 137 (46.4%) for depression; 109 (36.9%) screened positive for both conditions. Of the 217 (73.6%) HCW who had been tested for COVID-19, at least one positive result was reported in 49 (22.6%). Following a positive COVID-19 test, 45/49 (91.8%) stopped working and stayed home. In conclusion, we found a high incidence of COVID-19 infection among Brazilian HCW with high rates of anxiety and depression despite a good self-reported adherence to COVID-19 preventive measures. As such, our study highlights the urgent need for interventions to mitigate the psychosocial risks HCW in Brazil encounter during the COVID-19 pandemic.

Follow-Up Survey of the Impact of COVID-19 on People Living with HIV during the Second Semester of the Pandemic.

COVID-19 affects persons living with HIV (PLWH) both directly (via morbidity/mortality) and indirectly (via disruption of HIV care). From July-November 2020, an online survey was conducted to investigate the psychosocial well-being of PLWH and changes in HIV care during the second semester of the COVID-19 outbreak. Data were collected on the socio-demographic characteristics of PLWH, their psychosocial well-being, impact of COVID-19 preventive measures on their daily routines and HIV follow-up. Of the 247 responses analyzed (mean age: 44.5 ± 13.2 years; 73.7% male), 67 (27.1%) and 69 (27.9%) respondents screened positive for anxiety (GAD-2 score ≥ 3) and depression (PHQ-2 score ≥ 3), respectively. HIV care had returned to pre-COVID-19 state for 48.6% PLWH, and 108 (43.7%) had no HIV follow-up during the past month. Over three quarters (76.1%) of respondents expressed willingness to receive the COVID-19 vaccine. Compared to previous findings in April 2020, substance use increased from 58.6% to 67.2% (p < 0.001). Our findings suggest that the well-being and medical follow-up of PLWH are still affected after almost a year into the COVID-19 outbreak. Remote HIV follow-up (telemedicine) with psychosocial support should be envisaged in the medium to long-term. Given that most PLWH accept COVID-19 vaccination, they may be prioritized for this intervention.

Nivolumab and anti-HCV activity, a case report.

Exhaustion of antigen-specific T-cells in order to escape immune destruction is frequently seen in chronic viral infection and different types of cancer. Blockade of overexpressed negative co-stimulatory pathways, a process known as immune checkpoint modulation, is a promising novel therapy that could improve the treatment of liver diseases with features of T cell exhaustion. We present a case of a 54-year-old hepatitis C virus (HCV) positive patient with an acute flare of hepatitis during nivolumab treatment for a stage IV lung carcinoma, an anti-programmed death-1 (PD-1) immunotherapy. Retrospective testing of HCV RNA documented infection more than 6 months ago. Nivolumab treatment was associated with an alanine aminotransferase (ALT) flare reaching a peak value of 663 U/L, along with bilirubin levels of 0.74 mg/dL and no signs of coagulopathy. The assumption of a nivolumab-associated autoimmune hepatitis led to the interruption of the immune checkpoint inhibitor treatment. However, a subsequent 1-log decrease of HCV RNA load was noticed, which raised the possibility of an immune reconstitution against the HCV-infected hepatocytes with cell lysis. Liver biopsy specimen demonstrated no evidence for autoimmune liver disease or fibrosis. Clinical evolution was favorable and serum transaminases returned to normal levels and HCV RNA load increased to baseline values following nivolumab cessation. The current case suggests an anti-HCV activity of anti-PD-1 treatment in the setting of concomitant HCV viremia and lung carcinoma.

Neuropathological Changes in Nakalanga Syndrome-A Case Report.

Nakalanga syndrome is a clinical manifestation of onchocerciasis-associated epilepsy characterized by stunting, delayed or absent secondary sexual development and skeletal deformities, and is often accompanied by epileptic seizures. The pathophysiology of Nakalanga syndrome is unknown. Here, we describe the post-mortem findings of a 17-year-old female who died with Nakalanga syndrome in northern Uganda. Macroscopic and histopathological examination of all major organs (liver, lungs, kidney and heart), including the brain and the pituitary gland, was performed. The suspected cause of death was malaria, and all major organs and pituitary gland appeared normal, except the lungs, which were edematous consistent with the malaria. Neuropathological changes include signs of neuro-inflammation (gliosis and activated microglia), which co-localized with tau-reactive neurofibrillary tangles and threads. The pathology was most abundant in the frontal cortex, thalamic and hypothalamic regions, and mesencephalon. The choroid plexus showed psammoma bodies. These findings indicate accelerated aging, probably due to repeated seizures. The neuropathological findings were similar to other persons who died with onchocerciasis-associated epilepsy. Examination of the pituitary gland did not reveal new information concerning the underlying pathophysiological mechanism of Nakalanga syndrome. Therefore, more post-mortem studies should be performed.

Adherence to COVID-19 Prevention Measures in the Democratic Republic of the Congo, Results of Two Consecutive Online Surveys.

Adherence to preventive measures is essential to reduce the risk of COVID-19 transmission. Two online surveys were conducted in the Democratic Republic of the Congo (DRC) from 23 April to 8 June 2020, and from August 24th to September 8th, respectively. A total of 3268 (round 1) and 4160 (round 2) participants were included. In both surveys, there was a moderate level of adherence to regular handwashing (85% and 77%, respectively), wearing of facemasks (41.4% and 69%, respectively), and respecting physical distancing (58% and 43.4%, respectively). The second survey found that, working in private (OR = 2.31, CI: 1.66-3.22; p < 0.001) and public organizations (OR = 1.61, CI: 1.04-2.49; p = 0.032) and being a healthcare worker (OR = 2.19, CI: 1.57-3.05; p < 0.001) significantly increased the odds for better adherence. However, a unit increase in age (OR = 0.99, CI: 0.98-0.99; p < 0.026), having attained lower education levels (OR = 0.60, CI: 0.46-0.78; p < 0.001), living in a room (OR = 0.36, CI: 0.15-0.89; p = 0.027), living in a studio (OR = 0.26, CI: 0.11-0.61; p = 0.002) and apartment (OR = 0.29, CI: 0.10-0.82; p = 0.019) significantly decreased the odds for better adherence. We recommend a multi-sectorial approach to monitor and respond to the pandemic threat. While physical distancing may be difficult in Africa, it should be possible to increase the use of facemasks.