Prevalence of hepatitis C, hepatitis B and HIV and their therapeutic management in a French public psychiatric hospital.

INTRODUCTION: Several studies suggest that the prevalence of hepatitis C, hepatitis B and HIV are higher in psychiatric patients than in the general population; however, few French studies have been published. The aims of this study were to determine the seroprevalence of the three viruses, describe the profile of infected patients and evaluate the initiation of antiviral treatment in a population of patients hospitalized in a psychiatric hospital. METHOD: Between January and October 2020, screening for hepatitis C virus, hepatitis B virus and HIV was systematically offered to all patients admitted to the intersectoral reception and orientation unit of a psychiatric hospital. If serology was positive, viral load was automatically determined from the same blood sample. As direct-acting antivirals (DAAs) are not financed "in addition" to hospital charges, it was decided a priori to start treatment for HCV immediately before discharge. RESULTS: Between January 7 and October 1, 2020, 407 patients accepted screening. Of these patients, 17 (4.2%; 95% CI: 2.2-6.1%) were anti-HCV positive and two were anti-HIV+/anti-HCV- (0.49%). HCV RNA was detectable in 9/17 anti-HCV+ patients, with a prevalence of infection of 2.2% (CI: 0.8-3.6%). Drug use was identified in 16 anti-HCV+ patients (94%), ten with active drug use. Of the nine viraemic patients, only four received a prescription for DAA treatment at the end of hospitalization, and only one was followed up by his general practitioner with the confirmation of virological cure three months after treatment cessation. No patient tested positive for hepatitis B surface antigen, but 3% had serological markers indicating HBV past infection. The anti-HBV vaccination coverage rate was only 39% in the entire population and only 41% for patients with a history of drug use. CONCLUSION: Our study confirms that the prevalence of HCV infection is significantly higher in the psychiatric population than in the general population. By far, the main risk factor for HCV infection is drug use. This justifies the systematic performance of regular screening in this population. The way in which DAAs are financed in psychiatric hospitals seems to be a major obstacle to the initiation of treatment for chronic HCV infection during hospitalization and therefore to the elimination of HCV infection in the psychiatric population.

La réduction du risque d'infection périnatale chez les nouveau-nés de mères dont les soins prénatals étaient inappropriés.

Le risque que des infections maternelles ne soient ni décelées ni traitées augmente lorsque les soins prénatals sont inappropriés, ce qui met la santé de la mère et de son nouveau-né à risque. Lorsqu'une femme enceinte se présente tardivement pour recevoir des soins, les tests systématiques qui influent sur la prise en charge du nouveau-né devraient inclure l'antigène de surface de l'hépatite B (AgHBs), la sérologie du virus de l'hépatite C (VHC), du virus de l'immunodéficience humaine (VIH) et de la syphilis, de même que le dépistage de la Chlamydia trachomatis et de la Neisseria gonorrhoeae. Si la mère ne s'est pas soumise aux dépistages avant ou après l'accouchement et qu'elle n'est pas disponible pour s'y soumettre, il faudrait procéder au dépistage du VIH, du virus de l'hépatite B (VHB), du VHC et de la syphilis chez le nouveau-né. Le dépistage de la C. trachomatis et de la N. gonorrhoeae est toutefois réservé aux cas où le nouveau-né démontre des manifestations cliniques compatibles avec ces infections. Il est optimal d'obtenir rapidement les résultats du dépistage du VIH, du VHB et de la syphilis, car l'utilisation des traitements préventifs est circonscrite dans le temps. Il existe des interventions préventives précoces et efficaces pour les nouveau-nés à risque de VIH, de VHB, de syphilis ou de gonorrhée. Un suivi clinique étroit et des tests de suivi s'imposent auprès des nouveau-nés de mères dont les soins prénatals étaient inappropriés, car il est impossible d'exclure pleinement toutes les infections pendant la période périnatale.

[Hepatitis C in a psychiatric setting: A forgotten reservoir?] / Hépatite C en milieu psychiatrique : un réservoir oublié ?

Hepatitis C is a transmissible hepatic and extra-hepatic disease caused by the hepatitis C virus (HCV). HCV develops into a chronic infection among approximately 70% of the contaminated subjects. Chronic HCV infection is estimated to affect between 0.5% and 1 % of the general population in France, which causes an important burden of disease, in particular due to the occurrence of cirrhosis and liver cancer. New antiviral drugs now allow to cure more than 95% of patients in just a few weeks of treatment with very limited safety issues. This therapeutic revolution has led the World Health Organization and many national governments to aim for an elimination of HCV, which has been defined as a 90%-reduction of the incidence rate, and a 65%-reduction in the number of HCV-related deaths on the basis of the 2015 figures. In this respect, the French Ministry of Health has recently decided to extend the ability to prescribe the new antiviral drugs to any physician. However, the elimination campaign of HCV will also need to correctly identify, screen, and treat the main target populations. If people who inject drugs (PWIDs) certainly constitute the most important population concerned by the challenge of HCV elimination, more hidden reservoirs in which HCV transmission can insidiously evolve should be identified and specifically targeted as well. Inpatient psychiatric populations might constitute one of these hidden reservoirs. International data suggest that chronic HCV infection affects approximately 5% of psychiatric inpatients in Europe. This very high prevalence estimate can in part be due to the very frequent psychiatric disorders found among the current or former PWIDs. However, a part of the seropositive patients does not report a history of drug use, and other factors could contribute to the increased risk of contamination in this population including atypical routes of transmission related to institutional promiscuity. Exploring the general profile and risk-behaviors of the psychiatric inpatients found infected by the HCV is thus warranted for future studies. Screening and treating HCV in the specific population of psychiatric patients is part of the general public health objective of eliminating HCV at a national level. Moreover, it also directly fits into the individualized psychiatric care. Many recent data suggest that HCV also has a neural tropism, in particular within glial cells, such as astrocytes or oligodendrocytes. As such, HCV foments inflammatory processes in the brain and contributes to cognitive impairments and psychiatric symptoms such as anxiety or depression. At the individual level, treating HCV infection can improve the psychiatric state and increase patients' outcomes in terms of well-being and quality of life. For all these reasons, the field of psychiatry needs local and national actions for informing and training professionals about HCV screening and treating modalities. Patient and family associations also need to be involved in this general effort of micro-elimination. A key role should be assigned to the general practitioners embedded within inpatient psychiatric units. They are the best fitted professionals to screen, treat, and empower patients, to inform and train other caregivers of the psychiatric field, and to act as a relay with hepatology teams if required. Hospital pharmacists are other important stakeholders. In a national context in which the funding of psychiatric care, including medications, is based on predefined funding envelops, innovative initiatives will have to be set up by local or national health authorities, in partnership with pharmacists, to allow for the treatment of psychiatric inpatients. In conclusion, the world of psychiatry is a possible hidden reservoir of HCV and, as such, a part of the challenge for eliminating the virus. Patients, families, and caregivers will have to be correctly sensitized and trained to play their role in the process. Specific investigations will be required to better understand why such an increased prevalence of HCV is observed in this population. Specific adaptations of the cascade of care within psychiatric settings, including access to treatment, will need to be designed, implemented, and evaluated for reaching micro-elimination of HCV in psychiatry.

