HCV

HCVFrederik NevensHepatologieUZ Gasthuisberg KULeuven

WKBV september 2004

United States

World

Despite Public Health Efforts Many Patients are Still Affected

Source: National Health & Nutrition Examination Survey conducted 1988-1994

Source: National Institute of Health Consensus Development Conference Panel, Statement: Management of Hepatitis C. Hepatol 1997; 26S-10S

4 million

170 million

1

however, this does not mean that the public health issue has gone away, the prevalence still remains high - 4 times higher than HIV in some countries

HCV Related Disease Burden is Projected to Increase Substantially in the Coming Years

Need for liver transplantation

10 year increase from year 1998 (%)

Decompensated liver disease

Liver disease related death

Cirrhosis

Liver cancer

Source: Davis et al, 1998

100

200

300

400

500

600

1998base rate

CHC could potentially be a huge burden on the healthcare system. It is forecast that:the need for liver transplant will increase by some 528%liver related death will increase by 223%decompensated liver disease will increase by 279%hepatocellular carcinoma will increase by 68% Cirrhosis will increase by 61%

John - replace this with your own data if you feel more comfortable with it - we can replace the graphic for you if required

French Mortality Attributed toPrimary Liver Cancer (INSERM Data)

Source: Deuffic et alLancet 1998; 351: 214-215

Cases per year

Sheet:

In France it has quadrupled in the same time frame

Levertransplantatie: voornaamste oorzakenLeverziekte alcoholismeMeest frequente oorzaken- hepatitis C en B : 25%- leverkanker (hepatoom): 20%- ziekten van de galwegen: 15% (PBC, PSC)

Omvang van het probleem van Hepatitis C in VlaanderenOnderzoek 1993-94 (Van Damme e.a.)0,87 % HCV antistoffen2 % allochtonenOnderzoek 2001 (Cidex accident): 0,77 %85 % niet bewust HCV +Subgroepen: HCV + 70% IV druggebruiker90 % hemofilie patienten

Van Damme et al

Invloed op de gezondheid door HCV (1)1.Levercirrose en primaire leverkanker (HCC): 20 % na 15-20 jaar (pijnloze evolutie stille doder) mortaliteit tgv HCC laatste 10 jaar: x 2 1/3 van levertransplantaties wegens HCV

Invloed op de gezondheid door HCV (2)2. Chronisch vermoeidheidssyndroom: bij 50 % interfereert HCV met sociaal leven. bij 40 % interfereert HCV met professionele activiteit.3. Varia: geen / verhoogde premies van verzekering afwijzing job stopzetten job (chirurg, ) besmetting van moeder op kind (2 5 %)

Chronic Hepatitis C: Patients have a Significantly Reduced Quality of LifeReduction in quality of life vs normalNormalPhysical functioningVitalityGeneral healthBodily painRole-physicalSource: Bayliss et al Quality of Life Research 1998; 7:39-55Bayliss et al 1999 (submitted)Bonkovosky et al Hepatology 1999; 29:264-270Foster et al Hepatology 1998; 27:209-212Ware et al Hepatology 1999; (in press)Ware et al (in preparation) Social functioningRole emotionalMentalhealthSF-36 domain40455055

An Immediate Quality of Life Improvement is Seen in Virological RespondersPhysical functioningVitalityGeneral healthBodily painRole-physicalSocial functioningRole emotionalMentalHealthChange from baselineBetterWorseNon-mild diseaseMild diseaseSource: Schering-Plough Research Institute: data on file

Kosten door HCV: jaarlijkse kost per patient (euro)Frankrijk Belgi (Poynard et al) (Nevens et al,Buti et al.)

Chronische hepatitis zonder cirrose100125

Niet gedecompenseerde cirrose1.500250

Gedecompenseerde cirrose11.0008.125

HCC10.00010.000

Levertransplantatie jaar 175.00060.000

jaar 1+ _ 17.500

Geschatte totale kost/jaar Belgi: 700.000.000 BEF

Marginal Cost-effectiveness

Wie moet gescreend worden op HCVBloedtransfusies > 1990Voorgeschiedenis intraveneus druggebruikPiercing, tattoos (vooral in vreemde landen)Kinderen van HCV + moedersHIV (evolutie naar cirrose 2x tot 3x)

N.B.: geen SOA

Poynard et al J Hepatology 2001

Prof Leroux-Roels

Welke behandelingSoort therapie- F2 F3 F4 PEG-IFN + ribaverine- F0 F1 IFN + ribaverineDuur en dosis- genotype 1/4/5 : 48 weken / riba 800-1200 mg - genotype 2/3 : 24 weken / riba 800 mgTenzij na 3 m. geen 2 log daling : stop

Wie behandelenAlle patinten met histologisch chron. Hepatitis C en ALT

tenzij - contraindicatie INF en/of ribaverine - Child B/C cirrose

Reden van behandelingVoorkomen gecompliceerd leverlijden (=strikte indicatie) = Metavir fibrose score F2,F3,F4

Behandelen van een infectieuze ziekte (= relatieve indicatie)= Metavir fibrose score F0-F1

Ondersteunende therapieAnorexia : Seroxat 20 mgAsthenie : Serlain 50 mgAnderen en cirrose : Cipramil : 20 mg

Succes behandelingGenotype 1/4/5: 40 50 %Genotype 2 3: 75 80%

Zeuzem et al NEJM 2000

Directe Toekomst : non respondersFibrose remmers- E1 therapeutisch vaccin (fase 2a+)- Glycyrrhizin (ALT)Bijkomende immuunstimulatie- Histamine (fase 3 beeindigd)Bijkomend antiviraal effect- Amantadine (mogelijks rand significant effect)

E1 Therapeutic Vaccination Materials and MethodsC-terminally truncated recombinant form of the E1 proteinExpressed from an HCV subtype 1b strain consensus sequence, purified from mammalian cells20 mg E1 on alum in 0.5 ml single dose vials for IM injection

E1-induced humoral response

original DB

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0203-231951549128WEEK 5019/03/0203012NEVENS92.92381762127 |[DBN

