Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

A controlled study of treatment with recombinant interferon alpha in chronic hepatitis B virus infection: induction and maintenance schedules.

To determine the antiviral effect of recombinant-interferon (rIFN)-alpha in hepatitis B virus (HBV) chronic infection, a controlled study was carried out. A total of 20 HBsAg chronic carriers (18 chronic active hepatitis and 2 chronic persistent hepatitis) were included. All of them had remained HBeAg, HBV-DNA and HBV-DNA polymerase (HBV-DNAp) positive at least six months before treatment. The patients were randomly assigned to two groups: control (n = 10), and treatment (n = 10). A dose of 5.5 megaunits of rIFN-alpha/m2 body surface was administered every day for 21 days (induction) and twice a week for six months thereafter (maintenance). No basal differences were observed between the two groups. No case of intolerable toxicity was observed. One treated patient died in a car crash in the second month. At the end of the first week of therapy, 7/10 (70%) of the treated patients became HBV-DNAp negative. However, in the fifth month only 2 patients remained HBV-DNAp negative and also became HBV-DNA and HBeAg negative. In contrast, no changes in viral markers among control cases were observed. In conclusion, rIFN-alpha has an antiviral effect on chronic HBV infection; however, the induction plus maintenance schedule is not useful to obtain a permanent effect.

Vaccination against hepatitis B in renal dialysis units: short or normal vaccination schedule?

Three I.M. injections of hepatitis B vaccine (Merck Sharp & Dohme) were administered, according to the recommended schedule (0, 1, 6 mos), to seronegative individuals of one renal dialysis unit (33 patients, 58 health care personnel) and, according to a shorter regimen (0, 1, 3 mos), in another unit of similar characteristics (30 patients, 53 health care personnel). Staff members and renal patients received, respectively, 20 y 40 mcg of vaccine per injection. In the early vaccination phase, the two regimens did not lead to a difference in seroconversion rates nor in anti-HBs titers. After a 9-month surveillance, lower seroconversion rates, although not significant, were observed with the accelerated regimen among staff members (84.2%) and renal patients (79.2%) as compared with 93% and 87.5%, respectively, following the normal schedule. At the same time, anti-HBs titers were significantly lower (p less than 0.001) in the staff (316 RIA U) and patients (93 U) vaccinated according to the short regimen than in their respective counterparts (4196 and 1047 U) assigned to the normal schedule. A fourth dose of vaccine given to subjects with low and no anti-HBs titers significantly increased seroconversion and anti-HBs levels, although with little success among the former non-responders.

Receptors for polymerized human serum albumin and other hepatitis B virus markers during acute hepatitis B--predictive value of the outcome of the disease.

Polymerized human serum albumin virus receptors (pHSA-R) HBsAg, HBeAg, antiHBc-IgM, hepatitis B virus (HBV) DNA polymerase activity and HBV-DNA were studied in 47 acute hepatitis B patients, divided into three groups: 26 HBeAg(+) initially, with favorable outcome; 4 HBeAg (+), with chronic outcome; and 17 antiHBe (+), with favorable outcome. In the basal sample only 2 and 8 patients in Group I were HBV-DNAp and HBV-DNA positive, respectively, and became negative during the follow-up. In contrast all patients in Group II remained positive to both HBV-markers. After a one-month follow-up 100% of the patients in Group II were positive for pHSA-R and HBeAg, in contrast to 25% among those with a favorable outcome in Group I (p less than 0.005). Meanwhile, only 6 out of 17 patients in Group III remained positive for pHSA-R. A significant decrease in pHSA-R and HBsAg concentrations was observed in patients from Group I (p less than 0.005 and p less than 0.05, respectively) 15 days after the onset of the disease, while concentrations of both parameters did not vary in Group II. A significant decrease in HBsAg and pHSA-R concentrations was found in patients from Group III after 15 days (p less than 0.05) and one month follow-up (p less than 0.05), respectively. As a result, pHSA-R and HBeAg are the best prognostic indicators in acute hepatitis B. A decrease in HBsAg and pHSA-R concentrations two weeks after the onset may have predictive value.

Antiviral effect of recombinant gamma interferon in chronic hepatitis B virus infection: a pilot study.