Hepatitis B and C in the adult population of Bissau, Guinea-Bissau: a cross-sectional survey.

OBJECTIVE: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are prevalent in West Africa. To address the WHO 2030 goals of a 90% reduction in incidence and a 65% reduction in mortality for both infections, we assessed the prevalence of HBV and HCV from surveys in the general population. METHODS: Participants in this cross-sectional survey were included from randomly selected houses in a demographic surveillance site in Bissau, Guinea-Bissau. Participants were interviewed and had a blood sample drawn for viral analyses (HBsAg, anti-HBs, anti-HBc, anti-HCV and HCV RNA). Risk factors of HBV and HCV infection were determined by binomial regression adjusted for sex and age. RESULTS: A total of 2715 participants were included in this study. The overall HBsAg prevalence was 18.7% (95% CI: 17.3-20.2%). HBsAg was associated with male sex (adjusted risk ratio (aRR): 1.64), and prevalence decreased with age >34 years. HBV exposure was found in 91.9% of participants. Although 72.6% of individuals without sexual debut had been exposed to HBV, ever engaging in a sexual relationship was associated with higher risk of HBV exposure (aRR 1.18). The anti-HCV prevalence was 0.5% (95% CI: 0.3-0.9%), and 78.6% of those had detectable HCV RNA. Risk factors for anti-HCV sero-positivity were age above 55 (aRR 10.60), a history of blood transfusion (aRR 5.07) and being in a polygamous marriage (aRR 3.52). CONCLUSION: In Guinea-Bissau initiatives to implement treatment and widespread testing are needed to reach the WHO 2030 goals.

OBJECTIF: Le virus de l'hépatite B (VHB) et le virus de l'hépatite C (VHC) sont répandus en Afrique de l'Ouest. Pour atteindre les objectifs de 2030 de l'OMS d'une réduction de 90% de l'incidence et de 65% de la mortalité pour les deux infections, nous avons évalué la prévalence du VHB et du VHC à partir d'enquêtes dans la population générale. MÉTHODES: Les participants inclus dans cette enquête transversale provenaient de foyers sélectionnés au hasard dans un site de surveillance démographique à Bissau, en Guinée-Bissau. Les participants ont été interrogés et ont subi un prélèvement d'échantillon de sang pour des analyses virales (HBsAg, anti-HBs, anti-HBc, anti-HCV et ARN du HCV). Les facteurs de risque d'infection par le VHB et le VHC ont été déterminés par la régression binomiale ajustée en fonction du sexe et de l'âge. RÉSULTATS: 2.715 participants ont été inclus dans cette étude. La prévalence globale de l'HBsAg était de 18,7% (IC95%: 17,3-20,2%). L'HBsAg était associé au sexe masculin (rapport de risque ajusté (aRR): 1,64), et la prévalence diminuait avec l'âge >34 ans. Une exposition au VHB a été observée chez 91,9% des participants. Bien que 72,6% des personnes sans début d'activité sexuelle aient été exposées au VHB, le fait de s'engager dans des relations sexuelles était associé à un risque plus élevé d'exposition au VHB (aRR: 1,18). La prévalence d'anti-VHC était de 0,5% (IC95%: 0,3-0,9%) et 78,6% d'entre eux avaient de l'ARN du VHC détectable. Les facteurs de risque de séropositivité anti-VHC étaient l'âge de plus de 55 ans (aRR: 10,60), les antécédents de transfusion sanguine (aRR: 5,07) et le fait d'être dans un mariage polygame (aRR: 3,52). CONCLUSION: En Guinée-Bissau, des initiatives pour mettre en œuvre un traitement et des tests généralisés sont nécessaires pour atteindre les objectifs de l'OMS 2030.

Achieving a high cure rate with direct-acting antivirals for chronic Hepatitis C virus infection in Cameroon: a multi-clinic demonstration project.

OBJECTIVES: Highly effective direct-acting antivirals (DAAs) for Hepatitis C treatment are largely inaccessible in sub-Saharan Africa. Data on treatment feasibility and outcomes in clinical settings are limited. We assessed the feasibility of achieving a high (≥90%) cure rate with DAAs in six gastroenterology clinics in Cameroon. METHODS: Patients with chronic Hepatitis C virus (HCV) infection were treated for 12 or 24 weeks with ledipasvir/sofosbuvir, ledipasvir/sofosbuvir/ribavirin or sofosbuvir/ribavirin, depending on the stage of liver disease and HCV genotype. The cure rate was defined as the proportion of patients with a sustained virological response 12 weeks after treatment completion (SVR12) among all treatment completers. RESULTS: We identified 190 HCV RNA positive patients between September-2017 and August-2018, 161 (84.7%) of whom started treatment. 105 (65.2%) were female, median age was 61.3 years [IQR = 55.9-66.9] and 11 (6.8%) were HIV-positive. Median plasma HCV RNA was 6.0 log10 IU/mL [IQR = 5.6-6.4]. HCV genotypes identified were 1 (34.8%), 2 (13.7%), 4 (50.9%), 1 and 4 (0.6%); 46 (28.6%) strains of 160 single-genotype infections were non-subtypeable. Of 158 treatment completers, 152 (96.2%, 95%CI = 91.9-98.6%) achieved SVR12. Six patients did not achieve SVR12: five carried HCV with NS5A resistance mutations and one with NS5B resistance mutations. Three patients died before and two after treatment completion. The most common adverse events were asthenia (12.0%), headache (11.4%) and dizziness (18.9%). CONCLUSION: High cure rates of Hepatitis C with DAAs are achievable in clinical settings of Cameroon. However, the accessibility and provision of HCV screening, diagnosis, treatment, monitoring and care should be addressed for large-scale implementation.

