Alpha interferon therapy in children with chronic active hepatitis B and delta virus infection

Two children with chronic hepatitis B virus and delta virus infection were treated with alpha interferon. Both tolerated the therapy without complications, and one demonstrated clearance of the infection and development of immunity.     

Interferon antibodies in patients with chronic hepatitic C virus infection treated with recombinant interferon alpha-2 alpha

Patients treated with alpha-2a interferon for chronic hepatitis C may produce anti-interferon antibodies whose effect, if any, on the individual response to therapy has not been fully clarified. The prevalence and kinetics of anti-interferon, including those of neutralizing type, have been studied in 60 patients with chronic hepatitis C enrolled in a randomized controlled trial of recombinant alpha-2a interferon. Thirty patients received interferon while 30 were untreated controls. Two different methods, an enzyme immunoassay and an antiviral neutralization bioassay, were used and serial serum samples from each patient were analyzed. Enzyme immunoassay-positive anti-interferon appeared in 60.7% of treated patients within 6 months of therapy; antiviral neutralization bioassay-positive anti-interferon appeared in 52.9% of these enzyme immunoassay-positive patients, and was associated with high enzyme immunoassay reactivity and long-term persistence. Anti-interferon was detected in 75% of patients showing no response to interferon. Antibodies were also detected in three out of six patients who showed alanine aminotransferase normalization persisting up to the end of treatment and in 8 out of 14 patients who showed an initial marked reduction or even normalization of alanine aminotransferase, followed by reactivation of liver damage during treatment. Interestingly, patients who became anti-interferon positive before complete alanine aminotransferase normalization later showed reactivation of liver damage independently of interferon dose reduction, while patients who became positive for anti-interferon after complete alanine aminotransferase normalization either did not reactivate or did so only after interferon dose reduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients

Hepatitis C virus (HCV) infection is common in multi-transfused thalassaemic patients, and, in combination with transfusional iron overload, can result in progressive liver disease. Therapy with interferon-alpha causes a sustained loss of HCV in only 15-25% of patients, and there is as yet no established effective therapy for those who fail to respond. We have conducted a pilot study of combination anti-viral therapy for patients who failed to respond, or relapsed after an initial response to single-agent interferon-alpha. Patients were treated for 6 months with interferon-alpha 2b, given subcutaneously three mega units thrice weekly, together with ribavirin, orally 1 g daily. 11 patients were enrolled, their median age was 24.9 years. 8/10 evaluable patients had cirrhosis on biopsy, five were infected with HCV type 1 and all but one had initial HCV RNA titres > 10(6) genomes/ml. Five patients (45.5%) had a sustained virological response with loss of serum HCV RNA for > 6 months after finishing therapy. There was no clear association between response to therapy and age, histology, HCV genotype, or HCV RNA titre. Transfusion requirements were significantly increased during the treatment phase, probably due to ribavirin-induced haemolysis, and this necessitated intensification of iron chelation therapy. Serum ferritin levels decreased significantly in those who responded. These results suggest that combination therapy is potent in clearing HCV infection, and may provide effective second-line therapy for thalassaemic patients who have failed to respond to interferon-alpha monotherapy.     

Prevalence of infection with dengue virus among international travelers

BACKGROUND: Dengue has been recognized as a potential hazard to tourists. A prospective, controlled study in the outpatient clinic of a German infectious disease clinic was conducted to assess the prevalence of dengue virus infection among international travelers. METHODS: Serum samples from 130 patients with signs or recent history clinically compatible with dengue (fever, headache, muscle and joint pain, or rash), 95 matched controls with diarrhea, and 26 patients who never visited a country endemic for dengue were investigated. RESULTS: Nine (6.9%) of the 130 patients with compatible symptoms and 1 (1%) of the 95 controls with diarrhea developed rising antibody titers against dengue virus. Of these 10 patients with probable dengue infection, 6 had been to Thailand, 2 to Malaysia, and 1 each to Indonesia and Brazil. CONCLUSIONS: Infection with dengue virus appears to be a realistic threat to travelers to Southeast Asia. Symptoms commonly associated with dengue, such as fever, myalgia, arthralgia, and vomiting, can be helpful for diagnosis when present, but the absence of typical symptoms does not exclude infection.     

