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506 Pegylated interferon alpha-2b monotherapy and in combination with ribavirin in chronic hepatitis delta
S 188
POSTERS
~HBV QUASISPECIES SELECTED DURING LAMIVUDINE TREATMENT MAY CONTRIBUTE TO ADEFOVIR DIPIVOXIL RESISTANCE F. Moriconi 1, D. Flichman 1, R Ciccorossi 1, B. Coco 1, R. Sacco 1, F. Oliveri 1, E Colombatto 1, F. Bonino 2, M.R. Brunetto 1. 1UO
Gastroenterologia e Epatologia Azienda Ospedaliero Universitaria Pisana, Pisa, Italy," 2Direzione Scientifica Fondazione IRCCS Policlinico Milano, Milano, Italy B a c k g r o u n d and aim: Mutations in the catalytic domain of HBV reverse transcriptase (rt) were reported in patients (pts) under lamivudine (LMV), emtricitabine and telbivudine. Mutations affecting other regions of HBV rt were also reported, but at lower rates in pts under adefovir dipivoxil (ADV) or entecavir. Aim of the study was to analyse HBV rt heterogeneity in 34 chronic hepatitis B (CHB) patients under LAM+ADV rescue therapy after virologic breakthrough during LAM. Patients and Methods: The virologic response to combination therapy was evaluated at 48 and 96 weeks (w): 23 pts had HBV-DNA <200 copies/mL at 48 w (early responders, ER); 3 pts had HBV-DNA <200 cp/ml at 96 w (late responders, LR); the remaining 6 pts maintained detectable HBVDNA at 96 w (non responders, NR). B-C-D-E rt domains of HBV isolates were directly sequenced in 2 to 4 serum samples obtained before and during the combination therapy in 12 ER, 3 LR and all the 6 NR. Results: Baseline (before addition of ADV) viral loads were significantly different in the 3 groups (p <0.01): 6.2 (range 3.7 7.5) logs in ER, 8.6 (range 8.4 8.9) logs in LR and 7.1 (range 6.5 8.2) logs in NR. Before starting ADV we found YMDD mutations in 20 of 21 (95%) pts, associated with rtL180M substitution in 14 cases (70%). Additional mutations were not found in ER and LR, but in 4 of 6 NR: a new variant rtA181S in 2 (one was the only without YMDD mutation) and rtT184S in the other 2. During ADV treatment the HBV rt sequence remained unchanged. Conclusions: The finding of HBV rt variants (rtA181S and rtT184S) possibly responsible for the lower efficacy of ADV in baseline sera of 67% (4 of 6) of LMV resistant pts with ADV failure supports the view that LMV monotherapy can favour the emergence of a viral quasispecies with lower susceptibility to other nucleos(t)ide analogues. The evidence that baseline pre-ADV viral loads were lower in NR than in LR supports the hypothesis of direct role of HBV-rt variants in ADV treatment failure.
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CONVERSION OF LIVER TRANSPLANT RECIPIENTS WITH HEPATITIS B VIRUS FROM HEPATITIS B IMMUNE GLOBULIN (HBIG) AND LAMIVUDINE (LAM) TO ADEFOVIR DIPIVOXIL (ADV) AND LAM
G.W. Nell'1, V.C. Zacharias 1, M. Alonzo 1, N. Kemmer1, F. Weber 1, T.E. Kaiser 1, K. Safdar 1, E. Rideman 1, M. Thomas2, J. Martin 1, S. Rudich 2, A. Teval2, J. Buell 2. 1Department of Digestive Diseases,
University of Cincinnati Medical Cente~ 2Department of Surgery, University of Cincinnati Medical Center, USA Introduction: Conventional therapy to prevent HBV recurrence in liver transplant recipients consists of HBIg. Currently many centers use HBIg in combination with LAM, in hopes of preventing viral recurrence. However, the costs' of dual therapy, in particular HBIg, is quite expensive, more than $5,000 per month, and required for impertuity. Over the last 5 years several nucleosides and nucleotides have become available and oiler opportunity to replace HBIg as a primary armamentarium in the defense of HBV recurrence. The aim of this review is to investigate the safety and efficacy of converting HBIg and LAM therapy to ADV and LAM therapy. Methods: Retrospective review of all liver transplant patients with HBV converted from HBIg and LAM to ADV and LAM therapy. Data collected included; gender, age, HBV serological and DNA status (COBAS AmpliScreen PCR-based testing). Serologic testing was done every three months. Patients were followed for adverse drug events and HBV and immune