A pilot study has been designed in order to determine the tolerance and effectiveness of recombinant interferon gamma (rIFN-gamma) in chronic hepatitis B virus (HBV) infection. Eight HBsAg, HBeAg, HBV-DNAp and HBV-DNA-positive patients were randomly assigned to one of two groups. In group 1, 0.25 mg of rIFN-gamma/m2 body surface was administered daily for 28 days to 4 patients. In group 2, 0.10 mg of rIFN-gamma was administered to 4 patients under the same conditions. All the patients concluded the treatment and were observed over 11 more months. During treatment, 6 out of 8 patients showed decreased levels of HBV-DNA and HBV-DNAp. In addition, by the 8th month of follow-up, six patients became negative for HBV-DNAp and 2 for HBcAg; all patients remained positive for HBV-DNA. At the end of the study, only 2 patients remained negative for HBV-DNAp, 4 for HBcAg and one became negative for HBV-DNA. No differences in antiviral effect were observed between the two groups. Furthermore, the T4/T8 lymphocytes ratio increased during therapy. In conclusion, rIFN-gamma may play a role in the treatment of chronic HBV infection.

Different doses of recombinant alpha interferon in the treatment of chronic hepatitis B patients without antibodies against the human immunodeficiency virus.

A total of 24 chronic carriers of HBsAg, HBeAg and hepatitis B virus (HBV)-DNA were included in a controlled trial. The patients were randomly assigned to four groups: Group I (n = 6): control; group II (n = 6): 2.5 MU; group III (n = 6): 5 MU and group IV (n = 6): 10 MU rIFN-alpha/m2 body surface 3 times weekly i.m. during 6 months. At the end of the treatment, all patients under therapy, as well as 4 belonging to the control group, lost HBV-DNA polymerase. HBV-DNA became negative in 3 (50%), 1 (17%), and 2 (33%) patients from groups II, III, and IV, respectively, while all patients from the control group maintained HBV-DNA. At 15 months of follow-up, 6 patients (33%) under therapy (2 from each group) and 1 from the control group remained HBV-DNA-negative. Knodell's index decreased significantly on comparing basal and final liver biopsies among patients in group IV (16.0 +/- 1.9 vs 7.0 +/- 1.9, p less than 0.01), while no changes were observed in the other groups. Five patients (27%) developed anti-IFN antibodies during treatment. In summary, although low doses of rIFN-alpha (2.5-5 MU) had an antiviral effect on HBV replication, only patients treated with 10 MU showed a significant decrease in liver histological activities. In addition, the effectiveness of rIFN-alpha therapy may be negatively influenced by the appearance of anti-IFN antibodies.

[The assessment of cardiac involvement in a case of a thoracic injury from a firearm]. / Valoración de la afectación cardíaca en un caso de herida torácica por arma de fuego.

We report the case of a patient with a gunshot wound in the chest with a multiple small-caliber intrathoracic projectiles. The different noninvasive techniques employed to evaluate the anatomical location of these projectiles are discussed, together with their cardiac structural repercussions. The data provided by a simple chest X-ray, Computed Tomography (CT) and transthoracic echocardiography are commented on. A simple chest X-ray was unable to discern the location of the projectiles, in contrast to CT, which was able to identify both the number of projectiles and their location. The information provided was enhanced by transthoracic echocardiography, particularly in relation to those projectiles situated in anterior cardiac regions.

[Characteristics of atrial electrograms recorded in radiofrequency induced block lines in an experimental model]. / Características de los electrogramas auriculares registrados en las líneas de bloqueo producidas con radiofrecuencia en un modelo experimental.

AIM: To analyze and quantify atrial electrogram modifications following the induction of linear lesions in the atrial wall using radiofrequency ablation procedures. METHODS: An epicardial multiple electrode (221 unipolar electrodes) was used in 12 Langendorff perfused rabbit hearts to analyze atrial activation before and after radiofrequency induction of a linear lesion in the left atrial wall. After confirming the existence of conduction blockade in the lesion zone by epicardial mapping and propagation vector analysis, six electrodes each were selected in the lesioned and non-lesioned zones in all experiments, comparing the amplitude, maximum negative slope and morphology of the electrograms in both zones, before (control) and after radiofrequency delivery. RESULTS: Analysis of the reproducibility of the measurements in two consecutive cycles showed a variation of 1 +/- 5% for amplitude (NS) and 1 +/- 9% for maximum negative slope (NS). In the non-damaged zone, amplitude (105 +/- 22%) and slope (92 +/- 16%) (values normalized with respect to those recorded before radiofrequency) did not vary significantly following radiofrequency, and simple electrograms were the most frequent recordings (82 vs 83% in control; NS). Amplitude (19 +/- 7%, p < 0.001) and slope (24 +/- 11%; p < 0.001) decreased significantly in the lesion zone, as did the percentage of simple electrograms (6 vs 86% in control; p < 0,001). In this same zone the morphology could not be determined in 12% of the recordings, while multiple electrograms were obtained in 15% (vs 2% in control; p < 0.01), and the most frequent type corresponded to double electrograms (67 vs 12% in control, p < 0.001), with both components coinciding in time with atrial activation in the zones proximal and distal to the lesion line. CONCLUSIONS: Electrograms recorded directly in radiofrequency induce block lines show a significant decrease in amplitude and maximum negative slope. Double electrograms predominate in these recordings, both components of which represent activation on either side of the lesion. In a small proportion of cases simple and multiple electrograms can also be recorded in the block line.

