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1.
J Chemother ; 34(4): 207-220, 2022 Jul.
Article in English | MEDLINE | ID: mdl-34644236

ABSTRACT

SARS-CoV-2 infection (COVID-19) results predominantly in pulmonary involvement but a direct, virus-induced liver damage may also occur, whose mechanisms are being actively investigated. Accordingly, it appears of utmost importance to monitor liver function and carefully evaluate hepatic safety of the various drugs administered during COVID-19. In this respect, many drugs, biological agents and novel molecules, whose efficacy in COVID-19 is under scrutiny, have also been shown to potentially cause or worsen liver damage. In this article, we review safety data of established as well as promising agents for COVID-19.


Subject(s)
COVID-19 Drug Treatment , Antiviral Agents/adverse effects , Humans , Hydroxychloroquine , Liver , SARS-CoV-2
2.
Infection ; 48(4): 657, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32613530

ABSTRACT

The original version of this article unfortunately contained a mistake.

4.
Clin Microbiol Infect ; 25(8): 943-950, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31004767

ABSTRACT

BACKGROUND: Carbapenem resistance is defined as in vitro non-susceptibility to any carbapenem and/or documented production of a carbapenemase. This feature has rapidly spread worldwide among clinical isolates of Enterobacteriaceae, mostly Klebsiella spp., and is associated with diverse molecular mechanisms. Carbapenem resistance is often associated with resistance to all traditional ß-lactams and other classes of antibiotics, denoting a typical example of an extensively drug-resistant phenotype. OBJECTIVES: To summarize and interpret in a balanced manner the most clinically relevant data in terms of carbapenem-resistant Enterobacteriaceae (CRE) infection management. SOURCES: Data were extracted by PubMed and clinicaltrials.gov search and manual scrutiny among references of analysed articles. CONTENT: Features of newer and older, rediscovered antimicrobial options for CRE are described. Observational studies and randomized clinical trials (RCT) of CRE treatment are summarized, with a specific focus on the effects of monotherapy compared with combination treatment. IMPLICATIONS: The available evidence on the current management of CRE mostly comes from observational, non-comparative, retrospective, small studies, with a high risk of selection bias. Very little evidence comes from RCT. Conflicting results of RCT and observational studies call for caution before combination therapies are deemed superior to monotherapy. Data on newer agents have spurred enthusiasm but remain limited as concerns severe CRE infections. A balanced approach should guide the clinician in the choice of old or new drugs, and of monotherapies or combination regimens. Efforts should be made to perform adequately sized clinical trials answering well-defined research questions.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Carbapenem-Resistant Enterobacteriaceae/drug effects , Disease Management , Drug Resistance, Multiple, Bacterial , Enterobacteriaceae Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Enterobacteriaceae Infections/mortality , Humans , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Observational Studies as Topic , Randomized Controlled Trials as Topic
5.
J Viral Hepat ; 25(8): 920-929, 2018 08.
Article in English | MEDLINE | ID: mdl-29532619

ABSTRACT

It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients.


Subject(s)
Coinfection/complications , Fatty Liver/epidemiology , Fatty Liver/pathology , Hepatitis B, Chronic/complications , Hepatitis C, Chronic/complications , Adult , Female , Humans , Male , Middle Aged , Prevalence , Retrospective Studies
6.
Infection ; 44(5): 575-82, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27076347