0204-211901552969WEEK 5309/04/0203012NEVENS101.7195 |[DBN

0204-255031552978WEEK 5630/04/0203012NEVENS95.59130 |[DBN

0205-232791552986WEEK 5921/05/0203012NEVENS113.7163 |[DBN

0206-216391588416WEEK 6211/06/0203012NEVENS144.1171 |[DBN

0207-202381588436WEEK 6502/07/0203012NEVENS183.3150 |[DBN

0207-241051588447WEEK 6930/07/0203012NEVENS204.91118328132 |[DBN

0208-228931600385WEEK 7327/08/0203012NEVENS211.11291758126 |[DBN

0104-213971385005WEEK 017/04/0103013NEVENS438.827469186

0108-207011385068WEEK 1607/08/0103013NEVENS360.448169244

0110-230361451877WEEK 2816/10/0103013NEVENS31569750041

0203-206881451915WEEK 4805/03/0203013NEVENS311.141554147

0203-231961549127WEEK 5019/03/0203013NEVENS306.214840437

0204-211911552968WEEK 5309/04/0203013NEVENS309.448

0204-255021552977WEEK 5630/04/0203013NEVENS286.149

0205-232761552987WEEK 5921/05/0203013NEVENS268.738

0206-216381588417WEEK 6211/06/0203013NEVENS299.941

0207-202371588435WEEK 6502/07/0203013NEVENS393.549

0207-241071588446WEEK 6930/07/0203013NEVENS434.847468849

0208-228921600386WEEK 7327/08/0203013NEVENS393.3117621142

0104-201601385001WEEK 003/04/0103015NEVENS107.658712473

0107-223061385061WEEK 1624/07/0103015NEVENS10240196545

0110-230631451881WEEK 2816/10/0103015NEVENS107.715718353

0203-206921451918WEEK 4805/03/0203015NEVENS100.719725146

0203-245271549131WEEK 5026/03/0203015NEVENS93.5233615541

0204-224951552972WEEK 5316/04/0203015NEVENS72.433

0205-209591552980WEEK 5607/05/0203015NEVENS66.3747

0205-246331552988WEEK 5928/05/0203015NEVENS55.1240

0206-227541588418WEEK 6218/06/0203015NEVENS84.7949

0207-213981588433WEEK 6509/07/0203015NEVENS106.446

0208-205791600382WEEK 6906/08/0203015NEVENS114.3112868747

0209-201971600387WEEK 7303/09/0203015NEVENS96.1344632951

0104-210281385009WEEK 011/04/0103018NEVENS< 18.75121181198

0107-230041385067WEEK 1631/07/0103018NEVENS< 18.75322400096

0110-246461451886WEEK 2823/10/0103018NEVENS< 18.751402445124 |[DBN

0203-219061451913WEEK 4812/03/0203018NEVENS< 18.751366359217 |[DBN

0204-224981552962WEEK 5016/04/0203018NEVENS< 18.751365698129 |[DBN

0205-209561549138WEEK 5307/05/0203018NEVENS< 18.75155 |[DBN

0205-246301549146WEEK 5628/05/0203018NEVENS36.4170 |[DBN

0206-227561549153WEEK 5918/06/0203018NEVENS54.43173 |[DBN

0207-213991588420WEEK 6209/07/0203018NEVENS63.43213 |[DBN

0207-241061600377WEEK 6530/07/0203018NEVENS89.13156 |[DBN

0208-228911588454WEEK 6927/08/0203018NEVENS131.12455657216 |[DBN

0209-230571588465WEEK 7324/09/0203018NEVENS111.22909635190 |[DBN

0104-216981385012WEEK 019/04/0103020NEVENS2755.2357200138 |[DBN

0108-207001385073WEEK 1607/08/0103020NEVENS2798.123188498 |[DBN\

0110-246431451884WEEK 2823/10/0103020NEVENS3124.815938981

0203-219031451912WEEK 4812/03/0203020NEVENS3811.211812585

0203-245251549129WEEK 5026/03/0203020NEVENS347220404683

0204-224961552970WEEK 5316/04/0203020NEVENS4323.2106 |[DBN

0205-209571552979WEEK 5607/05/0203020NEVENS3622.4109 |[DBN

0205-246281552990WEEK 5928/05/0203020NEVENS4188.898 |[DBN\

0206-227511588421WEEK 6218/06/0203020NEVENS4460.896 |[DBN\

0207-213951588431WEEK 6509/07/0203020NEVENS5020.873

0208-211691600383WEEK 6912/08/0203020NEVENS4300.825750999 |[DBN\

0209-201991588469WEEK 7303/09/0203020NEVENS3795.264141670

0104-216971385013WEEK 019/04/0103021NEVENS21.544825631131 |[DBN

0108-206991385072WEEK 1607/08/0103021NEVENS57.342048696133 |[DBN

0110-246471451889WEEK 2823/10/0103021NEVENS55.171110833127 |[DBN

0203-219081451919WEEK 4812/03/0203021NEVENS32.111541237169 |[DBN

0204-224991552965WEEK 5016/04/0203021NEVENS31.522059439162 |[DBN

0205-209551549139WEEK 5307/05/0203021NEVENS75.7144 |[DBN

0205-246311552984WEEK 5628/05/0203021NEVENS117.9151 |[DBN

0206-227521549154WEEK 5918/06/0203021NEVENS20496

0207-213941588423WEEK 6209/07/0203021NEVENS297138 |[DBN

0207-241041600378WEEK 6530/07/0203021NEVENS345.4122 |[DBN

0208-226441588455WEEK 6926/08/0203021NEVENS331.22030252132 |[DBN

0209-230591588463WEEK 7324/09/0203021NEVENS393.21563257166 |[DBN

0104-213981385010WEEK 017/04/0103025NEVENS3926.414421269

0108-206971385069WEEK 1607/08/0103025NEVENS3609.622200977

0110-246481451888WEEK 2823/10/0103025NEVENS4471.730507169

0203-219071451908WEEK 4812/03/0203025NEVENS2459.218600077

0204-211871552963WEEK 5009/04/0203025NEVENS4083.238450373

0204-255061549135WEEK 5330/04/0203025NEVENS319281

0205-232771549143WEEK 5621/05/0203025NEVENS3516.886