OBJECTIFS: Les antiviraux à action directe (AAD) hautement efficaces pour le traitement de l'hépatite C sont largement inaccessibles en Afrique subsaharienne. Les données sur la faisabilité du traitement et les résultats en milieu clinique sont limités. Nous avons évalué la faisabilité d'atteindre un taux de guérison élevé (≥90%) avec les AAD dans six cliniques de gastro-entérologie au Cameroun. MÉTHODES: Les patients atteints d'une infection chronique par le virus de l'hépatite C (VHC) ont été traités pendant 12 ou 24 semaines avec le ledipasvir/sofosbuvir, le ledipasvir/sofosbuvir/ribavirine ou le sofosbuvir/ribavirine, selon le stade de la maladie du foie et le génotype du VHC. Le taux de guérison a été défini comme la proportion de patients présentant une réponse virologique soutenue 12 semaines après la fin du traitement (SVR12) parmi tous les patients ayant terminé le traitement. RÉSULTATS: Nous avons identifié 190 patients positifs pour l'ARN du VHC entre septembre 2017 et août 2018, dont 161 (84,7%) ont commencé le traitement. 105 (65,2%) étaient des femmes, l'âge médian était de 61,3 ans [IQR = 55,9-66,9] et 11 (6,8%) étaient positifs pour le VIH. L'ARN plasmatique médian était de 6,0 log10 UI/mL [IQR = 5,6-6,4]. Les génotypes du VHC identifiés étaient 1 (34,8%), 2 (13,7%), 4 (50,9%), 1 et 4 (0,6%); 46 (28,6%) souches provenant de 160 infections à génotype unique n'étaient pas sous-typables. Sur 158 patients ayant terminé le traitement, 152 (96,2%, IC95%: 91,9-98,6%) ont atteint la RVS12. Six patients n'ont pas atteint la RVS12: cinq portaient le VHC avec des mutations de résistance NS5A et un avec des mutations de résistance NS5B. Trois patients sont décédés avant et deux après la fin du traitement. Les événements indésirables les plus courants étaient l'asthénie (12,0%), les céphalées (11,4%) et les étourdissements (18,9%). CONCLUSION: Des taux élevés de guérison de l'hépatite C avec les AAD sont réalisables dans les milieux cliniques du Cameroun. Cependant, l'accessibilité et la fourniture du dépistage, le diagnostic, du traitement, de la surveillance et des soins du VHC devraient être adressés pour une mise en œuvre à grande échelle.

Micro-elimination of hepatitis C through testing of Egyptian pregnant women presenting at delivery: implications for screening policies.

OBJECTIVES: Despite the high burden of hepatitis C virus (HCV) infection in Egypt, screening of pregnant women is not yet universal, making national and global elimination unlikely. This study assessed the proportion of pregnant women who were screened for HCV infection at delivery, the prevalence and risk factors for HCV infection, the associated adverse neonatal outcomes, and the real-life linkage to care of infected women and follow-up of their infants' HCV status and timing of testing. METHODS: Data were collected from medical records of a retrospective cohort of all pregnant women who were admitted to a university hospital in Cairo for delivery between January and June 2018 (n = 6734). HCV antibody- and RNA-positive women and their infants were prospectively followed-up by phone interviews till September 2019. RESULTS: 2177 (32.3%) pregnant women were screened for HCV infection. 19 (0.9%) tested HCV antibody- and RNA-positive. Being ≥ 30 years old (ORa 3.6, 95% CI: 1.4-9.2; P = 0.009), history of abortion (ORa 3.5, 95% CI: 1.2-10.3; P = 0.022) and blood transfusion (ORa 29.1, 95% CI: 9.6-88.4; P < 0.001) were independent risk factors for infection. Adverse neonatal outcomes did not vary significantly among HCV antibody-positive and antibody-negative women. Only 13 (68.4%) HCV antibody- and RNA-positive women started treatment with direct-acting antivirals (DAAs) post-breastfeeding (two completed the treatment course and were cured). Four (21.1%) did not start treatment, and two (10.5%) were lost to follow-up. All infants of the 13 HCV antibody- and RNA-positive women who started DAA therapy tested HCV RNA-negative within their first year of life. CONCLUSION: Extending screening services to all pregnant women and better linkage to care are essential for the national elimination of HCV infection.

OBJECTIFS: Malgré la charge élevée de l'infection par le virus de l'hépatite C (VHC) en Egypte, le dépistage des femmes enceintes n'est pas encore universel, ce qui rend peu probable l'élimination nationale et mondiale. Cette étude a évalué la proportion de femmes enceintes qui ont été dépistées pour l'infection par le VHC à l'accouchement, la prévalence et les facteurs de risque d'infection par le VHC, les résultats néonatals indésirables associés et le ralliement réel avec les soins aux femmes infectées et le suivi du statut VHC de leurs nourrissons et le calendrier des tests. MÉTHODES: Les données ont été collectées à partir des dossiers médicaux d'une cohorte rétrospective de toutes les femmes enceintes admises dans un hôpital universitaire du Caire pour un accouchement entre janvier et juin 2018 (n = 6734). Les femmes testées positives pour les anticorps et l'ARN du VHC et leurs nourrissons ont fait l'objet d'un suivi prospectif par des entretiens téléphoniques jusqu'en septembre 2019. RÉSULTATS: 2.155 (32,3%) femmes enceintes ont été dépistées pour l'infection au VHC. 19 (0,9%) ont été testées positives pour les anticorps et l'ARN du VHC. Avoir ≥30 ans (ORa: 3,6 ; IC95%: 1,4-9,2; p = 0,009), les antécédents d'avortement (ORa : 3,5 ; IC 95%: 1,2-10,3; p = 0,022) et la transfusion sanguine (ORa: 29,1 ; IC95%: 9,6-88,4; p <0,001) étaient des facteurs de risque indépendants d'infection. Les résultats néonatals défavorables ne variaient pas de manière significative entre les femmes positives et négatives aux anticorps anti-VHC. Seules 13 (68,4%) femmes positives pour les anticorps et l'ARN du VHC ont commencé un traitement avec des antiviraux à action directe (AAD) après l'allaitement (deux ont terminé le traitement et ont été guéries). Quatre (21,1%) n'ont pas commencé le traitement et deux (10,5%) ont été perdus de vue. Tous les nourrissons des 13 femmes positives pour l'anticorps et l'ARN du VHC qui ont commencé un traitement par AAD ont été testés négatifs pour l'ARN du VHC au cours de leur première année de vie. CONCLUSION: L'extension des services de dépistage à toutes les femmes enceintes et un meilleur lien avec les soins sont essentiels pour l'élimination nationale de l'infection par le VHC.