ABSTRACT

INTRODUCTION: Occult hepatitis B infection (OBI), a virological condition characterized by a low release of Hepatitis B Virus (HBV) from liver cells and low HBV-DNA levels in serum and/or liver tissue of HBsAg-negative subjects, may reactivate in oncohematological patients undergoing immunosuppression by aggressive chemotherapy or hematopoietic stem cell transplantation. The entity of OBI reactivation varies from an increase in HBV replication without liver damage to an active HBV replication followed by liver cell necrosis, frequently severe and in some cases life threatening. Because of a possible severe outcome associated with OBI reactivation (hepatic failure or death due to the discontinuation of chemotherapy), prophylaxis with anti-HBV nucleot(s)ide analogues is recommended in relation to the foreseeable degree of immunosuppression. MATERIALS AND METHODS: This review article focuses on the clinical impact of OBI in the oncohematological setting and is addressed to all health care workers having in care oncohematological patients or involved in the treatment of HBV infection and OBI prophylaxis. CONCLUSION: International guidelines have indicated lamivudine prophylaxis in hematopoietic stem cell transplantation and when high-dose corticosteroids or anti-CD20 or anti-CD52 monoclonal antibodies are used. Entecavir or tenofovir should replace lamivudine for patients with advanced liver diseases for whom reactivation of OBI may be life threatening. When anti-CD20 or anti-CD52 sparing schedules or other non-aggressive chemotherapies are used, monitoring may be indicated, but very early treatment with highly effective antiviral drugs (entecavir or tenofovir) should be administered once a reactivation of OBI has occurred.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis B virus/physiology , Hepatitis B/drug therapy , Antiviral Agents/pharmacology , Disease Progression , Hepatitis B/diagnosis , Hepatitis B/virology , Hepatitis B virus/drug effects , Hepatitis B virus/immunology , Humans , Immunosuppression Therapy , Liver/virology , Risk Factors , Treatment Outcome , Virus Activation
7.
Transpl Infect Dis ; 18(3): 319-25, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26988401

ABSTRACT

BACKGROUND: Treatment of chronic hepatitis B (CHB) with polymerase inhibitors is key to prevent disease flares and progression toward advanced liver disease. Efficacy and tolerability of newer agents has been reported anecdotally in transplant recipients. METHODS: In this prospective, observational study, we assessed outcomes of therapy with tenofovir (TDF), entecavir (ETV), and telbivudine (LdT) in 13 heart transplant recipients (HTR) with CHB. RESULTS: Most patients were hepatitis B e antigen negative, had low baseline hepatitis B virus (HBV) DNA, and normal aminotransferases. Liver biopsy showed a median fibrosis score of 1.5 (range 0-4). Glomerular filtration rate (GFR) was <50 mL/min in 7 patients (54%). Two patients were started on de novo ETV before transplant. Eleven previously treated patients were switched to TDF (n = 9) or LdT (n = 2). Median treatment duration was 33 months (range 1-71). HBV DNA remained suppressed in 6 patients and became undetectable in 5. Aminotransferases went down to the normal range in all patients, with a single flare in 1 patient. One patient lost hepatitis B surface antigen. No cases occurred of hepatic decompensation, hepatocellular carcinoma, or liver-related death. The GFR remained largely stable, and no cases of TDF-related hyper-phosphaturia were observed. CONCLUSIONS: This study indicates that newer antivirals are effective and safe in HTR with CHB.


Subject(s)
Antiviral Agents/pharmacology , Guanine/analogs & derivatives , Heart Transplantation/adverse effects , Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Tenofovir/pharmacology , Thymidine/analogs & derivatives , Adult , Aged , Cohort Studies , DNA, Viral/analysis , Female , Follow-Up Studies , Guanine/pharmacology , Hepatitis B virus/genetics , Hepatitis B, Chronic/virology , Humans , Male , Middle Aged , Prospective Studies , Telbivudine , Thymidine/pharmacology , Treatment Outcome , Viremia
8.
Clin Microbiol Infect ; 21(6): 609.e1-4, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25749560

ABSTRACT

The impact of the cannabinoid receptor 2 (CB2) rs35761398 polymorphism on chronic hepatitis B (CHB) was evaluated in 106 consecutive biopsy-proven CHB patients naive for antiviral therapy. A histological activity index (HAI) > 8 (Ishak scoring) was more frequent in patients with CB2-63 RR than in those with CB2-63 QR or QQ (37% vs. 16.7%, p < 0.05). The logistic regression analysis identified CB2-63 RR (p < 0.05) and a fibrosis score >3 (p < 0.005) as independently associated with an HAI >8. The observation that the CB2-63 RR variant is an independent predictor of extensive necroinflammation opens up new prospects in the study of CHB.


