Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy.

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.

Telaprevir twice daily is noninferior to telaprevir every 8 hours for patients with chronic hepatitis C.

BACKGROUND & AIMS: We performed an open-label, multicenter, phase 3 study of the safety and efficacy of twice-daily telaprevir in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis. METHODS: Patients were randomly assigned to groups treated with telaprevir 1125 mg twice daily or 750 mg every 8 hours plus peginterferon alfa-2a and ribavirin for 12 weeks; patients were then treated with peginterferon alfa-2a and ribavirin alone for 12 weeks if their level of HCV RNA at week 4 was <25 IU/mL or for 36 weeks if their level was higher. The primary objective was to demonstrate noninferiority of telaprevir twice daily versus every 8 hours in producing a sustained virological response 12 weeks after the end of therapy (SVR12) (based on a -11% lower limit of the 95% lower confidence interval for the difference between groups). RESULTS: At baseline, of 740 patients, 85% had levels of HCV RNA ≥800,000 IU/mL, 28% had fibrosis (F3-F4), 14% had cirrhosis (F4), 57% were infected with HCV genotype 1a, and 71% had the non-CC IL28B genotype. Of patients who were treated with telaprevir twice daily, 74.3% achieved SVR12 compared with 72.8% of patients who were treated with telaprevir every 8 hours (difference in response, 1.5%; 95% confidence interval, -4.9% to 12.0%), so telaprevir twice daily is noninferior to telaprevir every 8 hours. All subgroups of patients who were treated with telaprevir twice daily versus those who were treated every 8 hours had similar rates of SVR12. The most frequent adverse events (AEs) in the telaprevir phase were fatigue (47%), pruritus (43%), anemia (42%), nausea (37%), rash (35%), and headache (26%); serious AEs were reported in 9% of patients. Rates of AEs and serious AEs were similar or slightly higher among patients treated with telaprevir every 8 hours. CONCLUSIONS: Based on a phase 3 trial, telaprevir twice daily is noninferior to every 8 hours in producing SVR12, with similar levels of safety and tolerability. These results support use of telaprevir twice daily in patients with chronic HCV genotype 1 infection, including those with cirrhosis. ClinicalTrials.gov, Number: NCT01241760.

An update on the management of hepatitis C: guidelines for protease inhibitor-based triple therapy from the Latin American Association for the Study of the Liver.

Hepatitis C is a common cause of end-stage liver disease, and the main indication for liver transplantation in Latin America. Treatment of hepatitis C infected patients improves important long-term outcomes as mortality. Sustained viral response is reached in near 50% of patients with the previous management based in pegylated interferon and ribavirin. Recently new drugs were available increasing sustained viral response significantly, changing the standard of care to triple therapy. This guidelines provides a framework for practitioner in Latin America, to the management of patients with hepatitis C chronic infection. 

Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial.

INTRODUCTION: A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care(pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin. MATERIAL AND METHODS: Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). RESULTS: The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 IU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6-72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. CONCLUSION: Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.

Infection with hepatitis C virus among health care workers in the Brazilian Western Amazon region (Rio Branco, State of Acre).

Clinical and epidemiologic studies on the hepatitis C virus (HCV) in the western Brazilian Amazon region are scarce. However, reports of clinical cases of hepatitis or pathologies associated to the HCV infection are frequent. In the state of Acre, there have been no studies on the population with the greatest exposure to parenteral transmission of virus infection. The objective of this study was to determine the prevalence of HCV infection among health care workers (HCWs) in this region. Of 2,338 HCWs, 646 were randomly selected for this study. The presence of antibody to HCV was determined. If these persons were antibody positive, they were tested for HCV RNA and the viral genotype was determined. The seroprevalence of antibody to HCV was 4.8% (31 of 646), and 3.7% (24 of 646) of those tested had detectable HCV RNA. Among these 24 viremic cases, HCV genotype 1 was most common (n = 16), followed by genotypes 3 (n = 6), 2 (n = 1), and an unidentified genotype. Infection with HCV (identified by a polymerase chain reaction) was more frequent among those with lower educational levels and lower incomes, those who lived for a longer period in the city of Rio Branco, those who reported intravenous use of vitamin complexes, those with a history of dental treatment, those with alcoholism, and women with history of caesarian parturition. The high prevalence of patients with HCV observed among HCWs in the city of Rio Branco and risk factors indicate the need for prevention and control programs, in addition to assistance programs, because this region is also hyperendemic for hepatitis B virus and hepatitis D virus.