Varicella-zoster virus infection in children with underlying human immunodeficiency virus infection

This article describes a prospective longitudinal study of varicella-zoster virus (VZV) infections in human immunodeficiency virus (HIV)-infected children, designed to determine their natural history of VZV infection and possible effects of VZV on the progression of HIV infection. Varicella was usually not a serious acute problem, and it did not seem to precede clinical deterioration. The rate of zoster was high: 70% in children with low levels of CD4+ lymphocytes at the time of development of varicella. It is predicted that immunization with live attenuated varicella vaccine is unlikely to be deleterious to HIV-infected children. Moreover, if they are immunized when they still have relatively normal levels of CD4+ lymphocytes, they may have a lower rate of reactivation of VZV than if they were allowed to develop natural varicella when their CD4+ cell counts have fallen to low levels as a result of progressive HIV infection.     

Efficacy of ribavirin plus interferon alpha on viraemia of GB virus-C/hepatitis G virus: comparison with interferon alpha alone

We investigated the efficacy of ribavirin plus interferon (IFN) alpha on GB virus-C (GBV-C)/hepatitis G virus (HGV) viraemia and compared it with that of interferon alpha alone in patients coinfected with hepatitis C virus (HCV) and GBV-C/HGV. Serum HCV and GBV-C/HGV-RNA were studied in eight patients with HCV and GBV-C/HGV coinfection, five received IFN alpha and three received oral ribavirin plus IFN alpha. Mean serum GBV-C/HGV titre at the end of therapy was significantly lower than the titre just before therapy and patients with lower pretreatment titre had a better sustained response rate. Sustained virological response of GBV-C/HGV to IFN alpha alone and ribavirin plus IFN alpha at the end of follow up was observed in one each, respectively. Thus, GBV-C/HGV in patients with HCV and GBV-C/HGV coinfection does respond to IFN alpha and ribavirin plus IFN alpha may not induce a higher sustained response.     

Responsiveness to interferon alpha treatment in patients with chronic hepatitis C coinfected with hepatitis G virus

BACKGROUND/AIMS: Patients with chronic hepatitis C are often coinfected with the new identified Flaviviridae-like agent, termed hepatitis G virus (HGV). The aim of the study was to investigate the responsiveness of hepatitis G virus to interferon alpha and to evaluate whether a hepatitis G virus coinfection negatively influences the outcome of treatment in chronic hepatitis C. METHODS: One hundred and fifteen patients with histologically proven chronic hepatitis C were treated with interferon alpha and investigated for the presence of hepatitis G virus coinfection by nested polymerase chain reaction with primers from the helicase region of hepatitis G virus. All patients received at least 3 MU (range 3-6) interferon alpha thrice weekly for at least 6 months (mean 8, range 6-12). Polymerase chain reaction products of seven pre- and post-treatment hepatitis G virus positive patients were directly sequenced for identification of sequence variability during the follow-up. RESULTS: Eighteen (16%) patients were coinfected with hepatitis G virus. Although nine (50%) of these patients became HGV RNA negative during interferon alpha therapy, only three patients (17%) remained HGV RNA negative at the end of follow-up (mean 24 months). The rate of sustained response of chronic hepatitis C was not significantly different between patients with hepatitis C virus infection and HCV/HGV coinfection (19% vs 28%). Severity of liver disease as determined by alanine aminotransferase levels, histology and hepatitis C virus viremia was not significantly different in patients with hepatitis C virus or HCV/HGV coinfection. Sequence analysis of the helicase region revealed that our isolates all belonged to the hepatitis G virus and not to the GBV-C like genotype. No amino acid exchanges during the observation period of up to 48 months were observed, indicating that this region is highly conserved. CONCLUSIONS: The responsiveness of hepatitis G virus to interferon alpha in chronic HCV/HGV coinfected patients is similar to that observed in chronic hepatitis C. Hepatitis G virus coinfection seems not to interfere with the efficacy of interferon alpha treatment in patients with chronic hepatitis C.     

