[Delta hepatitis in Africa: epidemiological and clinical particularities]. / Hépatites Delta en Afrique: particularités épidémiologiques et cliniques.

In 2022, the World Health Organization (WHO) estimated that hepatitis B virus (HBV) infections caused 1.5 million deaths, mostly attributable to complications from chronic infections, cirrhosis and hepatocellular carcinoma (HCC). Despite the availability of a vaccine, 296 million people were chronically infected in 2019. Asia and Africa are the continents most affected by this infection, with around 100 million people infected in Africa as a whole.Hepatitis Delta or D virus (HDV), which is a "satellite" virus of HBV, is often misunderstood and its diagnosis remains neglected. However, it is associated with acute fulminant forms and chronic forms of hepatitis leading to a more rapid evolution towards cirrhosis and HCC than during HBV mono-infection. Research on these two viruses HBV and HDV has progressed a lot in recent years, and new treatments are currently in development.In people living with the human immunodeficiency virus (PlHIV), liver disease is a major cause of morbidity and mortality. Due to common modes of transmission, dual or triple HIV/HBV or HIV/HBV/HDV infections are relatively common, particularly in HBV endemic regions such as Africa. However, while today most co-infected patients benefit from effective treatment against both HIV and HBV, the latter is not active against HDV. In Africa, hepatitis B and D have already been the subject of several studies. However, the frequency and clinical consequences of these co-infections have been little studied in the general population and in PlHIV.This review seeks to update the epidemiological and clinical data and the therapeutic perspectives of HDV co-infections or triple infections (HIV-HBV-HDV) in Africa.

Urinary HPV DNA testing as a tool for cervical cancer screening in women who are reluctant to have a Pap smear in France.

OBJECTIVES: In France, cervical cancer screening is based on human papillomavirus (HPV) testing on cervical samples (women aged 30-65) and cytological examination of Pap smears (25-29), but screening coverage is unsatisfactory. The CapU3 study aimed to propose urinary HPV testing on 13,535 women aged 35 to 65 who had not had a Pap smear since 2010. METHODS: High-risk HPV (HR-HPV) detection was performed using a real-time PCR (Anyplex II HPV 28 Detection, Seegene®). Women with HR-HPV positive results were encouraged to have a cervical smear as soon as possible to detect the presence of cervical lesions. RESULTS: The participation rate was 15.4%. Out of the 1,915 analyzed specimens, 1,711 and 190 were negative and positive, respectively, for at least 1 HR-HPV genotype. HR-HPV genotypes other than HPV-16 or HPV-18 were mostly detected as HPV-53 (23.7%) and HPV-68 (14.2%). A satisfactory gynecological follow-up was observed for HPV-positive women (92.1%). 23 abnormal smears were observed and eight high-grade cytological lesions after colposcopy and biopsy were diagnosed. CONCLUSIONS: As home HPV urinary testing is non-invasive and does not require medical attention, this method may be an alternative for women who are reluctant to have a Pap smear and thus extend screening coverage.

Natural non-homologous recombination led to the emergence of a duplicated V3-NS5A region in HCV-1b strains associated with hepatocellular carcinoma.

BACKGROUND: The emergence of new strains in RNA viruses is mainly due to mutations or intra and inter-genotype homologous recombination. Non-homologous recombinations may be deleterious and are rarely detected. In previous studies, we identified HCV-1b strains bearing two tandemly repeated V3 regions in the NS5A gene without ORF disruption. This polymorphism may be associated with an unfavorable course of liver disease and possibly involved in liver carcinogenesis. Here we aimed at characterizing the origin of these mutant strains and identifying the evolutionary mechanism on which the V3 duplication relies. METHODS: Direct sequencing of the entire NS5A and E1 genes was performed on 27 mutant strains. Quasispecies analyses in consecutive samples were also performed by cloning and sequencing the NS5A gene for all mutant and wild strains. We analyzed the mutant and wild-type sequence polymorphisms using Bayesian methods to infer the evolutionary history of and the molecular mechanism leading to the duplication-like event. RESULTS: Quasispecies were entirely composed of exclusively mutant or wild-type strains respectively. Mutant quasispecies were found to have been present since contamination and had persisted for at least 10 years. This V3 duplication-like event appears to have resulted from non-homologous recombination between HCV-1b wild-type strains around 100 years ago. The association between increased liver disease severity and these HCV-1b mutants may explain their persistence in chronically infected patients. CONCLUSIONS: These results emphasize the possible consequences of non-homologous recombination in the emergence and severity of new viral diseases.

