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Biomedical subjects

J A Quiroga

Publications and source records attributed to J A Quiroga.

At least 37 records · Page 2Linked to original sources
PubMed1998

Induction of interleukin-12 production in chronic hepatitis C virus infection correlates with the hepatocellular damage.

Interleukin (IL)-12 plays an essential role in host defense against infectious diseases. Serum IL-12 concentration and blood mononuclear cell production with or without specific interferon (IFN)-gamma priming were investigated in 65 chronic hepatitis C virus (HCV) patients and 25 healthy donors. HCV patients had higher serum IL-12 levels (P = .004) and produced higher amounts after IFN-gamma priming (P < .001) than donors. A subset of patients did not produce IL-12: They had lower serum levels (P = .032) and showed signs of liver piecemeal necrosis less frequently (P = .011). Patients with greater liver necroinflammatory activity produced more IL-12 than patients with minimal or mild activity and donors (P < .01). During IFN-alpha therapy for 16 HCV patients, individuals with end-of-treatment alanine aminotransferase normalization and clearance of viremia had higher serum levels and produced more IL-12 than those who did not (P < .05). These results suggest a role for IL-12 in the immunopathogenesis and outcome of HCV infection.

Adult↗
PubMed1998

Genetic diversity and tissue compartmentalization of the hepatitis C virus genome in blood mononuclear cells, liver, and serum from chronic hepatitis C patients.

The degree of genetic variability in the hypervariable region 1 of hepatitis C virus (HCV) was analyzed by cloning and sequencing HCV genomes obtained in paired samples of serum, liver tissue, and peripheral blood mononuclear cells (PBMC) from four chronic hepatitis C patients. Genetic variability in serum was higher than in liver tissue or PBMC at the level of complexity (the number of different sequences obtained from each type of tissue) as well as at the level of genetic distance between all pairs of sequences within each tissue (compared by the Student t test; P < 0.001 for two patients and P < 0.01 for another). The spectrum of viral genomes differed among the three types of tissue, as shown by segregation of sequences according to their tissue of origin in phylogenetic analysis and by statistical analysis of mean genetic distances observed between sequences obtained from different tissues (P < 0.001), but sequences from liver tissue and PBMC were more closely related to each other than to those from serum.

Adult↗
PubMed1998

[Treatment with lymphoblastoid alpha interferon in patients with chronic myeloid leukemia refractory to recombinant interferon alpha 2].

The results of the treatment with lymphoblastoid alpha interferon (IFN-alpha N1) in 10 patients with chronic myeloid leukaemia who had poor response to previous recombinant alpha interferon (rIFN-alpha) are presented. Eight of these patients had not developed anti-alpha 2 interferon antibodies, and 2 had non-neutralising anti-IFN antibodies. Three of the 10 patients received benefit from IFN-alpha N1 treatment. Two of them, with no response to rIFN alpha 2, attained complete haematologic response wit IFN-alpha N1. Cytogenetic responses although minimal, were achieved as well. The third patient, after receiving rIFN-alpha for 3 years with no response, had partial cytogenetic response after 4 months of treatment with IFN-alpha N1. These results suggest that IFN-alpha N1 when used in patients refractory to IFN-alpha N1. These results suggest that IFN-alpha N1 when used in patients refractory to IFN alpha 2 without anti-IFn alpha 2 neutralising antibodies may be useful in a minority of patients, although the frequency of cytogenetic responses is low.

Adult↗
PubMed1997

Multicenter randomized, controlled study of intramuscular administration of interferon-beta for the treatment of chronic hepatitis C.

The intramuscular administration of interferon-beta (IFN-beta) at a dosage of 6 million units three times per week for 6 months has been evaluated in 90 patients included in a multicenter, randomized, controlled trial for the treatment of chronic hepatitis C. Transaminase levels were significantly reduced in IFN-beta-treated patients (p = 0.015) and were significantly lower with respect to those of the untreated controls (p = 0.040 at 6 months). Four treated (8%) and one untreated (2.5%) patients had normal transaminase values after 6 months. At study end (12 months), three quarters of the IFN-beta-treated patients had sustained transaminase normalization, whereas the untreated case had relapsed. Hepatitis C viremia was cleared in 6 (12%) treated patients but in none of the untreated controls (p = 0.058). Side effects of IFN-beta were infrequent (a mild flu-like syndrome in < 10%, asthenia in 16%, anorexia in 8%, headaches and weight loss in 8%, and hair loss in 4%). Leukocyte and platelet counts decreased during IFN-beta treatment, but no dose modifications were necessary. Such decreases were not statistically significant when compared with the levels in the untreated controls. Intramuscular IFN-beta at the dosage used has little efficacy in the treatment of chronic hepatitis C. Because of IFN-beta tolerance, higher doses and alternate routes of injection might prove beneficial for the treatment of this disease.

