Biomedical subjects

V Carreño

Publications and source records attributed to V Carreño.

At least 19 recordsLinked to original sources

PubMed2002

Present treatment expectations and risks of chronic hepatitis C.

During recent years, the treatment of chronic hepatitis C has increased in efficacy. Initially, the only approved treatment for this disease was interferon-alpha (IFN-alpha) monotherapy, achieving a 15% rate of sustained response. Subsequently, a combination of IFN-alpha plus ribavirin showed a greater efficacy: up to 40% success with 3 MU of IFN-alpha three times weekly and 1000-1200 mg of ribavirin daily in naive patients and in those who had relapsed after a course of IFN-alpha therapy. Pegylated interferon (PEG-IFN), due to its better efficacy and tolerance, has displaced the use of recombinant IFN. Nevertheless, the sustained response rate mainly depends on HCV RNA load and HCV genotype. Presumably, in future, new strategies based on gene therapy will play an important role in the treatment of chronic hepatitis C.

Antiviral Agents↗

PubMed2002

In vitro infection of human peripheral blood mononuclear cells by a defective hepatitis B virus with a deletion in the PreS1 region of the viral genome.

Previously, we identified a defective hepatitis B virus (HBV) which contains a 183 nucleotide deletion in the PreS1 region of the viral genome affecting the S gene promoter in sera from hepatitis B surface antigen (HBsAg)-negative patients with serum HBV-DNA. The aim of this study was to analyse the infectivity of this mutant. Peripheral blood mononuclear cells (PBMC) from a healthy donor were incubated with serum samples from 2 HBsAg-negative patients with serum HBV-DNA (infected with wild-type and deletion mutant HBV), from an HBsAg carrier (infected with wild-type HBV) and from a healthy donor. After 1 week, HBV-DNA was detected by polymerase chain reaction (PCR) in all supernatants and cells incubated with the HBV-DNA-positive inocula. DNase and trypsin pretreatment confirmed intracellular localization of HBV-DNA in cells. HBV-RNA and covalently closed circular HBV-DNA were also detected in PBMC, indicating that the viral DNA infecting these cells was transcriptionally active. Deletion mutant and wild-type HBV were detected in the supernatants and cells infected with the two HBsAg-negative sera, while only wild-type HBV was detected in the supernatant and cells incubated with the serum from the HBsAg-carrier. In conclusion, this HBV deletion mutant can infect, replicate and release viral particles in in vitro infected PBMC.

Cells, Cultured↗

PubMed2001

Distribution of hepatitis C virus infection in liver biopsies from children and adults with chronic hepatitis C.

Chronic hepatitis C in children is characterized by milder forms of liver damage than those found in adults. Such a difference has been attributed to a low viral load in children that may lead to poor recognition of infected cells by the immune system. One approach that could be used to confirm this hypothesis may be to examine the number of infected hepatocytes in liver biopsies. Paraffin embedded liver biopsies from 21 children and 15 adults with chronic hepatitis C virus (HCV) infection (with a similar duration of the infection) were hybridized in situ and the percentage of infected hepatocytes was correlated with the histological activity index, alanine aminotransferase levels and HCV viraemia levels. Histological activity index and HCV viraemia levels were statistically higher (P < 0.05 and P < 0.01 respectively) in adults than in children, and the percentage of infected hepatocytes was higher in adults (11.0 +/- 19.7%) than in children (4.6 +/- 3.6%), although it did not reach statistical significance. Also, the percentage of infected hepatocytes correlated with HCV-RNA concentration in serum in both children (r = 0.683, P = 0.001) and adults (r = 0.768, P = 0.001). The results show that liver damage in children with chronic hepatitis C is not related to the extent of infection in the liver. This findings support the hypothesis of that liver injury in chronic HCV infection is mediated by the host immune response.

Adult↗

PubMed2001

TT virus detection in oral lichen planus lesions.