suppression therapy compliance. A cost benefit analysis was done for drug comparisons using United States currency values. Results: Patient demographics included: Male (n 6), Female (n 4), Age 44.1 years (range 33 to 65). The length of follow up from conversion was 15.2 months (range 11 to 20 months). Serological status at time of conversion revealed that DNA status remained negative in all patients, S Ag positive in 10/10, eAg positive in 5/10 and cAb positive in 6/10. No patients experienced an increase in transaminases while on ADV and LAM therapy. All patients were maintained on immune suppression monotherapy (tacrolimus) at 7 9 ng/mL. All patients reported compliance with dual therapy and there were no reports of adverse drug events. Annual costs for dual LAM and ADV therapy was $7,235 (range 6,550 to 8,225). Costs for HBIg with LAM on a monthly basis, was $9,225 (range 7,205 to 12,005). Conclusion: These results demonstrate beneficial effects of ADV and LAM in place of the standardized HBIg and LAM therapy. Safety and short term results show nucleoside therapy is adequate at preventing HBV viral recurrence. Lastly, the economic benefit for ADV and LAM vastly outweighed the HBIg and LAM group.
F'~
PEGYLATED INTERFERON ALPHA-2b MONOTHERAPY AND IN COMBINATION WITH RIBAVIRIN IN CHRONIC HEPATITIS DELTA
G.A. Niro 1, A. Ciancio 2, G.B. Gaeta 3, A. Marrone 4, A. Olivero 2, M. Stanzione 3, G. Stornaiuolo 3, A. Smedile 2 , A. Andriulli 1, M. Rizzetto 2 .
1Gastroenterology, CSS Hospital, S. Giovanni Rotondo, FG, Italy," 2Gastroenterology, Molinette Hospital and University, Turin, Italy," 3Dpt. of Infectious Diseases', Second University, Naples, Italy," 4Internal Medicine and Hepatology, Second University, Naples, Italy B a c k g r o u n d : Treatment for pts with chronic delta hepatitis (CHD) is conventional IFN. Moreover, Ribavirin (RBV) has been shown capable to inhibit RNA viruses in vitro. Aims: To investigate efficacy and safety of PEG-IFN with or without RBV. Methods: 38 HBsAg+ve, HDV-RNA+ve patients, with ALT > 1.5ULN and compensated liver disease received Peg-IFN alpha 2b (1.5 gg/kg) as monotherapy (n 16) or in combination with RBV (n 22), for the initial 48 weeks. Thereafter all patients were given PEG-IFN at the same dosage for a further 24 weeks and followed for 24wks off therapy. Main outcome was the proportion ofpts with a sustained virological and/or biochemical response (SVR and/or SBR). The majority of pts (30, 79%) had been previously treated with antiviral regimens (IFN/lamivudine). HDV-RNA was determined by a semi-quantitative single (sensitivity > 1000 genomes/mL) or nested (sensitivity 1 10 genomes/mL) PCR assay. Results: Twenty-seven patients (71%), 11 in the monotherapy and 16 in the combination tx, have completed the 72 weeks of treatment and the follow up period. At baseline HDV-RNA tested +ve by single PCR in 35 pts; at end of treatment (EOT) 14 pts were highly viremic, 8 were low viremic and 5 non viremic. Virological response was observed in 3 pts treated with Peg-IFN (19%) and 2 pts treated with Peg-IFN + RBV (9~ Biochemical response was achieved in 15 patients (39%), 6 treated with Peg-IFN (37.5%) and 9 with combination Tx (41%). In non-responder ALT dropped from a mean level of 4.2 to an EOT value of 1.8 • ULN. At end of follow up HDV-RNA tested negative in 7 patients (18%), 3 (19~ in monotherapy group and 4 (18%) in combination group. Biochemical response was maintained in 10 patients (26%), 4 of them (25%) treated with Peg-IFN and 6 (27%) with Peg-IFN + RBV. An inverse association was found between previous IFN/lamivudine therapy and virological response. Interferon and/or Ribavirin dose reduction were required in 18/38 patients (47%). Conclusions: In pts with CDH tx with PEG-IFN alpha-2b is associated with SVR in about 20% of cases, and RBV does not add to this benefit.