[The activation patterns during atrial fibrillation in an experimental model]. / Patrones de activación durante la fibrilación auricular en un modelo experimental.

INTRODUCTION AND OBJECTIVES: In atrial fibrillation, along with the mechanisms of complete reentry and random activation focal activation patterns have been described which have been attributed both to propagation from the endocardium and to the existence of zones with automatic activity. The objectives of present study are to analyze and quantify the atrial activation patterns in an experimental model of atrial fibrillation. MATERIAL AND METHODS: In 11 Langendorff-perfused rabbit hearts atrial fibrillation was induced by atrial burst pacing after right atrial dilatation with an intra-atrial balloon. A multiple electrode consisting of 121 electrodes and positioned in the right atrial free wall was used to construct the activation maps corresponding to 10 segments of 100 ms in 11 different episodes of sustained atrial fibrillation (one per experiment). RESULTS: Of the 110 segments analyzed, 44 (40%) corresponded to random activation patterns. Fifteen segments (14%) corresponded to complete reentry, and in these cases the number of consecutive rotations ranged from 1 to 2.25 (mean 1.4 +/- 0.4). In 49 segments (44%) a single activation front was seen to pass through the recording area without block; alternatively, two simultaneous fronts were recorded that did not re-excite the zone activated by the other. In two segments (2%) there was a focal activation pattern without evidence of propagation from the epicardium surrounding the activated zone. CONCLUSIONS: a) in the experimental atrial fibrillation model used, random activation patterns are more frequent than complete reentry patterns; b) complete reentry can occur in areas smaller than 1 cm2, and c) focal activation during atrial fibrillation is rare.

Hepatitis B surface antigen/IgM complexes: relation to receptors for polymerized human serum albumin, hepatitis B virus (HBV) DNA polymerase activity and HBV markers.

The presence and the level of hepatitis B surface antigen (HBsAg)/IgM complexes were determined in 54 chronic HBsAg carriers in relation to receptors for polymerized human serum albumin (pHSA-R) tested by specific radioimmunoassay, and to hepatitis B virus-DNA polymerase (HBV-DNAp). HBsAg/IgM complexes, correlated significantly with the HBsAg concentration but, at a similar HBsAg concentration, significant highest values of HBsAg/IgM complexes were found among HBeAg positive patients. In addition, a significant correlation was found between HBsAg/IgM complex levels, HBeAg titres and HBV-DNAp activity (r = 0.628, p less than 0.001 and r = 0.559, p less than 0.001, respectively). Moreover, a positive linear correlation was found when comparing HBsAg/IgM complexes and pHSA-R levels (r = 0.848, p less than 0.001). Patients who were positive for HBsAg/IgM complexes had a significantly higher glutamate-pyruvate transaminase (GPT) level than those who did not show any complexes. In conclusion, HBsAg/IgM complexes seemed to be indirectly related to HBV replication.

Different levels of hepatitis B virus replication among hepatitis Be antigen-positive chronic carriers.

Detection of hepatitis B virus DNA polymerase (HBV DNA-pol) activity and of HBV DNA sequences in serum allowed to distinguish the different degrees of HBV replication in chronic HBsAg carriers. The amount of HBV DNA in the serum of 48 HBsAg and HBeAg positive patients in relation with the presence or absence of HBV DNA-pol was determined by dot-blot hybridization. The HBeAg positive cases with HBV DNA-pol activity had significantly higher HBV DNA levels than those which were DNA-pol negative (p less than 0.001). However, no significant differences with respect to liver function tests (transaminase, albumin, gammaglobulin) or to the histological diagnosis were found between both groups. Quantitative detection of serum HBV DNA in HBsAg chronic carriers may be helpful for learning the natural history of HBV infection and monitoring the antiviral therapy.

[A controlled study of treatment with recombinant interferon alpha of chronic hepatitis due to the B virus in childhood]. / Estudio controlado de tratamiento con interferon alfa recombinante en la hepatitis crónica por virus B en la infancia.