Epidemiological studies have demonstrated a correlation between oral lichen planus and different liver diseases. The new virus termed TT virus (TTV) is highly prevalent in patients with chronic hepatitis of different etiology and it may be speculated that TT virus may be involved in the pathogenesis of oral lichen planus. This study examined the presence of TT virus DNA in serum by PCR and in oral mucosa biopsies by in situ hybridization from 20 patients with oral lichen planus (13 with chronic hepatitis and seven without liver disease). Serum and oral mucosa biopsies from six patients all with chronic hepatitis with leukoplakia were also studied as controls. TT virus DNA was positive in the serum of 17/20 (85%) of the patients with oral lichen planus and in all the controls. TT virus DNA hybridization signals were detected in mucosa biopsies from all the patients with TT virus DNA in serum but in none of the three cases without this marker. The percentage of positive cells ranged from 1.6-80%. No differences were found in the percentage of positive cells between TT virus positive patients with and without oral lichen planus and there was no relationship between the number of positive cells and the intensity of the inflammatory infiltrate. In conclusion, TT virus infects oral epithelial cells but the results do not support a role for TT virus in causing oral lichen planus.

Aged↗

PubMed2001

Multicenter randomized study comparing initial daily induction with high dose lymphoblastoid interferon vs. standard interferon treatment for chronic hepatitis C.

One hundred fifty-five chronic hepatitis C patients were assigned at random to receive natural lymphoblastoid interferon (IFN)alpha-n1, s.c., for 13 months in one of three treatment regimens: initial daily induction with 10 million units (MU) followed (group 1, n = 50) or not (group 2, n = 52) by 1 month of rest and then three times weekly 10 MU (2 months), 5 MU (2 months), and 3 MU (8 months); group 3 (n = 53) received tiw 5 MU (2 months) followed by 3 MU (11 months). By intention-to-treat analysis, ALT normalization at completion of treatment was greater in patients who received continuous IFNalpha-n1 therapy with initial daily induction (group 2: 24/52, 46%) compared with those given intermittent therapy with initial daily induction (group 1: 17/50, 34%) and those who received standard IFNalpha-n1 therapy (group 3, 18/53, 34%; P not significant). The sustained ALT response was 26%, 27% and 21% and the sustained virological response was 20%, 27%, and 19%, in groups 1, 2, and 3, respectively. A trend was observed towards a higher biochemical and virological end-of-treatment response in patients given induction therapy (17%) compared with standard therapy (6%, P = 0.053). Sustained biochemical and virological responses were 20%, 27%, and 17% in groups 1, 2, and 3, respectively. Platelet and leukocyte counts decreased following daily high-dose treatment and remained low until therapy cessation (P < 0.001). The data suggest that daily s.c. induction with 10 MU IFNalpha-n1 followed by intermittent or continuous maintenance therapy for 1 year does not improve the results achieved with the standard 1-year IFNalpha course in the treatment of chronic hepatitis C patients.

Adolescent↗

PubMed2001

In situ detection of hepatitis C virus RNA in salivary glands.

Chronic hepatitis C virus (HCV) infection has been associated with several extrahepatic manifestations, among these, to diseases with oral manifestations such as Sjögren's syndrome or sialadenitis. HCV-RNA has been detected in saliva and in salivary glands from patients with sialadenitis by polymerase chain reaction. However, morphological evidence of HCV replication in salivary gland cells is needed to support a role for HCV in causing sialadenitis or Sjögren's syndrome. We have used in situ hybridization and immunohistochemistry to analyze the presence of HCV-RNA of sense and antisense polarity and HCV core antigen, respectively, in salivary gland biopsies from 19 patients with chronic sialadenitis or Sjögren's syndrome (eight anti-HCV-positive; 11 anti-HCV-negative). HCV-RNA of both positive and negative polarity as well as HCV core antigen were detected in the epithelial cells of the salivary gland biopsies from all of the anti-HCV-positive patients but in none of the anti-HCV-negative cases. The percentage of HCV-infected cells ranged from 25 to 48.8% in the patients studied. In conclusion, we have shown that HCV infects and replicates in the epithelial cells from salivary glands of patients with Sjögren's syndrome or chronic sialadenitis. However, its implication in the pathogenesis of these diseases deserves future research.