POSTERS
~HBV QUASISPECIES SELECTED DURING LAMIVUDINE TREATMENT MAY CONTRIBUTE TO ADEFOVIR DIPIVOXIL RESISTANCE F. Moriconi 1, D. Flichman 1, R Ciccorossi 1, B. Coco 1, R. Sacco 1, F. Oliveri 1, E Colombatto 1, F. Bonino 2, M.R. Brunetto 1. 1UO
Gastroenterologia e Epatologia Azienda Ospedaliero Universitaria Pisana, Pisa, Italy," 2Direzione Scientifica Fondazione IRCCS Policlinico Milano, Milano, Italy B a c k g r o u n d and aim: Mutations in the catalytic domain of HBV reverse transcriptase (rt) were reported in patients (pts) under lamivudine (LMV), emtricitabine and telbivudine. Mutations affecting other regions of HBV rt were also reported, but at lower rates in pts under adefovir dipivoxil (ADV) or entecavir. Aim of the study was to analyse HBV rt heterogeneity in 34 chronic hepatitis B (CHB) patients under LAM+ADV rescue therapy after virologic breakthrough during LAM. Patients and Methods: The virologic response to combination therapy was evaluated at 48 and 96 weeks (w): 23 pts had HBV-DNA <200 copies/mL at 48 w (early responders, ER); 3 pts had HBV-DNA <200 cp/ml at 96 w (late responders, LR); the remaining 6 pts maintained detectable HBVDNA at 96 w (non responders, NR). B-C-D-E rt domains of HBV isolates were directly sequenced in 2 to 4 serum samples obtained before and during the combination therapy in 12 ER, 3 LR and all the 6 NR. Results: Baseline (before addition of ADV) viral loads were significantly different in the 3 groups (p <0.01): 6.2 (range 3.7 7.5) logs in ER, 8.6 (range 8.4 8.9) logs in LR and 7.1 (range 6.5 8.2) logs in NR. Before starting ADV we found YMDD mutations in 20 of 21 (95%) pts, associated with rtL180M substitution in 14 cases (70%). Additional mutations were not found in ER and LR, but in 4 of 6 NR: a new variant rtA181S in 2 (one was the only without YMDD mutation) and rtT184S in the other 2. During ADV treatment the HBV rt sequence remained unchanged. Conclusions: The finding of HBV rt variants (rtA181S and rtT184S) possibly responsible for the lower efficacy of ADV in baseline sera of 67% (4 of 6) of LMV resistant pts with ADV failure supports the view that LMV monotherapy can favour the emergence of a viral quasispecies with lower susceptibility to other nucleos(t)ide analogues. The evidence that baseline pre-ADV viral loads were lower in NR than in LR supports the hypothesis of direct role of HBV-rt variants in ADV treatment failure.
•
CONVERSION OF LIVER TRANSPLANT RECIPIENTS WITH HEPATITIS B VIRUS FROM HEPATITIS B IMMUNE GLOBULIN (HBIG) AND LAMIVUDINE (LAM) TO ADEFOVIR DIPIVOXIL (ADV) AND LAM
G.W. Nell'1, V.C. Zacharias 1, M. Alonzo 1, N. Kemmer1, F. Weber 1, T.E. Kaiser 1, K. Safdar 1, E. Rideman 1, M. Thomas2, J. Martin 1, S. Rudich 2, A. Teval2, J. Buell 2. 1Department of Digestive Diseases,
University of Cincinnati Medical Cente~ 2Department of Surgery, University of Cincinnati Medical Center, USA Introduction: Conventional therapy to prevent HBV recurrence in liver transplant recipients consists of HBIg. Currently many centers use HBIg in combination with LAM, in hopes of preventing viral recurrence. However, the costs' of dual therapy, in particular HBIg, is quite expensive, more than $5,000 per month, and required for impertuity. Over the last 5 years several nucleosides and nucleotides have become available and oiler opportunity to replace HBIg as a primary armamentarium in the defense of HBV recurrence. The aim of this review is to investigate the safety and efficacy of converting HBIg and LAM therapy to ADV and LAM therapy. Methods: Retrospective review of all liver transplant patients with HBV converted from HBIg and LAM to ADV and LAM therapy. Data collected included; gender, age, HBV serological and DNA status (COBAS AmpliScreen PCR-based testing). Serologic testing was done every three months. Patients were followed for adverse drug events and HBV and immune
suppression therapy compliance. A cost benefit analysis was done for drug comparisons using United States currency values. Results: Patient demographics included: Male (n 6), Female (n 4), Age 44.1 years (range 33 to 65). The length of follow up from conversion was 15.2 months (range 11 to 20 months). Serological status at time of conversion revealed that DNA status remained negative in all patients, S Ag positive in 10/10, eAg positive in 5/10 and cAb positive in 6/10. No patients experienced an increase in transaminases while on ADV and LAM therapy. All patients were maintained on immune suppression monotherapy (tacrolimus) at 7 9 ng/mL. All patients reported compliance with dual therapy and there were no reports of adverse drug events. Annual costs for dual LAM and ADV therapy was $7,235 (range 6,550 to 8,225). Costs for HBIg with LAM on a monthly basis, was $9,225 (range 7,205 to 12,005). Conclusion: These results demonstrate beneficial effects of ADV and LAM in place of the standardized HBIg and LAM therapy. Safety and short term results show nucleoside therapy is adequate at preventing HBV viral recurrence. Lastly, the economic benefit for ADV and LAM vastly outweighed the HBIg and LAM group.
