Clinical practice guidelines
Recommendations for the integral diagnosis of chronic viral hepatitis in a single analytical extractionRecomendaciones para el diagnóstico integral de las hepatitis virales crónicas en una única extracción analítica

https://doi.org/10.1016/j.gastre.2022.09.001Get rights and content

Abstract

The Spanish Society of Digestive Pathology (SEPD), the Spanish Association for the Study of the Liver (AEEH), the Spanish Society of Infections and Clinical Microbiology (SEIMC) and its Viral Hepatitis Study Group (GEHEP), and with the endorsement of the Alliance for the Elimination of Viral Hepatitis in Spain (AEHVE), have agreed on a document to carry out a comprehensive diagnosis of viral hepatitis (B, C and D), from a single blood sample; that is, a comprehensive diagnosis, in the hospital and/or at the point of care of the patient. We propose an algorithm, so that the positive result in a viral hepatitis serology (B, C and D), as well as human immunodeficiency virus (HIV), would trigger the analysis of the rest of the virus, including the viral load when necessary, in the same blood draw. In addition, we make two additional recommendations.

First, the need to rule out a previous hepatitis A virus (VHA) infection, to proceed with its vaccination in cases where IgG-type studies against this virus are negative and the vaccine is indicated. Second, the determination of the HIV serology. Finally, in case of a positive result for any of the viruses analyzed, there must be an automated alerts and initiate epidemiological monitoring.

Resumen

La Sociedad Española de Patología Digestiva (SEPD), la Asociación Española para el Estudio del Hígado (AEEH), la Sociedad Española de Infecciones y Microbiología Clínica (SEIMC) y su Grupo de Estudio de Hepatitis Víricas (GEHEP), y con el aval de la Alianza para la Eliminación de las Hepatitis Víricas en España (AEHVE), han consensuado un documento para realizar un diagnóstico integral de las hepatitis virales (B, C y D), a partir de una única extracción analítica; es decir diagnóstico integral, en el centro hospitalario y/o en el punto de atención del paciente. Proponemos un algoritmo, de manera que el resultado positivo en serología frente a los virus de las hepatitis (B, C y D), así como el virus de la inmunodeficiencia humana (VIH), activaría el análisis del resto de virus, incluyendo la carga viral cuando sea preciso, a partir de la misma extracción sanguínea. Además, hacemos dos recomendaciones adicionales. Por un lado, la necesidad de descartar una infección previa por el virus de la hepatitis A (VHA), para proceder a la vacunación en los casos en que los anticuerpos de tipo IgG frente a este virus sean negativos y la vacuna esté indicada. Y, por otro lado, la determinación de la serología del VIH. En caso de un resultado positivo para cualquiera de los virus analizados se deben emitir alertas automatizadas y activar la monitorización epidemiológica.

Introduction

Viral hepatitis caused by hepatitis B, C and D viruses (HBV, HCV and HDV) represents a significant threat to public health due to its high morbidity, mortality and transmissibility. It is estimated that there are around 354 million people with chronic hepatitis B or C in the world (296 million with hepatitis B and 58 million with hepatitis C),1 and 5% of those with HBV infection have HDV infection.1, 2 Global mortality attributable to viral hepatitis stands at 1.4 million deaths each year, with chronic hepatitis B and C being the most significant.3 In Spain, the prevalence of surface antigen (HBsAg) (0.6%) and antibodies against hepatitis B core antigen (anti-HBc) (8.2%) has not changed in recent years,4 while the latest published figures on hepatitis C present data showing lower seroprevalence (1–1.4%) and viraemic infection (0.2–0.3%) than in previous years.5 These figures increase in populations at risk or who are part of a vulnerable group, such as drug users, prison inmates, men who have sex with men (MSM) and immigrants from countries with high prevalence, as that is where the greatest number of cases are concentrated.6, 7 The morbidity and mortality associated with viral hepatitis is linked to the persistence of viral replication with progression from fibrosis to cirrhosis and the development of long-term liver complications. This damage can be aggravated if there is coinfection by different viruses, and even more so by the presence of HDV.8 It is estimated that one in six cases of cirrhosis occurring in patients with HBV are attributable to HDV coinfection.2