Directive clinique no 409 : Tests diagnostiques fœtaux intra-utérins en cas d'infection virale chronique maternelle.

OBJECTIF: La présente directive clinique révisée met à jour les renseignements sur la prestation de soins aux femmes atteintes d'une infection virale chronique devant se soumettre à un test diagnostique fœtal intra-utérin. POPULATION CIBLE: Femmes atteintes d'une infection virale chronique qui sont enceintes ou prévoient le devenir. OPTIONS: Tests de dépistage non invasifs à des fins diagnostiques : marqueurs placentaires sériques maternels avec ou sans mesure de la clarté nucale, échographie, ADN fœtal libre circulant dans le sang maternel; et tests diagnostiques fœtaux intra-utérins : amniocentèse, biopsie choriale (choriocentèse), cordocentèse. ISSUES: Les recommandations de la présente directive clinique pourraient réduire ou éliminer la morbi-mortalité chez les femmes atteintes d'une infection virale chronique et leurs nourrissons, ce qui est associé à d'importantes conséquences sur les plans de la santé et de l'économie. DONNéES PROBANTES: La littérature publiée a été recueillie au moyen de recherches dans les bases de données PubMed et Cochrane Library ainsi que dans les directives cliniques de sociétés médicales nationales et internationales (Société des obstétriciens et gynécologues du Canada, American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine et d'autres sociétés internationales) en utilisant un vocabulaire (amniocentesis, chorionic villus sampling, cordocentesis, procedure pregnancy loss risk, viral vertical transmission, fetal and neonatal infection) et des mots clés (maternal infection or exposure, hepatitis B, hepatitis C, human immunodeficiency virus) contrôlés et appropriés. Les résultats retenus se limitent aux revues systématiques, aux essais cliniques randomisés ou aux essais cliniques comparatifs (si disponibles) et aux études cas-témoins observationnelles ou études de série de cas publiées entre 2012 et 2019 en anglais ou en français. Les études publiées entre 1966 et 2002 ont déjà été examinées dans la directive clinique de la SOGC no 123, L'amniocentèse chez les femmes infectées par l'hépatite B, l'hépatite C ou le virus de l'immunodéficience humaine; les études publiées entre 2002 et 2012 ont quant à elles été examinées dans la directive clinique de la SOGC no 309, Interventions effractives prénatales chez les femmes qui présentent des infections par le virus de l'hépatite B, le virus de l'hépatite C et/ou le virus de l'immunodéficience humaine. De nouvelles recherches ont été effectuées dans la littérature jusqu'en août 2019, puis ont été intégrées à la présente directive clinique. MéTHODES DE VALIDATION: L'auteur a évalué la qualité des données probantes et la solidité des recommandations au moyen du cadre méthodologique GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Consulter l'annexe A en ligne (le tableau A1 pour les définitions et le tableau A2 pour les interprétations des recommandations fortes et faibles). PUBLIC VISé: Les utilisateurs prévus sont des fournisseurs de soins de maternité et les femmes atteintes d'une infection virale chronique. Cette directive fournit des renseignements pour renseigner et conseiller ces femmes et leur offrir des options de procréation. RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES).

Peg-interferon and ribavirin treatment in HIV/HCV co-infected patients in Thailand: efficacy, safety and pharmacokinetics.

OBJECTIVE: In Thailand, 7.2% of HIV patients are co-infected with hepatitis C virus (HCV), and these patients are treated with peg-interferon + ribavirin (PR) for their HCV infection. This study evaluates efficacy and safety of PR treatment and pharmacokinetics of ribavirin in this population. METHODS: HIV/HCV co-infected Thai patients were treated with PR for 24 or 48 weeks. Sustained virological response 24 weeks after the end of treatment (SVR24) was used to describe efficacy. (laboratory) safety parameters and ribavirin plasma concentrations were evaluated during study visits. Ribavirin concentrations were compared with t-tests for patients with and without anaemia (haemoglobin <10 g/dl) and SVR24. RESULTS: A total of 101 HIV/HCV co-infected patients were included; 88% were male (n = 88), and 46% were infected with genotype 3. The median (IQR) start dose was 14.28 mg/kg/day. SVR24 rate was 56%. All patients reported at least one (serious) adverse event, of which 28% of patients developed anaemia. Seven patients discontinued treatment due to toxicity issues. Geometric mean (IQR) ribavirin concentration was 1.81 (1.42-2.32) mg/l at week 8 of treatment. At week 8, patients with and without anaemia and SVR had ribavirin concentrations of 2.29 and 1.63 mg/l and 1.91 and 1.74 mg/l, respectively. CONCLUSIONS: PR treatment has comparable response rates and toxicity profile in Thai HIV/HCV co-infected patients as in Western HIV/HCV patients. However, ribavirin plasma concentrations were comparable with previously published studies in HIV/HCV co-infected patients, but both, just as SVR rate, were lower than in mono-infected patients.

Association between hepatitis C infection and cerebro-cardiovascular disease: analysis of a national population-based survey in Egypt.

OBJECTIVES: To examine the association between hepatitis C virus (HCV) infection, cardiovascular risk factors and cerebro-cardiovascular (CCV) disease. METHODS: The source of data was the Egypt Health Issues Survey conducted in 2015. Participants were 11 256 individuals with complete HCV testing, age 25-59 years. Data on demographics, cardiovascular risk factors, CCV disease (myocardial infarction and/or cerebral stroke) and HCV infection were retrieved. Descriptive, bivariate, multivariable logistic regression and sensitivity analyses were performed to determine the independent association of past HCV exposure or chronic infection with diabetes, hypertension and CCV disease. RESULTS: 3.9% of participants were antibody positive/RNA negative and considered to have past HCV exposure; 7.9% had detectable HCV-RNA and were considered to have chronic infection. Participants with negative antibodies and no history of liver disease (n = 9928) were the control group. In addition to the previously known risk factors, multivariable analyses revealed that diabetes was independently associated with past HCV exposure (OR = 1.71, 95% CI: 1.27-2.32) and HCV chronic infection (OR = 1.56, 95% CI: 1.23-1.97), whereas CCV disease was independently associated with past exposure (OR = 2.69, 95% CI: 1.62-4.46) and not with chronic infection. No evidence of an association between hypertension and either HCV status was found. CONCLUSION: The association of both past HCV exposure and chronic infection with diabetes and that of past HCV exposure with CCV disease may suggest targeting HCV-positive reactors for preventive and curative programmes addressing extrahepatic complications.

