LONGITUDINAL ANALYSIS OF QUANTITATIVE SERUM HBSAG IN HBV/HIV COINFECTED PATIENTS
E. Arendt 1, J. Jaroszewicz 1,2, M. Vogel 3, B. Zacher 1, M. Cornberg 1, M. Stoll 4, M.P. Manns 1, H. Wedemeyer 1, K. Wursthorn 1
1 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
2 Department of Infectious Diseases and Hepatology, Medical University in Bialystok, Bialystok, Poland
3 Department of Internal Medicine III, Bonn University, Bonn, Germany
4 Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany
Introduction: The course of hepatitis B is aggravated in HBV/HIV-coinfected individuals. We analyzed the course of quantitative HBsAg in coinfected patients and the influencing factors. Patients and methods: 51 patients with HBV/HIV-coinfection were analyzed for up to 6 years. Data on HBV-DNA and HIV-RNA as well as CD4/8 cell count, CDC classification, ALT and platelets were available at baseline. Results: At baseline, HAART patients (n=43) compared to patients without HAART (n=8) had lower HIV-RNA levels (1.96 vs. 3.18log10), CD4 counts (336 vs. 608 cells/µl) and had advanced HIV (CDC C3: 40% vs. 25%). Hepatitis B serological markers were similar. HBsAg decreased slowly over time (~0.1log10 IU/mL/year). 3 HBV/HIV-coinfected patients lost HBsAg, all received HAART. None of the patients with < 0.5log10 decrease after two years (n=24) had the chance of HBsAg clearance (p=0.11). Patients without HAART (n=8) had fluctuating levels in the first two years and no case with >0.5log10 decrease. Analysis of factors associated with HBsAg decline >10% after one, two and three years was performed. CD4 counts were significantly higher in patients with >10% decline of HBsAg within 2 years (406 vs. 288 cells/µl; p=0.05). Higher CD4 counts were also observed for patients >10% HBsAg decrease after 3 years (423 vs. 302 cells/µl). Higher ALT levels were detectable at all time points in the group with >10% HBsAg decline. Conclusions: HBsAg decline in HBV/HIV coinfected patients occurs slowly. CD4 cell count and ALT, i.e. markers of immune control at baseline are correlated with HBsAg decline during follow-up.
LAMIVUDINE TREATMENT IN CHILDREN WITH CHRONIC B HEPATITIS AND NEGATIVE HBE ANTIGEN
O. Belei, I. Simedrea, C. Daescu, T. Marcovici, A. Militaru
First Pediatric Clinic, University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania
Objective: Assessment of Lamivudine treatment in active chronic B hepatitis (CH–HBV) with negative HBeAg in children. Methods: We studied 30 patients aged between 7–16 years, diagnosed with CH–HBV and negative HbeAg, previously treated with Lamivudine 4 mg/kg/day for 24 months. In 18 cases Lamivudine treatment was preceded by AlphaInterpheron for 6 months, without results. All the patients have been monitored clinical and for liver function each month, viral markers–twice a year (HBsAg, HBs antibodies, HbeAg, IgM-HBc, DNA-HVB), immunological–twice a year(LTCD3, CD4, CD8, immunoglobulines level).The liver biopsy has been performed in all patients at the beginning of treatment and after treatment only in 7 cases. The histological study consisted in usual coloration (HE, Gomory), histochemical coloration (Orcein) and immunohistochemical coloration (for HbsAg, HbcAg). Results: Clinical manifestations of the disease have gradually regressed in most of the cases.Liver function normalized in 93%.The hepatocytholitic syndrome recorded a tendency to normalize:60% after 3 months, 80% after 6 months and 93% after 12 months of treatment.“S” system seroconversion appeared in 1 patient (3,3%).The virusologic respond rate(absence of DNA-HBV in serum) was 20% after 12 months and 39,9% after 24 months of treatment. In 23,3% of the patients that have been histological tested after 24 months of treatment, Knodell score decreased with 2 points. Conclusions: Clinical manifestations and hepatocytholitic syndrome have promptly and persistent responded during treatment. Serum clearance of DNA–HBV was 20% after 12 months and 39,9% after 24 months of treatment. “S”system seroconversion appeared in 3,3% of cases. The compliance and tolerance for Lamivudine treatment was very good.
DOES BASELINE HCV GENOTYPE HAVE AN IMPACT UPON TREATMENT OUTCOME OF ACUTE HCV INFECTION IN HIV CO-INFECTED INDIVIDUALS?