Adult↗

PubMed2001

Extended follow-up of anti-HBe-positive patients with chronic hepatitis B retreated with ribavirin and interferon-alpha.

In a pilot study of combination therapy with ribavirin and IFN alpha conducted in anti-HBe-positive individuals with chronic hepatitis B, 21% of patients achieved a sustained ALT normalization and clearance of hepatitis B virus (HBV) DNA as measured by PCR. The present work has assessed whether these sustained responses are lasting long-term. In addition, IFN gamma levels were tested serially in serum as a measure of the immune system activation during treatment. By extending the post-treatment follow-up period 2 years the occurrence of delayed HBV DNA relapses was observed. A low serum level of IFN gamma was detected during and after treatment. IFN gamma demonstrated a multiphasic time-course: the amount of IFN gamma increased in parallel with reductions in HBV DNA but also with ALT flare-ups. In conclusion, the extended follow-up study of anti-HBe-positive patients after combined treatment with ribavirin and IFN alpha has shown that sustained responses are lasting in 17% patients but also that a late onset HBV DNA relapse may occur.

Adult↗

PubMed2001

Interleukin-12 in the treatment of chronic hepatitis B and C.

Interleukin-12 plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. In two open label, multicenter, dose-escalation phase I/II studies tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) was assessed in the treatment of chronic hepatitis B and C. Forty-six patients with chronic hepatitis B and 60 patients with chronic hepatitis C were treated for 12 and 10 consecutive weeks, respectively. rHuIL-12 was generally well tolerated, but was associated with temporary decreases in neutrophils and lymphocyte counts, and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microg/kg compared with 0.25 microg/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon-gamma were also observed at the highest dose of 0.5 microg/kg. At the end of treatment HBV DNA clearance was greater in patients treated with 0.50 microg/kg (25%) or with 0.25 microg/kg (13%) compared with those given 0.03 microg/kg. In patients with chronic hepatitis C, HCV RNA remained detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3/16 patients (0.03 microg/kg), in 3/14 (0.10 microg/kg), in 6/15 (0.25 microg/kg), and in 8/15 patients of the 0.5 microg/kg dose group. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis B or C does not appear to be advantageous in comparison to other currently available treatments.

Adolescent↗

PubMed2001

Hepatitis B virus-specific T-cell proliferation and cytokine secretion in chronic hepatitis B e antibody-positive patients treated with ribavirin and interferon alpha.

Immune elimination of hepatitis B virus (HBV) during antiviral therapy depends on the activation of T-cell responses, which are generally impaired in chronic hepatitis B. HBV-specific T helper (Th)-cell reactivity has been assessed post-treatment in liver and peripheral blood of 18 anti-HBe-positive patients with chronic hepatitis B administered combined ribavirin/interferon alfa (IFN-alpha) therapy. The results showed that patients with undetectable HBV DNA by quantitative polymerase chain reaction under combination therapy were able to mount an HBV-specific CD4(+) Th-cell proliferative response and such T-cell reactivity is detectable 1 year after HBV DNA clearance. Hepatitis B virus core (HBcAg) and e (HBeAg) antigen-specific Th-cell proliferation was found more frequently in the liver and peripheral blood in those patients who sustained the alanine aminotransferase (ALT) normalization together with HBV DNA loss. However, HBV-specific IFN-gamma production in vitro in peripheral blood mononuclear cells augmented in 4 of 5 sustained responders and all 13 nonresponders, interleukin 10 (IL-10) production decreased in all 5 sustained responders but increased in 7 of 13 nonresponders. Furthermore, intrahepatic HBcAg plus HBeAg-specific Th-cell proliferation only occurred in sustained responders (2 of 3, 67%, vs. 0 of 9; P =.045) whose cells showed in vitro significantly increased productions in HBcAg/HBeAg-specific IFN-gamma and IL-12 compared with nonresponders in whom IFN-gamma and IL-12 productions decreased together with increased IL-10 secretion. In conclusion this study indicates that combined therapy with ribavirin and IFN-alpha for chronic hepatitis B not only significantly reduces viremia levels but also induces lasting CD4(+) T-cell proliferation and Th1 cytokine release at the site of infection, which may lead to sustained eradication of the HBV.