Effect of amantadine on depressive symptoms in chronic hepatitis C patients treated with pegylated interferon: a randomized, controlled pilot study.

OBJECTIVE: Assess the effect of amantadine on depressive symptoms during interferon alfa therapy for hepatitis C virus infection. METHODS: We performed a randomized, controlled trial with 14 hepatitis C virus-infected patients, treated with pegylated interferon alfa-2a 180 microg/wk plus ribavirin 1.200 mg/d. Eight patients were randomized to receive amantadine 200 mg/d, and 6 other individuals were randomized to control group without amantadine. Severity of depression and anxiety was measured using the Hospital Anxiety and Depression Scale, before starting re-treatment, and 4, 12, and 24 weeks after immunotherapy with pegylated interferon alfa-2a. Evaluations were performed by psychiatrists blinded in reference to the state of amantadine treatment. Friedman chi(2) test for repeated measures and Mann-Whitney test for nonparametric data were used to assess significant differences. RESULTS: From baseline to follow-up, no significant increase in mean Hospital Anxiety and Depression Scale scores of depressive symptoms were seen in amantadine group (P = 0.142), meanwhile there was a statistical increase of depression scores in the control group (P = 0.001). CONCLUSIONS: Our randomized pilot study, though small, clearly indicates that interferon alfa-induced depressive symptoms can be prevented by the use of amantadine. However, double-blind placebo-controlled trials with a higher sample size are required to confirm these preliminary findings.

Psychosis during peginterferon-alpha 2a and ribavirin therapy: case report.

Pegylated Interferon-alpha, combined with ribavirin, gives high sustained virological response in patients with hepatitis C virus, an important public health problem and one of the most frequent chronic infectious diseases worldwide. Though it has therapeutic benefits, treatment with IFN-alpha may be complicated by various side effects, especially symptoms of major depression and acute mania. Psychosis is a rare side effect, and its management usually includes discontinuation of IFN-alpha. We report a case of psychotic disorder that occurred during therapy with pegylated Interferon-alpha given associated with ribavirin. After good response to psychiatric treatment, it became possible to finish the anti-viral therapy.

Primary Biliary Cirrhosis and Primary Sjögren's Syndrome: Insights for the Stomatologist.

Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune disease characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Primary Sjögren's syndrome is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly the lachrymal and salivary glands, in the absence of other definitively diagnosed rheumatologic disease. We report a diagnosed case of primary Sjögren's syndrome associated with PBC. A 59-year-old Caucasian woman went to oral evaluation reporting dry mouth, difficulty in eating associated with burning mouth syndrome, dysgeusia and dysphagia. Intraoral examination revealed extensive cervical caries, gingivitis, gingival retraction, angular cheilitis and atrophic tongue. Hyposalivation was detected by salivary flow and Schirmer's test was positive. Antinuclear and antimitochondrial antibodies were both positive. Anti-Ro/SSA and anti-La/SSB antibodies were negative. A minor salivary gland biopsy of the lower lip was performed. Histopathologic analysis revealed lymphocytic infiltrate with destruction of salivary gland architecture in some areas and replacement of glandular tissues by mononuclear cells. Optimal management of PBC associated with Sjögren's syndrome requires a multidisciplinary approach as the key to optimal patient care. Dental practitioners should be able to recognize the clinical features of this associated condition. Appropriate dental care may prevent tooth decay, periodontal disease and oral infections as well as improve the patient's quality of life.

Is the interferon-α-triggered depressive episode a self-limited kind of depression? Four cases of persistent affective symptoms after antiviral treatment in HCV-infected individuals.