C. Boesecke 1, H.J. Stellbrink 2, S. Mauss 3, E. Page 4, M. Nelson 4, S. Bhagani 5, M. Guiguet 6, C. Katlama 6, M. Vogel 1, J.K. Rockstroh 1
1 Bonn University Hospital, Bonn, Germany
2 ICH Study Center, Hamburg, Germany
3 Center for HIV and Hepatogastroenterology, Dusseldorf, Germany
4 Chelsea and Westminster Hospital, London, UK
5 Royal Free Hospital, London, UK 6 Inserm U943, UPMC-Paris06 UMR S943, Paris, France
Background: The recent epidemic of acute hepatitis C (HCV) infection among HIV co-infected MSM highlights the need to identify factors for optimal HCV treatment outcome. Methods: 238 male HIV-infected patients from 4 European countries with diagnosed acute HCV infection were treated early with pegylated interferon (pegIFN) and ribavirin (RBV) (n=207) or pegylated interferon alone (n=31) and evaluated for SVR. Results: Median age was 39 years. Main routes of transmission were MSM (94%) and IVDU (3%). 66,4% of patients were infected with HCV GT 1, 5,9% with GT 2, 12,2% with GT 3 and 15,5% with GT 4. Median baseline HCV RNA was 770.259IU/ml, median CD4 T cell count 474 cells/ul. 66,4% of patients received HAART. By univariate analysis, there were no statistical differences at baseline for HCV or HIV characteristics between patients with GT 1/4 infection (group 1) and with GT 2/3 infection (group 2). Overall SVR rate was 67,6% (161/238). Interestingly, SVR rates were significantly higher in group 2 when compared with group 1 (81,4% vs. 64,6% respectively; p=0.046). By uni- and multivariate analysis, RVR (p≤0,0001, OR (95%CI) 4,6 (2,336-9,059)) and HCV GT 2 and 3 (p=0.043, OR (95%CI) 2,945 (1,034-8,385)) were significantly associated with SVR. Conclusions: Early antiviral treatment of acute HCV infection in HIV co-infected individuals results in SVR rates which are significantly higher than those seen in chronic HCV co-infection. The even higher SVR rates for acute HCV GT 2 and 3 infections suggest different cure rates depending on HCV genotype similar to chronic HCV therapy.
THE VALUE OF ACOUSTIC RADIATION FORCE IMPULSE ELASTOGRAPHY (ARFI) FOR THE ASSESSMENT OF CHRONIC HBV AND HCV HEPATITIS
S. Bota, I. Sporea, R. Sirli, A. Popescu, M. Danila, M. Sendroiu, D. Suseanu
University of Medicine and Pharmacy, Timisoara, Romania
Introduction: ARFI is a new noninvasive method used mainly for the assessment of liver fibrosis. Aim: to assess the value of ARFI for the noninvasive evaluation of liver fibrosis. Methods: We have studied 94 patients with chronic hepatitis (38 HBV and 56 HCV), mean age 46.7±12.7 years, 39 women and 55 men. In each patient we performed in the same session ARFI evaluation (10 measurements in left lateral position, a median value was obtained, expressed in m/s) and liver biopsy. Results: The distribution of liver fibrosis in the study group, classified according to the Metavir score was: F0-1 patient (1.06%), F1-7 (7.4%), F2-40 (42.5%), F3-28 (29.8%) and F4-18 (19.1%). Valid ARFI measurements were obtained in all patients. For the whole group we found a direct, linear correlation (r=0.527) between ARFI and fibrosis (p<0.0001). The correlation was stronger in patients with HCV vs. HBV hepatitis, but not statistically significant (r=0.557 vs. r=0.49, p=0.67). In the 82 patients (87.3%) with IQR (interquartile range interval) <30% and SR (success rate) ≥60 %, the correlation was also stronger in patients with HCV vs. HBV hepatitis, but not statistically significant (r=0.640 vs. r=0.562, p=0.59). Conclusions: ARFI is a good method for the noninvasive assessment of fibrosis in chronic HBV and HCV hepatitis.
THE VALUE OF TRANSIENT ELASTOGRAPHY AND ACOUSTIC RADIATION FORCE IMPULSE ELASTOGRAPHY (ARFI) IN CHRONIC HCV HEPATITIS
S. Bota, I. Sporea, R. Sirli, A. Popescu, M. Danila, M. Sendroiu, D. Suseanu
Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania
Introduction: Elastographic methods (Transient Elastography-TE, ARFI) are increasingly used for the noninvasive assessment of liver fibrosis. Aim: To assess the concordance between the liver stiffness (LS) values measured by TE and ARFI with histological liver fibrosis evaluated by means of liver biopsy (LB)(according to the Metavir score) in patients with chronic HCV hepatitis. Methods: We studied 54 patients(p), mean age 51.6±8.8 years. In each patient we performed in the same session LS measurements by means of TE, ARFI, LB. The cut-off values, resulted from our previous studies, used to differentiate fibrosis (F) severity were: for TE (kPa) F1-6.4; F2-6.8; F3-9; F4-13.8 and for ARFI (m/s): F1-1.19; F2-1.21; F3-1.58; F4-1.82. Results: LS measurement by means of TE was indeterminable or invalid (IQR=interquartile range interval≥30% and/or SR=success rate<60%) in 11 patients (20.3%) and by means of ARFI in 8 cases (14.8%). A direct, strong correlation was found between TE measurements and fibrosis (r=0.673), also between ARFI in fibrosis (r=0.603)(p=0.55). In the 40 patients (74.1%) with valid ARFI and TE measurements the following differences between the estimated degrees of fibrosis were recorded: -0 (concordance): ARFI vs.LB: 14p(35%), TE vs. LB: 14p(35%), ARFI vs. TE: 16p(40%) -1 point: ARFI vs. LB : 12p(30%), TE vs. LB: 11p(27.5%), ARFI vs. TE: 12p(30%) - ≥2 points: 14p(35%), TE vs. LB: 15p(37.5%), ARFI vs. TE: 12p(30%) Conclusions: LS measurement by means of ARFI and TE had similar value in the noninvasive assessment of liver fibrosis as compared to the current gold-standard - liver biopsy.