0206-216351549152WEEK 5911/06/0203025NEVENS3792104 |[DBN

0207-202361588427WEEK 6202/07/0203025NEVENS3203.285

0207-233071588440WEEK 6523/07/0203025NEVENS3590.479

0208-218481588450WEEK 6919/08/0203025NEVENS3737.619769191 |[DBN\

0209-221181588466WEEK 7317/09/0203025NEVENS2944.337728694 |[DBN\

0104-213991385011WEEK 017/04/0103026NEVENS133.84544056191 |[DBN

0108-206981385071WEEK 1607/08/0103026NEVENS117.86803039282 |[DBN

0110-230621451880WEEK 2816/10/0103026NEVENS117.11470757215 |[DBN

0203-206911451909WEEK 4805/03/0203026NEVENS1341071429283 |[DBN

0204-211891552961WEEK 5009/04/0203026NEVENS129.63185526255 |[DBN

0204-255051549136WEEK 5330/04/0203026NEVENS120.2231 |[DBN

0205-232751552983WEEK 5621/05/0203026NEVENS127.3258 |[DBN

0206-216371552992WEEK 5911/06/0203026NEVENS176.6236 |[DBN

0207-202391588428WEEK 6202/07/0203026NEVENS206.8191 |[DBN

0207-233081588439WEEK 6523/07/0203026NEVENS411.6185 |[DBN

0208-220141588449WEEK 6920/08/0203026NEVENS4743543072197 |[DBN

0209-230561588462WEEK 7324/09/0203026NEVENS437.62304506284 |[DBN

0104-210221400565WEEK 011/04/0104002ELEWAUT39.312328431158 |[DBN

0108-201271400573WEEK 1601/08/0104002ELEWAUT267.61367543264 |[DBN

0110-250101451968WEEK 2824/10/0104002ELEWAUT165.31128240135 |[DBN

0203-221741451988WEEK 4813/03/0204002ELEWAUT68.632001295120 |[DBN

0204-215151559332WEEK 5010/04/0204002ELEWAUT82.48270733799

0204-255271559335WEEK 5330/04/0204002ELEWAUT94.8483

0205-236001559338WEEK 5622/05/0204002ELEWAUT112.297

0206-218941559341WEEK 5912/06/0204002ELEWAUT124.192

0207-204801559344WEEK 6203/07/0204002ELEWAUT160.4124 |[DBN

0207-234711559347WEEK 6524/07/0204002ELEWAUT168.6166 |[DBN

0208-221721559350WEEK 6921/08/0204002ELEWAUT154.61245233100

0209-223161559353WEEK 7318/09/0204002ELEWAUT154.5801862125 |[DBN

0104-212901390536WEEK 013/04/0105001SPRENGERS42.24446561169 |[DBN

0108-211481390571WEEK 1610/08/0105001SPRENGERS41.4935650085

0110-260091451935WEEK 2829/10/0105001SPRENGERS35.03465701109

0203-209451451948WEEK 4806/03/0205001SPRENGERS34.49617271114

0204-222731549165WEEK 5015/04/0205001SPRENGERS37.51113943100

0204-252351549173WEEK 5329/04/0205001SPRENGERS38.7298

0205-255201549181WEEK 5631/05/0205001SPRENGERS59.1561

0206-235861549189WEEK 5921/06/0205001SPRENGERS483.6112

0207-222311589465WEEK 6215/07/0205001SPRENGERS267.2117

0208-204331589471WEEK 6505/08/0205001SPRENGERS222.459

0209-200251589477WEEK 6902/09/0205001SPRENGERS208110733369

0209-228251589483WEEK 7323/09/0205001SPRENGERS140.495726855

0104-212911390537WEEK 013/04/0105002SPRENGERS37.24142327390

0108-204501390569WEEK 1603/08/0105002SPRENGERS360.8115142997

0110-257601496921WEEK 2826/10/0105002SPRENGERS323.8120912997

0203-214751451950WEEK 4808/03/0205002SPRENGERS210.3135075996

0203-251851549164WEEK 5029/03/0205002SPRENGERS188.8268855990

0204-235841549172WEEK 5319/04/0205002SPRENGERS1333.497

0205-217311549179WEEK 5610/05/0205002SPRENGERS198499

0205-255181549188WEEK 5931/05/0205002SPRENGERS2059.290

0206-235871589463WEEK 6221/06/0205002SPRENGERS252076

0207-229961589469WEEK 6519/07/0205002SPRENGERS2308.878

0208-217571589475WEEK 6916/08/0205002SPRENGERS2413.1208117468

0209-208771589480WEEK 7306/09/0205002SPRENGERS1820.8341277560

0104-215281390539WEEK 018/04/0105004SPRENGERS< 18.75890331132 |[DBN

0108-205561390570WEEK 1606/08/0105004SPRENGERS326.8242017599

0110-260101451936WEEK 2829/10/0105004SPRENGERS308.361070055




0205-207431549178WEEK 5606/05/0205004SPRENGERS1589.6109

0205-243391549186WEEK 5927/05/0205004SPRENGERS1636.878


0207-222331589470WEEK 6515/07/0205004SPRENGERS1511.278

0208-210791589474WEEK 6909/08/0205004SPRENGERS1382.445022990

0209-210351589481WEEK 7309/09/0205004SPRENGERS978.486678885

0104-212921390538WEEK 013/04/0105006SPRENGERS54.3132910782

0108-204511390568WEEK 1603/08/0105006SPRENGERS61.1959846772

0110-240981462206WEEK 2819/10/0105006SPRENGERS64.0534772568

0203-202251451947WEEK 4801/03/0205006SPRENGERS61.4425408282

0203-251841549162WEEK 5029/03/0205006SPRENGERS62.0142923175

0204-235851549171WEEK 5319/04/0205006SPRENGERS58.4179

0205-217301549180WEEK 5610/05/0205006SPRENGERS60.7178

0205-255191549187WEEK 5931/05/0205006SPRENGERS12783

0206-235881589462WEEK 6221/06/0205006SPRENGERS374.686

0207-222321589468WEEK 6515/07/0205006SPRENGERS597.685

0208-217561589476WEEK 6916/08/0205006SPRENGERS701.142443271

0209-218091589482WEEK 7313/09/0205006SPRENGERS624.830955074

ind graphs

&L&F

ind graphs

95.87

