Treatment of chronic hepatitis B with alpha-interferon. Present and future.
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Chronic Disease↗
Biomedical subjects
J A Quiroga
Publications and source records attributed to J A Quiroga.
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.
Adult↗
Detection of antibody to calmodulin in chronic viral hepatitis: lack of correlation with virus replication and hepatocellular damage.
We have analyzed the presence of IgG and IgM anti-calmodulin antibodies (anti-CaM) by ELISA in patients with chronic hepatitis due to B, delta and C viruses as well as in patients with other liver diseases. The specificity of the assay was demonstrated by preadsorption of positive serum with calmodulin (CaM) but not with myosin light chain. Among 164 patients with chronic viral hepatitis (B, delta and C) and 50 with non-viral hepatitis, 27 and 26%, respectively, had auto antibodies against CaM. There was a significantly increased frequency (37%) of these auto-antibodies in chronic delta infection as compared to that (21%) of patients with chronic B hepatitis (p less than 0.05). An intermediate incidence of anti-CaM, (24%) was found in chronic C infection. The frequency of anti-CaM was not related to the level of hepatitis B virus (HBV) or hepatitis delta virus (HDV) replication. A high occurrence of anti-CaM in the presence of liver membrane antibody (p less than 0.03) was observed. During follow-up of patients with chronic delta-hepatitis, the presence of anti-CaM was consistently observed, when the isotype was IgM, but transiently when it was IgG. The occurrence of anti-CaM correlated neither with ALT levels nor with histological diagnosis. Antibodies to CaM, are present in liver diseases especially in chronic delta-hepatitis, and do not play a pathogenic role on hepatocellular damage.
Adolescent↗
Analysis of serum pre-S antigens in chronic hepatitis B virus infection in relation to the expression pattern of hepatitis B virus DNA in the liver.
Pre-S antigens have been analyzed in the serum of patients with chronic hepatitis B virus (HBV) infection according to the expression pattern of HBV DNA in the liver. Pre-S1 and pre-S2 have been identified (1) in all viremic cases with free replicative forms of viral DNA irrespective of the simultaneous detection of integrated sequences; (2) in 2 out of 3 patients with only integrated HBV DNA, and (3) in 19 patients who lacked viral DNA sequences detectable in the host genome. The amounts of hepatitis B surface and pre-S antigens were significantly higher in high-viremic versus low-viremic patients and correlated with the hepatocellular expression of HBV DNA. Conversely, the pre-S-to-hepatitis B surface antigen ratios were lower in the presence of viral DNA sequences in the liver. In summary, detection and level of pre-S antigens are closely related to the hepatocellular expression of viral DNA and seem to reflect reliably different stages of the virus life cycle during the course of HBV infection.
Adult↗
Recombinant gamma-interferon as adjuvant to hepatitis B vaccine in hemodialysis patients.
Patients undergoing long-term hemodialysis are at high risk of acquiring hepatitis B yet tend to have poor rates of response to hepatitis B vaccine. The effect of recombinant human gamma-interferon (2 million units/m2) on the response to a recombinant hepatitis B vaccine was evaluated in a prospective, randomized controlled trial in 81 hemodialysis patients. A similar proportion of both groups of vaccinees ultimately developed antibody to HBsAg including 81% of the 41 recipients of vaccine alone (group I) and 89% of the 40 recipients of vaccine with gamma-interferon (group II). However, the antibody to HBsAg response occurred earlier in recipients of vaccine with gamma-interferon, so that at 4 mo 63% of group I and 88% of group II had antibody to HBsAg (p less than 0.025). Furthermore, titers of antibody to HBsAg tended to be higher in the vaccinees given interferon; the final geometric mean titers were 232 IU/L in group I and 330 IU/L in group II (p = not significant). Retrospective testing for antibody to hepatitis C virus revealed that 21 (26%) hemodialysis patients were seropositive at entry into this trial, but the presence of antibody to hepatitis C virus did not appear to affect the response rate to the hepatitis B vaccine. These results suggest that the effects of gamma-interferon as an adjuvant in increasing the response rate to hepatitis B vaccination deserve further evaluation perhaps most appropriately in persons who have not responded to an initial course of vaccine.
Adult↗
Prolonged treatment (18 months) of chronic hepatitis C with recombinant alpha-interferon in comparison with a control group.
The effectiveness of recombinant alpha-interferon was evaluated in chronic non-A, non-B hepatitis of parenteral transmission. Thirty patients were randomly allocated two groups: control group (without treatment) and treatment group (alpha-interferon 5 mega units thrice weekly for 2 months, and then 1.5 mega units until the eighteenth month). Retrospectively, 26 patients had anti-hepatitis C antibodies. After the first month, 40% of the treated patients had normal serum alanine aminotransferase levels, and no one in the control group (p less than 0.05). After 18 months of treatment, 40% (6/15) of treated patients and 7% (1/14) of controls had normal serum transaminases (p less than 0.05). Interferon was well tolerated. A decrease in the Knodell Index score on final biopsy was found in treated patients (p less than 0.05), with no variations in the control group. Relapse within 7 months after the end of treatment occurred in two out of six complete responders. Thus, recombinant alpha-interferon therapy given for 18 months normalizes serum transaminases and improves histological lesions in chronic hepatitis C of parenteral epidemiology. This long-term interferon schedule is well tolerated.