OBJECTIVES: To discuss relevant aspects in a series of cases in which interferon-α-triggered depressive symptoms persisted up to 4 years after therapy cessation in HCV-infected patients. METHODS: Two experienced psychiatrists (AGA and LCQ) identified these four cases in a systematic evaluation program of HCV patients in the Hepatology Unit of the Teaching Hospital at the Federal University of Bahia, Brazil. Lifetime psychiatric diagnoses were confirmed by the Mini International Neuropsychiatric Interview (MINI Plus), and a questionnaire was submitted in order to gather clinical and sociodemographic characteristics. RESULTS: In three out of the four cases identified, major depression diagnosis was reached after more than 12 months of interferon-α therapy interruption and, in one case, depression recurred 6 months after antiviral treatment cessation in a patient on antidepressants. The only case that referred a past history of psychiatric diagnosis reported no offer of mental health care despite the presence of a major depressive episode with psychotic features and suicidal behaviour during the cytokine usage. CONCLUSIONS: Interferon-α-triggered depression may remain undiagnosed even in tertiary university hospitals, may persist years after the antiviral therapy cessation, and may recur even in patients on adequate antidepressant treatment.

The effect of early virological response in health-related quality of life in HCV-infected patients.

Twenty-nine HCV-infected patients were treated with pegylated interferon alpha. Diagnosis was based on serum HCV RNA-PCR positive results and liver biopsy. All patients had elevated serum levels of alanine aminotransferase at the time of the study, but liver disease was compensated. Patients were evaluated at baseline treatment and after 4 and 12 weeks of antiviral treatment with the Medical Outcomes Study 36-item Short-Form Health Survey. The Mini-International Neuropsychiatric Interview was used to exclude previous or current psychiatric diagnoses. Both patients and psychiatrists were blind to the HCV RNA status, and serum HCV RNA test results only became available after the visit at week 12. After antiviral treatment, 16 patients (55.2%) were classified as nonresponders and 13 (44.8%) were classified as responders. When compared to nonresponders, responders had a greater improvement in the HRQOL scores for the mental health domain (P < .019). Differences in other domains were not significant. The present study confirms that active viral infection is one possible reason for the poor Health-Related Quality of Life in this population.

Incidence of psychiatric side effects during pegylated interferon- alpha retreatment in nonresponder hepatitis C virus-infected patients.

OBJECTIVE: Evaluate the incidence of mental disorders using pegylated interferon plus ribavirin retreatment in nonresponder hepatitis C virus-infected patients. METHOD: The Mini-International Neuropsychiatric Interview (MINI) was used to evaluate 30 hepatitis C virus-infected interferon-nonresponder patients at baseline and following 4, 12 and 24 weeks of pegylated interferon retreatment. RESULTS: During the pegylated interferon/ribavirin retreatment, 5(16.6%) patients developed psychiatric side effects: 3(10%) were diagnosed with major depressive disorder, 1(3.3%) had a brief psychotic disorder and 1(3.3%) presented with panic attacks. CONCLUSION: This is the first prospective study evaluating the incidence of neuropsychiatric side effects during interferon retreatment of hepatitis C virus-infected patients, suggesting that the risk of acquiring serious psychiatric symptoms during retreatment with interferon-alpha (IFN-alpha) may not be higher than during the first antiviral therapy. This finding challenges the hypothesis that during a second treatment with IFN-alpha, patients with hepatitis C may be at greater risk for neuropsychiatric side effects than naïve patients.

Anti-Golgi complex antibodies during pegylated-interferon therapy for hepatitis C.

BACKGROUND/AIM: Pegylated interferon (Peg-IFN) plus ribavirin is the standard therapy for hepatitis C. Peg-IFN has several antiviral mechanisms, but its role in hepatitis C treatment seems to be related to its immunomodulatory effect. Ribavirin, an antiviral agent, potentiates IFN activity when added to it. Both drugs are associated with adverse reactions of different magnitudes. Autoimmune phenomena have been reported with this treatment. In this paper, we describe cases of ALT/GGT flares during Peg-IFN plus ribavirin treatment, which related to the appearance of anti-Golgi antibody and disease progress. METHODS: We investigated three patients with hepatitis C and severe ALT/GGT flares during Peg-IFN and ribavirin treatment coinciding with anti-Golgi complex antibody as the only marker of autoimmunity. We then reviewed the medical files and tested anti-Golgi antibody in stored sera from 25 patients treated with conventional IFN and in 14 patients treated with Peg-IFN. RESULTS: The three patients were male, over 45 years of age; all were relapsers and non-responders. Anti-Golgi antibody was positive during treatment coinciding with ALT/GGT flares but with hepatitis C virus (HCV)-RNA negativity, disappearing after stopping treatment, with normalization of ALT/AST levels. One patient had progression of fibrosis from F2 to F3 despite negativity of HCV-RNA. In the last group, only two patients treated with Peg-IFN experienced ALT/GGT flares but without anti-Golgi antibody CONCLUSIONS: The presence of anti-Golgi complex antibody could be a marker of a temporary autoimmune phenomenon and progressive disease.

