Fernando Lopes Gonçales Junior

Viral hepatitis in patients infected with human immunodeficiency virus

From 1992 to 1995 we studied 232 (69% male, 87% Caucasian) anti-human immunodeficiency virus (anti-HIV) positive Brazilian patients, through a questionnaire; HIV had been acquired sexually by 50%, from blood by 32%, sexually and/or from blood by 16.4% and by an unknown route by 1.7%. Intravenous drug use was reported by 29%; it was the most important risk factor for HIV transmission. The alanine aminotransferase quotient (qALT) was >1 for 40% of the patients, 93.6% had anti-hepatitis A virus antibody, 5.3% presented hepatitis B surface antigen, 44% were anti-hepatitis B core antigen positive and 53.8% were anti-hepatitis C virus (anti-HCV) positive. The anti-HCV test showed a significant association with qALT>1. Patients for whom the probable HIV transmission route was blood had a 10.8 times greater risk of being anti-HCV positive than patients infected by other routes. Among 30 patients submitted to liver biopsy, 18 presented chronic hepatitis.

Occult hepatitis B virus infection in immunocompromised patients

Occult hepatitis B infection is characterized by hepatitis B virus (HBV) DNA in the serum in the absence of hepatitis B surface antigen (HBsAg). We assessed occult HBV infection prevalence in two groups of immunocompromised patients (maintenance hemodialysis patients and HIV-positive patients) presenting HBsAg-negative and anti-HBc positive serological patterns, co-infected or not by HCV. Thirty-four hemodialysis anti-HIV negative patients, 159 HIV-positive patients and 150 blood donors who were anti-HBc positive (control group) were selected. HBV-DNA was detected by nested-PCR. Occult hepatitis B infection was not observed in the hemodialysis patients group but was found in 5% of the HIV-patients and in 4% of the blood donors. Immunosuppression in HIV positive patients was not a determining factor for occult HBV infection. In addition, no significant relationship between HBV-DNA and HCV co-infection in the HIV-positive patient group was found. A lack of significant associations was also observed between positivity for HBV-DNA and CD4 count, viral load and previous lamivudine treatment in these HIV-positive patients.

The influence of occult infection with hepatitis B virus on liver histology and response to interferon treatment in chronic hepatitis C patients

Occult hepatitis B virus (HBV) infections have been identified in patients with chronic hepatitis C virus (HCV) infection, although the clinical relevance of occult HBV infection remains controversial. We searched for serum HBV DNA in 106 HBsAg negative/anti-HBc positive patients with chronic HCV infection and in 150 blood donors HBsAg negative/anti-HBc positive/anti-HCV negative (control group) by nested-PCR. HCV genotyping was done in 98 patients and percutaneous needle liver biopsies were performed in 59 patients. Fifty-two patients were treated for HCV infection with interferon alone (n=4) or combined with ribavirin (n=48) during one year. At the end and 24 weeks after stopping therapy, they were tested for HCV-RNA to evaluate the sustained virological response (SVR). Among the 106 HCV-positive patients, 15 (14%) were HBV-DNA positive and among the 150 HCV-negative blood donors, 6 (4%) were HBV-DNA positive. Liver biopsy gave a diagnosis of liver cirrhosis in 2/10 (20%) of the HBV-DNA positive patients and in 6/49 (12%) of the HBV-DNA negative patients. The degree of liver fibrosis and portal inflammation was similar in HCV-infected patients HBV-DNA, irrespective of HBV-DNA status. SVR was obtained in 37.5% of the HBV-DNA positive patients and in 20.5% of the HBV-DNA negative patients; this difference was not significant. In conclusion, these data suggested that occult HBV infection, which occurs at a relatively high frequency among Brazilian HCV-infected patients, was not associated with more severe grades of inflammation, liver fibrosis or cirrhosis development and did not affect the SVR rates when the patients were treated with interferon or with interferon plus ribavirin.

Hepatitis E Virus Immunoglobulin G Antibodies in Different Populations in Campinas, Brazil

ABSTRACT The seroprevalence of anti-hepatitis E virus (HEV) antibodies was investigated by enzyme immunoassay in 205 volunteer blood donors, 214 women who attended a center for anonymous testing for human immunodeficiency virus (HIV) infection, and 170 hospital employees in Campinas, a city in southeastern Brazil. The prevalence of anti-HEV antibodies ranged from 2.6% (3 of 117) in health care professionals to 17.7% (38 of 214) in women who considered themselves at risk for HIV. The prevalence of anti-HEV antibodies in health care professionals was not significantly different from that in healthy blood donors (3.0%, 5 of 165) and blood donors with raised alanine aminotransferase levels (7.5%, 3 of 40). The prevalence of anti-HEV antibodies (13.2%, 7 of 53) in cleaning service workers at a University hospital was similar to that among women at risk for HIV infection. These results suggest that HEV is circulating in southeastern Brazil and that low socioeconomic status is an important risk factor for HEV infection in this region.