The natural history of chronic hepatitis B virus (HBV) infection in children may lead to hepatic cirrhosis and hepatoma. Since the antiviral effect of recombinant interferon alpha (rIFN-alpha) in the treatment of chronic hepatitis in adults has been proven, a controlled study of therapy using rIFN-alpha in children chronic hepatitis due to HBV has been carried out. Twenty-four children (4-14 years old) HBsAg, HBeAg and HBV-DNA positive were randomly allocated to one of three groups: 1) n = 8, control; II) n = 8, who received 10 MU/m2 of rIFN-alpha (Boehringer Ingelheim)/m2 body surface, I.M., twice a week for six months and III) n = 8, treated with 7.5 MU/m2 under the same conditions. No basal differences between the three groups were observed. No intolerable toxicity was observed and all children completed the treatment period. At the end of the therapy, 5 patients in groups I (1 case), II (2 cases) and III (2 cases), had lost circulating HBV-DNA. With respect to HBeAg, 3 patients (one from each group) were negative by the sixth month, developing anti-HBe. Decreases in ALT levels among rIFN-alpha responder patients were observed, while no changes occurred in the rest. A significant decrease in the percentage of HBcAg positive hepatocytes was detected only among treated patients, when comparing the basal and final liver biopsies. In summary, rIFN-alpha therapy in children is well tolerated. In addition, these results suggest that rIFN-alpha has an antiviral effect.

[Cancer of the middle third of the choledochus: an infrequent diagnosis]. / Cáncer de tercio medio de colédoco: un diagnóstico infrecuente.

We report the case of an 80-year-old woman with a previous history of HBP, hysterectomy due to cancer of the uterus and cholelithiasis, who was admitted in our hospital because of diffuse abdominal pain, marked jaundice, choluria and acholia during one week, together with anorexia and loss of weight. Blood chemistry results disclosed a total bilirubin of 11 mg/dl, a direct bilirubin of 8 mg/dl, GGTP 826 U/I, alkaline phosphatase 287 U/I, AST 285 U/I, ALT 837 U/I and LDH 242 U/I. The CA 19-9 marker was higher than 500 U/ml. The abdominal ultrasound examination did not show any space-occupying lesions; the extra and intrahepatic bile ducts were very dilated and the gall bladder showed multiple stones within its contents. The endoscopic retrograde cholangiopancreatography (ERCP) showed a homogeneous filiform defect at the middle third of the common bile duct of approximately 1 cm in length and with a marked dilatation of the bile ducts. A percutaneous drainage of the bile tree was performed, but the patient died.

Receptors for polymerized human serum albumin in plasma derived hepatitis B vaccines.

The presence of polymerized human serum albumin receptors (pHSA-R) in two hepatitis B virus (HBV) plasma derived vaccines (HB-Vax, Merck Sharp and Dohme; Hevac-B, Pasteur) was detected by three methods, using pHSA polystyrene coated beads and 125I-anti-HBs (method 1) and polyclonal (method 2) or monoclonal (method 3) peroxidase conjugated anti-HBs. Only a very weak reaction was found for pHSA-R in HB-Vax vaccine when the tests were performed in undiluted vaccine. No reactivity in 1/100 dilution (normally used to test pHSA-R in serum samples) was observed. In contrast, Hevac-B vaccine contained pHSA-R activity in 1/100 dilution as tested by any of the three methods. Furthermore, the level of pHSA-R detected in Hevac-B vaccine is similar to that observed in asymptomatic HBsAg carriers with the same HBsAg concentration. In summary, Hevac-B vaccine contains pHSA-R, whilst HB-Vax shows only weakly reacting pHSA-R, probably insufficient to develop anti-pHSA-R antibodies.

Hemagglutination and immunofluorescence studies on polymerized human serum albumin binding activity in chronic hepatitis B virus infection.