Subject(s)
Hepatitis B, Chronic/genetics , Hepatitis B, Chronic/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Polymorphism, Genetic , Receptor, Cannabinoid, CB2/genetics , Severity of Illness Index , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult
9.
Eur J Clin Microbiol Infect Dis ; 33(4): 559-67, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24081499

ABSTRACT

The purpose of this investigation was to evaluate the role of IL28-B polymorphism in the clearance of hepatitis C virus (HCV) in chronic hepatitis B virus (HBV)/HCV coinfection during a long-term follow-up. Thirty-four consecutive patients with HBV surface antigen (HBsAg)-positive/anti-HCV-positive chronic hepatitis were retrospectively enrolled at their first liver biopsy (LB). For all patients, a documented clinical, serological and virological follow-up of at least 3 years (range 3-16 years) after LB and a sample of whole blood for genetic evaluation were available. Of the 24 patients with detectable serum HBV-DNA and HCV-RNA at their first observation, three cleared both HBV-DNA and HCV-RNA, 12 HCV-RNA and five HBV-DNA. Of the seven HBV DNA-positive/HCV RNA-negative patients at enrolment, three cleared HBV-DNA and one remained HBV DNA-positive and became HCV RNA-positive. All three HBV DNA-negative/HCV RNA-positive patients remained unchanged. Compared with the 12 patients with HCV persistence, the 15 patients who cleared HCV were younger, had lower serum alanine aminotransferase (ALT), HCV load, and histological activity index (HAI) and fibrosis score, more frequently had IL28-B CC variant, had been receiving an interferon-based treatment and less frequently cleared serum HBV-DNA. To investigate the relationship between the IL28-B variants and clearance of HCV, excluding the confounding effect of interferon-based treatment, the Mantel-Haenszel test was used, which indicated an association between HCV clearance and IL28-B variants (p = 0.009). In chronic HBV/HCV coinfection, a long-term follow-up showed a frequent spontaneous or treatment-related clearance of active replication of one or both viruses and identified the IL28-B CC genotype as an independent predictor of HCV clearance.


Subject(s)
Hepatitis B, Chronic/virology , Hepatitis C, Chronic/virology , Interleukins/genetics , Adult , Coinfection , Female , Hepatitis B, Chronic/genetics , Hepatitis B, Chronic/immunology , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/immunology , Humans , Interferons , Interleukins/immunology , Male , Middle Aged , Polymorphism, Single Nucleotide , Retrospective Studies
10.
J Viral Hepat ; 20(8): 517-23, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23808989

ABSTRACT

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis.


Subject(s)
Abdominal Fat/metabolism , Apolipoprotein C-III/genetics , Fatty Liver/genetics , Hepatitis C, Chronic/genetics , Lipase/genetics , Membrane Proteins/genetics , Adult , Aged , Aged, 80 and over , Fatty Liver/pathology , Female , Genotype , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/pathology , Humans , Italy , Male , Middle Aged , Mutant Proteins/genetics , Mutation, Missense , Polymorphism, Single Nucleotide , Young Adult
11.
J Viral Hepat ; 19(5): 346-52, 2012 May.
Article in English | MEDLINE | ID: mdl-22497814