Consensus of the Brazilian Society of Infectious Diseases on the management and treatment of hepatitis C

Each year and every day the results of clinical trials and basic research provide us with a great deal of new information regarding viral hepatitis. We on the Viral Hepatitis Committee of the Sociedade Brasileira de Infectologia have been working to standardize the major issues surrounding day-to-day practice in treating patients infected with the hepatitis B or C virus (HBV or HCV). We have decided to address in alternate years HBV together with hepatitis delta (HDV) and HCV in our annual Consensus on clinical management. Last year we published the first HBV Consensus. This year we submit our HCV Consensus which primarily serves to update the 2002 and 2004 SPI Consensuses. We distributed the principal topics among the Committee members revised their work and compiled it into a Proceedings Supplement which elucidates the highlights of the Consensus. A deeper review was written and referenced (it is our advice to the reader to read the Proceedings as well). A meeting was then held in Mogi das Cruzes in order to discuss in a very practical and directed way the issues most relevant to the Consensus from public policies to the most complex therapeutic points. The results are summarized in a question/ answer topic/statement format in this issue of the BJID. The main message of our statement was that we need to have the courage to act in favor of life. Many of us have adopted certain practices based on very new knowledge despite a lack of formal or official policies to support such practices. Some of us have been awaiting new compounds while patients are dying of chronic liver diseases. Unfortunately the news from the battlefield is not so good. New compounds have been very disappointing (low potency viral resistance ineffective without interferon and various side effects some serious). It is also difficult to incorporate new policies into everyday practice. However strategies such as optimizing the use of pegylated interferon/ribavirin and encouraging treatment compliance as well asfinding new ways to monitor and slow liver disease progression are effective and should be put into practice. Most importantly the low-dose maintenance of pegylated interferon seems to be very promising and the use of interferon alpha has saved lives. That is why we choose to expound upon what we believe to be the current standard of care and the gold standard for dealing with this hard to treat virus as well as with the chronic complications of HCV infection. Our position will be reevaluated over the next two years. Until then we are confident that our guide will be of great value to the readers. Finally we would like to thank Roche and Schering Plough for the educational grants provided to the SBI. However we must stress that neither company attempted to influence any of the decisions made by our consensus group. (authors)

The epidemiology and control of schistosomiasis mansoni where Biomphalaria tenagophila is the snail host

Desde 1980, esta-se estudando a epidemiologia e o controle da esquistossomose mansonica no Municipio de Pedro de Toledo (Estado de Sao Paulo, Brasil). Em 1980 a prevalencia avaliada por exame de fezes (metodo de Kato-Katz) foi de 22,8%. Estatisticamente, ao nivel de 5%, nao houve diferenca nas prevalencias observadas nas zonas rural e urbana. A intensidade de infeccao foi baixa (media geometrica de 58,5 ovos por grama de fezes). As maiores prevalencias e intensidades de infeccao foram registradas na faixa etaria de 5 a 29 anos. Geralmente a transmissao da endemia verificou-se durante o lazer. Apenas 0,4% de B. tenagophila mostraram-se positivos para cercarias de S. mansoni. A maioria dos portadores era assintomatico. O programa de controle foi intensificado apos avaliacao dos dados de 1980, resultando em diminuicao acentuada da prevalencia de 22,8% em 1980 para 6%. Esta prevalencia residual vem se mantendo ate 1987. Agora iniciamos estudos para investigar as possiveis causas dessa prevalencia residual.