Adult↗
PubMed1997

Tolerance and efficacy of subcutaneous interferon-beta administered for treatment of chronic hepatitis C.

We studied tolerance to subcutaneous (s.c.) administration of 6 million units of interferon-beta (IFN-beta), given three times per week for 6 months, and its efficacy in the treatment of 15 patients with chronic hepatitis C. At the end of the treatment, alanine aminotransferase (ALT) levels were significantly reduced (p = 0.024) in all patients, and 4 (27%) had a normal ALT value. However, at the end of the study (12 months), only 1 of these 4 had a sustained response. No patient cleared hepatitis C virus (HCV) RNA completely, but the RNA could be detected only by polymerase chain reaction (PCR) in the sustained responder. Adverse side effects to the s.c. IFN-beta were infrequent. Leukocyte (p = 0.012) and platelet (p = 0.013) counts decreased significantly during treatment but did not necessitate dose modifications. Thus, although s.c. IFN-beta at the dosage used had little efficacy in the treatment of chronic hepatitis C, the excellent tolerance to the treatment suggests that the effects of higher doses should be explored.

Adult↗
PubMed1997

Biological properties of interleukin-12 and its therapeutic use in persistent hepatitis B virus and hepatitis C virus infection.

Interleukin (IL)-12 is a pleiotropic cytokine produced by antigen-presenting cells in response to diverse stimuli. IL-12 is a key molecule in the regulation of host's immune responses. In particular, IL-12 influences the balance between the T-helper cells type 1 (TH1) and type 2 (TH2); it modulates macrophage responses through the control of interferon-gamma synthesis by TH1 cells; and, suppresses IgE class antibody production (has a suppressive effect on allergic reactions) and promotes a shift in the IgG subclasses. IL-12 enhances resistance to several infectious diseases, is a powerful antitumor agent in vivo, and acts as a vaccine adjuvant. The biological properties of IL-12 point to the potential therapeutic use in persistent hepatitis B virus and hepatitis C virus infection.

Animals↗
PubMed1997

Impaired interferon induction of human MxA protein in chronic hepatitis B virus infection.

MxA protein is interferon inducible, and its role as an antiviral mediator is being studied in various viral diseases. Several cytokines, including type 1 interferons (alpha and beta), interleukins 2 and 12, and granulocyte, macrophage, and granulocyte-macrophage colony-stimulating factors, were tested for their ability to induce human MxA protein synthesis in peripheral blood mononuclear cells from 15 chronic hepatitis B virus-infected patients and 6 healthy subjects as controls. Constitutive MxA expression was scarce in patients and controls but increased significantly in response to type I interferons. MxA responsiveness to interferon alpha was diminished significantly in chronic hepatitis B patients, compared with healthy donors (P < 0.05); this effect was more marked in patients with high viremia levels. Interleukins 2 and 12, and none of the colony-stimulating factors tested, induced low, but detectable, MxA protein levels. These results indicate that chronic infection by hepatitis B virus may impair activation of the immune cells and their capacity to respond to type 1 interferons.

Adult↗
PubMed1996

Hepatitis E virus seroprevalence in acute viral hepatitis in a developed country confirmed by a supplemental assay.

Hepatitis E virus (HEV) infection is prevalent among cases of acute viral hepatitis in young adults in developing countries. HEV infection is not restricted to endemic areas, but would appear to be worldwide in distribution. In order to document the incidence of HEV infection in acute hepatitis cases in a developed country, IgG and IgM anti-HEV antibodies and HEV RNA were tested in 101 Caucasian patients with acute viral hepatitis; 92 of these cases had markers of acute viral hepatitis other than HEV. Forty-seven (46.5%) cases had IgG anti-HEV; IgM anti-HEV and HEV viremia were not detected. As the incidence of anti-HEV was higher than would be expected, the possibility of the occurrence of false positive results was subsequently investigated. Supplemental antibody testing, using a broadly reactive epitope region, reduced the frequency of anti-HEV to 17%. Therefore, supplemental antibody testing confirms the hepatitis E virus seroprevalence in a developed country. Since IgM anti-HEV and HEV viremia were not detected, persons with IgG anti-HEV may be "subclinical HEV cases," or have long-lived antibodies in their circulation.