Hepatitis B can be prevented by vaccination, which is highly effective, while active disease is treated with nucleos(t)ide analogues, which are effective in controlling viral replication.9, 10, 11 Direct-acting antivirals (DAAs) against HCV achieve high rates of sustained viral response (SVR) that result in cure of the infection in most patients.12 Treatment of viral hepatitis prevents the development of cirrhosis, decreases the risk of hepatocellular carcinoma and liver transplantation, and improves survival.9, 13, 14, 15, 16, 17 In addition, treatment for hepatitis C has proven to be cost-effective, even reducing the social burden of the disease.18, 19, 20, 21 A recent study shows a very significant decrease in hospitalisations for HCV cirrhosis since the introduction of DAAs, which could be a marginal cause of admissions in the future.22 Likewise, the treatment helps to control the transmission of the virus, which has been reflected in a significant decrease in the prevalence of infection after the introduction of DAAs in recent years.

In the case of hepatitis D, a drug conditionally approved by the European Medicines Agency (EMA), bulevirtide, manages to normalise alanine aminotransferase (ALT) values and decrease HDV-RNA values by two logs or to undetectable levels in a significant percentage of cases.23

Advances in treatment motivated the World Health Organization (WHO) to establish in 2016 objectives focused on reducing the incidence of hepatitis B and C by 90% and mortality by 65%, in order to achieve its eradication in the year 2030.1 In recent years, most countries have established measures aimed at meeting these objectives, achieving an estimated decrease in infections of 6.8 million compared to 2015.24 In Spain, thanks to the collective efforts to implement targeted actions to, among other things, establish screening strategies and search for patients with unknown infection, it has been possible to diagnose and treat a large number of people, above all with hepatitis C,25 and we are on the path towards its eradication.26 But these efforts have been diminished by the COVID-19 pandemic, which has seriously affected health services, causing most of the health resources, especially microbiology services,27 to be used to mitigate it, damaging the care of patients with other diseases such as viral hepatitis. The closure of health centres and hospitals, together with access restrictions, have caused significant delays in diagnosis and the stagnation of treatment initiation.28, 29, 30, 31 In addition, this situation has worsened in vulnerable groups that go to community centres, such as harm reduction centres.32 The stoppage of micro-elimination programmes has generated a sharp drop in diagnoses of 25% in health centres and 56% in community centres.33 These delays will cause late diagnosis of the disease34 with the consequent loss of opportunity for cure in its early phases that would modify its natural history. Recent studies show that the absence of adequate care in patients with hepatitis C as a consequence of the pandemic will cause significant increases in the associated morbidity and mortality and its cost.35, 36 Therefore, in order to minimise the impact of the SARS-CoV-2 pandemic and remain in line with the eradication objectives, it is necessary to adopt measures that reinforce screening programmes, restore the care cascade for viral hepatitis and allow early treatment.37, 38, 39, 40 There is also a need to emphasise and further promote already existing effective measures aimed at diagnostic simplification, such as one-step diagnosis (OSD) and point-of-care (PoC) diagnosis, along with early warning systems in microbiology laboratories, as well as continue with micro-elimination strategies aimed at populations at risk or vulnerable groups.

This document provides a series of recommendations made by expert professionals in the diagnosis and management of viral hepatitis and endorsed by scientific societies, which allow the comprehensive diagnosis of chronic viral hepatitis (B, C and D) from a single blood sample. Likewise, other recommendations are established aimed at health professionals, services and programmes, in order to prevent infections, facilitate early diagnosis, guarantee follow-up and access to treatment, as well as the dissemination of information on hepatitis and, finally, facilitate the continuous improvement of health models.

Section snippets

Methods

In preparing the consensus document, a systematic review of the literature was carried out to collect and synthesise recent evidence on the diagnosis of viral hepatitis (B, C and D). In addition, a search was made in the grey literature, including clinical guidelines, conference summaries, information from regional health systems and official organisations. The review focused on the diagnosis of chronic viral hepatitis, diagnosis simplification and PoC diagnosis.

