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Challenges and Opportunities in Hepatitis

Challenges and Opportunities in Hepatitis

Menezes, G. B. L., Almeida, D., Pacheco, S. R., De Campos, M., Gouvêa, M. S. G., Pinho, J. R. R., De Paula Do Nascimento, R., Freire, S. M., Schaer, R., & Schinoni, M. (2023)


Introduction: Hepatitis E virus infection can lead to severe liver disease and unregulated hepatitis in patients with a history of previous chronic liver disease of different etiologies.

Objective: To determine the seroprevalence of hepatitis E in untreated carriers of hepatitis C virus, hepatitis B virus, autoimmune hepatitis and in patients with drug-induced liver disease.

Materials and Methods: This is a cross-sectional study with a total sample of 301 outpatient hepatology volunteers. The detection of anti-HEV IgM and IgG antibodies was determined using the ELISA (RecomWell anti-HEV IgG and IgM, Mikrogen®, Germany), One-step real-time PCR was used for the detection of HEV-RNA (Taqman, Life Technologies TM, Foster City, CA, USA).

Results: The overall prevalence of anti-HEV IgG and IgM in the population studied was 12.95% and 2.3%, respectively. The prevalence by group were: anti-HEV IgG: hepatitis C virus with 13.2%, hepatitis B virus with 13%, autoimmune hepatitis with 8.1 and drug-induced liver disease with 21.1. Patients with HCV chronic hepatitis and positive HCV IgG serology showed an increase in transaminase levels in 66.7% (10/15) of the cases, while in the seronegative patients this increase was present in 42.4% (42/99) of the cases (p<0.05).

Conclusions: A high seroprevalence of HEV was observed. Among the patients with serology concomitantly positive for anti HEV IgG and IgM, 57.1% (4/7) had higher levels of TGO and TGP, suggesting acute HEV infection. A relationship between hepatitis C and E virus co-infection and elevated transaminase levels has been demonstrated. Future studies with evaluation of several clinical parameters are necessary.

Salava, K., Patel, R., Newman, E. D., Nicoholas, P. D., Grassi, D. M., Thomas, S., Chronowski, J., Pugliese, D., & Cote, J. (2023)


Objective: To close laboratory screening care gaps via rheumatology-pharmacy co-management in patients starting disease-modifying antirheumatic drugs.

Methods: Laboratory data were obtained from patients who started disease-modifying antirheumatic drugs (DMARDs) during the pre-and post-intervention periods. The intervention consisted of a rheumatology-pharmacy collaborative screening with guideline-driven DMARD protocol for hepatitis B, hepatitis C, and tuberculosis. The care gap closure for patients starting any type of DMARDs such as a conventional synthetic disease-modifying antirheumatic drug (csDMARD), a biologic disease-modifying antirheumatic drug (bDMARD), or a targeted synthetic disease-modifying antirheumatic drug (tsDMARD), was defined as meeting hepatitis screening completion. The care gap closure for patients starting a bDMARD or tsDMARD alone was defined as meeting both the hepatitis and tuberculosis screening completion. The Chi square method was used for the statistical analysis of the data comparing laboratory screening rates of rheumatologists’ pre-intervention versus rheumatologist-pharmacist co-management post-intervention. Post-intervention, subgroup analysis of laboratory screening rates among rheumatologists alone versus rheumatologist-pharmacist co-management was also performed.

Results: During the 30-month period 6/1/2019 to 11/30/2021, hepatitis screening for patients on DMARDs improved from 77% with rheumatologists alone to 82% with co-management post-intervention (P=0.005), whereas hepatitis/tuberculosis screening for patients on bDMARDs/tsDMARDs improved from 75% to 85% respectively (P=0.005). In post-intervention subgroup analysis, hepatitis screening for patients on DMARDs improved from 80% with rheumatologists alone to 95% with co-management(P=0.00), whereas hepatitis/tuberculosis screening for patients on bDMARDs/tsDMARDs improved from 83% to 94% respectively (P=0.033).