Duplication of the V3 domain in hepatitis C virus (1b) NS5A protein: Clonal analysis and physicochemical properties related to hepatocellular carcinoma occurrence.

BACKGROUND: Hepatitis C virus non-structural protein 5A is known to play a role in development of hepatocellular carcinoma (HCC) via interactions with host cell pathways. OBJECTIVES: Hepatitis C virus genotype 1b strains presenting a wide insertion of 31 amino acids in the non-structural protein 5A V3 domain (V3 DI) were studied to determine whether this V3-like additional domain (V3 DII) was associated with HCC occurrence. STUDY DESIGN: Seventy-four patients' sera were screened for V3 DII presence regarding clinical status. RESULTS: Three strains with duplicated V3 were detected among patients with progression to HCC (n=28), two strains among patients with liver cirrhosis (Ci, n=27) and none among patients with chronic hepatitis (Chr, n=19). Phylogenetic trees built from V3 DI and V3 DII sequences indicated that the latter clustered separately. In between-group clonal analysis, V3 DII sequences from the HCC group were found to be more distant from HCV-J than V3 DI sequences (p<0.0001). Between-group comparisons showed significant differences in genetic distances from HCV-J, in HCC V3 DI and HCC V3 DII compared to Ci V3 DI and Ci V3 DII sequences (p<0.0001). HCC V3 DII domain and its junction with V3 DI exhibited higher Shannon entropy values and enrichment in disorder-promoting residues. CONCLUSIONS: Taken together, our results suggest that V3 DII evolution may differ in strains associated with HCC occurrence. The presence of an intrinsically "disordered" V3 duplicate may alter the NS5A protein network. Further investigations are necessary to elucidate the potential impact of V3 duplication in the context of carcinogenesis.

Home-based urinary HPV DNA testing in women who do not attend cervical cancer screening clinics.

In France, cervical cancer screening is currently based on cytological examination of a Pap smear for women aged 25 to 65, but screening coverage is unsatisfactory. Previous studies have shown that self-sampling for human papillomavirus (HPV) testing increases rates of compliance. With this purpose in mind, we performed the CapU study to evaluate the acceptance of a urinary HPV test. Letters proposing a new cervical cancer screening method using at-home urine self-sampling were sent to 5000 women aged 40-65 years who had not had a Pap smear over the past three years. The participating patients had to send their urine samples to the Angers Hospital Virology Laboratory for analysis using real-time PCR. Of the 771 samples received, 687 were analyzed. High-risk HPV were detected in 29 women. In follow-up, 28 women with positive urinary HPV results had a Pap smear or colposcopy done. The cytological results showed nine abnormal Pap smears, among which histology studies confirmed three cases of cervical intraepithelial neoplasia grade III lesions. Our study shows that urinary HPV testing may be pertinent to women who do not have cervical Pap smears done and lead to the diagnosis of high-grade cervical lesions.

IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells.