ABSTRACT

HCV genotypes 2- or 3-infected patients with a rapid virological response (RVR) to therapy with pegylated interferon and ribavirins who have a low viral load, noncirrhotic and nonobese may be considered for a shorter course of treatment. However, no studies have assessed host-viral factors associated with relapse in genotype 2 and 3 separately. Accordingly, we assessed whether 12 weeks of pegylated interferon and ribavirin was an optimized regimen for treatment of HCV genotype 2 and 3 with positive predictors of response. Power and sample size were a priori calculated and 96 consecutive chronic hepatitis C patients (53, genotype 2 and 43, genotype 3) without cirrhosis who were not obese and who achieved a RVR to therapy with peg-IFN-α-2a and ribavirin were enrolled. Fibrosis, steatosis, homeostatic model assessment-insulin resistance and HCV RNA were predefined variables to be evaluated in relapse. An intention-to-treat analysis was performed. SVR rates were 98% and 84% for genotype 2 and 3, respectively. Analysis of genotype 3 patients who had relapse showed a negative correlation with steatosis (P < 0.0001) and HCV RNA (P < 0.015). Multivariate analysis showed that steatosis was the independent predictor of relapse (OR, 0.988; 95% CI, 0.981-0.993; P < 0.001). Genotype 3 patients with steatosis had a relapse rate of 36.4% and 15.8% in those with high and low viral load, respectively, whereas there was no relapse in those without steatosis. In conclusion, a 12-week course of therapy is sufficient for patients without cirrhosis, not obese and infected with HCV genotype 2 achieve a RVR. This is not the case for genotype 3. Steatosis is the independent predictor of relapse. New therapeutic strategies are necessary for this subgroup of HCV genotype 3.


Subject(s)
Fatty Liver/diagnosis , Hepacivirus/classification , Hepatitis C/drug therapy , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , RNA, Viral/genetics , Ribavirin/administration & dosage , Adult , Antiviral Agents/administration & dosage , Female , Genotype , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepatitis C/pathology , Hepatitis C/virology , Humans , Male , Middle Aged , Prognosis , Recombinant Proteins/administration & dosage , Recurrence , Treatment Outcome
12.
Intervirology ; 53(3): 183-7, 2010.
Article in English | MEDLINE | ID: mdl-20197685

ABSTRACT

Hepatitis B surface antigen (HBsAg) is considered the best marker for the diagnosis of hepatitis B virus (HBV) infection. Mutations of the s gene involving amino acid substitutions within the a determinant could affect the sensitivity of diagnostic tests. In the present study, HBsAg mutants were detected in 3 immunocompromised patients, previously found to be HBsAg negative and anti-HBs positive. All patients had high levels of HBV-DNA, whereas HBsAg tests gave discordant results. Immunosuppression can cause viral reactivation of occult HBV infection in these patients and favour the selection of HBsAg a determinant mutants.


Subject(s)
Hepatitis B Surface Antigens/blood , Hepatitis B Surface Antigens/genetics , Hepatitis B virus/genetics , Hepatitis B virus/isolation & purification , Hepatitis B/diagnosis , Mutation, Missense , Aged , DNA, Viral/blood , Female , Hepatitis B Antibodies/blood , Humans , Immunoassay , Immunocompromised Host , Male , Middle Aged , Sensitivity and Specificity
13.
J Viral Hepat ; 15(10): 740-6, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18482281

ABSTRACT

SUMMARY: (A) A reduced activity of microsomal triglyceride transfer protein (MTP), a key enzyme of assembly/secretion of lipoproteins, is related to HCV steatosis. Host genetic background may influence development of steatosis. The aim of the study was to investigate the association between MTP-493 G/T gene polymorphism, fat liver accumulation and fibrosis progression in HCV infected patients. A total of 102 naïve patients with liver biopsy proven chronic hepatitis C were evaluated for MTP-493 G/T gene polymorphism, HCV RNA, HCV genotype, HOMA-IR, serum adiponectin, TNF-alpha and serum lipid levels. HCV genotype 3 infected patients carrying the T allele of the MTP gene polymorphism showed higher degree of steatosis than those carrying GG genotype (3.45 +/- 0.37 vs 1.30 +/- 0.45, respectively; P < 0.001). MTP'T' allele carriers also had higher HCV RNA serum levels (P < 0.01) and hepatic fibrosis (P < 0.001). Irrespective of MTP genotype, patients with HCV genotype 3 had lower levels of cholesterol, ApoB, HDL and LDL. In HCV genotype non-3 infected patients no parameters were associated with MTP gene polymorphism. In conclusion the presence of T allele of MTP-493G/T gene polymorphism predisposes patients infested with HCV genotype 3 to develop higher degree of fatty liver accumulation.


