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TENOFOVIR
EFFECTIVELY INHIBITS VIRAL REPLICATION IN DIFFERENT PATIENT
GROUPS WITH LAMIVUDINE RESISTANT HBV INFECTION
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F. van Bommel*, 1 T. Wunsche, 2
D. Schurmann, 2 K. Reinke, 3 B. Wiedenmann, 1 U. Hopf, 1 T.
Berg, 1 *Presenting Author 1Medizinische Klinik M. S.
Hepatologie Und Gastroenterologie, Charite Campus Virchow
Klinikum, 2Medizinische Klinik M. S. Infektiologie, Charite
Campus Virchow Klinikum, 3Medizinische Klinik M. S.
Nephrologie Und Internistische Intensivmedizin, Charite
Campus Virchow Klinikum, Berlin, Germany
The development of resistant mutants during the course of
lamivudine-therapy is often associated with progression of
chronic hepatitis B virus (HBV) infection. In a pilot-study
we could demonstrate that tenofovir, an acyclic nucleotid-analogue
and congender of adefovir affects lamivudine-resistent HBV
replication in vivo with high efficacy. The aim of this
study was to document long-term effectiveness and safety of
tenofovir in different patients groups with chronic HBV-infection.
19 patients (10 HBV/HIV-coinfected, 4 patients with chronic
HBV-infection after renal transplantation, and 5 with
chronic hepatitis B; mean age 49 years [47-58]) who suffered
viral breakthrough after 2-3 years of lamivudine-therapy
were included in the study. All patients received 245 mg
tenofovir daily for at least 24 weeks (mean 53, 7 weeks,
range 24-72 weeks). At baseline, HBV DNA levels were > 20 x
106 copies/ml (HBV-Monitor, Roche) in all patients.
Lamivudine-resistant mutations within the polymerase-gene
were detected using a Line Probe Assay (INNO-LIPA HBV DR,
Innogenetics).
During tenofovir treatment a mean log decline of 3.7 ± 0.87
(range: 2.82-4.83) of HBV viremia was shown and HBV DNA
became undetectable in 17/19 patients by the quantitative
assay. No severe or clinically relevant side effects were
observed. Viral resistance to tenofovir was not observed
during the follow-up of up to 72 weeks, although the number
of mutations in the YMDD motif increased in patients in whom
lamivudine treatment was maintained. The results demonstrate
that tenofovir has a significant suppressive effect on the
replication of lamivudine-resistant HBV-mutants even in
immune-suppressed patients. |
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LIVER FIBROSIS
REGRESSES BETTER WITH PEGINTERFERON ALPHA AND
URSODEOXYCHOLIC ACID TREATMENT THAN SPONTANEOUS RECOVERY
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I. Tasci*, 1 M.R. Mas, 1 S.A.
Vural, 2 N. Mas, 3 M. Serdar, 4 B. Comert, 1 G. Alcigir, 2
I.H. Kocar, 1 *Presenting Author 1Internal Medicine, Gulhane
Medical School, 2Pathology, Veterinarian Faculty Of Ankara
University, 3Anatomy, Hacettepe University, 4Biochemistry,
Gulhane Medical School, Ankara, Turkey
Fibrosis and cirrhosis are common complications of chronic
liver diseases. An imbalance between fibrogenesis and
fibrolysis results in scarring of the liver parenchyma. We
aimed to investigate the possible antifibrotic effectiveness
of a newly modified interferon molecule peginterferon a2b
(PEG-IFN) which has better antiviral activity and
ursodeoxycholic acid (UDCA). Liver fibrosis was established
on 60 male Sprague Dawley rats with CCl4 in 12 weeks. After
cessation of CCL4 Group I was left for spontaneous recovery.
Group II was treated with PEG-IFN 1.5mg/kg/week, Group III
with UDCA 25 mg/kg/day and Group IV with combination of both
drugs. All rats were killed at week 16. Histopathologic
fibrosis scores, tissue hidroxyprolin, TIMP-1 and MMP-13
levels were determined. Apoptosis was detected by TUNEL
staining. Fibrosis scores were lower in both Group II, III
and IV than Group I (p<0.05, p<0.05, p<0.007, respectively).
Tissue hidroxyprolin levels were significantly decreased in
Group II, III and IV when compared to Group I (p<0.05,
p=0.00, p<0.001, respectively). Lower liver TIMP-1 and
higher MMP-13 levels were measured in Group II, III, and
Group IV than Group I (p=0.007, p=0.05, p<0.001 for TIMP and
p<0.001, p=0.02, p<0.001, for MMP, respectively). Apoptosis
was significantly increased in Group II, III and IV when
compared to Group I (p<0.001, p<0.05, p<0.05, respectively).