Peripheral insulin resistance during treatment of chronic hepatitis C with peguilated interferon plus ribavirin.

UNLABELLED: Patients with hepatitis C virus (HCV) infection present higher risk of developing type-2 diabetes mellitus (DM). However, the mechanism of this association and the role of antiviral treatment are still unclear. The objective of this study was to investigate the relationship between the use of peguilated interferon and the development of insulin resistance (IR) in these patients. METHODS: HOMA index was evaluated in 30 HCV-infected patients just before and during the first 6 months of treatment with peguilated interferon plus ribavirin. Anthropometrical parameters and glucose/cholesterol profile were also monitored. RESULTS: No changes in HOMA after 6 months of treatment were observed. Glucose levels decreased but not significantly (P = 0.059). Patients with higher HOMA index after 6 months of treatment also presented higher aminotransferase levels (P = 0.03), higher fat index on computed tomography (P = 0.011), longer time of exposure to the virus (P = 0.021), and a positive smoking history when compared to non-insulin resistant patients (P = 0.045). There was no influence of fibrosis stage on liver biopsy in the insulin-resistance development. CONCLUSIONS: No changes in the IR were observed after 6 months of treatment. Insulin resistance is related to the abdominal fat and anthropometrical parameters rather than to the antiviral treatment.

Intrafamilial prevalence of hepatitis B virus in Western Brazilian Amazon region: epidemiologic and biomolecular study.

BACKGROUND: Hepatitis B is endemic in the Amazon region. METHODS: Serological markers for hepatitis B virus (HBV) were determined in 266 household members for hepatitis B surface antigen (HBsAg)-positive women (G1) and 395 household members for HBsAg-negative women (G2), randomly selected in Acre State Women's Medical Care Program, in order to evaluate the prevalence of HBV in this population. Before blood sample collection an epidemiological questionnaire was applied. RESULTS: The overall prevalence of HBV carriers (HBsAg) and exposed individuals (anti-HBc, IgG) was, respectively, 21.1% and 60.5% in G1 and 2.8% and 27.4% in G2 (P < 0.0000001). The frequency of HBsAg was higher among siblings from group G1 (75%) compared to the absence of any HBsAg-positive sibling in G2 (P < 0.00006). The HBV markers in other family members was as follows: G1 parents, 27.3% vs 4.5% (P < 0.03), sexual partners, 21.1% vs 2.5% (P < 0.04), and offspring, 10.4% vs 1.5% (P < 0.04). A low prevalence of HBsAg and anti-HBc (IgG) was observed for the last offspring of G2 mothers compared to the high prevalence among children of G1 mothers (0% vs 18.2%, P < 0.01 and 2.3% vs 59.1%, P < 0.0000005, respectively), with children younger than 1 year being the most affected. The frequency of the habit of sharing toothbrushes and the presence of at least one HBsAg carrier were higher in G1 than in G2 (P < 0.0001 and P < 0.000002), respectively. Genotypes A, D and G were found to be predominant by Innolipa test. There were cases that reacted to more than one genotype. CONCLUSION: Intrafamilial transmission of HBV is evident in the present study and is possibly associated with the presence of more than one HBV carrier in the family and the shared use of toothbrushes among household contacts. Genotype analysis confirms intrafamilial transmission.

Detection of hepatitis C virus RNA in saliva is not related to oral health status or viral load.