Subject(s)
Carrier Proteins/genetics , Fatty Liver/genetics , Fatty Liver/metabolism , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/physiopathology , Polymorphism, Genetic , Adolescent , Adult , Aged , Carrier Proteins/metabolism , Fatty Liver/physiopathology , Female , Genotype , Hepacivirus , Hepatitis C, Chronic/metabolism , Hepatitis C, Chronic/virology , Humans , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/physiopathology , Liver Cirrhosis/virology , Male , Microsomes , Middle Aged
14.
Aliment Pharmacol Ther ; 24(9): 1349-57, 2006 Nov 01.
Article in English | MEDLINE | ID: mdl-17059516

ABSTRACT

BACKGROUND: Steatosis and insulin resistance (IR) have a pathogenic role in chronic hepatitis C (HCV). Adipocytokines balance modulates hepatic lipid content and IR. AIM: To evaluate serum adipocytokines and relationship with virological, histological and metabolic parameters in chronic HCV. METHODS: Adiponectin and tumour necrosis factor-alpha (TNF-alpha) levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 161 non-diabetic chronic HCV patients. RESULTS: Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of TNF-alpha, HOMA, alanine aminotransferase, gamma-glutamiltransferase and Histological Activity Index (HAI) and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Higher tumour necrosis factor-alpha levels were observed in patients with low adiponectin levels. The extension of steatosis was inversely correlated with adiponectin levels. A correlation between grade of steatosis with HOMA-IR and fibrosis was observed. HCV genotype 3-infected patients showed lower adiponectin levels than those with other genotypes. An independent predictor of low adiponectin levels in genotype 3 infection was the extension of steatosis. Liver fibrosis score was associated with steatosis, HAI and age. CONCLUSIONS: Chronic HCV patients with steatosis showed a serum adiponectin/TNF-alpha imbalance that is associated with IR. Reduced adiponectin levels may be involved in the pathogenesis of steatosis, which in turn accelerates progression of fibrosis in chronic HCV.


Subject(s)
Adiponectin/metabolism , Blood Glucose/metabolism , Fatty Liver/etiology , Hepatitis C, Chronic/complications , Insulin Resistance/physiology , Tumor Necrosis Factor-alpha/metabolism , Adolescent , Adult , Aged , Fatty Liver/blood , Female , Genotype , Hepatitis C, Chronic/blood , Humans , Male , Middle Aged
15.
Aliment Pharmacol Ther ; 22 Suppl 2: 52-5, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16225474

ABSTRACT

Steatosis is a common feature of chronic hepatitis C, and may be caused directly by the virus, as in genotype 3 infection, or be associated with host metabolic factors. The interaction of hepatitis C virus core protein with the lipoprotein secretion pathways causes the characteristic alterations of lipid metabolism observed in hepatitis C virus-related steatosis. Several pathogenic mechanisms are likely involved into the pathogenesis of hepatitis C virus-related steatosis, including hyper-homocysteinaemia, hypoadiponectinaemia and insulin resistance. Steatosis is a major determinant of the liver damage progression in chronic hepatitis C (CHC), and negatively affects the response rate to the interferon (IFN)-based anti-viral treatment. Moreover, recent evidence suggests that steatosis may contribute to liver carcinogenesis. Chronic hepatitis C is a recognized risk factor for type 2 diabetes and it could be implicated into the pathogenesis of atherosclerosis. The role of hepatitis C virus (HCV)-related steatosis in these epidemiological associations remains to be determined.


Subject(s)
Fatty Liver/complications , Hepatitis C/complications , Adiponectin/blood , Antiviral Agents/therapeutic use , Chronic Disease , Fatty Liver/physiopathology , Hepatitis C/drug therapy , Hepatitis C/physiopathology , Homocysteine/blood , Humans , Insulin Resistance/physiology , Interferons/therapeutic use , Lipid Metabolism/physiology , Liver Cirrhosis/complications
16.
Aliment Pharmacol Ther ; 22(8): 707-14, 2005 Oct 15.
Article in English | MEDLINE | ID: mdl-16197491