New use of an old drug: chloroquine reduces viral and ALT levels in HCV non-responders (a randomized, triple-blind, placebo-controlled pilot trial).

Hepatitis C virus (HCV) infection induces autophagy, but the virus assimilates the autophagic response into its own life cycle. Chloroquine (CQ) is an autophagy inhibitor that is clinically used to treat malaria. The aims of this pilot clinical trial were to evaluate the therapeutic potential and short-term safety of CQ in patients with chronic HCV genotype 1, who were unresponsive to a combination of pegylated interferon alpha and ribavirin. Ten non-responders to previous antiviral treatment(s) were randomized to receive either CQ (150 mg daily for 8 weeks) or placebo, and were followed for 4 weeks after CQ therapy. HCV RNA load and plasma alanine transaminase (ALT) levels were measured at baseline, week 4 (initial response), week 8 (end-of-treatment response), and at the end of 12 weeks. A significant decrease in HCV RNA after the treatments (week 8) was observed in all patients in the CQ group (P = 0.04). However, HCV RNA levels increased within 4 weeks after discontinuation of CQ treatment although they were still lower than baseline. In addition, the ALT normalized during treatment in the CQ group. However, this response was also lost after treatment cessation. This study provides preliminary evidence that CQ is possibly a safe treatment option for HCV non-responders.

Genome-wide analysis for identification of adaptive diversification between hepatitis C virus subtypes 1a and 1b.

Hepatitis C virus (HCV) is a major cause of liver disease and has been estimated to infect approximately 2%-3% of the world's population. HCV genotype 1 is the subject of intense research and clinical investigations because of its worldwide prevalence and poor access to treatment for patients in developing countries and marginalized populations. The predominant subtypes 1a and 1b of HCV genotype 1 present considerable differences in epidemiological features. However, the genetic signature underlying such phenotypic functional divergence is still an open question. Here, we performed a genome-wide evolutionary study on HCV subtypes 1a and 1b. The results show that adaptive selection has driven the diversification between these subtypes. Furthermore, the major adaptive divergence-related changes have occurred on proteins E1, NS4B, NS5A, and NS5B. Structurally, a number of adaptively selected sites cluster in functional regions potentially relevant to (i) membrane attachment and (ii) the interactions with viral and host cell factors and the genome template. These results might provide helpful hints about the molecular determinants of epidemiological divergence between HCV 1a and 1b.

[Cutaneous adverse events of telaprevir/peginterferon/ribavirin therapy for chronic hepatitis C: A multicenter prospective cohort study]. / Effets secondaires cutanés de l'association télaprévir/peg-interféron/ribavirine pour le traitement de l'hépatite C chronique : étude prospective d'une cohorte multicentrique.

BACKGROUND: Telaprevir, sale of which was suspended, has been approved in combination with pegylated interferon and ribavirin (triple therapy) in the treatment of chronic hepatitis C virus (HCV). Skin eruptions and isolated cases of severe cutaneous adverse reactions (SCAR) have been reported. AIMS: Our aim was to assess the incidence of skin eruption and the clinical characteristics of mucocutaneous adverse events (AE), and to identify potential risk factors for telaprevir-associated skin eruption. PATIENTS AND METHODS: A prospective observational multicenter follow-up cohort study with monthly controls by a dermatologist and additional examinations in case of any undercurrent AE. RESULTS: Among the 48 enrolled patients, the incidence of skin eruption was 58.4%, consisting mainly of maculopapular and eczematous lesions and only one case of SCAR. Telaprevir was discontinued in 6% of patients due to severe rash, whereas peginterferon and ribavirin were continued. The median time to onset of rash following telaprevir initiation was 25 days (range: 3-79 days). The rash was preceded by skin dryness and associated with pruritus in 100% and 90% of patients, respectively. Of those presenting with skin eruption, 37.5% also complained of conjunctival or oral lesions, or of anorectal symptoms. Neither a past history of dermatological conditions nor sociodemographic or viral status was predictive factor for skin rash. CONCLUSIONS: Telaprevir-related dermatitis has a high incidence but is mostly of mild intensity. In most cases, tri-therapy was continued under close dermatological follow-up allowing rapid detection of rare instances of severe drug eruptions. Ribavirin and Interferon were thus continued even in the event of diffuse eruptions, enabling confirmation of the causative role of telaprevir in these eruptions.

Hepatitis C virus acquisition among Egyptians: analysis of a 10-year surveillance of acute hepatitis C.

OBJECTIVE: To identify current risk factors for hepatitis C virus (HCV) acquisition among Egyptians. METHODS: Patients with acute HCV were identified through a surveillance system of acute hepatitis in four fever hospitals in Egypt between 2002 and 2012. Case-control analysis was conducted, cases being incident acute symptomatic HCV and controls being acute hepatitis A identified at the same hospitals. The questionnaire covered iatrogenic, community and household exposures to HCV in the 1-6 months prior to onset of symptoms. Multivariate models were built to identify risk factors associated with HCV acquisition among non-drug users and drug users separately. RESULTS: Among non-drug users, hospital admission was independently associated with acute HCV infection (OR = 4.2, 95% CI = 1.7-10.5). Several iatrogenic procedures, for example admission in a surgery unit, sutures, IV injections and IV infusions, highly correlated with hospital admission, were also associated with acute HCV infection and could have been used in the final model instead of hospital admission. Among drug users, identified risk factors were multiple sexual relations (OR = 4.0, 95% CI = 1.1-14.7), intravenous drug use (OR = 3.9, 95% CI = 1.2-13.0) and shaving at the barbershops (OR = 8.7, 95% CI = 2.4-31.4). Illiteracy and marriage were significant risk factors in both groups. CONCLUSION: Invasive medical procedures are still a major risk for acquiring new HCV infections in Egypt, as is illicit drug use in spreading HCV infection.