Hepatites pós-transfusionais na cidade de Campinas, SP, Brasil: II. Presença dos anticorpos anti-HBc e anti-HCV em candidatos a doadores de sangue e ocorrência de hepatites pós-transfusionais pelo vírus C nos receptores de sangue ou derivados

We have analysed anti-HBc and anti-HCV antibodies in serum samples from 799 donors which had their blood or derivates transfused to 111 recipients. Anti-HBc and anti-HCV were reactive in respectively 9 and 2.1% of the donors tested. We have observed that among the 111 recipients, 44 had received at least one positive anti-HBc unit and 67 had been transfused only with negative anti-HBc, units. The risk of developing hepatitis C virus was 4.5 times higher for the recipients who received at least one positive anti-HBc unit. If the test for anti-HBc had been made for the blood donors in the serological screening, about 56% of the HCV cases in the recipients could have been avoided. The population of recipients who received at least one reacting unit of anti-HCV, presented a risk 29 times higher of developing this hepatitis, as compared to the transfused recipients with all anti-HCV negative units. Testing blood from donors for anti-HCV would avoid 79% of the post-transfusional HCV cases. Brazilian candidates to blood donors seem to be carriers either simultaneously or sequentially to hepatitis virus B and C, since 44.4% of the positive anti-HCV were also positive for anti-HBc. Testing for anti-HBc and anti-HCV in blood screening must be indicated in order to prevent post-transfusional hepatitis transmission in our community.

Disease burden of chronic hepatitis C in Brazil.

BACKGROUND Hepatitis C virus infection is a major cause of cirrhosis; hepatocellular carcinoma; and liver transplantation. The aim of this study was to estimate hepatitis C virus disease progression and the burden of disease from a nationwide perspective. METHODS Using a model developed to forecast hepatitis C virus disease progression and the number of cases at each stage of liver disease; hepatitis C virus-infected population and associated disease progression in Brazil were quantified. The impact of two different strategies was compared: higher sustained virological response and treatment eligibility rates (1) or higher diagnosis and treatment rates associated with increased sustained virological response rates (2). RESULTS The number of infected individuals is estimated to decline by 35% by 2030 (1,255,000 individuals); while the number of cases of compensated (n=325,900) and decompensated (n=45,000) cirrhosis; hepatocellular carcinoma (n=19,100); and liver-related deaths (n=16,700) is supposed to peak between 2028 and 2032. In strategy 2; treated cases increased over tenfold in 2020 (118,800 treated) as compared to 2013 (11,740 treated); with sustained virological response increased to 90% and treatment eligibility to 95%. Under this strategy; the number of infected individuals decreased by 90% between 2013 and 2030. Compared to the base case; liver-related deaths decreased by 70% by 2030; while hepatitis C virus-related liver cancer and decompensated cirrhosis decreased by 75 and 80%; respectively. CONCLUSIONS While the incidence and prevalence of hepatitis C virus in Brazil are decreasing; cases of advanced liver disease continue to rise. Besides higher sustained virological response rates; new strategies focused on increasing the proportion of diagnosed patients and eligibility to treatment should be adopted in order to reduce the burden of hepatitis C virus infection in Brazil.