Adult↗

PubMed2001

Expression of factor VII in the liver of patients with liver disease: correlations with the disease severity and impairment in the hemostasis.

Factor VII (FVII) plasma levels in patients with liver disease may be below the normal range. However, no data are available on FVII expression in liver biopsies from patients with liver diseases other than cirrhosis. We have analyzed the expression of FVII by in situ hybridization in liver biopsies from 50 patients in comparison with the procoagulant activity of FVII, and with the plasma levels as activated FVII (FVIIa) and FVII antigen. The level of FVIIa was significantly lower in stage 4 liver fibrosis patients than in the remaining ones (P < 0.05). The percentage of hepatocytes expressing FVII was significantly lower in stage 4 liver fibrosis patients (4.1+/-1.3%) than in stage 3 (22.7+/-6.1%), stage 2 (31.5+/-6.1%), stage 1 (43.7+/-8.2%) and stage 0 patients (63.8+/-4.4%) (P < 0.001). These percentages correlated inversely in a statistically significant way with the histological activity index and the liver function tests. We have demonstrated that the FVIIa plasma levels in patients with chronic liver disease other than cirrhosis may be below the normal range in the absence of blood coagulation impairment. The percentage of hepatocytes expressing FVII decreases as the severity of liver damage increases.

Adult↗

PubMed2001

Association of HLA-DR genes with mild idiopathic adulthood biliary ductopenia.

OBJECTIVE: Mild idiopathic adulthood ductopenia (MIAD) is an asymptomatic chronic cholestatic liver disease characterized by the loss of interlobular bile ducts in <50% of the portal tracts. Although the underlying cause of MIAD is unknown, the host factors may contribute to the patient's susceptibility to the disease. The aim of this work was to investigate the immunogenetics in the pathogenesis of MIAD. METHODS: We prospectively studied 22 Caucasian patients with MIAD. Peripheral blood was collected, and HLA-DR typing was performed by polymerase chain reaction with sequence-specific primers followed by sequencing for subtyping. Results were compared with those from 140 age- and sex-matched controls. RESULTS: There was no significant association between HLA-DRB1 alleles and the disease, although a trend was found in MIAD patients with the DRB1*1502 allele (five of 44 vs four of 280 in controls; p corrected = 0.055; chi2 = 13.9). Multiple HLA-DRB1 alleles (*04, *11, *15) showed increased frequencies in MIAD patients. Further subtyping revealed a motif (positions 25-32 of the beta1 chain) present in 17 (77.3%) patients, which was significantly associated with MIAD (p = 0.049; chi2 = 3.87). Seven patients (31.8%) and 21 (15%) controls coded for this motif in their two alleles (p = 0.068; chi2 = 3.76). Among MIAD patients, those seven had abnormal ALT levels (p = 0.017) and their gamma-glutamyltransferase and ALT values tended to be more increased. CONCLUSIONS: These results provide evidence of an immunogenetic basis of susceptibility to MIAD in Caucasian individuals.

Adult↗

PubMed2001

Prevalence of hepatitis B, hepatitis C, GB virus C/hepatitis G and TT viruses in predialysis and hemodialysis patients.