Acute Disease↗
PubMed1996

Recombinant human granulocyte colony-stimulating factor reduces hepatitis C virus replication in mononuclear cells from chronic hepatitis C patients.

Hepatitis C virus infects mononuclear leukocytes of patients with chronic hepatitis C. Treatment with rhG-CSF led to a dose-related reduction in the genomic and antigenomic hepatitis C viral strands in cultures of mitogen-stimulated, naturally-infected peripheral blood mononuclear cells from patients with chronic hepatitis C. Hepatitis C virus genomic strand of subtype 1b was suppressed in 5 of 11 cases, and concurrently with suppression of the viral antigenomic strand in two of them. The treatment also resulted in a significantly increased release of interleukin 6, but not of other cytokines. However, the biological response of hepatitis C virus-infected mononuclear cells to treatment with recombinant human granulocyte colony-stimulating factor was unrelated to any particular pattern of cytokine production.

Antiviral Agents↗
PubMed1996

Granulocyte-macrophage colony-stimulating factor as adjuvant therapy for factor as adjuvant therapy for interferon alpha treatment of chronic hepatitis C.

The safety and efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant therapy for interferon alpha (IFN-alpha) treatment has been evaluated in 20 non-cirrhotic patients with chronic hepatitis C virus (HCV) infection. Adjuvant therapy with GM-CSF plus IFN-alpha was associated with less myelosuppression than with IFN-alpha alone (P < .01), although the rate of local adverse reactions increased. GM-CSF adjuvant therapy led to a 50% biochemical response (transaminase values within the normal range at therapy end) and to reductions in HCV RNA concentrations (median HCV RNA reduction of 99%, range 8-100%), which were similarly observed in single IFN-alpha recipients (median HCV RNA reduction of 91%, range 38-100%). However, HCV RNA became undetectable in three biochemical responders to the GM-CSF adjuvant therapy, but in only one biochemical non-responder to IFN-alpha alone. The use of GM-CSF as adjuvant therapy is safe and, although it has not improved the biochemical response, it might potentiate the virologic response to IFN-alpha treatment alone.

Adult↗
PubMed1996

Patterns of immune responses to the host-encoded GOR and hepatitis C virus core-derived epitopes with relation to hepatitis C viremia, genotypes, and liver disease severity.

Antibody responses to the GOR epitope and hepatitis C virus (HCV) core were investigated in 136 patients with chronic HCV infection. Patient age (P = .011) and necroinflammatory activity (P < .001) were significantly greater in 92 (67.6%) patients with anti-GOR than in 44 (32.4%) patients without anti-GOR. HCV RNA concentration was significantly higher in patients with anti-GOR (P = .031). HCV 1a or 1b genotypes were also found according to anti-GOR status. GOR and HCV core (amino acids 5-19) antibody responses correlated significantly (rs = .615, P < .001). Anti-HCV core(5-19) was detected in 67 (73%) of 92 patients with and in 14 (32%) of 44 without anti-GOR (P < .001). Patients with concurrent anti-GOR and anti-HCV core(5-19) had significantly greater necroinflammatory activity (P = .003). By multivariate analysis, anti-HCV core(5-19), patient age, and necroinflammatory activity were correlated with anti-GOR response (P < .001). Reactivity to the GOR autoepitope correlates with HCV core response and liver necroinflammatory activity, thus suggesting an immunopathogenic role in chronic hepatitis C.

Adult↗
PubMed1996

New and forthcoming therapies for viral hepatitis.

Therapies for chronic viral hepatitis B and C are aimed at clearing the virus and producing a sustained immunity. Manipulation of the biological response would confer an antiviral state and modulate the immune responses. For the development of new therapeutic agents against hepatitis viruses, reliable in vitro models are needed to study drug effects. Forthcoming therapies might combine natural or synthetic antiviral compounds and cytokines, together with novel approaches including anti-sense oligonucleotides and ribozymes.

Granulocyte Colony-Stimulating Factor↗
PubMed1995

Sequence of non-structural regions 3 and 5 of hepatitis C virus genomes from Spanish patients: existence of a predominant variant related to type 1b.