The binding activity of polymerized human serum albumin was determined in 202 HBsAg carriers. The presence of polymerized human serum albumin receptor sites was tested by hemagglutination and differentiated from antihuman albumin antibodies by immunofluorescence, isolation of IgG and IgM fractions and testing of HBsAg anti-HBs immune complexes. A granular pattern with anti-HBs was specific for polymerized human serum albumin receptor sites as demonstrated with purified HBsAg. In addition, a linear pattern with fluoresceinated antihuman immunoglobulins might suggest the presence of antihuman albumin antibodies (which was generally due to an IgG antibody). However, a granular pattern with fluoresceinated antihuman immunoglobulins may indicate the presence of HBsAg anti-HBs immune complexes. A weak linear pattern was also observed simultaneously in these cases, probably due to IgM antihuman albumin antibodies or an antipolymerized human serum albumin receptor site antibody. Of 202 HBsAg-positive patients, 71 showed polymerized human serum albumin receptor sites activity. The highest percentage of polymerized human serum albumin receptor sites was found among patients showing HBeAg and hepatitis B virus DNA polymerase positivity (96%), followed by HBeAg positivity and hepatitis B virus DNA polymerase negativity (48%), and anti-HBe positivity and hepatitis B virus DNA polymerase negativity (17%). In addition, a significant correlation between polymerized human serum albumin titers and hepatitis B virus DNA polymerase was found (r = 0.573, p less than 0.01). However, at similar HBeAg titer, patients who were positive for hepatitis B virus DNA polymerase had a higher polymerized human serum albumin receptor sites titer than those who were negative for hepatitis B virus DNA polymerase.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of chronic delta infection with recombinant human interferon alpha 2c at high doses.

Superinfection by hepatitis delta virus (HDV) in hepatitis B virus chronic carriers is normally associated with a progressive liver injury. For this reason, the aim of the present study was to determine the efficacy of recombinant interferon alpha (rIFN-alpha) treatment of chronic delta hepatitis, by giving high doses of rIFN-alpha 2c during a prolonged period. A total of 20 HBsAg, anti-HD carriers with a chronic active hepatitis were randomly allocated in two groups: (I) n = 10, control and (II) n = 10, treated with 10 MU/m2 body surface of rIFN-alpha, twice weekly, intramuscularly (im) during 6 months. Basally, all patients presented HDAg in the liver and serum IgM anti-HD. Serum HDV-RNA was positive in 8 and 7 patients from groups I and II, respectively. The interferon therapy was well tolerated and all patients finished the treatment period. During the first 6 months, a decrease in ALT levels among treated patients (255 +/- 98 vs. 193 +/- 117) was observed. In addition, a transient drop in HDV-RNA levels was also observed. No changes in anti-HD titer, IgM anti-HD and HBsAg concentration were detected. At the end of the follow-up period (15 months) two treated patients had lost IgM anti-HD. In addition, another two patients were HDV-RNA negative. In conclusion, no permanent antiviral effects of rIFN-alpha 2c in chronic delta hepatitis, using this schedule, was achieved.

Long-term follow-up of hepatitis B chronic carriers who responded to interferon therapy.

We studied the long-term outcome of patients with chronic hepatitis B virus (HBV) infection who responded to interferon (IFN) therapy. Between 1983 and 1988, 120 patients were included in 5 different protocols; 94 patients were treated with IFN and 26 were controls. Loss of serum HBV-DNA was considered a partial response and occurred in 34 of the treated patients and in 10 of the controls. Only the partial-response patients were followed up for 14-64 months (mean 46 months). HBeAg disappeared in 32/34 of the partial-response treated patients and in 9/10 of the controls. During the follow-up period, 6/34 (18%) treated patients and 1/10 controls suffered a reactivation of the disease with reappearance of HBV-DNA. Only 8/34 (23%) treated patients and 1/10 of the controls lost HBsAg; no statistical differences were observed in baseline characteristics between HBsAg-negative patients and patients who remained HBsAg-positive. Of eight HBsAg-negative treated patients, four were serum HBV-DNA-negative upon polymerase chain reaction and thus formed the HBsAg-negative control cases. Although the frequency of HBsAg loss in treated patients is relatively low, the improvement in liver disease obtained from IFN therapy is sustained over a long period.

Detection of serum inhibitory factor for lymphocyte stimulation in chronic viral hepatitis: relationship with the replication level.

Sera from 111 patients with chronic viral hepatitis and from 55 cases with other liver disorders were assayed for serum inhibitory factor. The prevalence of this immunosuppressive factor was very similar between chronic hepatitis B (61%), chronic hepatitis delta (57%) and chronic hepatitis C (68%). At the same time, serum inhibitory factor was never detected in the other disorders studied. The presence of this inhibitory factor was detected in a significantly higher percentage (p less than 0.05) of HBeAg, HBV-DNA positive cases (75%) than in anti-HBe positive, HBV-DNA negative cases (44.4%). In chronic hepatitis delta, this immunosuppressive factor was also related to HDV-RNA positivity. The detection of this serum immunosuppressive factor in chronic viral hepatitis and its association with a high viral replication level implies a possible role of this factor in the immune pathogenic mechanism in infectious viral hepatitis.