Adult↗
Changes in anti-idiotype antibodies against anti-HBs during recombinant interferon treatment of chronic hepatitis B.
To determine the possible changes in the presence and level of anti-idiotype (anti-Id) antibodies against anti-HBs induced by recombinant interferon (rIFN) therapy in chronic hepatitis B virus (HBV) infection, a study of patients under rIFN treatment has been carried out. A total of 62 (38 treated and 24 controls), HBeAg and HBV-DNA positive HBsAg carriers were tested serially for the presence of IgG and IgM anti-Id antibodies. According to serological evolution, treated patients were divided in responders (HBeAg and HBV-DNA became negative) (n = 18) and nonresponders (n = 20). Control patients were also classified as having spontaneous seroconversion (n = 11) and without changes (n = 13). Basally all patients had IgG and IgM anti-Id. At the end of the follow-up period (15th month), a significant decrease was observed in the percentage of cases positive to anti-Id among rIFN-responders (IgG, 67%, p less than 0.01; IgM, 44%, p less than 0.001). In contrast, only one nonresponder lost IgM anti-Id during the study. Among controls, only one with spontaneous loss of HBV-DNA and HBeAg clearance became negative to both IgG and IgM anti-Id. In addition, in the basal sample, the rIFN-responders had significantly lower anti-Id levels than the nonresponders (p less than 0.05). Similar results were obtained when comparing the controls with or without spontaneous response (p less than 0.05). Furthermore, a significant decrease in the anti-Id levels among the rIFN responders at the 9th month was detected (p less than 0.01). In summary, the anti-Id antibodies decreased significantly in patients who became HBV-DNA negative following rIFN administration. This result confirms the close relationship between HBV replication and the anti-idiotype against anti-HBs.
Adolescent↗
Detection of HBeAg/anti-HBe immune complexes in the reactivation of hepatitis B virus replication among anti-HBe chronic carriers.
Sixty-four chronic hepatitis B surface antigen (HBsAg) carriers with hepatitis B e antibody (anti-HBe) were followed in order to detect reactivations of hepatitis B virus (HBV) infection and to assess the incidence and specificity of hepatitis B e antigen/hepatitis B e antibody (HBeAg/anti-HBe) immune complexes (ICs). In 18 out of 19 patients who suffered an increase in alanine transaminase (ALT) values, serum HBV-DNA reappeared co-occurring with the peak(s) of transaminases. HBeAg/Anti-HBe immune complexes were detected in 17/18 (94.4%) patients positive for HBV-DNA. In nine of them, the appearance of immune complexes co-occurred with prednisone therapy, in two following seroconversion after recombinant interferon alpha-2A treatment, and spontaneously in the remaining seven patients. When ALT levels dropped to normal values, immune complexes as well as HBV-DNA became undetectable. In conclusion, the detection of HBeAg/anti-HBe immune complexes seems to be a specific method to detect HBV replication among anti-HBe positive patients.
Antigen-Antibody Complex↗
[Vaccines against the hepatitis B virus. The outstanding problems].
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Hepatitis B↗
Interferon and hepatitis B vaccine in haemodialysis patients.
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Follow-Up Studies↗
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.
Adult↗
Assessment of hepatitis B virus DNA levels in chronic HBsAg carriers with or without hepatitis delta virus superinfection.
In order to document the incidence of hepatitis delta virus (HDV) replication markers and their relationship to HBV replication, 91 HBsAg chronic carriers were studied. Of these, 51 were anti-HD-positive (19 HBeAg-positive and 32 anti-HBe-positive). Liver HDAg was found in 75% of anti-HD-positive patients. Of the 19 patients who had anti-HD and HBeAg, 13 were HBV-DNA-positive. None of the anti-HBe patients were HBV-DNA-positive. No differences with respect to HBV-DNA concentration were observed between anti-HD-positive and -negative patients. Liver HDAg was detected with similar frequency in patients who were HBeAg- and HBV-DNA-positive (63.6%) and in those who were anti-HBe-positive (78.5%), with no statistically significant difference. HBcAg and HDAg were simultaneously detected in 36% of the anti-HD cases. Patients with anti-HD and HBV-DNA had the highest levels of transaminases (SGPT). Our results suggest that in certain patients HDV and HBV replication coexists without mutual inhibition.
Adult↗
Elevation of 2',5'-oligoadenylate synthetase activity and HLA-I associated beta 2-microglobulin in response to recombinant interferon-gamma administration in chronic HBeAg-positive hepatitis.