98.26

87.85

85.96

85.39

81.67

96.03

117

138

370

530.4

458.4

pat 01-006

DB fig

305.5

348.5

315.4

312.6

286

327

337.1

422.8

403.6

448

461.2

402

pat 01-009

median PLC

1440.8

1368.6

1412

1327.2

1377.4

1256.5

1269

1401.8

1418.7

1509.4

1641.6

1506.4

pat 01-010

median E1

95.27

319.5

318.8

205.4

216

223.6

249.3

277.6

312

332.5

313.8

347.8

pat 01-011

graphs median profile

178

163

179.7

61.36

67.36

93.1

121.3

134.3

163.7

157.2

154

103.1

pat 01-012

DB change

104.1

109.9

110.4

112.1

123.6

120.9

157.9

177.6

217.4

219

233.6

228

pat 01-015

change analysis

50.4

574.2

1251.5

367.5

297.3

822.4

1082.4

1215.2

1046.4

916

835.2

689.8

pat 01-016

batch1vs2

0

195

513.4

163

135.6

353.4

508.4

967.4

1611.2

2361.6

1032

815.2

pat 01-017

101.2

103.8

106.3

108.2

102.5

93.43

123.8

154.4

274.4

452.4

855.2

667.7

pat 02-002

44.24

70.58

102.2

50.05

43.87

76.86

164

229

340.1

378.3

435.2

415.2

pat 02-009

93.12

108.1

124.1

88.36

82.91

73.19

91.68

115.5

135.8

197.1

397.2

324.6

pat 02-010

53.13

56.03

53.92

49.51

52.27

54.47

72.48

85.02

85.45

76.75

78.34

74.13

pat 02-011

0

18.76

0

0

0

0

25.08

45.22

58.38

64.94

76.99

55.01

pat 02-012

23.05

50.22

51.56

35.26

34.24

69.89

295.2

222.2

311.2

520.8

643.6

593.6

pat 02-013

316.4

446.2

382.6

290.4

314.8

383.7

410.4

507.2

487.6

492.4

590.8

483.2

pat 02-014

25.17

266.4

152.6

48.9

44.5

148.2

522.4

598.4

1016

1261.6

1553.6

1670.4

pat 03-002

67.88

116.8

137.1

99.98

83.76

105.4

140.4

210

211

334.6

395.6

382.6

pat 03-006

105

301

408

267.6

271.8

436

2606.4

3071

3184

2068.8

1836.8

1151.8

pat 03-007

163.8

681.9

678.8

330.6

324.2

622

1196.8

1032.8

1227.2

1008

946.4

733.1

pat 03-008

147.8

187

188.7

132.8

142.3

106.9

235

265.2

416.2

448.4

670.4

671.9

pat 03-011

95.81

106.6

105.5

94.47

92.92

101.7

95.59

113.7

144.1

183.3

204.9

211.1

pat 03-012

438.8

360.4

315

311.1

306.2

309.4

286.1

268.7

299.9

393.5

434.8

393.3

pat 03-013

107.6

102

107.7

100.7

93.52

72.4

66.37

55.12

84.79

106.4

114.3

96.13

pat 03-015

0

0

0

0

0

0

36.4

54.43

63.43

89.13

131.1

111.2

pat 03-018

2755.2

2798.1

3124.8

3811.2

3472

4323.2

3622.4

4188.8

4460.8

5020.8

4300.8

3795.2

pat 03-020

21.54

57.34

55.17

32.11

31.52

75.7

117.9

204

297

345.4

331.2

393.2

pat 03-021

3926.4

3609.6

4471.7

2459.2

4083.2

3192

3516.8

3792

3203.2

3590.4

3737.6

2944.3

pat 03-025

39.31

267.6

165.3

68.63

82.48

94.84

112.2

124.1

160.4

168.6

154.6

154.5

pat 04-002

42.24

41.49

35.03

34.49

37.5

38.72

59.15

483.6

267.2

222.4

208

140.4

pat 05-001

37.24

360.8

323.8

210.3

188.8

1333.4

1984

2059.2

2520

2308.8

2413.1

1820.8

pat 05-002

0

326.8

308.3

153.6

138.7

550.8

1589.6

1636.8

1511.2

1511.2

1382.4

978.4

pat 05-004

54.31

61.19

64.05

61.44

62.01

58.41

60.71

127

374.6

597.6

701.1

624.8

pat 05-006

133.8

117.8

117.1

134

129.6

120.2

127.3

176.6

206.8

411.6

474

437.6

pat 03-026

BARC NRREQ.NR.VISITDOSPAT.NR.INVESTIGATOR9HCVE19HCVRN9GPT37

0103-219931384876WEEK 019/03/0101006DE VOS95.872360130173 |[DBN

0107-206601384936WEEK 1606/07/0101006DE VOS98.262084638223 |[DBN

0109-252331451760WEEK 2828/09/0101006DE VOS87.852117626127 |[DBN

0202-226011451788WEEK 4815/02/0201006DE VOS85.961741611138 |[DBN

0203-241101552544WEEK 5022/03/0201006DE VOS85.391566964115

0204-220731552555WEEK 5312/04/0201006DE VOS81.67139 |[DBN

0205-205701552566WEEK 5603/05/0201006DE VOS96.03122 |[DBN

0205-241561552577WEEK 5924/05/0201006DE VOS117120 |[DBN

0206-223021587082WEEK 6214/06/0201006DE VOS138131 |[DBN

0207-210061587093WEEK 6505/07/0201006DE VOS370114

0208-203281587107WEEK 6902/08/0201006DE VOS530.42580990124 |[DBN

0208-232291587115WEEK 7329/08/0201006DE VOS458.41870796121 |[DBN

0103-221411384879WEEK 020/03/0101009DE VOS305.5334335099

0107-209121384938WEEK 1610/07/0101009DE VOS348.55977778113

0110-202741451762WEEK 2802/10/0101009DE VOS315.4399813191

0202-231071451790WEEK 4819/02/0201009DE VOS312.6296209975

0203-245231552546WEEK 5026/03/0201009DE VOS286337500088

0204-224911552557WEEK 5316/04/0201009DE VOS32795

0205-209531552568WEEK 5607/05/0201009DE VOS337.192

0205-246061552579WEEK 5928/05/0201009DE VOS422.886