There was significantly higher apoptosis in Group II than
III and IV (p<0.06, p<0.05, respectively). In conclusion,
treatment with both peginterferon a2b and ursodeoxycholic
acid improves CCL4 induced rat liver fibrosis. Significantly
higher effects can be obtained using these agents in
combination. |
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EFFECT OF HBV
AND HCV COINFECTION ON ANTI-VIRAL T CELL RESPONSES
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C. Boni*, B. Amadei, S. Urbani,
G. Elia, A. Cavalli, S. Cerioni, M. Malpeli, G. Missale, C.
Ferrari, *Presenting Author Department Of Infectious
Diseases And Hepatology, Azienda Ospedaliera Universitaria
Di Parma, Parma, Italy
In HCV infection, HCV-specific CD8+ lymphocytes show various
degrees of impairment of antiviral function. To assess if
this HCV-related impairment is limited to HCV-specific T
cells or can affect also cell-mediated immune responses to
other pathogens, we analyzed virus-specific T cell responses
of 3 patients infected simultaneously with HCV and HBV (2
with chronic hepatitis C and acute HBV infection who cleared
successfully HBV but remained HCV-RNA positive; one with
simultaneous acute HBV and HCV infections who cleared HCV
but developed chronic hepatitis B) and 5 patients with acute
HBV infection alone, as controls. The cell-mediated immune
response was studied with four HLA A2/HCV-specific and six
HLA-A2/HBV-specific tetramers. Frequencies and perforin
content of HBV- and HCV-specific T cells were analyzed
ex-vivo, while IFN-_ production, proliferation and cytolytic
activity were analyzed upon peptide stimulation.
The two patients with acute hepatitis B associated with
chronic HCV infection showed multispecific and strong HBV-specific
cytotoxic T lymphocyte (CTL) responses. The HCV-specific CTL
response was only transient and weak although HCV RNA
dropped at low or undetectable levels at the time of HBV
coinfection. The third patient did not develop HBV-specific
CTL responses but displayed a strong and sustained HCV-specific
CTL response.
In conclusion, the lack of effect of chronic HCV infection
on the T cell-response to another virus with tropism for the
same organ suggests that the HCV inhibitory effect is
selective for HCV-specific T cell responses; moreover, the
immune response primed by HBV infection can only partially
and transiently control HCV infection. |
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A
RANDOMIZED CONTROLLED TRIAL OF PEGYLATED-INTERFERON ALPHA-2B
+ RIBAVIRIN VS INTERFERON ALPHA-2B + RIBAVIRIN IN HIV
CO-INFECTED PATIENTS
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S. Pol*, C. Perronne, F. Carrat,
F. Banisadr, P. Morand, F. Lunel, E. Rosenthal, *Presenting
Author ANRS HC02 - Ribavic, Paris, France
Background: HCV-related morbidity and mortality is
increasing in HIV-infected subjects and treatment of
hepatitis C became a significant issue. Aim: To compare the
safety and efficacy of a 48 week-course of the standard
(IFNalpha2b: 3 MU x3/w, n=210) to the pegylated
(PEG-IFNalpha2b: 1.5 mg/kg x1/w, n=206) interferon +
ribavirin combination (800mg/d, > 12 mg/kg/d). Methods: A
randomized trial in HCV-RNA-positive pts with chronic
hepatitis, CD4 > 200 and stable HIV-RNA. Results: The 416
pts (40 y, 73% M, 79% IVDU) were given HAART in 80%; they
had a mean CD4 cell count of 515 + or - 228/ml, HIV RNA <
200 in 60% (mean viral load in others: 3.48 + or - 0.8
logs). Mean Metavir score was A 1.8 + or - 0.7, F 2.3 + or -
1.0; 39% of pts had F3-F4. A EOT virologic response was
observed in 27% of IFN group pts and 44% of PEG group pts
(p=0.009), varying with genotypes: 19% in 1 and 4 vs 57% in
2 and 3. Treatment was discontinued in 124 pts (30%) and
severe adverse events occurred in 99 (24%) (42 IFN & 57
PEG-p=0.08). A significant decrease (p < 0.001) was observed
at the early stage of treatment (W12) in Hb, lymphocytes and
more marked with PEG-IFN for neutrophils (p=0.0035) and
platelets (p=0.02). Conclusions: A 48 weeks course of
PEG-IFNalpha2b + ribavirin achieves more frequently a
therapeutic virologic response than the standard combination
in co-infected patients and appears as the reference
therapy. |
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