We have analyzed the immunomodulatory effect of 5 and 2 MU of recombinant interferon-gamma (rIFN-gamma) administered to 8 carriers of HBsAg with histologically proven chronic active liver disease. After the rIFN-gamma administration, T8 lymphocyte subsets showed a significant decrease (basal vs. 4 weeks, p less than 0.05) and T4/T8 ratios were higher than the basal values in 6/8 patients. Serum levels of the HLA class I-associated beta 2-microglobulin increased significantly in all patients within the first week of treatment, both with the high (p less than 0.01) and the low (p less than 0.05) rIFN-gamma dose. Then, differences between the two doses reached statistical significance (p less than 0.03). Similar results (p less than 0.05) were obtained by measuring the 2',5'-oligoadenylate (2-5A) synthetase activity, co-occurring with the decreases in HBV-DNA polymerase and HBV-DNA, although no differences were found between the two doses. In addition, levels of 2-5A synthetase correlated significantly with those of beta 2-microglobulin (r = 0.743, p less than 0.01). On the other hand, after the rIFN-gamma administration, all the patients had liver membrane antibodies (LMA) in their serum (p less than 0.05); only two patients (who were anti-HD positive) showed LMA at the end of the follow-up. rIFN-gamma has both antiviral and immunomodulatory effects in HBeAg carriers with chronic liver disease.
2',5'-Oligoadenylate Synthetase↗
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.
Adult↗
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.
Chronic Disease↗
Changes of hepatitis B virus (HBV) markers during prolonged recombinant interferon alpha-2A treatment of chronic HBV infection.
Eleven HBsAg chronic carriers were treated with recombinant-interferon (rIFN)-alpha-2A with either 20 X 10(6) (n = 6) or 10 X 10(6) IU/m2 body surface (n = 5), i.m. twice weekly for 6 months. HBV-markers were tested monthly for 15 months. Throughout the follow-up, 6 patients (54%) became HBeAg, HBV-DNAp and HBV-DNA negative (responders). In addition, 8 were HBcAg-negative, 10 anti-HBc-IgM-negative and 2 HBsAg/IgM complexes negative. All patients gave polymerized human serum albumin receptors and HBsAg-positive results. The low rIFN dose seems to be more efficient for clearing HBV-markers than the high dose. Responder patients already showed lower (P less than 0.05) HBsAg concentration and HBsAg/IgM complexes levels in their basal samples as compared to non-responders, and exhibited under rIFN treatment significant decreases (P less than 0.05) in all HBV-markers studied. In conclusion, the most reliable HBV-markers to be assayed in the evaluation of antiviral therapy are HBV-DNA, HBV-DNAp or HBcAg. The testing of pHSA-R, HBsAg/IgM complexes and anti-HBc-IgM does not seem to be very useful.
Adolescent↗
Identification of different degrees of hepatitis B virus (HBV) replication by serological (HBV-DNAp, HBcAg and HBV-DNA) and histological (HBcAg) methods.
The incidence of HBV-DNA polymerase, HBV-DNA and serum and liver HBcAg in 104 chronic HBsAg carriers was studied. HBV-DNA was the most frequently detected marker, followed by HBcAg and HBV-DNAp. According to their individual or combined presence, four different serological patterns of viral replication were discerned: 53 patients had all these markers, 30 had HBV-DNA but lacked HBV-DNAp (15 with and 15 without HBcAg) and 21 had no such markers detectable. The simultaneous positivity for all of those markers was observed only in HBeAg-positive patients. HBV-DNA alone or along with HBcAg was found in a similar incidence irrespective of the HBe system. Liver HBcAg was found in all but four patients with and in four without HBV-DNA. Viral DNA concentration was significantly (p less than 0.001) higher when HBV-DNAp tested positive. Indeed, HBeAg rather than anti-HBe patients had higher (p less than 0.005) levels of HBV-DNA. In HBeAg-positive patients, the nuclear HBcAg staining was significantly (p less than 0.05) higher when HBV-DNAp tested positive. In DNA polymerase-negative patients, but positive for HBV-DNA, those with or without HBcAg had a similar percentage of core antigen staining. The same distribution was seen in anti-HBe, HBV-DNA-positive patients. However, the mean percentage of hepatocytes displaying cytoplasmic HBcAg did not differ significantly among patients with HBV-DNA, irrespective of the HBe system and the HBV-DNAp status. Such patients had significantly (p less than 0.001) higher ALT levels than those without viral DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Liver membrane antibodies in chronic delta hepatitis.
The correlation between the presence of liver membrane antibodies (LMA) and delta superinfection in chronic hepatitis B was studied in 136 chronic hepatitis patients, 20 hepatitis B surface antigen asymptomatic carriers and 50 healthy controls, by testing for the presence of LMA, hepatitis B virus markers and anti-delta (anti-HD). Neither anti-HD nor LMA were detected in controls or in asymptomatic carriers. LMA positivity was statistically higher (p less than 0.001) in anti-HD-positive patients than in those with no anti-HD. Gamma globulin and glutamic pyruvic transaminase values were increased both in anti-HD- and LMA-positive patients with respect to those who were negative. In conclusion, a close association between the positivity to anti-HD and the presence of circulating LMA was found.
Adult↗