0206-227601587084WEEK 6218/06/0201009DE VOS403.686

0207-213781587095WEEK 6509/07/0201009DE VOS44884

0208-203261587104WEEK 6902/08/0201009DE VOS461.2199066175

0209-201791587117WEEK 7303/09/0201009DE VOS402310274075

0103-221441384880WEEK 020/03/0101010DE VOS1440.8300726042

0107-209151384939WEEK 1610/07/0101010DE VOS1368.6103333337

0110-202761451763WEEK 2802/10/0101010DE VOS1412248000039

0202-231101451791WEEK 4819/02/0201010DE VOS1327.2160303330

0203-245201552547WEEK 5026/03/0201010DE VOS1377.4148795632

0204-224931552558WEEK 5316/04/0201010DE VOS1256.530

0205-209501552569WEEK 5607/05/0201010DE VOS126931

0205-246091552580WEEK 5928/05/0201010DE VOS1401.833

0206-227591587085WEEK 6218/06/0201010DE VOS1418.731

0207-213801587096WEEK 6509/07/0201010DE VOS1509.435

0208-212741587112WEEK 6913/08/0201010DE VOS1641.6204787640

0209-201771587118WEEK 7303/09/0201010DE VOS1506.4411818235

0103-221421384878WEEK 020/03/0101011DE VOS95.271385480224 |[DBN

0107-209161384941WEEK 1610/07/0101011DE VOS319.51446667181 |[DBN

0110-202771451764WEEK 2802/10/0101011DE VOS318.81752976209 |[DBN

0202-231091451792WEEK 4819/02/0201011DE VOS205.41146230230 |[DBN

0203-245221552548WEEK 5026/03/0201011DE VOS2162826000197 |[DBN

0204-224921552559WEEK 5316/04/0201011DE VOS223.6215 |[DBN

0205-209511552570WEEK 5607/05/0201011DE VOS249.3216 |[DBN

0205-246081552581WEEK 5928/05/0201011DE VOS277.6186 |[DBN

0206-227571587086WEEK 6218/06/0201011DE VOS312199 |[DBN

0207-213791587097WEEK 6509/07/0201011DE VOS332.5184 |[DBN

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0209-223161559353WEEK 7318/09/0204002ELEWAUT154.5801862125 |[DBN


0108-211481390571WEEK 1610/08/0105001SPRENGERS41.4935650085

0110-260091451935WEEK 2829/10/0105001SPRENGERS35.03465701109

0203-209451451948WEEK 4806/03/0205001SPRENGERS34.49617271114

0204-222731549165WEEK 5015/04/0205001SPRENGERS37.51113943100

0204-252351549173WEEK 5329/04/0205001SPRENGERS38.7298

0205-255201549181WEEK 5631/05/0205001SPRENGERS59.1561

0206-235861549189WEEK 5921/06/0205001SPRENGERS483.6112

0207-222311589465WEEK 6215/07/0205001SPRENGERS267.2117

0208-204331589471WEEK 6505/08/0205001SPRENGERS222.459

0209-200251589477WEEK 6902/09/0205001SPRENGERS208110733369

0209-228251589483WEEK 7323/09/0205001SPRENGERS140.495726855

0104-212911390537WEEK 013/04/0105002SPRENGERS37.24142327390

0108-204501390569WEEK 1603/08/0105002SPRENGERS360.8115142997

0110-257601496921WEEK 2826/10/0105002SPRENGERS323.8120912997

0203-214751451950WEEK 4808/03/0205002SPRENGERS210.3135075996

0203-251851549164WEEK 5029/03/0205002SPRENGERS188.8268855990

0204-235841549172WEEK 5319/04/0205002SPRENGERS1333.497

0205-217311549179WEEK 5610/05/0205002SPRENGERS198499

0205-255181549188WEEK 5931/05/0205002SPRENGERS2059.290

0206-235871589463WEEK 6221/06/0205002SPRENGERS252076

0207-229961589469WEEK 6519/07/0205002SPRENGERS2308.878

0208-217571589475WEEK 6916/08/0205002SPRENGERS2413.1208117468

0209-208771589480WEEK 7306/09/0205002SPRENGERS1820.8341277560

0104-215281390539WEEK 018/04/0105004SPRENGERS0890331132 |[DBN

0108-205561390570WEEK 1606/08/0105004SPRENGERS326.8242017599

0110-260101451936WEEK 2829/10/0105004SPRENGERS308.361070055




0205-207431549178WEEK 5606/05/0205004SPRENGERS1589.6109

0205-243391549186WEEK 5927/05/0205004SPRENGERS1636.878


0207-222331589470WEEK 6515/07/0205004SPRENGERS1511.278

0208-210791589474WEEK 6909/08/0205004SPRENGERS1382.445022990

0209-210351589481WEEK 7309/09/0205004SPRENGERS978.486678885

0104-212921390538WEEK 013/04/0105006SPRENGERS54.3132910782

0108-204511390568WEEK 1603/08/0105006SPRENGERS61.1959846772

0110-240981462206WEEK 2819/10/0105006SPRENGERS64.0534772568

0203-202251451947WEEK 4801/03/0205006SPRENGERS61.4425408282

0203-251841549162WEEK 5029/03/0205006SPRENGERS62.0142923175

0204-235851549171WEEK 5319/04/0205006SPRENGERS58.4179

0205-217301549180WEEK 5610/05/0205006SPRENGERS60.7178

0205-255191549187WEEK 5931/05/0205006SPRENGERS12783

0206-235881589462WEEK 6221/06/0205006SPRENGERS374.686

0207-222321589468WEEK 6515/07/0205006SPRENGERS597.685

0208-217561589476WEEK 6916/08/0205006SPRENGERS701.142443271

0209-218091589482WEEK 7313/09/0205006SPRENGERS624.830955074

147.8101.254.31

187103.861.19

188.7106.364.05

134108.261.44

142.3102.562.01

120.293.4358.41

235123.860.71

268.7176.6127

374.6274.4206.8

452.4411.6370

701.1530.4434.8

667.7458.4393.3

Anti-E1 Ab (mU/ml)