Laboratory Testing for Hepatitis C

Serological diagnosis of patients infected with the hepatitisC virus (HCV) can be performed using two categories of tests:indirect tests, which detect antibodies against HCV; and directtests, which detect, quantify, or characterize components ofthe viral particle, such as HCV RNA testing and testing fordetection of the HCV core antigen.Anti-HCV antibodies are usually detected using third- andfourth-generation immunoenzymatic assays – enzymeimmunoassay (EIA)/enzyme-linked immunosorbent assay(ELISA) 3 and EIA/ELISA 4, respectively – which containHCV core antigens and HCV nonstructural genes. Thespecificity of the EIA tests available on the market that detectanti-HCV was determined to be higher than 99%, whereastheir sensitivity, which was more difficult to determine due tothe lack of gold standard tests with high sensitivity, was 95-99% [1]. However, false-positive results for anti-HCV canoccasionally occur, especially in populations with prevalencerates below 10% [2-4].There are many reasons why laboratories do not routinelyuse a supplementary test based on immunoblot analysis, suchas the recombinant immunoblot assay, to complement thediagnosis of HCV infection. In addition to the high cost ofsuch a test, the lack of laboratory standards that can evaluateits performance and interpretation, in conjunction with itsactual accuracy, is among the principal reasons. Furthermore,this type of test does not distinguish past from presentinfection, and its use is only indicated for confirmation of EIAresults.In contrast, the use of nucleic acid testing (NAT) makes itpossible to differentiate between viremic and nonviremicindividuals by detection of HCV RNA, allowing the clinician adifferentiated approach to anti-HCV-positive individuals.However, there can be situations in which HCV RNA is notdetected (negative HCV RNA) and the individual has activeinfection with HCV. This can occur in individuals in whomanti-HCV antibody titers are high and RNA titers are low [5].Therefore, HCV RNA might not be detectable in certainindividuals in the acute phase of the disease. However, thesefindings are transient, and chronic infection can develop [6].In addition, HCV RNA intermittent positivity has beenobserved in individuals chronically infected with HCV [6-8].Negativity of HCV RNA results can indicate resolved infection.In 15 to 25% of those anti-HCV positive individuals whoacquired the infection after 45 years of age, the infectionresolves spontaneously. This percentage increases to 40-45%in those who acquired the HCV infection in childhood oryoung adulthood [9].Different tests based on polymerase chain reaction (PCR)have been developed to directly detect the viral particle. Onecharacteristic of real-time PCR is amplification coupled withdetection, which allows the evaluation of the number of viralgenomes at the onset of and throughout the reaction.Qualitative detection of HCV RNA by reverse transcriptase(RT)-PCR is generally accepted as the most sensitive andstandardized test to date [10,11]. Nevertheless, there is variabilityamong the results from different laboratories, as evidenced bythe use of international panels of proficiency. The accuracyand reliability of the results are directly related to the laboratoryprocedures adopted in the performance of the tests [12]. Thelack of preliminary care in sample collection, in conjunctionwith the time involved in preparing and separating the samples,can result in incorrect results. It is extremely important that alllaboratory procedures comply with Good Laboratory Practiceand strictly follow the protocols standardized by themanufacturers of the diagnostic kits and reagents.The gold standard consists of the careful use of NAT,standardized for detection of HCV RNA, together with EIAs(specificity in conjunction with sensitivity).An alternative to aid diagnosis is the use of the ratiobetween optical density and cut-off value (OD/COV) or thesample/cut-off ratio as an indicator of the true positivity ofthe test. Studies carried out in Brazil show that, in EIAs,reagents with OD/COV greater than 3 are repeatedly associatedwith 100% true-positive results (positive predictive value) andpresent approximately 92% positivity for HCV RNA by RT-PCR [13]. In terms of the population studied, the positivepredictive value is increased when accompanied by riskfactors, high levels of alanine aminotransferase (ALT), or liverdisease.In immunocompetent patients, EIAs present excellentreproducibility; however, in hemodialyzed orimmunocompromised patients, EIA sensitivity is significantlyreduced [14].In low-risk populations, such as blood donors, or inrandom population screening, i.e., in populations that do notpresent risk factors for the acquisition of HCV infection,negative EIA results are sufficient to rule out the presence ofHCV. However, false-positive results can occur in thesepopulations. In such cases, a qualitative study of HCV RNAshould be performed to confirm the diagnosis.In high-risk populations, when there is clinical suspicion ofHCV infection, positive EIA results confirm the exposure toHCV. A qualitative study of HCV RNA should be performed todistinguish individuals with chronic infection from those whohave eliminated the HCV spontaneously.In patients with chronic hepatitis of unknown cause andnegative anti-HCV EIA results, especially inimmunocompromised patients [14], a qualitative study of HCVRNA should be performed. The presence of HCV RNA confirmsthe diagnosis, although a negative result does not rule outHCV infection. In such cases, it is recommended that a newHCV RNA study be performed six months after the first study.Detection of the HCV core antigen by EIA can be an alternativefor early diagnosis of HCV infection.

Hepatites pós-transfusionais na cidade de Campinas, SP, Brasil: I. Incidência, agentes etiológicos e aspectos clínico-epidemiológicos da hepatite por vírus C

We have followed up 111 transfusion receptors in the ambulatory, for at least 180 days, in order to evaluate the occurence of post-transfusional hepatitis and the etiological agents involved in the disease in the city of Campinas, state of Sao Paulo, Brazil. At the end of the study we have diagnosed this hepatitis in 18 (16.2%) subjects. Out of these 18 subjects, 16 (89%) were caused by hepatitis C virus, 1 (5.5%) caused by hepatitis B virus and 1 (5.5%) with undetermined etiology, 15 months after transfusion. The average incubation period of HCV was 71 days and 23% of the HCV positive receptors remained with increased AST/ ALT for more than 6 months. Late serum conversion was observed for anti-HCV in 71.4% of the subjects, averaging 135 days after the transfusion. An ALT dosage and anti-HCV determination, 3 and 6 months after transfusion would diagnose, respectively, 71 and 93% of the cases which developed post-transfusional HCV.