Patients with chronic renal failure on hemodialysis have a high risk of infections with viruses such as hepatitis B (HBV), hepatitis C (HCV), GB virus C/hepatitis G (GBV-C/HGV) and TT (TTV) viruses. The prevalence of HBV, HCV, GBV-C/HGV and TTV in patients with chronic renal failure who are on conservative management before entering into a hemodialysis program (predialysis) in comparison with hemodialyzed patients was studied to elucidate whether the high prevalence of these viruses is influenced by that observed in the predialysis stage. The presence of hepatitis B virus surface antigen (HBsAg), HCV RNA, GBV-C/HGV RNA and TTV DNA was analyzed in sera from 80 patients with chronic renal failure (35 on predialysis and 45 on hemodialysis). HBsAg, HCV RNA, GBV-C/HGV RNA and TTV DNA were detected in one (2.8%), six (17.1%), eight (22.5%) and 16 (45.7%) of the 35 patients on predialysis. Two (5.7%) of these patients were coinfected with HCV and GBV-C/HGV, whereas six (17.1%) had GBV-C/HGV and TTV coinfection. In the 45 hemodialyzed patients, HBsAg, HCV RNA, GBV-C/HGV RNA and TTV DNA were detected in one (2.2%), two (4.4%), seven (15.5%) and 26 (57.7%). One (2.2%) patient had HBV and TTV coinfection, two (4.4%) HCV and TTV coinfection whereas four (8.8%) were coinfected with GBV-C/HGV and TTV. No differences regarding age, gender, previous surgery and number of transfusions were found between infected and uninfected patients within and between both groups. In conclusion, the prevalence of the viruses studied in predialysis may influence their prevalence in dialysis units.

Aged↗

PubMed2000

Fluorescent "in situ" hybridization of hepatitis C virus RNA in peripheral blood mononuclear cells from patients with chronic hepatitis C.

Although the liver is the main target for hepatitis C virus (HCV) infection, HCV RNA of positive and negative polarity has also been detected in peripheral blood mononuclear cells (PBMCs) by polymerase chain reaction. However, no data have been published on the relationship between the number of HCV-infected PBMCs and serum viremia levels. To address this issue, PBMC samples from 20 patients with chronic hepatitis C were examined by fluorescent "in situ" hybridization. Serum viremia levels and viral load in infected PBMC were measured using the Amplicor Monitor test. HCV was detected in all PBMC samples corresponding to the HCV-positive patients. Fluorescent signals were found mainly in the cytoplasm of the cell. The percentage of positive cells ranged from 0.08% to 4%, with a statistical correlation with the viral load in PBMC (r = 0.69; p =. 001) but not with the serum viremia levels (r = 0.23). It was demonstrated that HCV infection of PBMCs is a common feature of HCV chronic carriers. The results suggest that HCV infection of PBMCs does not contribute significantly to HCV viremia.

Hepacivirus↗

PubMed2000

Pilot study of combination therapy with ribavirin and interferon alfa for the retreatment of chronic hepatitis B e antibody-positive patients.

Twenty-four patients with chronic hepatitis B virus (HBV), antibody to hepatitis B e antigen (anti-HBe), HBV DNA positivity, and alanine transaminase (ALT) elevation who failed previous interferon alfa (IFN-alpha) therapy were included in a pilot study of combination therapy with ribavirin and IFN-alpha. The patients received daily oral ribavirin (1,000-1,200 mg according to body weight) plus 5 million units (MU) IFN-alpha2b three times a week for 12 months and were followed-up for 12 months. The median viremia level decreased significantly at the end of treatment (1.2 x 10(3) copies/mL) and follow-up (4.0 x 10(2) copies/mL) compared with the baseline (3.0 x 10(6) copies/mL; P <.05). After 12 months, 8 of 24 (33%) patients had cleared HBV DNA and 12 (50%) had normal ALT levels. At the end of the study virological and biochemical response was 50% and 21%, respectively. Thus, virological and biochemical response sustained in 5 of 24 (21%) patients retreated with ribavirin and IFN-alpha; none of them lost hepatitis B surface antigen (HBsAg). Liver histology improved in 2 of 4 sustained responders but in none of the 12 nonresponders with paired biopsies (P =.05). The response was independent of dose and duration of previous treatment, viral load, or the distribution of HBV precore wild-type/mutant variants. However, sustained responders had significantly higher necroinflammation (P =.036) and fibrosis (P =.007) scores. IFN-alpha-related side effects were mild and reversible on discontinuation. In 4 (17%) patients who suffered nausea and diarrhea the ribavirin dosage was reduced by 50% after 1 month of therapy and finally discontinued in all of them. No patient had liver disease decompensation. In summary, combination therapy with ribavirin and IFN-alpha may be efficacious to treat viremic anti-HBe-positive patients with chronic hepatitis B who have failed previous IFN therapy.