RESPONSE TO STANDARD OF CARE ANTIVIRAL TREATMENT IN PATIENTS WITH HCV LIVER CIRRHOSIS - A META-ANALYSIS
S. Bota 1, I. Sporea 1, A. Popescu 1, R. Sirli 1, A. Neghina 2, M. Danila 1, M. Strain 1, M. Sendroiu 1, D. Suseanu 1
1 Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Timisoara, Romania
2 Department of Biochemistry, University of Medicine and Pharmacy, Timisoara, Romania
Introduction: Patients with HCV liver cirrhosis are a category difficult to treat. Aim: to establish the sustained virological response (SVR) rates in HCV patients with liver cirrhosis treated with standard of care therapy (PegInterferon and Ribavirin for 48 weeks). Methods: Searching the PubMed, Medline, Lilacs, Scopus, Ovid and Medscape databases we identified all the articles published until December 2010 (studies that included only HCV cirrhotic patients). These studies evaluated the sustained virologic response (SVR) after standard of care treatment: PegInterferon alpha 2a (doses ranging between 135-180 µg/week) or PegInterferon alpha 2b (1 or 1.5 µg/kg/week) and Ribavirin (doses ranging between 800-1200 mg/day). We used the following key words: HCV cirrhois, sustained virological response (SVR), peginterferon, HCV treatement. After disposal of material published only in abstract and exclusion of papers that did not include only cirrhotics or in which the treatment was not the standard of care, 11 papers were included into the metaanalysis (7 cohort studies and 4 randomized clinical trials). Results: The 11 studies included 1133 patients with HCV liver cirrhosis. The overall SVR rate was 33.8% (CI-confidence interval=31.06-35.6%). SVR was significantly higher in patients with genotype 2+3 (351patients) vs. those with genotype 1+4 (687 patients): 37.8% (CI=32.8-43.2%) vs. 21.6% (CI=18.7-25%)(p<0.0001). Conclusions: Given the low SVR rate among genotype1+4 cirrhotic patients, of only approximately 21%, efforts should be made in order to earlier identify and treat patients with chronic HCV hepatopathies.
AN EXPLORATION OF THE ASSOCIATION BETWEEN ATTACHMENT STYLE, STIGMA, AND DEPRESSION AMONG PATIENTS LIVING WITH HCV
C.M. Cabrera 1, C.K. Kim 2, B.L. Louise 2, T.G.A. Giorgio 2, C Curtis 2, G. Gary 2
1 University of Ottawa, Canada
2 The Ottawa Hospital, Canada
Attachment theory may be useful when examining health-related behaviours in Hepatitis C (HCV) patients. It proposes that developmental experiences have internalized into cognitive models affecting our perceptions. Reports indicate, chronic pain patients with an anxious attachment style were more depressed and had more healthcare visits while diabetic patients with avoidant attachment style had poorer treatment adherence. This study examined how attachment style relates to depression and stigma in HCV patients. Between June-December 2008, 97 HCV patients seen at the hepatitis clinic at The Ottawa Hospital were recruited into a questionnaire study. The questionnaires included: demographics, ECR-S, CES-D, and the HCV Stigma Scale. Results indicated that the mean level of anxious attachment within the HCV patient sample (n=76, 78% recruitment rate) was not significantly different from that of a non-clinical sample. However, the mean avoidance attachment score of the HCV sample was significantly greater than that of the non-clinical group. Moreover, attachment avoidance was significantly positively correlated to self-reported HCV stigma (r=.39, p<.00) and depression (r=.28, p<.04). Among HCV patients an avoidant attachment style is related to greater depression and HCV stigma. The combination of feeling stigmatized, depressed, and having an avoidant style of coping may place HCV patients at higher risk for treatment non-adherence. Also, the independence and self-sufficiency characteristic of avoidant attachment may impede adherence. These results suggest that it may be important to consider the attachment style of HCV patients when assessing for potential adherence barriers and could serve as an ‘early warning’ system to identify vulnerable patients.
ANCHORING INTERFERON ALPHA TO APOLIPOPROTEIN A-I REDUCES HEMATOLOGICAL TOXICITY WHILE ENHANCING IMMUNOSTIMULATORY PROPERTIES
J. Fioravanti, I. González, J. Medina-Echeverz, E. Larrea, N. Ardaiz, G. González-Aseguinolaza, J. Prieto, P. Berraondo
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
Interferon alpha (IFNa) is widely used for the treatment of viral hepatitis but substantial toxicity hampers its clinical use. In this work, we aimed at improving the efficacy of IFNa therapy by increasing IFNa half-life and providing liver tropism. We selected apolipoprotein A-I (ApoA-I) as the stabilizing and targeting moiety. We generated plasmids encoding IFNa, albumin bound to IFNa (ALF) or IFNa linked to ApoA-I (IA) and mice were treated either by hydrodynamic administration of the plasmids or by injection of the corresponding recombinant proteins or HDLs containing IA. The plasma half-life of IA was intermediate between IFNa and ALF. IA was targeted to the liver and induced higher hepatic expression of interferon-stimulated-genes than IFNa or even ALF. IA exhibits stronger in vivo antiviral activity than IFNa and the hematologic cytopenic effects of IA are milder than those observed when using IFNa or ALF. In contrast to IFNa, IA does not cause activation-dependent cell death of lymphocytes in vitro. Accordingly, in vivo studies showed that IA boosts T cell immune responses more efficiently than IFNa or ALF. The difference in immunostimulatory activity between IFNa and IA disappears in scavenger receptor class B type I (SR-BI) knock-out mice, suggesting that cross-talk between SR-BI and IFNa receptor is essential for enhanced induction of cytotoxic T cells by IA. Therefore, anchoring IFNa to ApoA-I is an efficient mean to promote liver targeting of a stabilized formulation of IFNa while boosting its immunostimulatory activities and reducing hematological toxicity.