Response of patients with dual hepatitis B virus and C virus infection to interferon therapy

Patients with dual infection with hepatitis B virus (HBV) and delta virus (HDV) responded poorly to interferon (IFN) therapy. Little is known about the effect of IFN therapy in patients with HBV and hepatitis C virus (HCV) dual infection. The patients in two randomized controlled trials with chronic HBV infection were retrospectively assayed for HCV markers. The HBV responses to IFN therapy in patients with and without HCV markers were compared. An open trial was conducted in 4 patients who had lost their serum HBV surface antigen (HBsAg) but had continuing HCV viremia and hepatitis. Of the 15 patients seropositive for HCV marker(s), only 1 (6.7%) responded with seroclearance of HBV DNA and HBV e antigen, as compared with 46 (28%) of 164 HCV-negative patients (p = 0.058). Icteric hepatitis developed in 1 patient on emergence of serum HCV RNA in association with seroclearance of HBV DNA. In contrast, good response was demonstrated in 3 of the 4 patients who had lost serum HBsAg before therapy. The results suggest that IFN therapy is not only of limited value in patients with dual infection with HBV and HCV but also has a potential risk of severe hepatitis if the clearance of one virus removes its suppressive effect on and facilitates the emergence of the other. However, patients with continuing HCV hepatitis after termination of the chronic HBsAg carrier state responded well to IFN therapy.     

Recognition of synthetic oligopeptides from nonstructural proteins NS1 and NS3 of dengue-4 virus by sera from dengue virus-infected children

OBJECTIVE: To investigate the correlation between soluble forms of the intercellular adhesion molecule (sICAM-1) and vascular cell adhesion molecule (sVCAM-1) and the severity of pre-eclampsia or its possible consequences for fetal growth. DESIGN: Prospective observational study. SETTING: Institute of Medical Genetics, University of Oslo, Department of Medical Genetics and Haematological Research Laboratory, Ullev?l University Hospital; and the Department of Obstetrics and Gynaecology, The National Hospital, Oslo, Norway. PARTICIPANTS: Seventy-six women with normotensive pregnancies and 157 women with pre-eclampsia divided into three subgroups: mild, severe and pre-eclampsia with fetal growth retardation. METHODS: ELISA-measurements of plasma sICAM-1 and sVCAM-1 were performed in a group of healthy pregnant normotensive women and three groups of women with varying degrees of pre-eclampsia. RESULTS: sICAM-1 concentrations were higher in the pre-eclampsia group compared with the control group, but this difference was not statistically significant. Plasma concentrations of sVCAM-1 were significantly greater (P < 0.0001) in all pre-eclampsia subgroups (835.34, 855.25 and 964.05 ng/mL) compared with the control group (667.62 ng/mL). Within the pre-eclampsia group, plasma concentration of sVCAM-1 was significantly higher in the subgroup exhibiting fetal growth retardation (P = 0.03) compared with mild pre-eclampsia. CONCLUSION: The observed increases in plasma concentrations of sVCAM-1 suggest that measurements of this adhesion molecule may be useful in monitoring pregnancies with respect to the development of pre-eclampsia or fetal growth retardation.     

Three cases of dengue 1 virus infection from islands in the Gulf of Thailand

Three Australian tourists who recently travelled to islands in the Gulf of Thailand developed febrile illnesses associated with myalgias, thrombocytopenia, and atypical lymphocytosis. Dengue 1 virus was isolated from all three patients. The patients' clinical features and serological and virological investigations are presented. These cases highlight the need for awareness of dengue amongst travellers and the preventive precautions required when visiting endemic regions. After the urgent exclusion of malaria, dengue should be considered in the differential diagnosis of febrile persons who have recently returned from endemic regions.     

Interferon alpha in the treatment of prolonged hepatitis A virus infection

Hepatitis A viral infection usually lasts up to 12 weeks, but in 3-16% of patients relapses may occur and the course of the disease is protracted. The outcome of hepatitis A is always good, so that antiviral therapy is not necessary. However, from the aspect of patients with protracted course of the disease up to a year, it might be important to restore clinical recovery in a shorter period of time. Knowing about antiviral and immunomodulatory effects of endogenous interferon (virally activated) in treatment of protracted hepatitis A, we introduced interferon-alpha in the 12th week of the disease and followed-up its effects on the further course of the disease. The study comprised 80 patients with established diagnosis of acute protracted hepatitis A, excluding hepatitis B, Epstein-Barr, cytomegalovirus, adenovirus or toxic liver lesion. In 40 patients treated with interferon we followed up the activity of aminotransferases and persistence of IgM-anti-HAV in correlation with the same parameters in 40 patients treated symptomatically. The registered persistence of aminotransferases' pathological activity was 20:30 weeks (interferon: symptomatic therapy). In greater doses interferon affected the length of persistence IgM-anti-HAV, 20:34 weeks (interferon: symptomatic therapy).     