OBJECTIVE: Interleukin-26 (IL-26) is a member of the IL-10 cytokine family, first discovered based on its peculiar expression by virus-transformed T cells. IL-26 is overexpressed in chronic inflammation (rheumatoid arthritis and Crohn's disease) and induces proinflammatory cytokines by myeloid cells and some epithelial cells. We thus investigated the expression and potential role of IL-26 in chronic HCV infection, a pathology associated with chronic inflammation. DESIGN: IL-26 was quantified in a cohort of chronically HCV-infected patients, naive of treatment and its expression in the liver biopsies investigated by immunohistochemistry. We also analysed the ability of IL-26 to modulate the activity of natural killer (NK) cells, which control HCV infection. RESULTS: The serum levels of IL-26 are enhanced in chronically HCV-infected patients, mainly in those with severe liver inflammation. Immunohistochemistry reveals an intense IL-26 staining in liver lesions, mainly in infiltrating CD3+ cells. We also show that NK cells from healthy subjects and from HCV-infected patients are sensitive to IL-26. IL-26 upregulates membrane tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression on CD16- CD56(bright) NK cells, enabling them to kill HCV-infected hepatoma cells, with the same efficacy as interferon (IFN)-α-treated NK cells. IL-26 also induces the expression of the antiviral cytokines IFN-ß and IFN-γ, and of the proinflammatory cytokines IL-1ß and TNF-α by NK cells. CONCLUSIONS: This study highlights IL-26 as a new player in the inflammatory and antiviral immune responses associated with chronic HCV infection.

Systemic diseases and biotherapies: understanding, evaluating, and preventing the risk of hepatitis B reactivation.

Hepatitis B virus (HBV) reactivation can occur in chronic carriers of the HBV surface antigen (HBsAg) and constitutes a well-known complication of immunosuppressive therapy. HBV reactivation has also been reported after contact with the HBV. The increasing use of biological agents (TNFα antagonists, rituximab, abatacept, and tocilizumab) to treat systemic diseases has resulted in numerous publications about the risk of HBV reactivation. The relevant scientific societies have issued recommendations designed to prevent HBV reactivation. The main measures consist of screening for markers indicating chronic HBV infection (HBsAg) or HBV infection in the distant past (antibodies to the HBV core antigen) before initiating biological therapies, vaccinating marker-negative patients, and considering close follow-up or antiviral treatment before immunosuppressive treatment initiation or in the event of HBV reactivation. Here, we discuss the pathophysiological mechanisms underlying HBV reactivation during biological treatments, most notably in patients with occult HBV infection or markers for remote HBV infection, whose hepatocyte nuclei may contain a resistance form of HBV DNA known as covalently closed circular DNA (cccDNA). Assessment of the risk of reactivation relies on the HBV status, drugs used, and data from the literature. Finally, we discuss the various recommendations and modalities for HBV vaccination, preemptive treatment, and patient management, according to the level of risk and to the circumstances in which reactivation occurs.

A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C.

UNLABELLED: We conducted a national retrospective survey on hospital practitioners to evaluate the magnitude of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) prescriptions in patients treated for chronic hepatitis C. Four hundred seventy-one questionnaires were sent, and 274 practitioners (58.2%) responded. Forty-six percent of practitioners used EPO, and 31% used G-CSF. The total number of HCV-infected patients receiving antiviral therapy per year was estimated at 6,630 patients, of whom 8.8% and 4% received EPO and G-CSF, respectively. EPO-beta was the main EPO molecule prescribed at a median dose of 30,000 IU/wk (range: 2,000-80,000). The indications for prescribing EPO varied greatly, including "fragile patients" (34%), "low" Hb level (8-11 g/dL) (19%), "rapid decline" in Hb level (2-5 g/dL during the first month of therapy) (12%), and symptomatic anemic patients (7%). G-CSF was mainly prescribed for a "low" level of neutrophils ranging from 400 to 750 neutrophils/mm3. In multivariate analysis, independent predictors of EPO and G-CSF prescription were age of practitioner less than 45 years (EPO: OR = 1.96, P = 0.03; G-CSF: OR = 2.27, P = 0.004), practice in university hospital (EPO: OR = 5.89, P < 0.0001; G-CSF: OR = 2.39, P = 0.003), and the high number of CHC treated/year (EPO: OR = 6.18, P < 0.0001; G-CSF: OR = 2.58, P = 0.002). CONCLUSION: Our survey reveals an important rate of EPO and G-CSF prescriptions but with considerable disparity in the schedule of injections, the molecules used, and above all the indications. The suitable role of EPO and G-CSF as complements to HCV therapy urgently needs to be clarified.