RIBAVIRIN LEVELS ARE NOT ASSOCIATED WITH TREATMENT RESPONSE IN HCV MONOINFECTED AND HIV-HCV COINFECTED PATIENTS
P. Ingiliz 1, I. Krznaric 1, W. Andreas 2, D. Behrendt 1, M. Obermeier 2 A. Carganico 1, S. Dupke 1, A. Baumgarten 1, T. Berg 2
1 Medical Center for Infectious Diseases, Berlin, Germany
2 Medical Laboratory Berg, Berlin, Germany
Introduction. The standard of care for the treatment of hepatitis c virus (HCV) infection is a combination of pegylated interferon and ribavirin (RBV). As ribavirin can cause hemolytic anemia the optimal dose of RBV is often adjusted by hemoglobin decrease. Monitoring of RBV levels may therefore be useful. Methods. RBV trough level measurements in the steady state in treated HCV patients. Treatment response was documented by a drop in HCV RNA (2 log) at week 12 (EVR). Ribavirin levels (RL) were compared to hemoglobin (hb) levels and hb decline (Δhb). RL were measured by HPLC. Results. In 42 patients a total number of 63 RL and EVR data were available. 16 (38%) patients were HCV monoinfected, 26 (62%) were HIV –HCV coinfected. Genotypes: 27 GT1 (64%), 2 GT2(5%), 7 GT3 (17%) und 4 GT4 (10%). High RL were correlated with low hb levels (p<0.001). The median RL was 1705ng/mL (range 28-4190). In patients with GT 1/4 the median RL was 1877ng/mL, and 1032ng/mL in patients with GT 2/3 (p<0.001). In patients with EVR the median RL was 1944ng/mL, and 1712ng/mL in patients without EVR (not significant, ns). Median hb levels in patients with EVR were 11.9g/dL, and 11.4g/dL without EVR (ns). Patients with genotype 1/4 had significantly higher Δhb (2.6g/dL) than patients with genotype 2/3 (1.7g/dL), p=0.05. Conclusions: HCV treated patients with genotype 1/4 have significantly higher ribavirin levels. High RL correlate with low hb levels. In this study, RL and hb were not associated with better treatment response.
TREATMENT OF CHRONIC HEPATITIS C WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH HIV/HCV OR CHCV-INFECTION IN A REAL-LIFE SETTING IN GERMANY
P. Ingiliz 1, T. Lutz 2, A. Baumgarten 1, E. Wellmann 3, J.K. Rockstroh 4, S. Mauss 5
1 Medical Center for Infectious Diseases (MIB), Berlin, Germany
2 Infektiologikum, Frankfurt, Germany
3 Roche Pharma AG, Grenzach-Wyhlen, Germany
4 Medical Department, University of Bonn, Bonn, Germany 5 Center for Gastroenterology and Hepatology, Duesseldorf, Germany
HCV/HIV-infection and related concomitant diseases have become more and more important. Here, we describe differences between cHCV and cHCV/HIV-infected patients in outcome of cHCV treatment with peginterferon alfa 2a + RBV in the worldwide largest cHCV cohort. Methods: Noninterventional prospective multicenter German cohort, started January 2008. Interim analysis (Feb 2011) of patients who reached end of treatment. Results: Interim analysis including 278 cHCV/HIV co-infected (CI) and 4437 mono-cHCV-infected (MI) patients. Missing HCV-PCR for given timepoint was recorded as failure. Baseline-characteristics: 84.9(CI), 62.3(MI) % of the patients were male, BMI was 23.0 (CI), 25.5 (MI) kg/m2, naןve/relapse/non-responder/re-infection: 82.4/5.0/8.6/4.0(CI), 88.3/5.5/5.6/0.6(MI) %, main source of infection (>1 answer possible): ivDu 33.1(CI), 45.8(MI) %, sexual transmission 48.6 (CI), 3.8 (MI)%. 56.8% of the CI-Group and 69.0% of the MI-Group completed the planned course. Reasons for discontinuation (>1 answer possible) were non-response (58.3% in CI, 45.7 % in MI) and patient request (21.7% in CI, 15.2% in MI). Distribution of genotypes, were for cHCV/HIV-coinfection 221/278 GT1/4(79.5%); 57/278 GT2/3(20.5%) and for cHCV-monoinfection GT1/4: 2716/4437(61.2%); GT2/3:1721/4437(38.8%). RVR: HCV/HIV-coinfection total 22.3%,GT1/4 17.6%, GT2/3 40.4% and total 33.1%, GT1/4 20.7%, GT2/3 52.7% for HCV-patients. SVR (available for 196 CI/3524 MI patients): HCV/HIV-coinfection: total 37.2%, GT1/4 38.3%, GT2/3 33.34% and HCV-monoinfection total 46.0%, GT1/4 39.5%, GT2/3 56.3%. Conclusions: PEG+RBV were almost equal effective short term with regard to RVR in patients with HIV/HCV- or HCV-infection.