Detection of alpha-interferon in nasopharyngeal secretions and sera in children infected with respiratory syncytial virus

We investigated the relationship between respiratory syncytial virus (RSV) antigen and interferon (IFN) in nasopharyngeal secretions (NPS) and sera obtained from 252 patients infected with RSV. A total of 146 (57.9%) of 252 patients had IFN in NPS with a mean titer of 28 units/ml and IFN was detected in 164 (71.6%) of 229 patients in the acute stage sera with a mean titer of 28 units/ml. IFN activities were neutralized with antiserum to IFN-alpha. RSV antigen in NPS decreased on Day 5 and later in parallel with the change of mean titer of IFN in NPS. IFN in NPS was detected in 40 to 60% of the samples with some fluctuation in the acute stage. Within 4 days IFN was detected in more than 70% of the sera whereas on Day 5 and later the IFN positivity rate decreased in sera. RSV antigen in NPS decreased in the older patient groups. No significant change of positive rate of IFN in NPS was observed in different age groups and the mean titer of IFN in NPS and sera did not vary with age, except in those younger than 3 months and older than 3 years of age.     

Evaluation of the protective efficacy of a recombinant dengue envelope B domain fusion protein against dengue 2 virus infection in mice

1. The influence of Ca2+ on the effects of glucagon on glycolysis was investigated in the isolated perfused rat liver. Livers from fed rats were perfused in an open system with Krebs/Henseleit-bicarbonate buffer (pH 7.4). Glucose release, lactate plus pyruvate production (glycolysis) and oxygen uptake were measured. The following results were obtained: 2. In livers perfused with Ca(2+)-free Krebs/Henseleit-bicarbonate buffer and after depletion of the intracellular pools, the initial and transient stimulation of glycolysis, which is normally observed shortly after the onset of glucagon infusion, was more pronounced when compared to livers perfused with normal perfusion fluid (2.5 mM Ca2+) and without previous depletion of the intracellular pools (controls); the subsequent inhibition of glycolysis was delayed in Ca(2+)-free perfused livers and was less pronounced in comparison with the controls at the end of the glucagon infusion period (20 min). 3. Perfusion with a Ca(2+)-free medium supplemented with EDTA, without previous depletion of the intracellular pools, also produced a substantial reduction in the effects of glucagon on glycolysis. 4. Ca(2+)-free perfusion did not affect the stimulative action of glucagon on glucose release (glycogenolysis) and oxygen uptake. 5. Glycolysis inhibition by cAMP also was abolished in Ca(2+)-free perfused livers, and the initial stimulation was enhanced. 6. Mn2+, a metal ion known as a competitor of Ca2+, considerably reduced the action of glucagon on glycolysis; Mn2+ did not affect the basal rates of glycolysis. 7. Sr2+, a metal ion that is often recognized as Ca2+ by several biological structures and processes, increased the inhibitory action of glucagon on glycolysis. 8. Several organic compounds, which directly or indirectly take part in Ca2+ fluxes, were also able to diminish (e.g., verapamil) or even to abolish (carbenoxolone) the inhibitory action of glucagon on glycolysis. 9. It was concluded that, under the conditions of the living cell, Ca2+ is important for glycolysis inhibition by glucagon. In principle at least, the results can be explained in terms of the known Ca2+ dependencies of several protein kinases and protein phosphatases.     

Immune response to mouse mammary tumor virus in mice lacking the alpha/beta interferon or the gamma interferon receptor

Mouse mammary tumor virus (MMTV) is a retrovirus which induces a strong immune response and a dramatic increase in the number of infected cells through the expression of a superantigen (SAg). Many cytokines are likely to be involved in the interaction between MMTV and the immune system. In particular, alpha/beta interferon (IFN-alpha/beta) and gamma interferon (IFN-gamma) exert many antiviral and immunomodulatory activities and play a critical role in other viral infections. In this study, we have investigated the importance of interferons during MMTV infection by using mice with a disrupted IFN-alpha/beta or IFN-gamma receptor gene. We found that the SAg response to MMTV was not modified in IFN-alpha/betaR(0/0) and IFN-gammaR(0/0) mice. This was true both for the early expansion of B and T cells induced by the SAg and for the deletion of SAg-reactive cells at later stages of the infection. In addition, no increase in the amount of proviral DNA was detected in tissues of IFN-alpha/betaR(0/0) and IFN-gammaR(0/0) mice, suggesting that interferons are not essential antiviral defense mechanisms during MMTV infection. In contrast, IFN-gammaR(0/0) mice had increased amounts of IL-4 mRNA and an altered usage of immunoglobulin isotypes with a reduced frequency of IgG2a- and IgG3-producing cells. This was associated with lower titers of virus-specific antibodies in serum early after infection, although efficient titers were reached later.     