Several hepatitis C viruses (HCV) have been described. In this study, the prevalence of HCV subtypes 1a, 1b, 2a and 2b has been studied by means of specific PCR in 93 serum samples of Spanish patients. Among these, the HCV-1b subtype was the most frequently detected (62%). Complementary DNA fragments from non-structural region 3 (NS3) and 5 (NS5), obtained from serum samples of three Spanish patients, were amplified by PCR and the products were cloned and sequenced. Comparison of the sequence obtained with those previously published shows the highest homology (91.7% in NS3 and 91.8% in NS5) with the HCV-1b subtype. The incidence of the local variant was analysed among the HCV-1b-infected patients. In order to distinguish between the local and HCV-1b prototype subtype, a new specific PCR assay was designed using primers from NS5. In the majority of the 76 HCV-1b-infected patients, the local variant was the only subtype detected (53%). These findings support the existence of a local variant, belonging to the HCV-1b subtype.

Amino Acid Sequence↗
PubMed1995

Risks and benefits of interferon-alpha in the treatment of hepatitis.

The high worldwide prevalence of chronic viral hepatitis, as well as its progressive course, have led to the performance of multiple clinical studies. The natural history of the disease is different depending on the infecting virus; thus, the evolution to liver cirrhosis and/or hepatocellular carcinoma for the hepatitis B, C and delta (D) viruses in chronic hepatitis is 15, 20 and 75%, respectively. Different therapeutic agents have been used in attempts to modify the natural course of these diseases, interferon-alpha (IFN alpha) having proved to be the most effective. In 30 to 50% of patients, treatment with IFN alpha has achieved inhibition of viral replication, as well as normalisation of aminotransferase levels. Moreover, in a majority of patients, histological improvement is observed, principally in piece-meal necrosis and portal inflammation. The dosage currently recommended for treatment of chronic hepatitis B is 30 to 35MU weekly for a minimum of 4 months; when there is a co-existing delta virus infection, the total dosage employed should be greater. For hepatitis C, the minimum effective dosage is 9MU weekly, and a treatment duration of 12 months is recommended. The administration of IFN alpha produces a series of dose-dependent adverse effects, which are reversible on suspension of the medication. The most frequent of these adverse reactions is the 'flu-like' syndrome, which is self-limited and generally well tolerated. Secondary haematological alterations (leucopenia and thrombocytopenia) are the most frequent cause of reduction in dosage or suspension of treatment, although the latter is not normally necessary. The proportion of patients requiring dosage modification or suspension of treatment fluctuates between 5 and 15%. Taking the evolution of chronic hepatitis into account, there can be no doubt that all patients with this disease should be offered treatment. At present, the drug of choice is IFN alpha, as it slows disease progression and it is generally well tolerated.

Hepatitis↗
PubMed1995

Immunoglobulin M antibody to hepatitis C virus core antigen: correlations with viral replication, histological activity, and liver disease outcome.

Immunoglobulin M (IgM) antibody to hepatitis C core antigen (anti-HCV-core) was tested by enzyme immunoassay against a synthetic peptide representing amino acids 1 to 62 of the core protein. Of 214 patients with different categories of histological activity, 193 (90%) showed positive results for IgM anti-HCV-core, and 207 (97%) had HCV RNA; most cases (186, 87%) had both markers detectable simultaneously. No differences in the frequency of IgM anti-HCV-core were observed with respect to epidemiological, biochemical, or histological parameters. In 175 interferon alfa (IFN-alpha) recipients, and in 39 untreated controls, pretreatment IgM anti-HCV-core frequencies were similar: 28 of 32 (88%) in sustained responders; 55 of 61 (90%) in responders with relapse; 72 of 82 (88%) in nonresponders; and 38 of 39 (97%) in untreated controls. After IFN-alpha therapy, IgM anti-HCV-core levels became undetectable with significantly greater frequency in sustained responders (P = .014); a similar trend was observed for HCV RNA (P < .0001). IgM anti-HCV-core levels decreased after therapy in responders (P < .001) but increased in nonresponders. Fifty-one cases were longitudinally tested in relation to long-term disease outcome. Both markers remained detectable in most nonresponders with persistent liver disease, in most responders before relapse, and in all but one case at the time of biochemical relapse. IgM anti-HCV-core and HCV RNA became undetectable in most sustained responders, but reappeared despite a long-lasting transaminase normalization, behaving as asymptomatic HCV carriers; the possibility that disease reactivation may take place years afterwards cannot be excluded.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Biologic response modifiers in chronic hepatitis C.

Biologic response modifiers include various colony-stimulating factors and interleukins such as granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-2. Their use as therapy has proven to be beneficial in the treatment of various diseases, and in preventing hematologic disorders. Their biologic effects and the rationale for their use in chronic viral hepatitis, alone or in combination with interferon-alpha, are reviewed with respect to the treatment of chronic hepatitis C.

Chronic Disease↗