MMP-9 IS ALTERED BY RIBAVIRIN AND INTERFERON IN THP-1 CELLS AND IN HIV/HCV CO-INFECTED PATIENTS
A. Kennedy 1, M. Hennessy 1, C. Bergin 2, F. Mulcahy 2, S. Hopkins 3, J.P. Spiers 1
1 Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland
2 Department of Gentiourinary Medicine and Infectious Diseases, St James's Hospital, Dublin, Ireland
3 Department of Infection and Immunity, Royal Free Hospital, London, United Kingdom
Matrix metalloproteinases (MMPs) are central to tissue remodelling during HIV/HCV infection. This study assesses the potential for RBV/IFNα to modulate MMPs in THP-1 monocyte/macrophages and in a HIV/HCV patient cohort. Phorbol-12-myristate-13-acetate (PMA) activated THP-1 cells were treated with RBV and/or IFNα. Blood was reserved from HIV/HCV co-infected patients, HIV and HCV mono-infected patients, and healthy controls. HIV/HCV patients were re-sampled at day 3 and 14 after initiation of RBV/p-IFNα therapy. Samples were subjected to gelatin zymography, real-time RT-PCR, and/or ELISA. Data underwent one-way ANOVA and were expressed as mean±SEM. P<0.05 indicated statistical significance. In THP-1 cells, RBV/IFNα decreased MMP-9 activity (60±1.4vs100±3.1 AU) and increased MMP-9 mRNA expression (164±20vs100±9.3 % difference) at 48hrs compared to PMA controls. Reduced MMP-9 activity was mediated by IFNα, as RBV increased activity. At the transcriptional level, IFNα failed to attenuate increases in MMP-9 mRNA by RBV above PMA controls. Temporal assessment revealed that IFNα reduced MMP-9 mRNA compared to PMA at 24hrs by 65%. Baseline plasma MMP-9 abundance was 3 fold higher in HIV/HCV and HIV patients against HCV patients and healthy controls. RBV/p-IFNα decreased plasma MMP-9 abundance by 70% in HIV/HCV patients when measured after 3 and 14 days of therapy. These data demonstrate that RBV/IFNα reduces plasma MMP-9 abundance in vivo and reduces MMP-9 activity in vitro through monocyte/macrophages. Differential effects on MMP-9 mRNA in vitro may be explained by post-transcriptional regulation arising from earlier IFNα-induced decreases in expression. RBV/IFNα may therefore mediate tissue remodelling associated with HIV/HCV co-infection through effects on MMP-9.
NO REDUCTION OF HCV VIRAL LOAD IN HIV PATIENTS CO-INFECTED WITH HCV GENOTYPE 1 DURING A 30 DAYS COURSE OF NITAZOXANIDE MONOTHERAPY
N. Laufer 1&2, L. Abusamra 1, A. Gun 3, A. Krolewiecki 3, H. Pérez 1, H. Salomón 2, J. Quarleri 2, P. Cahn 1&3
1 Hospital Juan A Fernández, Infectious Diseases Division, Buenos Aires, Argentina
2 Centro Nacional de Referencia para el Sida, University of Buenos Aires, Buenos Aires, Argentina 3 Fundación Huésped, Buenos Aires, Argentina
Background: Treatment with Peg-interferon and ribavirin for HIV/HCV co-infected patients has suboptimal rates of response, with up to 60% of them failing to respond. There are new drugs in development for treatment of chronic HCV, among them nitazoxanide (NTZ) has been evaluated as monotherapy and combined with PEG-INF/RBV in genotype 4 HCV mono-infected patients. Methods: Twelve HIV/HCV genotype 1 co-infected patients were enrolled prospectively to receive a 30 days course of oral NTZ 500mg bid. Two patients discontinued treatment. Blood was drawn at baseline; 24h, 48h, 72h, 96h, 120h, and weeks 1, 2, 3 and 4. HCV viral load (VL) (Bayer VERSANT® HCV RNA 3.0 Assay) was evaluated at each time point. Descriptive statistics and non-parametric test were used. Results: All the patients were on HAART with HIV-VL <50 copies/mL, CD4 466 cells/μL (SD147), HCV VL( log10 IU/mL) at baseline: 6.10(SD 0.47), 24h: 6.23(SD 0.49), 48h: 6.11(SD 0.48), 72h: 6.07(SD 0.49), 96h: 6.14(SD 0.47), 120h: 6.25(SD 0.45), week 1: 6.25(SD 0.44), week 2: 6.12(SD 0.62), week 3: 6.24(SD 0.43) and week 4: 6.29(SD 0.41); with no statistical differences (p 0.66). No toxicities were observed, 30% of patients referred gastrointestinal symptoms. Discussion: A 30 day course of oral NTZ 500mg b.i.d was well tolerated in this group of HIV-patients coinfected with HCV genotype 1. Nevertheless no changes in HCV VL were observed during treatment. This data suggests that despite the promising results reported for HCV-monoinfected patients with genotype 4, NTZ exhibited poor activity as monotherapy in HIV/HCV-coinfected patients with genotype 1.