F'~
PEGYLATED INTERFERON ALPHA-2b MONOTHERAPY AND IN COMBINATION WITH RIBAVIRIN IN CHRONIC HEPATITIS DELTA
G.A. Niro 1, A. Ciancio 2, G.B. Gaeta 3, A. Marrone 4, A. Olivero 2, M. Stanzione 3, G. Stornaiuolo 3, A. Smedile 2 , A. Andriulli 1, M. Rizzetto 2 .
1Gastroenterology, CSS Hospital, S. Giovanni Rotondo, FG, Italy," 2Gastroenterology, Molinette Hospital and University, Turin, Italy," 3Dpt. of Infectious Diseases', Second University, Naples, Italy," 4Internal Medicine and Hepatology, Second University, Naples, Italy B a c k g r o u n d : Treatment for pts with chronic delta hepatitis (CHD) is conventional IFN. Moreover, Ribavirin (RBV) has been shown capable to inhibit RNA viruses in vitro. Aims: To investigate efficacy and safety of PEG-IFN with or without RBV. Methods: 38 HBsAg+ve, HDV-RNA+ve patients, with ALT > 1.5ULN and compensated liver disease received Peg-IFN alpha 2b (1.5 gg/kg) as monotherapy (n 16) or in combination with RBV (n 22), for the initial 48 weeks. Thereafter all patients were given PEG-IFN at the same dosage for a further 24 weeks and followed for 24wks off therapy. Main outcome was the proportion ofpts with a sustained virological and/or biochemical response (SVR and/or SBR). The majority of pts (30, 79%) had been previously treated with antiviral regimens (IFN/lamivudine). HDV-RNA was determined by a semi-quantitative single (sensitivity > 1000 genomes/mL) or nested (sensitivity 1 10 genomes/mL) PCR assay. Results: Twenty-seven patients (71%), 11 in the monotherapy and 16 in the combination tx, have completed the 72 weeks of treatment and the follow up period. At baseline HDV-RNA tested +ve by single PCR in 35 pts; at end of treatment (EOT) 14 pts were highly viremic, 8 were low viremic and 5 non viremic. Virological response was observed in 3 pts treated with Peg-IFN (19%) and 2 pts treated with Peg-IFN + RBV (9~ Biochemical response was achieved in 15 patients (39%), 6 treated with Peg-IFN (37.5%) and 9 with combination Tx (41%). In non-responder ALT dropped from a mean level of 4.2 to an EOT value of 1.8 • ULN. At end of follow up HDV-RNA tested negative in 7 patients (18%), 3 (19~ in monotherapy group and 4 (18%) in combination group. Biochemical response was maintained in 10 patients (26%), 4 of them (25%) treated with Peg-IFN and 6 (27%) with Peg-IFN + RBV. An inverse association was found between previous IFN/lamivudine therapy and virological response. Interferon and/or Ribavirin dose reduction were required in 18/38 patients (47%). Conclusions: In pts with CDH tx with PEG-IFN alpha-2b is associated with SVR in about 20% of cases, and RBV does not add to this benefit.