Prevalence of hepatitis C virus in mothers and their children in Malawi.

OBJECTIVES: Hepatitis C virus (HCV) prevalence is poorly mapped in the East African region; with the advent of novel HCV therapies, better epidemiological data are required to target the infection. We sought to estimate HCV prevalence in healthy Malawian mothers and assess mother-to-child transmission (MTCT); context is provided by reviewing previously published HCV prevalence data from the region. METHODS: Using ELISA screening and confirmatory blot, serological testing of 418 healthy Malawian mothers for HCV was performed. To examine MTCT, the children of any positive women were also tested for HCV; all children had malignant disease unrelated to hepatocellular carcinoma. We compared our results to published literature on HCV prevalence in Malawi and its neighbouring countries. RESULTS: Three of 418 women were HCV reactive by ELISA; two were confirmed positive by immunoblot (0.5%). One child of an HCV-infected mother was HCV seropositive. The literature review revealed HCV prevalence ranging from 0 to 7.2% in the region, being highest in Tanzania and specifically for cohorts of inpatients and HIV-co-infected people. The overall estimated prevalence of HCV in Malawi was 1.0% (95%CI 0.7-1.4) when all studies were included (including this one), but lower in healthy cohorts alone at 0.3% (95%CI 0.1-1.2). CONCLUSIONS: This is the first study using confirmatory tests to examine HCV prevalence in healthy Malawian mothers; the prevalence was low. Future studies need to address the source of infection in healthy women.

HCV reflex testing: A single-sample, low-contamination method that improves the diagnostic efficiency of HCV testing among patients in Alberta, Canada.

BACKGROUND: Hepatitis C virus (HCV) can be cured with antiviral treatments. Diagnosis normally requires two blood samples, one for serology screening and one for molecular confirmation. This multi-step process creates barriers in patient care and decreases testing for hard-to-reach populations. We used the cobas® 6800 to detect HCV RNA after antibody testing to investigate whether a single-sample reflex testing method is effective and efficient for diagnosing HCV-positive patients. METHODS: HCV RNA-positive clinical samples (n = 152) were interchangeably loaded on the ARCHITECT i2000SR with negative samples (n = 152) in a checkerboard fashion, tested for HCV antibodies using fixed probes, and directly transferred to the cobas 6800 for molecular testing. Contamination rates, sensitivity, and specificity were determined by comparing Abbott m2000 and cobas 6800 viral loads. After implementing reflex testing, clinical data over a 6-month period were analyzed for diagnostic efficiency. RESULTS: Contamination was present in 5 of 152 pairs (3.29%) after reflex testing. Sensitivity and specificity were 99.3% (95% CI 95.1% to 99.9%) and 100% (95% CI 97.5% to 100%), respectively, using the cobas 6800 assay after serotesting. Approximately 97% of clinical patients received a conclusive test result with the reflex-testing algorithm. For HCV-positive patients, mean diagnostic turnaround times were significantly lower using reflex testing versus the two-sample method (4 versus 39 days; p < 0.0001). CONCLUSIONS: HCV reflex testing demonstrated low levels of contamination without compromising the integrity of the molecular assay. Implementation in clinical laboratories would increase the efficiency of diagnosis and decrease steps in the continuum of care for patients.

HISTORIQUE: Il est possible de vaincre le virus de l'hépatite C (VHC) par des traitements antirétroviraux. Pour poser un diagnostic, il faut normalement deux prélèvements de sang : l'un pour le dépistage sérologique et l'autre pour la confirmation moléculaire. Ce processus en plusieurs étapes crée des obstacles dans les soins aux patients et limite le dépistage auprès des populations difficiles à atteindre. Les auteurs ont utilisé la plateforme cobasMD 6800 pour déceler l'ARN du VHC après des tests de détection des anticorps et pour explorer si une méthode de dépistage réflexe à échantillon unique est efficace et efficiente lors du diagnostic des patients positifs au VHC. MÉTHODOLOGIE : Les chercheurs ont placé les échantillons cliniques positifs à l'ARN du VHC (n = 152) en échiquier avec des échantillons négatifs (n = 152) dans l'analyseur ARCHITECT i2000SR, ont dépisté les anticorps du VHC à l'aide de sondes fixes, puis ont transféré les échantillons directement sur la plateforme cobas 6800 en vue du test moléculaire. Ils ont établi les taux de contamination, la sensibilité et la spécificité en comparant les charges virales des plateformes Abbott m2000 et cobas 6800. Après le dépistage réflexe, ils ont analysé les données cliniques sur une période de six mois pour en établir l'efficience diagnostique. RÉSULTATS : Les chercheurs ont constaté une contamination dans cinq des 152 paires (3,29 %) après le dépistage réflexe. Après l'examen sérologique, ils ont obtenu une sensibilité de 99,3 % (IC à 95 %, de 95,1 % à 99,9 %) et une spécificité de 100 % (IC à 95 %, de 97,5 % à 100 %) au moyen de la plateforme cobas 6800. Environ 97 % des patients cliniques ont reçu un test concluant selon l'algorithme du dépistage réflexe. Chez les patients positifs au VHC, le délai diagnostique moyen était considérablement plus court après le dépistage réflexe qu'après la méthode à deux échantillons (quatre jours plutôt que 39; p < 0,0001). CONCLUSIONS : Le dépistage réflexe du VHC a démontré de faibles taux de contamination sans compromettre l'intégrité du dosage moléculaire. Son adoption en laboratoire clinique accroîtrait l'efficience du diagnostic et réduirait le nombre d'étapes dans le continuum des soins aux patients.