ABSTRACT

BACKGROUND: Drug-resistant mutants may emerge in patients with chronic hepatitis B receiving lamivudine therapy. AIM: To evaluate whether different viral mutational patterns may be associated with clinical reactivation during lamivudine treatment in patients with chronic B hepatitis. METHODS: Eight anti-hepatitis B e-positive patients with (group A) and 14 patients without clinical exacerbation (five anti-hepatitis B e-positive, group B1; nine hepatitis B e antigen-positive, group B2) during lamivudine treatment were investigated. RESULTS: 'Polymerase region': M204V/I variants were found in all group A patients, but in none of group B1 (P=0.0007) and in four of nine of group B2 (44%; P=0.02) patients. The L180M substitution was detected in four of eight (50%) of group A and in none of groups B1 and B2. 'Core promoter': the double basic core promoter (A1762T/G1764A) variant was detected in seven of eight (87%) of group A and in one of five (20%; P=0.03) of group B1 and one of nine (11%; P=0.002) of group B2 patients. 'Precore': the G1896A stop codon mutation was present in seven of eight (87%) of group A and in zero of five (P=0.004) of group B1 and one of nine (11%; P=0.002) of group B2. CONCLUSIONS: Different mutational patterns were observed in the lamivudine-treated patients with and without exacerbation. There was an association of the basic core promoter and stop codon mutations with lamivudine resistance in patients with disease exacerbation.


Subject(s)
Hepatitis B e Antigens/blood , Hepatitis B virus/physiology , Hepatitis B, Chronic/drug therapy , Lamivudine/therapeutic use , Mutation , Adult , Amino Acid Sequence , Codon, Terminator/genetics , DNA, Viral/blood , Drug Resistance, Viral/genetics , Female , Follow-Up Studies , Hepatitis B e Antigens/immunology , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Hepatitis B, Chronic/pathology , Hepatitis B, Chronic/virology , Humans , Male , Middle Aged , Molecular Sequence Data , Promoter Regions, Genetic/genetics , Reverse Transcriptase Inhibitors/therapeutic use , Virus Activation/genetics
17.
J Viral Hepat ; 12(2): 186-91, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15720534

ABSTRACT

Alpha-interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)-DNA was evaluated during treatment and core-promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV-DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti-HBe seroconversion. One patient presented core-promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three-phase sequential combined lamivudine/IFN treatment reduced HBV-DNA serum level, but did not lead to HBeAg and HBV-DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.


Subject(s)
Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/drug therapy , Interferon-alpha/therapeutic use , Lamivudine/therapeutic use , Adolescent , Adult , Age Factors , Child , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Female , Follow-Up Studies , Hepatitis B virus/drug effects , Humans , Interferon alpha-2 , Liver Function Tests , Male , Probability , Prospective Studies , Recombinant Proteins , Risk Assessment , Sampling Studies , Severity of Illness Index , Statistics, Nonparametric , Treatment Outcome
18.
Intervirology ; 46(4): 222-6, 2003.
Article in English | MEDLINE | ID: mdl-12931030

ABSTRACT

OBJECTIVE: To investigate the correlation of serum hepatitis B e antigen (HBeAg) levels with the presence of core promoter (CP) mutations, hepatitis B virus (HBV) viremia and the response to interferon (IFN) in patients with chronic hepatitis B. METHODS: Fourteen HBeAg-positive patients received alpha-2a IFN. Diluted serum samples of responders were tested for HBeAg positivity at dilutions of 1:40, 1:160 and 1:640 at the following time points: T0 (before starting IFN), T1 [at peak alanine aminotransferase (ALT) preceding HBeAg seroconversion], T2 (at ALT normalisation) and T3 (end of treatment). Nonresponder samples were similarly tested at times T0 and T3. The HBV CP and precore regions were sequenced at the same time points as for HBeAg testing. RESULTS: Six of 14 patients (43%) responded to IFN treatment and had lower HBeAg levels than nonresponders at T0 (p = 0.003). Five of 6 responders (83%) and none of the nonresponders had the A1762T/G1764A CP mutations (0/8, p < 0.003). At T0, HBeAg was negative at the 1:640 dilution in 5 of the 6 responders, who also had lower HBV DNA levels than nonresponders (p = 0.003). During IFN treatment, HBeAg levels decreased and HBV DNA became negative at T1 in responders. CONCLUSIONS: Low serum HBeAg and HBV DNA levels correlate with the presence of CP mutations and response to IFN treatment and can be considered as predictive markers of response to IFN.