Q3

median

Q1

weeks

Placebo/E1 patients (n=9/9)

107.667.8825.17

348.5195102

382.6165.3105.5

267.6100.750.05

271.893.5252.27

436120.975.7

1082.4249.3112.2

1032.8229124.1

1227.2312160.4

1261.6378.3183.3

1032435.2204.9

815.2402211.1

Q3

median

Q1

weeks

anti-E1 Ab (mU/ml)

median profile of E1/E1 patients

patientprevious trtW0W16W28W48W50W53W56W59W62W65W69W73mean end trtabs change

01628485053565962656973

01006PLC95.8798.2687.8585.9685.3981.6796.03117138370530.4458.4494.4398.53

01010PLC1440.81368.614121327.21377.41256.512691401.81418.71509.41641.61506.41574133.2

02002PLC101.2103.8106.3108.2102.593.43123.8154.4274.4452.4855.2667.7761.45660.25

03011PLC147.8187188.7132.8142.3106.9235265.2416.2448.4670.4671.9671.15523.35

03013PLC438.8360.4315311.1306.2309.4286.1268.7299.9393.5434.8393.3414.05-24.75

03018PLC00000036.454.4363.4389.13131.1111.2121.15121.15

03026PLC133.8117.8117.1134129.6120.2127.3176.6206.8411.6474437.6455.8322

05001PLC42.2441.4935.0334.4937.538.7259.15483.6267.2222.4208140.4174.2131.96

05006PLC54.3161.1964.0561.4462.0158.4160.71127374.6597.6701.1624.8662.95608.64

median101.2103.8106.3108.2102.593.43123.8176.6274.4411.6530.4458.4494.4322

Q154.3161.1964.0561.4462.0158.4160.71127206.8370434.8393.3

Q3147.8187188.7134142.3120.2235268.7374.6452.4701.1667.7

01009vaccine305.5348.5315.4312.6286327337.1422.8403.6448461.2402431.6126.1

01011vaccine95.27319.5318.8205.4216223.6249.3277.6312332.5313.8347.8330.8235.53

01012vaccine178163179.761.3667.3693.1121.3134.3163.7157.2154103.1128.55-49.45

01013vaccine00000000000000

01015vaccine104.1109.9110.4112.1123.6120.9157.9177.6217.4219233.6228230.8126.7

01016vaccine50.4574.21251.5367.5297.3822.41082.41215.21046.4916835.2689.8762.5712.1

01017vaccine0195513.4163135.6353.4508.4967.41611.22361.61032815.2923.6923.6

02009vaccine44.2470.58102.250.0543.8776.86164229340.1378.3435.2415.2425.2380.96

02010vaccine93.12108.1124.188.3682.9173.1991.68115.5135.8197.1397.2324.6360.9267.78

02011vaccine53.1356.0353.9249.5152.2754.4772.4885.0285.4576.7578.3474.1376.23523.105

02012vaccine018.76000025.0845.2258.3864.9476.9955.016666

02013vaccine23.0550.2251.5635.2634.2469.89295.2222.2311.2520.8643.6593.6618.6595.55

02014vaccine316.4446.2382.6290.4314.8383.7410.4507.2487.6492.4590.8483.2537220.6

03002vaccine25.17266.4152.648.944.5148.2522.4598.410161261.61553.61670.416121586.83

03006vaccine67.88116.8137.199.9883.76105.4140.4210211334.6395.6382.6389.1321.22

03007vaccine105301408267.6271.84362606.4307131842068.81836.81151.81494.31389.3

03008vaccine163.8681.9678.8330.6324.26221196.81032.81227.21008946.4733.1839.75675.95

03012vaccine95.81106.6105.594.4792.92101.795.59113.7144.1183.3204.9211.1208112.19

03015vaccine107.6102107.7100.793.5272.466.3755.1284.79106.4114.396.13105.215-2.385

03020vaccine2755.22798.13124.83811.234724323.23622.44188.84460.85020.84300.83795.240481292.8

03021vaccine21.5457.3455.1732.1131.5275.7117.9204297345.4331.2393.2362.2340.66

03025vaccine3926.43609.64471.72459.24083.231923516.837923203.23590.43737.62944.33340.95-585.45

04002vaccine39.31267.6165.368.6382.4894.84112.2124.1160.4168.6154.6154.5154.55115.24

05002vaccine37.24360.8323.8210.3188.81333.419842059.225202308.82413.11820.82116.952079.71

05004vaccine0326.8308.3153.6138.7550.81589.61636.81511.21511.21382.4978.41180.41180.4

median67.88195165.3100.793.52120.9249.3229312378.3435.2402

Q125.17102105.550.0552.2775.7112.2124.1160.4183.3204.9211.1

Q3107.6348.5382.6267.6271.84361082.41032.81227.21261.61032815.2

000

000

000

000

000

000

000

000

000

median

Q1

Q3

weeks

E1 Ab

median profile E1 Ab - PLC

000

000

000

000

median

Q1

Q3

weeks

E1 Ab

median profile E1 Ab - HCV E1

patientprevious trtW0W16W28W48W50W53W56W59W62W65W69W73mean end trtabs changeAb_b (902)diff (W0-Ab_b)

01006PLC95.8798.2687.8585.9685.3981.6796.03117138370530.4458.4494.4398.5396-0.13

01009vaccine305.5348.5315.4312.6286327337.1422.8403.6448461.2402431.6126.1338.9-33.4

01010PLC1440.81368.614121327.21377.41256.512691401.81418.71509.41641.61506.41574133.21851-410.2

01011vaccine95.27319.5318.8205.4216223.6249.3277.6312332.5313.8347.8330.8235.5395.6-0.33

01012vaccine178163179.761.3667.3693.1121.3134.3163.7157.2154103.1128.55-49.45279.9-101.9