Adult↗

PubMed2000

Randomized controlled trial of recombinant human granulocyte-macrophage colony-stimulating factor for the treatment of chronic hepatitis c.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously to 45 chronic hepatitis C patients, randomly assigned to receive 0.5, 1 or 2 microg GM-CSF/kg b.w. daily/6 weeks (n=30), or no treatment (n=15). Alanine transaminase (ALT) values normalized in four out of 10 (40%) patients administered 2 microg GM-CSF [1 cleared hepatitis C virus (HCV) RNA] but in none given 0.5 or 1 microg or untreated controls (P=0.0079). Following 4 weeks of rest, patients received 5 million units of interferon (IFN)alpha2b every other day/6 months, alone (n=30), or combined with 2 microg GM-CSF/daily for 3 months (n=15). At treatment end, ALT levels in patients administered the combination normalized more frequently than in those given monotherapy (73% vs 47%, P=0.089). Viraemia decreased significantly in 11/15 (73%) patients administered GM-CSF/IFNalpha2b combination (mean log HCV RNA copies/ml+/-SEM: 4.13+/-0.40 vs 5.29+/-0.23;P=0.011), and in 20/30 (67%) receiving IFNalpha2b monotherapy (4.27+/-0.28 vs 5. 31+/-0.14;P=0.004); 27% and 20% of patients given the combination and monotherapy, respectively, cleared HCV RNA. One patient in each regime had a sustained response after 12 months. 2', 5'-Oligoadenylate synthetase activity (2-5AS) increased during GM-CSF therapy (P=0.033 with the 2 microg dose). 2-5AS increased more in the GM-CSF/IFN-alpha2b combination than with IFNalpha2b monotherapy (P<0.02). GM-CSF provoked a skin reaction at the injection site, accompanied by moderate and reversible rises in eosinophil and leucocyte counts. In summary, daily s.c. GM-CSF administration is safe and shows effects against HCV; the GM-CSF/IFNalpha2b combination has an additional-but transient-antiviral activity in chronic hepatitis C.

Adolescent↗

PubMed2000

Role of haemodialysis and hepatitis c virus infection in spontaneous and induced cytokine production of patients with chronic renal disease.

Cytokines modulate general and virus infection-related host immune responses. We have investigated cytokine responses in chronic renal disease patients with regard to haemodialysis and hepatitis C virus (HCV) infection. Compared with healthy subjects with normal renal function (n=15), non-dialyzed/renal disease individuals without HCV infection (n=11) showed increased production of tumour necrosis factor (TNF)-alpha, interleukin (IL-)6, IL-10, interferon (IFN-)gamma and IL-12 by blood mononuclear cells (P<0.05). These inflammatory cytokine responses were abolished in haemodialysis patients (n=37;P<0.05), except for IL-12. This hyporesponsiveness in haemodialysis patients was more evident in stimulatory conditions, as shown by the consistent inhibition of IFN-gamma production, and the failure of exogenous IFN-gamma to prime for IL-12 inducibility (P<0.01). The disturbed cytokine response appeared to focus in the T-helper lymphocyte phenotype 1 (Th(1)) because the stimulation of IL-6 and IL-10 (Th(2)phenotype cytokines) was not impaired. The pattern of response was similar among haemodialysis patients with (n=24) or without (n=13) HCV infection. However, HCV-positive haemodialysis patients had a blunted TNF-alpha response (P<0.05) and failed to increase the stimulated IFN-gamma and IL-12 production (P<0.01) compared with chronic hepatitis C patients without renal disease (n=25). On the contrary, IL-10 stimulation was higher in HCV-positive haemodialysis patients (P<0.01). These results disclose the presence in haemodialysis patients of markedly abnormal general and HCV infection-related cytokine responses; the inhibitory alterations appear to affect predominantly the stimulated responses via the Th(1)subset and its relationship with monocyte response with possible pathogenic and therapeutic implications.