Conclusion: By integrating clinical pharmacists into our rheumatology clinic, we significantly improved hepatitis and tuberculosis laboratory screening in our immunosuppressed rheumatic population.

Implications: Rheumatologists can consider integrating clinical pharmacists into their practices to improve patient safety by closing laboratory screening care gaps in the immunosuppressed rheumatic population.

Chen, P., & Han, S. (2022)


Hepatitis B (HBV) in special populations within this article is considered as acute on chronic liver failure due to HBV, coinfection with Hepatitis C (HCV), Hepatitis D (HDV), or Human Immunodeficiency Virus (HIV), and HBV infection in patients who are in immunosuppressive states due to specific therapies and liver transplant recipients. Patients within these special populations are at higher risk of liver-related complications such as fibrosis, accelerated cirrhosis, acute on chronic liver failure, and/or development of hepatocellular carcinoma (HCC). Given their respective complex pathophysiology, specific treatment approaches are required for each population. With the introduction of effective antiviral HBV therapies over the past decade and the respective treatment options for the special population diseases, patient outcomes have seen improvement. With the advent of HCV direct antivirals, treatment of HBV-HCV coinfection has been more successful and consistently shown high rates of sustained virologic response. Treatment of HBV-HDV coinfection remains primarily as interferon-based, though new promising therapies have shown greater improvement in viral suppression. HBV-HIV coinfection has also shown promising results given overlapping mechanisms for treatment and specific regimens should be chosen to decrease risk of resistance. HBV reactivation in patients undergoing immunosuppressive therapies have been reported and guidelines recommend close monitoring and in certain cases, HBV antiviral therapy prophylaxis. With the effective HBV therapies, the perception of HBV as a contraindication for liver transplant has been diminishing and prolonged graft survival with effective antiviral therapies have shown promising outcomes.

acheco, S. R., Schinoni, M., Stöcker, A., Paraná, R., Reis, M. G. D., & Silva, L. (2023)


Mutations of genotypic resistance to nucleotide analogues Entecavirand Tenofovirhave been described in patients undergoing treatment and virgins for hepatitis B virus. The present study demonstrated in a sample of 263 patients with chronic HBV from the North and Northeast of Brazil, a mutation rate of resistance to nucleotide analogues of 3.8% (10). Of the 10 patients who had genotypic resistance mutations, only 1 had no genotypic resistance mutation for the first line treatment for hepatitis B, entecavir and tenofovir.Due to the emergence of vaccine escape mutations and resistance mutations to antiviral treatment, and the severity of liver disease caused by HBV, screening for genetic mutations is important due to the impact on therapeutic management.

Holmes, L., Deepika, K., Williams, J., Ogundele, B., Philipcien, G., Enwere, M., Jain, S., Dasari, N., Alur, R. S., Adhikari, R., & Ogungbade, G. (2022c)


Purpose: Viral infections had been historically observed in chronic disease development and complications including although not limited to hepatitis C, influenza A, cytomegalovirus (CMV), Epstein bar virus (EBV), HIV and herpes simplex. Epidemiologic data had implicated CMV, herpes simplex and hepatitis C in type II diabetes (T2D). With the observed increased incidence T2D in COVID-19 among children and adults, this review aimed to examine scientific literature on immune and endocrine systems dysregulation in T2D and pancreatic neoplasm. 

Materials & Method: A qualitative systematic review (QSR) was utilized in assessing the immune system deregulation and endocrine system involvement in chronic disease development such as T2D. The PubMed was the main search engine in studies identification with several search terms such as “SARS-CoV-2 and T2D”, “COVID-19 and T2D”, SARS-CoV-2 and insulin resistant”, etc.  