01013vaccine0000000000000022.3-22.3

01015vaccine104.1109.9110.4112.1123.6120.9157.9177.6217.4219233.6228230.8126.7110.9-6.8

01016vaccine50.4574.21251.5367.5297.3822.41082.41215.21046.4916835.2689.8762.5712.149.90.5

01017vaccine0195513.4163135.6353.4508.4967.41611.22361.61032815.2923.6923.600

02002PLC101.2103.8106.3108.2102.593.43123.8154.4274.4452.4855.2667.7761.45660.2598.52.7

02009vaccine44.2470.58102.250.0543.8776.86164229340.1378.3435.2415.2425.2380.967.336.94

02010vaccine93.12108.1124.188.3682.9173.1991.68115.5135.8197.1397.2324.6360.9267.78125-31.88

02011vaccine53.1356.0353.9249.5152.2754.4772.4885.0285.4576.7578.3474.1376.23523.10549.63.53

02012vaccine018.76000025.0845.2258.3864.9476.9955.01666600

02013vaccine23.0550.2251.5635.2634.2469.89295.2222.2311.2520.8643.6593.6618.6595.5528-4.95

02014vaccine316.4446.2382.6290.4314.8383.7410.4507.2487.6492.4590.8483.2537220.6447.8-131.4

03002vaccine25.17266.4152.648.944.5148.2522.4598.410161261.61553.61670.416121586.83025.17

03006vaccine67.88116.8137.199.9883.76105.4140.4210211334.6395.6382.6389.1321.2278.9-11.02

03007vaccine105301408267.6271.84362606.4307131842068.81836.81151.81494.31389.3112.5-7.5

03008vaccine163.8681.9678.8330.6324.26221196.81032.81227.21008946.4733.1839.75675.95214.8-51

03011PLC147.8187188.7132.8142.3106.9235265.2416.2448.4670.4671.9671.15523.35154-6.2

03012vaccine95.81106.6105.594.4792.92101.795.59113.7144.1183.3204.9211.1208112.19102.2-6.39

03013PLC438.8360.4315311.1306.2309.4286.1268.7299.9393.5434.8393.3414.05-24.75412.726.1

03015vaccine107.6102107.7100.793.5272.466.3755.1284.79106.4114.396.13105.215-2.385149-41.4

03018PLC00000036.454.4363.4389.13131.1111.2121.15121.1500

03020vaccine2755.22798.13124.83811.234724323.23622.44188.84460.85020.84300.83795.240481292.84148-1392.8

03021vaccine21.5457.3455.1732.1131.5275.7117.9204297345.4331.2393.2362.2340.6623.9-2.36

03025vaccine3926.43609.64471.72459.24083.231923516.837923203.23590.43737.62944.33340.95-585.453497429.4

03026PLC133.8117.8117.1134129.6120.2127.3176.6206.8411.6474437.6455.8322139.3-5.5

04002vaccine39.31267.6165.368.6382.4894.84112.2124.1160.4168.6154.6154.5154.55115.2434.94.41

05001PLC42.2441.4935.0334.4937.538.7259.15483.6267.2222.4208140.4174.2131.9643.9-1.66

05002vaccine37.24360.8323.8210.3188.81333.419842059.225202308.82413.11820.82116.952079.7128.19.14

05004vaccine0326.8308.3153.6138.7550.81589.61636.81511.21511.21382.4978.41180.41180.435-35

05006PLC54.3161.1964.0561.4462.0158.4160.71127374.6597.6701.1624.8662.95608.6454.6-0.29

patientprevious trtW0W16W28W48W50W53W56W59W62W65W69W73mean end trtabs change

01006PLC95.8798.2687.8585.9685.3981.6796.03117138370530.4458.4494.4398.53

01010PLC1440.81368.614121327.21377.41256.512691401.81418.71509.41641.61506.41574133.2

02002PLC101.2103.8106.3108.2102.593.43123.8154.4274.4452.4855.2667.7761.45660.25

03011PLC147.8187188.7132.8142.3106.9235265.2416.2448.4670.4671.9671.15523.35

03013PLC438.8360.4315311.1306.2309.4286.1268.7299.9393.5434.8393.3414.05-24.75

03018PLC00000036.454.4363.4389.13131.1111.2121.15121.15

03026PLC133.8117.8117.1134129.6120.2127.3176.6206.8411.6474437.6455.8322

05001PLC42.2441.4935.0334.4937.538.7259.15483.6267.2222.4208140.4174.2131.96

05006PLC54.3161.1964.0561.4462.0158.4160.71127374.6597.6701.1624.8662.95608.64

PLC Average319.37Confidence Level(95.0%)187.3504195487

PLC StdDev243.7336891979

01009vaccine305.5348.5315.4312.6286327337.1422.8403.6448461.2402431.6126.1

01011vaccine95.27319.5318.8205.4216223.6249.3277.6312332.5313.8347.8330.8235.53

01012vaccine178163179.761.3667.3693.1121.3134.3163.7157.2154103.1128.55-49.45

01013vaccine00000000000000

01015vaccine104.1109.9110.4112.1123.6120.9157.9177.6217.4219233.6228230.8126.7

01016vaccine50.4574.21251.5367.5297.3822.41082.41215.21046.4916835.2689.8762.5712.1

01017vaccine0195513.4163135.6353.4508.4967.41611.22361.61032815.2923.6923.6

02009vaccine44.2470.58102.250.0543.8776.86164229340.1378.3435.2415.2425.2380.96

02010vaccine93.12108.1124.188.3682.9173.1991.68115.5135.8197.1397.2324.6360.9267.78

02011vaccine53.1356.0353.9249.5152.2754.4772.4885.0285.4576.7578.3474.1376.23523.105

02012vaccine018.76000025.0845.2258.3864.9476.9955.016666

02013vaccine23.0550.2251.5635.2634.2469.89295.2222.2311.2520.8643.6593.6618.6595.55

02014vaccine316.4446.2382.6290.4314.8383.7410.4507.2487.6492.4590.8483.2537220.6

03002vaccine25.17266.4152.648.944.5148.2522.4598.410161261.61553.61670.416121586.83