Meanwhile, a scientific

Justification for the comprehensive diagnosis of viral hepatitis

Screening for HBV and HCV infections is mainly based on age and risk factors for acquiring the infection.10, 11, 12, 41, 42, 43 However, there is a diversity of criteria regarding who should be targeted for HDV screening. The clinical guidelines of the AEEH and the European Association for the Study of the Liver (EASL) recommend HDV detection in all patients infected with HBV,11, 41 while the recommendations of the American Association for the Study of Liver Diseases (AASLD), despite its high

Recommendations for a comprehensive diagnosis of viral hepatitis

In line with the above, a series of recommendations are made aimed at carrying out a comprehensive diagnosis of chronic viral hepatitis (B, C and D) (Table 1, Fig. 1).

Other diagnostic recommendations

Patients with chronic viral hepatitis are at increased risk of having other infections such as hepatitis A virus (HAV) or HIV infection, due to common risk factors for exposure.1, 55 Coinfection can alter the natural history of each of these viruses and cause an increase in comorbidity and associated mortality.55 Hepatitis A is an acute infection, and people who have it usually recover without treatment. Although in Spain it was an almost non-existent infection, since 2016 there have been

Diagnostic simplification

The prevalence of viral hepatitis, specifically hepatitis C, has decreased notably after the adoption of actions aimed at its eradication24 but, there are still underdiagnosed populations, with high prevalence, such as at-risk or vulnerable groups, in whom its detection and subsequent access to treatment remain a challenge.7

The traditional diagnosis of infections in our country requires several visits to the specialist. First, a serology test is performed and, if it is positive, the viral load

Preferential care at the point of care

There are certain vulnerable groups with high prevalence in which most of the new diagnoses of viral hepatitis are concentrated, who, due to their characteristics, do not regularly attend health services. In these groups there is a high risk of loss at all stages of the care cascade,80 and performing the test by venipuncture may mean a rejection of access to screening. The use of rapid and dried blood tests allow a decentralised diagnosis,81 that is, a serological and virological diagnosis of

Automated alerts

Although diagnosis of infection has increased in recent years, there are still many people infected and not detected by the health system. Setting up alert systems incorporated into the patient's electronic medical record, based on clinical data related to the risk of infection, would help to identify and notify the specialist of the need to perform serology tests in case of any possible viral hepatitis, thus facilitating early diagnosis.103 These alerts are useful in primary care and are based

Education, prevention and dissemination programmes

Chronic viral hepatitis is a disease that usually does not present symptoms until advanced stages. For this reason, it is essential to train and raise awareness among health professionals, especially in primary care, about the importance of detecting undiagnosed cases in the general population, as well as about risk factors.13 Likewise, decentralisation of the screening and treatment process also generates the need to train non-health personnel to reduce stigma and increase screening acceptance.

Conclusions

Diagnosis of infection with hepatitis B, C, and D viruses remains a public health challenge. There are still a large number of people who are unaware of their infection status. Establishing diagnosis and linkage to treatment are key to achieving the WHO 2030 target worldwide. The comprehensive diagnosis of viral hepatitis (B, C and D) from a single blood sample allows faster diagnosis, reduces the number of visits to the health centre, avoids losses to follow-up, and facilitates access to

Funding

This study has been financed by Gilead Sciences Spain (financing without conflict of interest and not conditioned on the design of the study, the collection, analysis and interpretation of the data, the writing of the article or the decision to send the article for its publication).

Conflicts of interest

Javier Crespo: consultant and/or speaker and/or participated in sponsored clinical trials and/or received research grants and support from Gilead Sciences, AbbVie, MSD, Shionogi, Intercept Pharmaceuticals, Janssen Pharmaceuticals Inc, Celgene and Alexion (all outside the work here submitted).

Joaquín Cabezas: receives grants from Gilead and Abbvie; speaker for Gilead and Abbvie.

Antonio Aguilera: declares that he has no conflict of interest.

María Buti: consultant and speaker for Gilead and Abbvie.

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