OUTBREAK OF ACUTE HEPATITIS C AMONG HIV-INFECTED MSM IN MADRID
A. Montoya-Ferrer 1, D.S. Fierer 2, B. Alvarez-Alvarez 1, M. Gorgolas 1, M. Fernandez-Guerrero 1
1 Fundación Jiménez Díaz, Madrid, Spain
2 Mount Sinai Hospital, New York, USA
OBJECTIVES: To describe the first outbreak of acute hepatitis C in Spain. METHODS: 4 cases of acute hepatitis C in HIV-infected MSM will be described. Information was gathered at the Unit of Infectious Diseases of Fundación Jiménez Díaz Hospital (Madrid, Spain). RESULTS: All patients were on antiretroviral treatment, with well-controlled HIV infection. All but one, who described mild asthenia, were completely asymptomatic at the time of diagnosis. Liver aminotransferase levels were elevated between 2.5 and 5 times the upper limit of normal range. HCV antibodies were tested 24 and 48 months before acute HCV diagnosis only in two patients, with negative results. Aminotransferase levels had been normal at these time points for all the patients. Three patients had been diagnosed with STI in the previous 6 months. Only one patient reported participation in group sex or use of recreational drugs and another one reported unprotected receptive anal intercourse. All patients denied parenteral risk factors. CONCLUSIONS: To our knowledge, this is the first report of sexually transmitted HCV infection among HIV-infected MSM in Spain. Our hospital attends patients from downtown Madrid and the largest MSM community in Spain (Chueca district), which is a frequent place for sexual contacts. Awareness of this infection is low among HIV-infected MSM and a risk for epidemic exists. Information campaigns by specialists and general practitioners may be needed for the population at risk. HCV testing when investigating an STI on any MSM and in the evaluation of newly elevated liver aminotransferase levels might be also warranted.
UNDETECTABLE HCV RNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) MAY ALLOW SHORTER TREATMENT DURATION IN HIV/HCV CO-INFECTION
E. Page 1, A. Cox 2, M. Anderson 1, B. Gazzard 1, M. Atkins 2, M. Nelson 1
1 Chelsea and Westminster Hospital, London, UK
2 Imperial College NHS Healthcare Trust, London, UK
Background: Duration of HCV treatment in HIV/HCV co-infection remains intolerable to many. Evidence of clearance from sanctuary sites may allow shorter duration of treatment. Methods: 5 individuals who were felt would benefit from shortened treatment durations had PBMC HCV RNA measured. PBMCs were isolated and reconstituted in PBS to 1X107 cells/vial. Intracellular HCV RNA was extracted using QIAamp RNA Blood MiniKit (Qiagen). Reverse transcriptase PCR was performed using a modification of the COBAS TaqMan HCV Test for use with the high pure system (Roche Diagnostics). HCV RNA could be detected to at least 600 IU/1X107 cells. Results: Three individuals had chronic hepatitis C. One with genotype 3 virus suffered severe toxicity and despite not achieving a RVR treatment was discontinued at 24 weeks. At this time a PBMC HCV RNA returned as undetectable. The other two individuals with genotype 1a virus had low baseline serum HCV RNA levels, with undetectable serum HCV RNA at week 1 and PBMC HCV RNA at week 12 when treatment was discontinued. All three achieved a SVR. More recently two individuals with borderline acute HCV (diagnosed 1 to 2 years after infection) have achieved a RVR and negative PBMC HCV RNA at week 20. Thus treatment was discontinued at week 24. Both achieved ETR and SVR are expected in May 2011. Conclusion: Demonstration of an undetectable HCV RNA in PBMC at the end of treatment may allow shorter durations of therapy in certain HIV/HCV co-infected individuals. A controlled trial is required to confirm these findings.
HEPATITIS OUTREACH NETWORK (HONE): HBV AND HCV SCREENING OF EGYPTIAN POPULATIONS IN NEW YORK/NEW JERSEY WITH LINKAGE TO CARE
P.V. Perumalswami 1, A. Regab 2, L. Kapelusznik 1, F. Di Clemente 1, H. Orabee 2, A. Worku 1, S. Schaefer 1, S. Tantawi 2, S. Factor 1, S. L. Friedman 1, H. Shapiro 1, Y. Valladares 1, D.T. Dieterich 1
1 Mount Sinai School of Medicine, New York City, USA
2 Harbor Light Community Health
Background: HONE together with community organizations and the NYC Department of Health, screens foreign-born communities at risk for HBV & HCV and links to care. Methods: We offered at-risk, adult English and Arabic speaking communities’ informal didactics followed by free HBV and HCV screening. All participants completed questionnaires. Testing included HBsAg/anti-HBc/anti-HBs/HCVAb/serum ALT. Persons HBsAg+ and/or HCVAb+ were invited for a medical visit. Results: 7 didactic sessions were followed by 2 screening events from June to July, 2010. 209 persons were screened, 182 (87%) consented to study. Of those screened 146 were from Egypt (80%) and the rest from India, Morocco, Pakistan and Tunisia. Mean age was 43y (range 18-78) and 63% were male. Mean ALT was 27 U/L (range 3-132); mean BMI 29. 26 subjects (14.2%) were HCVAb+, and none were HBsAg+. Of those HCVAb+, 96% were from Egypt. HCVAb+ subjects had a mean ALT 38 (95% CI [23, 52]) vs. a mean ALT 22 (95% CI [18,25]) for HCVAb- subjects, (p<0.0001). 112 (61.5%) subjects had all HBV markers negative, indicating an opportunity to vaccinate. 52.7% were uninsured and 50.3% did not have a primary physician. All participants were given results with recommendations, including free HBV vaccines. 16 HCV Ab+ patients attended a follow up visit. Conclusions: Among Egyptian and Middle Eastern/South Asian communities screened in NYC in 2010 for HONE, the overall HCVAb+ prevalence was 14.2% with 61.5% opportunity to vaccinate against HBV. This establishes the importance of ethnic urban screening programs with linkage to care.