Hepatitis C is a worldwide public health problem and its transmission is clearly associated with the parenteral route, however, the virus has also been isolated from other body fluids. Hepatitis C virus (HCV) RNA has been detected in saliva, yet the relationship between HCV and oral pathology is not clearly understood. Therefore, an investigation on HCV-RNA in saliva and its correlation with oral pathology was undertaken. Saliva and blood samples were collected from 50 anti-HCV positive patients and from 25 patients with non-HCV chronic liver disease. HCV-RNA was detected in all of the saliva samples from the HCV positive group. None of the saliva or serum samples from the non-HCV group were positive for HCV-RNA. The patients were examined for dental and oral health (dentate, partially dentate, edentulous, evidence of gum disease, or mucosal lesions); however, no correlation was found between HCV-RNA in saliva, oral health, and viral load. These results suggest that HCV-RNA presence in saliva is independent of the viral load and the oral pathology of HCV positive individuals.

Frequency of celiac disease and its serological markers in patients with autoimmune hepatitis

Transglutaminase (anti-tTG) and anti-endomysial (AEA) antibodies were reported to occur in patients with autoimmune hepatitis (AIH) as well as in subjects with advanced cirrhosis, but the prevalence of celiac disease (CD) in patients with AIH is either negligible or unknown. The frequency of IgA anti-tTG and IgA AEA was determined in 64 patients (54 females, mean age 19[5-67] years ) with AIH diagnosed according to international criteria. Patients with positive or intermediate results for those antibodies were submitted to duodenal biopsy and HLA-DQ2 or DQ8 typing. Anti-tTG and AEA were detected in 6 (9 por cento) and one patient (1.6 por cento) with AIH, respectively. Positive and borderline results for IgA anti-tTG were detected, respectively, in two (3 por cento) and four (6 por cento) patients. Only one patient with HLA-DQ2 and IgA anti-tTG and IgA AEA had CD on duodenal biopsy. Two patients with either positive or borderline results for IgA anti-tTG antibody and HLA-DQ2 had normal histology on duodenal biopsy. IgA anti-tTG antibody and/or AEA were observed in 9% of AIH patients, but CD was confirmed in only one of them. The occurrence of IgA anti-tTG antibody in the other patients could be ascribed to the presence of chronic liver disease or to latent or potential CD.

Psychosis during peginterferon-alpha2a and ribavirin therapy: case report

Pegylated Interferon-alpha, combined with ribavirin, gives high sustained virological response in patients with hepatitis C virus, an important public health problem and one of the most frequent chronic infectious diseases worldwide. Though it has therapeutic benefits, treatment with IFN-alpha may be complicated by various side effects, especially symptoms of major depression and acute mania. Psychosis is a rare side effect, and its management usually includes discontinuation of IFN-alpha. We report a case of psychotic disorder that occurred during therapy with pegylated Interferon-alpha given associated with ribavirin. After good response to psychiatric treatment, it became possible to finish the anti-viral therapy.

VHC e HTLV-I: aspectos clínicos e epidemiológicos da co-infecção / VHC and HTLV- I: clinical and epidemiologic aspects of co-infection

O vírus da hepatite C (VHC), que infecta cerca de 3 por cento da população mundial, o que equivale aproximadamente a 170 milhões de pessoas, e o human T-cell lymphotropic virus-I (HTLV-I), responsável por infecção endêmica em diversas regiões do mundo, são entidades que possuem uma alta prevalência em nosso meio. A co-infecção pelos dois vírus ainda é muito pouco entendida nos seus aspectos clínicos e epidemiológicos. É de especial importância o seu conhecimento por médicos baianos, uma vez que o Estado da Bahia é um dos possíveis locais em que a co-infecção tem impacto epidemiológico importante. Existe um grande conhecimento acerca de cada vírus individualmente, porém as repercussões da co-infecção têm sido muito pouco estudadas. Por suas características de infectarem células do sistema imune e levarem a diferentes modulações na resposta imunológica do organismo, esperam-se alterações na evolução natural da infecção por estes dois vírus. Através da revisão sistemática de publicações, procurou-se levantar dados sobre a co-infecção VHC/HTLV-I e seus efeitos sobre o organismo. Devido à escassez de trabalhos publicados acerca deste tema, concluiu-se que há uma grande lacuna de conhecimento a ser explorada. Dessa forma, objetiva-se uma revisão bibliográfica útil ao médico clínico sobre o recente avanço do conhecimento da co-infecção, a fim de colaborar para o entendimento do impacto na vida de pacientes infectados por esses dois vírus