Results: Viral pathogens such as CMV, influenza A, and herpes simplex and hepatitis C infections have been implicated in decreased insulin sensitivity (IS) and increased insulin resistant (IR). Similarly, these pathogenic microbes increased the T2D incidence and complications. SARS-CoV-2 a COVID-19 causative pathogen had been observed in increased risk and incidence of T2D among children and adults. While data are not currently available on the precise mechanistic process, SARS-CoV-2 viral infection in T2D incidence may be explained by excess pro-inflammatory cytokines elaboration (cytokine storm) resulting in increased IR and decreased IS, leading to glucose intolerance and T2D. Further COVID-19 may increase pancreatic neoplasm in populations with increased incidence of COVID-19, due to pancreatic beta cells and insulin receptors dysregulation and cellular dysfunctionality as abnormal cellular proliferation.

Conclusions/Recommendation: SARS-CoV-2 a causative pathogen in COVID-19 morbidity is associated with increased incidence of T2D, which is explained in part by immune and endocrine system integration dysregulation, resulting in cytokine storm, decreased IS and increased IR, implying glucose intolerance and T2D. Additionally this pathogenic microbe may result in increasing incidence of pancreatic neoplasm, a malignant neoplasm with the worst prognosis and excess mortality due to late stage at diagnosis and marginalized biomarkers of susceptibility and morbidity.  

Kishida, Y. (2023)


Background: Persistent hepatitis C virus (HCV) infection results from inefficient innate and adaptive immune responses and exhausted virus-specific T-cell responses. Host cytokines and innate immune responses play important roles in controlling HCV infection. Innate immune responses modulate adaptive immune responses. These responses have recently been shown to have roles in antiviral therapy for chronic HCV infection. My previous study has indicated that viral clearance early in the course of therapy is associated with the restoration of innate and adaptive immune responses, and thus has potential as a novel therapeutic strategy for chronic hepatitis C (CHC).

Methods: The efficacy and safety of induction therapy (IT) with natural (n)-interferon (IFN)-beta followed by pegylated-IFN-alpha and ribavirin (PR) alone (group A, n = 30) were compared with those of IT with a protease inhibitor (PI) (Simeprevir or Vaniprevir) plus PR (group B, n = 13) in patients with CHC with genotype 1b and high viral load.

Results: During IT with n-IFN-beta, the virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4; 30% and 16% (p = 0.6989) at week 12; and 47% and 20% (p = 0.0887) at week 24. During and after treatment with PR alone, or PI plus PR, the virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4: 53% and 91% (p = 0.006745) at week 8; 57% and 91% (p = 0.001126) at week 12; 57% and 100% (p = 0.001845) at the end of the treatment; and 57% and 80% (p = 0.005166) after treatment cessation.

Conclusion: IT with PI plus PR restored the innate immune response, was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in patients with intractable CHC. Thus, IT with PI plus PR is beneficial for patients with intractable CHC. Steps for augmenting immune responses must be identified.

Tougar, S., Maghrabi, O., Elkhaouri, I., Machrouh, W., Mabchour, M., & Charra, B. (2023)


Cytomegalovirus (CMV)is a member of the Herpes viridae family, its seroprevalence is high in the general population. CMV infection in the immunocompromised is a serious, sometimes fatal complication that can affect several organs. For immunocompetent patients, this infection is usually pauci- or asymptomatic, which evolves spontaneously favorably and does not require specific treatment. However, the primary infection can be exceptionally serious with multivisceral involvement, for which antiviral treatment is indicated with generally a quickly favorable response. In this article, we present an unusual case of hepatitis and pancreatitis due to CMV in an immunocompetent patient.  The diagnosis was retained after excluding the most frequent and potential causes of acute hepatitis, with a brief review of the literature.

Dutta, A., Ghosh, R., Pandit, A., Ray, A. K., Bhattacharya, D., Chakraborty, A. P., Chakraborty, U., Dubey, S., & Benito‐León, J. (2022)


Background: Cerebral venous thrombosis (CVT) following either human immunodeficiency virus (HIV) infection or hepatitis B virus (HBV) infection is a very rare condition. Moreover, it has never been reported as the presenting manifestation of HIV and HBV co-infection, even more so when the patient had a normal CD4 count and no demonstrable opportunistic infections. We aimed to report the first case of an adult Indian male, an intravenous drug abuser who developed CVT as the presenting manifestation of HIV-HBV co-infection.