INTRAOCULAR COMPLICATIONS DURING ANTIVIRAL THERAPY FOR HEPATITIS C ARE COMMON AND MORE FREQUENT IN PATIENTS WITH HYPERTENSION AND/OR DIABETES: A PROSPECTIVE, LONGITUDINAL STUDY
G. Sebastiani 1, S. Vujosevic 2, E. Midena 2, D.Tempesta 1
1 Department of Digestive Diseases, Hepatology and Clinical Nutrition, Dell'Angelo Hospital, Venice, Italy
2 Department of Ophthalmology, University of Padova, Padova, Italy
Treatment of hepatitis C consists of pegylated interferon-alpha (PEG-IFNα) and ribavirin. Opthalmological complications have been occasionally described but prospective, longitudinal data are lacking. We have investigated the prevalence of opthalmological complications during antiviral therapy in 97 consecutive HCV patients. 44.7% of patients were treated with PEG-IFNα 2b, 55.3% of patients with PEG-IFNα 2a. Opthalmological examination was performed before therapy (baseline), at 3 and 6 months (3T and 6T, respectively) of therapy and 3 months after end of therapy (3ET). The drop-out rate was 10.5%. All patients underwent the baseline and 3T examination, 89.5% underwent 6T and 3ET examination. Overall, 30.5% of patients developed a “de novo” opthalmological event. At baseline, 30.1% of patients had hypertension and/or diabetes (“at risk” subgroup) and had an abnormal opthalmological examination more frequently than the subgroup “without risk” (27.6% vs. 4.4%, p=0.001). Prevalence of opthalmological events in the two subgroups was as follows: 51.7% vs. 17.6% at 3T, p=0.0006; 74% vs. 21.5% at 6T, p<0.0001; 29.6% vs. 4.6%, p=0.0007. The most frequent opthalmological complications were cotton wool spots (60%) and retinal haemorrhages (35%). In one (3.4%) “at risk” patient, who developed retinal venous occlusion at 6T, the therapy was discontinued. All other patients continued the therapy. No significant difference in the frequency of opthalmological complications between the two PEG-IFNs was observed. Conclusions: Opthalmological complications are frequent during treatment with PEG-IFNα and ribavirin, especially in patients with hypertension and/or diabetes, who may develop serious complications. Opthalmological monitoring should be considered for patients with hypertension and/or diabetes.
INTERFERON AND RIBAVIRIN COMBINATION THERAPY INCREASES VITAMIN D LEVELS
A. Soumekh, K. Bichoupan, C. Constable, P. Benedict, M.L.C. Vachon, D.T. Dieterich, A.D. Branch
Mount Sinai School of Medicine
Background: Emerging data suggest that high 25(OH)D levels improve treatment outcomes. Ribavirin's mechanism of action is unknown. We hypothesized that treatment raises 25(OH)D levels, thereby enhancing efficacy. Methods: Subjects had HIV/HCV co-infection. All gave informed consent and completed at least 24 weeks of HRN-004, a multi-center retreatment trial of peg-IFN-alpha-2a/ribavirin. The Diasorin assay determined 25(OH)D in baseline (N=88) and 24-week samples (N=70). Changes in 25(OH)D and calcium were analyzed using the Wilcoxon Signed Ranks Test. Results: Most subjects were male; 86% had genotype 1 HCV; 15% (N=13) achieved an SVR. As predicted, 25(OH)D levels increased significantly during treatment, by a median of 2.20 ng/ml, p=0.037. Serum calcium, corrected for albumin, decreased significantly, by a median of -0.13 mg/dl, p=0.037, and fell below the lower-limit-of-normal in 12 subjects. In a multivariate logistic regression model, baseline 25(OH)D >18 ng/ml was the only variable significantly associated with SVR (OR, 5.077, p=0.043). Serum 25(OH)D and genotype were the only factors associated with cEVR (OR, 4.251, p=0.024; OR 12.105, P=0.005, respectively). Changes in 25(OH)D were significantly associated with EVR (OR, 1.059, p=0.050). Conclusions: We report two important findings about IFN/RBV treatment: Vitamin D levels increase, and calcium levels fall. Because treatment success is positively associated with vitamin D increases, the on-treatment increase in 25(OH)D may be a newly-discovered component of drug action. The drop in calcium may have adverse consequences, e.g., on bone. The potential of vitamin D and calcium supplements to improve outcome and to protect bone merits investigation (DA031095;DK090317).
IMMUNOPROPHYLAXIS OF RECURRENT HBV POST LIVER TRANSPLANTATION IN THE NUCLEOSIDE ANALOGS ERA: STILL INDISPENSIBLE?