Subject(s)
Hepatitis B e Antigens/blood , Hepatitis B e Antigens/genetics , Hepatitis B virus/genetics , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , Interferon-alpha/therapeutic use , Adolescent , Adult , DNA, Viral/blood , DNA, Viral/genetics , Female , Genes, Viral , Humans , Interferon alpha-2 , Male , Mutation , Promoter Regions, Genetic , Recombinant Proteins , Time Factors , Viremia/drug therapy , Viremia/virology
19.
J Med Virol ; 65(3): 470-2, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11596080

ABSTRACT

Reactivation of hepatitis B e antigen (HBeAg) negative chronic hepatitis B virus (HBV) infection due to selection of precore variant virus is an uncommon complication of previous hepatitis B infection, and virtually unrecognised in children and adolescents. A child who had received treatment with methylprednisolone and antilymphocyte globulin for severe aplastic anaemia developed high levels of detectable HBV DNA associated with hepatitis B e antibody (anti-HBe) positivity. HBV DNA was extracted, amplified and the core and precore regions sequenced from 2 samples. A mixture of wild-type and the precore variants A(1896) and A(1899) was detected in both samples, with the wild-type predominating in the second sample. Reinfection was excluded by phylogenetic analysis using Phylip and the neighbour-joining method. Precore variant Hepatitis B virus can be transmitted to children as a primary infection, and it is important that aggressive liver disease, particularly in the presence of the anti-HBe phenotype, be investigated. Further studies are needed to determine the frequency of these variants.


Subject(s)
Anemia, Aplastic/complications , Genetic Variation , Hepatitis B virus/growth & development , Hepatitis B/virology , Virus Activation , Child , DNA, Viral/blood , Hepatitis B/complications , Hepatitis B Antibodies/blood , Hepatitis B e Antigens/blood , Hepatitis B e Antigens/genetics , Hepatitis B e Antigens/immunology , Hepatitis B virus/genetics , Humans , Male , Mutation
20.
Clin Transplant ; 14(4 Pt 1): 282-6, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10945197

ABSTRACT

Pulmonary aspergillosis is a severe complication in heart transplant recipients. The drug of choice for this infection is amphotericin B, but its use is limited because of its side effects. We observed six cases of pulmonary aspergillosis in a group of 200 patients who had received heart transplants from January 1988 to January 1999. Predisposing factors such as previous rejection, neutropenia and/or cytomegalovirus reactivation were present in all patients. The clinical presentation was characterized by fever and a non-productive cough. X-rays showed monolateral or diffuse infiltrate with or without nodular lesions. The median interval between symptoms and diagnosis was 5 d (range 4-7). Diagnosis was made by culturing trans-tracheal aspirate samples. Aspergillus fumigatus was isolated in 3 patients and A. niger in the other 3. All patients were treated with itraconazole at 200-400 mg/day for 20-60 d and all recovered. One patient treated with the lowest dosage for the shortest term had a recurrence after 1 month and needed a second 30-day course of itraconazole at a higher dosage. No significant side effects were registered. Itraconazole is effective in the therapy of pulmonary aspergillosis, particularly when an early diagnosis is made.


Subject(s)
Antifungal Agents/therapeutic use , Aspergillosis/prevention & control , Heart Transplantation , Itraconazole/therapeutic use , Lung Diseases, Fungal/prevention & control , Postoperative Complications/prevention & control , Adult , Aspergillosis/diagnosis , Aspergillosis/drug therapy , Female , Humans , Lung Diseases, Fungal/diagnosis , Lung Diseases, Fungal/drug therapy , Male , Middle Aged , Postoperative Complications/diagnosis , Postoperative Complications/therapy , Time Factors , Treatment Outcome
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