Methods: Patient data were obtained from medical records from the Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India.

Results: A 25-year-old male with a history of intravenous drug abuse and a normal CD4 count developed CVT as the presenting manifestation of HIV-HBV co-infection. His CD4 count was normal, and he had no demonstrable opportunistic infections. He had an uneventful recovery of the condition (CVT) following the institution of conventional anticoagulation therapy alongside anti-retroviral therapy.

Conclusion: Whether illicit drug abuse or HIV/HBV infection itself or all in combination led to this thrombotic event cannot be precisely established. Notwithstanding, we recommend serologic testing for HIV and HBV in patients suffering from CVT with high-risk behavior.

André-Jean, R., Bouchkira, H., Arnaud, H., Jeremy, H., Berengere, R., & Hugues, W. (2022)


Introduction and objective: HCV treatment for all was effective in France since 2017. HCV testing, diagnosis and treatment of drugs users and precarious people remain low. Lost follow-up was too important since several stages are necessary. Pangenotypic direct antiviral agents were available. Point-of-care HCV RNA testing offers advantage over antibody testing, enabling diagnosis of active infection with real time measure in a single visit. It is missing link between HCV RDT, liver fibrosis evaluation by FIBROSCAN and treatment. Validated Xpert HCV Viral Load assay CEPHEID, fast training technique, allow developing projects of diagnosis to treatment session. Our objective was to evaluate test to cure session allowing the access in 5 hours to an antiviral treatment to vulnerable and precarious populations (drug users, migrants, psychiatric patients).

Materials and methodsEligible patients had to have known positive serology or risk behavior, an unknown or unchecked viral load after antiviral treatment; 5 to 7 patients were recruited per each session by social or nursing interview. Between 9 am and 2 pm these patients had access to measure of the hepatic fibrosis by FIBROSCAN, HCV viral load in real time by CEPHEID Xpert HCV Viral load finger-stick samples, social interview, shared educational evaluation, collective workshops, especially harm reduction, depiction of results by hepatologist and prescription of DAA (sofosbuvir velpastasvir combination) allowed delivery of 1st month of treatment. Specific social and nursing follow-up was made during and after treatment. Compliance and sustained virological rate were determinate at week 12.

Results: From October 2019 to December 2021, 223 sessions were realized on 27 sites: 9 drug units, one prison, 17 social units; 1602 patients with drug using history were screened; 427 patients had HCV positive serology and 24 patients did not come; 403 FIBROSCAN measures and 403 measures of viral load in real time were realized. Mean value of liver stiffness was 8.2 and 29% of patients were F3 or F4: 229 patients were HCV RNA positive (56.8%), 57 declared knew their HCV status; 228 treatments began same day, only 1 was delayed due to default social rights; 120 patients had a negative viral load spontaneously and 54 following prior treatment; 399 social interviews and 405 collective workshops were realized. On 31st January 2022, 207 antiviral treatments were completed and 199 patients were cured; 12 patients interrupted treatment; 3 patients relapsed and 5 reinfections; 89% of patients were satisfied with this program.

Conclusions: Despite 3 months interruption by COVID 19 pandemic lockdown and sanitary restrictions, 94% of positive participants were linked to care and cure with this mobile clinic model, by screening and RNA real time measure in unity of place adapted to precarious public, patients distant from system of care had access immediately to treatment.