Chronic Disease↗

PubMed2000

Detection of TT virus DNA in liver biopsies by in situ hybridization.

A novel hepatitis-associated virus named TT virus (TTV) has been isolated. However, its hepatotropism has not been proven. We have retrospectively analyzed the presence of TTV-DNA by polymerase chain reaction (PCR) and in situ hybridization in liver biopsies from 30 patients with liver disease (15 TTV-DNA-positive and 15 TTV-DNA-negative in serum), and prospectively in serum and liver from eight patients with normal liver histology. TTV-DNA was detected by PCR in the liver from the 15 patients with serum TTV-DNA and in serum and liver of two of the eight patients without liver disease. TTV-DNA titers in liver were 10 times higher than in serum, although no correlation between TTV-DNA titers in serum and liver were observed. In situ hybridization shows positive signals in the hepatocytes of the 17 patients infected by TTV but in none of the TTV-DNA-negative patients by PCR. No morphological changes were observed in the hepatocytes showing hybridization signals. The percentage of positive hepatocytes ranged from 2.1% to 30% and correlated with the TTV-DNA titers in liver (r = 0.54; P = 0.037). In conclusion, our results show that TTV is able to infect liver cells although they do not support a role for TTV in causing liver disease.

Adult↗

PubMed2000

A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B.

BACKGROUND/AIMS: Interleukin-12 (IL-12) may be active against hepatitis B virus (HBV). The objective of the study was to assess the tolerability, activity, pharmacokinetics, and pharmacodynamics of three dose levels (0.03 microg/kg b.w., n=15; 0.25 microg/kg b.w., n=15; 0.50 microg/kg b.w., n=16) of recombinant human (rHu) IL-12 given s.c. once a week for 12 consecutive weeks. METHODS: Forty-six patients with chronic hepatitis B, HBV DNA positivity and aminotransferase elevation were included in a multicenter prospective randomized phase I/II study. RESULTS: Compared with the baseline, HBV DNA levels had decreased significantly at the end of rHuIL-12 treatment and after the 12-week follow-up period (p<0.001). The response to rHuIL-12 treatment was dose-dependent: at the end of the study HBV DNA clearance was greater in patients treated with 0.50 microg/kg b.w. (25%) or with 0.25 microg/kg b.w. (13%) compared with those given 0.03 microg/kg b.w. (7%). Moreover, HBeAg became undetectable at the end of follow-up in five of the patients given the 0.25microg/kg (2/15) or the 0.50 microg/kg (3/16) dose. The drug pharmacology showed that IL-12 had an estimated half-life of 30 h with levels remaining detectable for more than 48 h after rHuIL-12 administration. The serum levels of IL-12, interferon-gamma, IL-10, neopterin and beta2-microglobulin as well as the area under the curve (AUC) were rHuIL-12 dose-related. Side effects were observed more frequently with higher doses, including moderate decreases in lymphocyte and neutrophil counts; three patients withdrew prematurely from treatment. The local reaction observed at the injection site was unrelated to the drug dose. Only one patient showed detectable antibody levels to rHuIL-12 without clinical impact. CONCLUSIONS: Treatment with rHuIL-12 at the doses investigated is safe and tolerable, and appears to be active against HBV in patients with chronic hepatitis B.

Adjuvants, Immunologic↗