V.E. Syutkin 1, O.I. Andreytseva 1, D.E. Syutkina 2, A. Salienko 1, A.V. Zhao 3
1 Liver Surgery and Transplantation Centre, Institute of Emergency Medicine, Moscow, Russian Federation
2 Moscow State University, Moscow, Russian Federation
3 Chair of Transplantology of the 3d Moscow Medical University, Moscow, Russian Federation
Despite the fact that a lot of nucleos(t)ide analogs (NA) approved to treat HBV infection, long-term hepatitis B immunoglobulin (HBIG) administration for HBV recurrence prevention still remain the standard of care at most centers worldwide that provide liver transplantation (LT). Aim. To study whether combined prophylaxis (CP) with HBIG and NA is superior than NA monoprophylaxis for prevention of HBV recurrence after LTx. Patients and methods. We analyzed outcomes of liver transplant recipients which were transplanted for end-stage HBsAg+ liver diseases. Nine pts completed CP with HBIG (6 -12 Mo) and NA (18 Mo). HBIG started in the anhepatic phase (10.000 IU) are followed by daily dosing 2.000 IU during the first week after LTx, and subsequent treatment varies 1.000 -2.000 IU twice a month to maintain trough anti-HBs titers > 100 IU/L (median FU – 18 Mo after CP cessation). Six pts received antiviral monoprophylaxis with NA and two pts remained without any prophylaxis (median FU – 36 Mo after LTx). Results. None of the pts died or re-transplanted from HBV-related causes or developed advanced liver fibrosis. Recurrent HBV-infection occurred in 3 out of 9 pts (CP group) and in 4 out of 8 others. Acute hepatitis with severe graft dysfunction occurred in only one case and resolved under treatment with consequent HBsAg loss. Conclusion. HBIG in combination with NA can achieve the same prophylactic efficacy as NA monoprophylaxis.
IS THE PRIMARY IMMUNOSUPPRESSIVE DRUG (CYCLOSPORIN A OR TACROLIMUS) PLAYING A ROLE ON THE RESPONSE TO ANTIVIRAL TREATMENT FOR POST-TRANSPLANT HCV RECURRENCE?
V. Vero 1, L. Pasulo 2, F.R. Ponziani 1, S. Fagiuoli 2
1 Gemelli Hospital, Rome, Italy
2 Riuniti Hospital, Bergamo, Italy
Background: HCV-related cirrhosis is the most common indication for liver transplantation. Standard immunosuppression, based on Calcineurin inhibitors (CNI) may also affect HCV replication and response to antiviral therapy. Aim: to evaluate the impact of CNI on SVR in a population of HCV transplanted patients undergoing antiviral therapy for HCV recurrence. Patients and methods: A multicenter database of 12 Italian Centres was set up to carry on a retrospective analysis of 464 liver transplant recipients, treated for HCV recurrence, from 1992 to 2008. Patients were considered eligible for combination interferon plus ribavirin-based therapy according to defined criteria .Antiviral treatment was aimed for 48 weeks regardless of viral genotype (73,9% genotype 1); median follow up was 87± 45 months. Immunosuppressive therapy was based on cyclosporine in 39% of cases, on tacrolimus in 56,9%. Results: SVR rate was 34,1%. EOT was significantly higher in the Cyclosporine group (64%) compared with the Tacrolimus (54,5%) (p= 0,04): a longer interval between OLT and starting of antiviral therapy (32,7 vs 19,2 months), higher daily dose of Ribavirin (659,9 versus 561,9 mg) were associated with virological response in the Cyclosporin group. Acute and chronic rejection rate (p=0,536 and p=0,585 respectively) and pre-treatment staging score, were no different between the two groups. No difference in SVR rate and in patients survival was observed (88% survival in Cyclosporin group vs 87%). At multivariate analysis Cyclosporine was confirmed as an independent significant predictor of EOT (p=0,04) , regardless of viremia, donor and recipient features, genotype, distance from OLT, olt-recurrence interval, fibrosis stage and treatment dose and duration. Conclusions: EOT response to antiviral treatment for post-OLT HCV recurrence is significantly higher among Cyclosporin treated recipients, however no differences in SVR and patient survival was observed.
THE PRESENCE OF DIABETES REDUCES SVR AFTER ANTIVIRAL THERAPY FOR POST-TRANSPLANT HCV RECURRENCE
V. Vero 1, L. Pasulo 2, F.R. Ponziani 1, S. Fagiuoli 2
1 Gemelli Hospital, Rome, Italy
2 Riuniti Hospital, Bergamo, Italy
Background: The antiviral treatment of HCV recurrence is the only available strategy in the attempt to prevent progression of the disease and graft failure after liver transplantation: the achievement of SVR (sustained virological response) appears to improve both histological picture and patient survival. Diabetes and insulin-resistance are well known negative prognostic factors for antiviral treatment in the non-transplant setting. Few data are available in the transplant setting. Aim: to evaluate the impact of diabetes on SVR in liver transplant recipients undergoing an antiviral treatment for HCV recurrence. Patients and methods: data from a multicenter database of 464 patients transplanted for HCV-related ESLD in 12 Italian Centers from 1992 to 2008 were retrospectively collected. All patients underwent a treatment with interferon and Ribavirin for histologically proven HCV recurrence. Mean age at LT was 53,5 yrs, 73,9% were genotype 1,151 patients (32,5%) were diabetics. Results: Overall SVR in our population was 34,1%: 25,3% in diabetic patients compared with 40,6% in non diabetics (p = 0,04). Among diabetics, the use of insulin (71% of the diabetics) was associated with a lower rate of end of treatment response ( EOT):49% vs 67,4% in non-insulin dependent diabetics ( p=0,04). The pre treatment viremia is the only factor that significantly differs between the two group (diabetics vs non diabetics: p=0,01); whereas no differences in term of donor and recipient characteristics, genotype, duration of antiviral therapy, distance from olt, interval olt-recurrence, pre treatment fibrosis, emerged at the analysis. At multivariate analysis the presence of diabetes was confirmed as independent negative predictor of SVR ( p=0,05). Conclusions: The presence of diabetes and the need for insulin emerge as negative prognostic factors for the response (SVR and EOT) to antiviral treatment for HCV recurrence post-liver transplantation.