Floreani, A., Gabbia, D., & Martin, S. (2023)


IgG4-related disease (IgG4-RD) is a rare condition characterized by an immune-mediated fibro-inflammation affecting various organs (liver, pancreas, heart, kidney, brain among others) with peculiar histopathologic feature. Few epidemiological data have been published so far, although a dramatic increase in the number of patients diagnosed with IgG4-RD has been recorded in the last years. The clinical manifestations of IgG4-RD involve frequently liver and pancreas. Specifically, a crucial challenge in differential diagnosis is IgG4-related sclerosing cholangitis which is frequently accompanied by pancreatic involvement. Inflammatory alterations of liver parenchyma have also been described, with a new nosology of IgG4-autoimmune hepatitis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-RD. The first-ever epidemiological study to estimate the point prevalence of IgG4-related sclerosing cholangitis has been recently conducted in Japan. Moreover, several demographic studies on IgG4-RD involving liver and pancreas have been published in other countries, although the majority of them are cohort studies and data on incidence/prevalence are lacking. This review aims to update the recent epidemiological and clinical knowledge of IgG4-RD involving liver and pancreas, focusing also on the risk of malignancy.

Tinguria, M. (2023)


Celiac disease (CD) is an immune mediated disorder characterised by intolerance to glutens in certain grains like whet, barley, and rye. The exposure to gliadin protein component in the susceptible individuals leads to an inflammatory reaction damaging small bowel mucosa with progressive disappearance of intestinal villi. The damaged intestinal mucosa leads to malabsorption. The usual symptoms of celiac disease include diarrhea, steatorrhea, weight loss, fatigue, and abdominal pain. Diagnosis is based on clinical features, duodenal biopsy, elevated levels of anti-gliadin antibodies and response to gluten free diet. Contrary to common belief, celiac disease is a protein systemic disease rather than merely a pure digestive alteration. Celiac disease is closely associated with genes that code HLA -II antigens mainly of DQ2 and DQ8 classes, production of disease specific antibodies (i.e., endomysial antibodies), multiorgan involvement, comorbidity with other autoimmune diseases (shared autoimmunity), familial aggregation, and immune system dysregulation.

The clinical presentation of celiac disease can be variable. In mild form, patients can be almost asymptomatic whereas in the most severe form, the patients are at increased risk of life-threatening complications. Celiac disease has a well-known association with other autoimmune diseases such as autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), diabetes mellitus, autoimmune thyroid diseases, skin diseases such as dermatitis herpetiformis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, psoriasis, sarcoidosis, immune thrombocytopenic purpura, and pancreatitis. In addition, celiac disease may be associated with rare but potentially serious complications such as, collagenous sprue, ulcerative jejunoileitis, refractory celiac disease (RCD), enteropathy associated T-cell lymphoma, small bowel adenocarcinoma (SBA), hyposplenism, and cavitating mesenteric lymph node syndrome (CMLNS). The present article describes clinicopathologic features of these rare but serious complications of celiac disease.

Ducoulombier, O., Díaz, S., Sosa, E., Chávez, F., Morales, A., Nájera, M., & Salazar, F. (2023)


Introduction: Osteoarticular tuberculosis poses a significant diagnostic and therapeutic challenge in developing countries, where the absence of molecular tools demands reliance on clinical suspicion and histopathological findings for diagnoses. Here, we present a compilation of case studies on osteoarticular tuberculosis for academic reference and support to aid primary care physicians in providing the best possible patient care.

Methods: Retrospective analysis of cases diagnosed with osteoarticular tuberculosis through biopsy from 2010 to 2020 at a Mexican Traumatology and Orthopedics Hospital, examined using descriptive statistics.

Results: Thirty-three patients were registered: 23 men (70%) and 10 women (30%). The most affected regions included the spine in 28 cases (84%), the hip in 3 (9%), and the elbow and sternoclavicular joints in 1 case each. The main clinical manifestations were paravertebral abscesses in 16 patients (48%), discitis in 12 (36%) and arthritis in 5 (15%), while the primary associated diseases were immunosuppression in 8 cases (24%), 2 cases with hepatitis (6%) and 3 with hypertension (9%).

Discussion: Tuberculosis is endemic in Mexico, similar to other developing countries, with numerous reported cases of osteoarticular tuberculosis. This study highlights the importance of using alternative diagnostic tools when molecular tests and cultures are not accessible to general practitioners and orthopedic physicians who treat patients with clinical suspicion of osteoarticular tuberculosis.

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