Regressão espontânea do carcinoma hepatocelular: foco nos fatores de risco associados / Spontaneous regression of hepatocellular carcinoma: focusing in the associated risk factors

ABSTRACT Background: Spontaneous regression (SR) is defined as the partial or complete disappearance of a tumor, in the absence of a specific treatment. Evidence of the SR in hepatocellular carcinoma (HCC) is rare. Objective: The authors aimed to review all the cases of SR of HCC in two reference centers of Southern Brazil, highlighting the main characteristics. Methods: Data of all patients with HCC were retrospectively reviewed looking for the occurrence of SR in patients from two tertiary centers in Southern Brazil, in the last five years. The diagnosis of cirrhosis was established according to clinical, laboratory and imaging data, as well as upper endoscopy or histopathological examination when necessary. The diagnosis of HCC was based on typical findings according to radiologic criteria (LIRADS) or histopathological examination. Spontaneous regression was defined as a partial or complete involution of a HCC in the absence of a specific therapy. Results: From all cases of HCC in the last 5 years (n=433), there were five cases of SR. Three (60%) were men, the mean age was 62.6 (50.0-76.0) years, and the etiology was HCV in 3 (60%). Complete regression was observed in three patients (60%), one patient (20%) presented partial regression, and one (20%) relapesed and died. The time of follow-up varied between 12 and 21 months. In this presentation, it was highlighted one case of SR observed after COVID-19 infection in a patient with cirrhosis. The possible mechanisms involved in this situation were reviewed, emphasizing the most common like hypoxia and immunological. There were also one patient submitted to a surgical procedure as a possible fator involved and three patients without obvious risk factors. Conclusion: This phenomenon will possibly contribute to a better understanding of the pathophysiological mechanisms of HCC.

RESUMO Contexto: A evidência da regressão espontânea (RE) no carcinoma hepatocelular (CHC) é rara. Objetivo: Revisar todos os casos de RE de CHC em dois centros de referência do Sul do Brasil, destacando as principais características. Métodos: Os dados de todos os pacientes com CHC foram revisados retrospectivamente buscando a ocorrência de RE em pacientes de dois centros terciários do Sul do Brasil, nos últimos 5 anos. O diagnóstico de cirrose foi estabelecido de acordo com dados clínicos, laboratoriais e de imagem, além de endoscopia digestiva alta ou exame histopatológico quando necessário. O diagnóstico de CHC foi baseado em achados típicos de acordo com critérios radiológicos (LIRADS) ou exame histopatológico. A RE foi definida como uma involução parcial ou completa de um CHC na ausência de terapia específica. Resultados: Do total de casos de CHC nos últimos 5 anos (n=433), houve cinco casos de RE. Três (60%) eram homens, a média de idade foi de 62,6 (50,0-76,0) anos, a etiologia foi virus da hepatite C em 3 (60%). A regressão completa foi observada em três pacientes (60%), um paciente (20%) apresentou regressão parcial e um (20%) apresentou recidiva e evoluiu a óbito. O tempo de seguimento variou entre 12 e 21 meses. Nesta apresentação foi destacado um caso (20%) de RE observado após infecção por COVID-19 em paciente com cirrose. Foram revisados os possíveis mecanismos envolvidos nesta situação, enfatizando os mais comuns como hipóxia e imunológicos. Houve também um paciente submetido a procedimento cirúrgico como possível fator envolvido e três pacientes sem fatores de risco evidentes. Conclusão: Este fenômeno possivelmente contribuirá para uma melhor compreensão dos mecanismos fisiopatológicos do CHC.

Occurrence of hepatitis B and C virus infection in socioeconomic population strata from Recife, Pernambuco, Northeast Brazil / Ocorrência da infecção pelo vírus das hepatites B e C em estratos socioeconômicos populacionais do município de Recife, Pernambuco, Nordeste do Brasil

ABSTRACT Objective: To estimate the probability of infection with hepatitis B (HBV) and C (HCV) viruses in different socioeconomic strata of the population of Recife, Northeast Brazil. Methods: Study carried out from samples obtained in a survey of residents of a large urban center that had a population base and stratified sampling with random selection of households using the "Brazil Sample" package in the R software. HBV (HBsAg) and anti-HCV was performed using immunochromatographic tests. In cases positive for HBsAg, anti-HBc and HBeAg were tested using chemiluminescence, as well as HBV-DNA using real-time PCR. For cases positive for anti-HCV, the search for this antibody was repeated by chemiluminescence and for HCV-RNA by real-time PCR. The occurrence of HBsAg and anti-HCV cases in the general population was estimated based on a theoretical negative binomial distribution. Results: Among 2,070 samples examined, 5 (0.24%) were HBsAg and 2 (0.1%) anti-HCV positive. The majority of cases had self-reported skin color as black/brown (6/7), education level up to high school (6/7), a steady partner (5/7) and lived in an area of low socioeconomic status (5/7). Conclusion : The occurrence of HBsAg and anti-HCV was lower than those previously found in population-based studies and slightly lower than the most recent estimates. Individuals with lower socioeconomic status should be a priority target of public health policies.

RESUMO Objetivo: Estimar a probabilidade da ocorrência de infecção pelos vírus das hepatites B (HBV) e C (HCV) em diferentes estratos socioeconômicos da população de Recife, Nordeste do Brasil. Métodos: Estudo realizado com base em amostras obtidas em um inquérito de residentes de um grande centro urbano que teve base populacional e amostragem estratificada com seleção aleatória dos domicílios por meio do pacote "Amostra Brasil" no software R. A pesquisa do antígeno de superfície do HBV (HBsAg) e do anti-HCV foi realizada por testes imunocromatográficos. Nos casos positivos para HBsAg, foram realizadas pesquisas do anti-HBc e do HBeAg por quimioluminescência, bem como do HBV-DNA, por meio de PCR em tempo real. Para os casos positivos para anti-HCV, foi repetida a pesquisa desse anticorpo por quimioluminescência e do HCV-RNA por PCR em tempo real. A ocorrência de casos HBsAg e anti-HCV na população geral foi estimada com base em uma distribuição teórica binomial negativa. Resultados: Dentre 2.070 amostras examinadas, cinco (0,24%) foram HBsAg e duas (0,1%) anti-HCV positivas. A maioria dos casos tinha cor de pele autorreferida como preta/parda (6/7), nível de escolaridade até o ensino médio (6/7), companheiro fixo (5/7) e morava em área de baixo estrato socioeconômico (5/7). Conclusão: A ocorrência de HBsAg e anti-HCV foi inferior às anteriormente encontradas em estudos de base populacional e pouco menor do que as estimativas mais recentes. Indivíduos que apresentam menor condição socioeconômica devem ser alvo prioritário das políticas públicas de saúde.