Hepatitis G virus infection in hemodialysis patients and the effects of interferon treatment

OBJECTIVE: To characterize the nature of hepatitis G virus (HGV) infections in hemodialysis patients and to determine the responsiveness of HGV to antiviral therapy in these patients. METHODS: HGV, a recently identified flavivirus, is associated with non-A-E viral hepatitis infections. We studied HGV infections in hepatitis C virus (HCV)-infected hemodialysis patients over a 1-yr period, using two independent PCR assays and nucleic acid sequencing. Thirty-four of 63 study patients were treated with interferon. RESULTS: We observed a 27% prevalence (17/63 patients) and a 4% annual incidence of HGV infections in the study population. HGV was not detected in any of the 10 HGV-infected patients immediately after interferon therapy. Although seven of these 10 patients developed HGV relapses, three had long-term responses. The interferon responsiveness of HGV and HCV appeared to be unrelated. In contrast, all seven untreated HGV-infected patients remained viremic. Sequence analyses of the different HGV isolates revealed only very limited genetic variability in the polymerase chain reaction-amplified regions of HGV during 1 yr of observation. CONCLUSIONS: Our data suggest that HCV-infected hemodialysis patients are at substantial risk of acquiring HGV infection and that HGV infections are prevalent in this population. In addition, HGV infections become chronic but are responsive to interferon treatment.     

Evaluation of a rapid immunochromatographic test for diagnosis of dengue virus infection

A rapid (<7-min) immunochromatographic test for immunoglobulin M (IgM) and IgG antibodies to dengue viruses was evaluated by using hospital admission and discharge sera from 124 patients. The reference laboratory diagnosis was based on the results of virus isolation, hemagglutination-inhibition assay (HAI), and enzyme immunoassay (EIA). By the standard assays, patients experienced primary dengue virus infection (n = 30), secondary dengue virus infection (n = 48), Japanese encephalitis (JE) virus infection (n = 20), or no flavivirus infection (n = 26). The rapid test demonstrated 100% sensitivity in the diagnosis of dengue virus infection and was able to distinguish between primary and secondary dengue virus infections through the separate determinations of IgM and IgG. For all patients with primary dengue virus infection a positive test for IgM to dengue virus and a negative test for IgG to dengue virus were obtained, whereas for 46 of 48 patients (96%) with secondary dengue virus infection, a positive test for IgG to dengue virus with or without a positive test for IgM to dengue virus was obtained. The remaining two patients with secondary dengue virus infection had positive IgM test results and negative IgG test results. Furthermore, the rapid test was positive for patients confirmed to be infected with different dengue virus serotypes (12 infected with dengue virus serotype 1, 4 infected with dengue virus serotype 2, 3 infected with dengue virus serotype 3, and 2 infected with dengue virus serotype 4). The specificity of the test for nonflavivirus infections was 88% (3 of 26 positive), while for JE virus infections the specificity of the test was only 50% (10 of 20). However, most patients with secondary dengue virus infection were positive for both IgM and IgG antibodies to dengue virus, while no patients with JE virus infection had this profile, so cross-reactivity was only a concern for a small proportion of patients with secondary dengue infections. The rapid test demonstrated a good correlation with the reference EIA and HAI and should be useful for the rapid diagnosis of dengue virus infections.     

Nephrotic syndrome complicating treatment with interferon alpha

We report two cases of nephrotic syndrome with minimal glomerular change complicating alpha-interferon therapy. CASE REPORTS: The first patient was a 60-year-old man with Waldenstr?m's disease who was given 1 million units of alpha-interferon three times a week for 22 months. Acute renal failure developed when a second protocol was started. Renal biopsy revealed intraglomerular deposits and no cellular proliferation. Total remission could not be achieved with corticosteroids. The second case was a 46-year-old man given high dose alpha-interferon (15 million units 3 times a week) for lymph node metastasis of a malignant melanoma. A nephrotic syndrome without renal failure developed during the third month of treatment. Minimal glomerular involvement was seen. Symptomatic treatment led to resolution of the nephrotic syndrome. DISCUSSION: Nine other cases of nephrotic syndrome complicating alpha-interferon therapy have been reported in the literature.