Hepatitis A, B and C prevalence among transgender women and travestis in five Brazilian capitals between 2019-2021 / Prevalência das hepatites A, B e C entre mulheres trans e travestis em cinco capitais brasileiras entre 2019-2021

ABSTRACT Objective: To estimate the prevalence and factors associated with hepatitis A, B, and C in transgender women and travestis's networks, in 5 regions of Brazil. Methods: This cross-sectional study includedtransgender women and travestis in five Brazilian capitals (Campo Grande, Manaus, Porto Alegre, Salvador, and São Paulo), between December/2019 and July/2021. All samples were subjected to detection of serological markers of hepatitis virus A (HAV), B (HBV), and C (HCV) infections through rapid tests and chemiluminescent microparticle immunoassays. Positive samples in the screening tests were submitted to detect HBV DNA and HCV-RNA by real-time PCR and genotyped by Sanger sequencing. Results: Analysis of 1,317 samples showed network prevalence rates of 69.1%, 25.1%, and 1.5% for HAV, HBV, and HCV exposure, respectively. A high susceptibility rate to HBV infection (35.7%) and low prevalence of vaccine response markers (40%) were also observed. Age greater than 26 years, self-declared black/brown skin color, having only primary education, history of incarceration, and use of a condom in the last sexual intercourse with a casual partner were associated with total anti-HAV. Exposure to HBV was associated with age greater than 26 years, self-declared black/brown, history of being a sex worker, and incarceration. Age > 37 years, history of sexual abuse, and frequent alcohol consumption were associated with hepatitis C infection. Conclusion: The highest prevalence of HAV in this population was found in the North and Northeast regions, and the prevalence found was higher than that in the general population, suggesting greater vulnerability. The prevalence of HCV infection in our study was similar to that observed in the general population.

RESUMO Objetivo: Estimar as prevalências e fatores associados com as hepatites A, B e C em mulheres trans e travestis em cinco regiões do Brasil. Métodos: Estudo transversal com mulheres trans e travestis em cinco capitais brasileiras (Campo Grande, Manaus, Porto Alegre, Salvador e São Paulo), entre dezembro/2019 e julho/2021. As amostras foram submetidas à detecção de marcadores das infecções pelos vírus das hepatites A (HAV), B (HBV) e C (HCV), utilizando-se testes rápidos e quimioluminescência. Amostras positivas foram submetidas à detecção de HBV-DNA e HCV-RNA por PCR em tempo real e genotipadas por sequenciamento de Sanger. Resultados: As análises de 1.317 amostras indicaram taxas de prevalências nas mulheres trans e travestis recrutadas de 69,1%, 24,4% e 1,5% para exposição ao HAV, HBV e HCV, respectivamente. Elevada taxa de suscetibilidade ao HBV (35,7%) e baixa prevalência do marcador vacinal (40,0%) foram observadas. Mostraram-se associadas à presença de anti-HAV: idade maior que 26 anos, autodeclarar-se preta-parda, ter apenas educação básica, história de encarceramento e uso de preservativo na última relação sexual com parceiro casual. Quanto à exposição ao HBV, foi associada a idade maior que 26 anos, cor da pele preto-parda, ter sido profissional do sexo e história de encarceramento. Idade maior de 37 anos, história de abuso sexual e consumo frequente de álcool foram associadas ao HCV. Conclusão: As maiores prevalências de HAV nessa população encontram-se nas regiões Norte e Nordeste. Com relação ao HBV, a prevalência encontrada foi superior à encontrada na população geral, sugerindo maior vulnerabilidade. A prevalência do HCV foi semelhante à encontrada na população geral.

Factors associated with prior testing for HIV, Syphilis, and Hepatitis B and C among transgender women and travestis in Brazil / Fatores associados à realização de testagem prévia para HIV, sífilis e hepatites B e C entre mulheres trans e travestis no Brasil

ABSTRACT Objective: To investigate the prior testing for HIV, syphilis, hepatitis B (HBV), and hepatitis C (HCV) among transgender women and travestis (TGW) in five Brazilian cities and identify factors associated with each of these previous tests. Methods: This is a cross-sectional study with the recruitment of TGW through respondent-driven sampling (TransOdara Study). The investigated outcome variable was prior testing for HIV, syphilis, HBV, and HCV in the last 12 months. The association between sociodemographic and behavioral factors with the outcome was analyzed using a binomial logistic regression with mixed effects. Adjusted odds ratios (aOR) and 95% confidence intervals (CI95%) were estimated. Results: The proportions of individuals with prior testing in the past year were as follows: 56.3% for HIV, 58.0% for syphilis, 42.1% for HBV, and 44.7% for HCV. Negative associations with prior testing were observed for individuals aged 35 years or older, whereas positive associations were found for those with high school education, those who experienced verbal or psychological violence in the last 12 months, and those who had commercial or casual partners in the last 6 months. Conclusion: There was low frequency of testing in the 12 months preceding the study for HIV, syphilis, HBV, and HCV compared to the guidelines established by the Ministry of Health. Expanding access to and engagement with healthcare and prevention services for TGW is an essential strategy in reducing the transmission chain of HIV and other sexually transmitted infections (STIs).

RESUMO Objetivo: Investigar a realização de testagem prévia de HIV, sífilis, hepatites B (HBV) e C (HCV) entre mulheres trans e travestis (MTT) em cinco cidades brasileiras e identificar fatores associados à testagem. Métodos: Trata-se de um estudo de corte transversal, com recrutamento de MTT através do respondent-driven sampling (Projeto TransOdara). A variável de desfecho investigada foi realização de testagem prévia HIV, Sífilis, HBV e HCV nos últimos 12 meses. A associação entre fatores sociodemográficos e comportamentais com o desfecho foi analisada usando modelo de regressão logística binomial com efeitos mistos. Estimou-se odds ratio ajustada (aOR) e intervalos de confiança a 95% (IC95%). Resultados: As proporções de pessoas com realização prévia de testagem foram: 56,3% para HIV, 58,0% para sífilis, 42,1% para HBV e 44,7% para HCV. Observaram-se associação negativa da testagem prévia com idade de 35 anos ou mais e associação positiva com ter ensino médio, ter sofrido violência verbal ou psicológica nos últimos 12 meses e ter tido parceiro comercial ou casual nos últimos seis meses. Conclusão: Verificou-se baixa frequência de testagem nos últimos 12 meses anteriores ao estudo para HIV, Sífilis, HBV e HCV em comparação às orientações estipuladas pelo Ministério da Saúde. A ampliação do acesso e vinculação aos serviços de atenção e prevenção para as MTT é uma estratégia essencial para a redução da cadeia de transmissão do HIV e outras infecções sexualmente transmissíveis.