03006vaccine67.88116.8137.199.9883.76105.4140.4210211334.6395.6382.6389.1321.22

03007vaccine105301408267.6271.84362606.4307131842068.81836.81151.81494.31389.3

03008vaccine163.8681.9678.8330.6324.26221196.81032.81227.21008946.4733.1839.75675.95

03012vaccine95.81106.6105.594.4792.92101.795.59113.7144.1183.3204.9211.1208112.19

03015vaccine107.6102107.7100.793.5272.466.3755.1284.79106.4114.396.13105.215-2.385

03020vaccine2755.22798.13124.83811.234724323.23622.44188.84460.85020.84300.83795.240481292.8

03021vaccine21.5457.3455.1732.1131.5275.7117.9204297345.4331.2393.2362.2340.66

03025vaccine3926.43609.64471.72459.24083.231923516.837923203.23590.43737.62944.33340.95-585.45

04002vaccine39.31267.6165.368.6382.4894.84112.2124.1160.4168.6154.6154.5154.55115.24

05002vaccine37.24360.8323.8210.3188.81333.419842059.225202308.82413.11820.82116.952079.71

05004vaccine0326.8308.3153.6138.7550.81589.61636.81511.21511.21382.4978.41180.41180.4

vaccine Average485.4016Confidence Level(95.0%)253.7212494716

vaccine StdDev614.6651449091

Grand Average441.4520588235

Grand StdDev542.8653489728

PAT.NR.TreatmentVISITDOSHCVE1 batch 2HCVE1 batch 1batch2-batch1t-Test: Paired Two Sample for MeansHCVE1 batch 2HCVE1 batch 1

01006PLCWEEK 019/03/0195.8790.415.46Mean385.8573608398470.1227111816

01006PLCWEEK 1606/07/0198.2698.67-0.41HCVE1 batch 2HCVE1 batch 1Variance655424.9375951648.625

01006PLCWEEK 2828/09/0187.8588.78-0.93Mean385.8573529412470.1227205882Observations136136

01006PLCWEEK 4815/02/0285.9698.61-12.65Variance655424.941905534951648.640276247Missing0

01009vaccinWEEK 020/03/01305.50372.8-67.3Observations136136variance of difference113546.359375

01009vaccinWEEK 1610/07/01348.50496-147.5Pearson Correlation0.9455475079Mean of differences-84.2653427124

01009vaccinWEEK 2802/10/01315.40460.2-144.8Hypothesized Mean Difference0Hypothesized Mean Difference0

01009vaccinWEEK 4819/02/02312.60538.4-225.8df135Degrees of Freedom135

01010PLCWEEK 020/03/011440.801707.2-266.4t Stat-2.9162986641t-Statistics-2.9162976742

01010PLCWEEK 1610/07/011368.602027.2-658.6P(T

E1-Induced T-Cell ProliferationCourse 1Course 2

Chart1

422

6822

640

88100

E1/E1 (n=26/25)

Placebo/E1 (n=9/9)

% Patients with SI>3

Sheet1

0End0End

E1/E1 (n=26/25)4686488

Placebo/E1 (n=9/9)22220100

Sheet1

E1/E1 (n=26/25)

Placebo/E1 (n=9/9)

% Patients with SI>3

Sheet2

Sheet3

Serum ALT% change from baselineSignificant decrease in ALT from baseline from week 16 onwards

Total Ishak score after 17 months of E1 therapeutic vaccination**At least 6 portal tracts were evaluated for each liver biopsy**Improvement or worsening defined as >= 2 points change from baseline

Improved

n (%)

Stabilized

n (%)

Worsened

n (%)

Total Ishak **

9 (38%)

10 (42%)

5 (21%)

Ishak Fibrosis Score Evolutionexpected natural evolution*observed evolution after E1 with 95% CIend of treatment (17 months)baselinechange from baseline0.47*Ryder S. et al. Hepatology 2002;36(4 Pt. 2), 607 Ghany M. et al. Gastroenterology 2003;124:97-104 (age subgroup 46-69 yr)

Chart7

0.600

-0.040.47-0.04

-0.68

Sheet1

0.6-0.04-0.68

0.40.40.4

00.47

00.4

0-0.04

00.4

Sheet1

000

000

0

Sheet2

expected natural evolution

evolution after E1 with 95% CII

Change in Ishak fibrosis score after E1

change from baseline

baselineI

end of treatment (17 months)

Sheet2

0.600

-0.040.47-0.04

-0.68

expected natural evolution

evolution after E1 with 95% CII

Change in Ishak fibrosis score after E1

change from baseline

baselineI

end of treatment (17 months)

Before E1 Study Treatment After 17 months of E1Liver Fibrosis10 out of 24 patients showed diminished perisinusoidal fibrosis (Sirius Red stain)

Significant association of the immunological, histological, and biochemical responses

Addendum: interpretatie HCV testenHCV AS -.

HCV AS +ALT nl.

HCV AS +ALT .

Role Physical measures the degree of physical incapacitationGeneral Health is the patients evaluation of his/her healthVitality assesses the energetic level of the individualLow scores for these modalities resonate the non-specific but common symptoms that most patients with CHC have: Physical weakness, tiredness, lack of drive and asthenia

The public health problem associated with the rising incidence of liver transplant is exacerbated by the fact that there is a growing shortage of donor organs

Results for anti-E1 antibody increase were compared for 25 E1/E1 patients after 4 injections of E1 at 4-week intervals (at week 16) with 9 placebo/E1 patients after 4 injections of E1 at 3-week intervals (at week 62) in their first course of E1. The median changes for anti-E1 antibodies after 4 E1 injections were 44.7 mU/ml for 4-week intervals and 75 mU/ml for 3-week intervals, thus indicating that a 3 week interval regimen induces a somewhat stronger humoral immune response in a shorter period of time.

Levels of anti-E1 antibodies clearly increased further after course 1 in E1/E1 patients, from a median of 165 mU/ml at week 28 to 425 at week 69/73. Especially in those patients showing the highest increase, there was a plateau phase or even a decrease in detectable antibody level which already started after the last injection was administered (week 69). Further research is ongoing to explain this finding This slide shows the percentage of patients with significant T-cell proliferative responses to E1. In yellow the group with 2 E1 courses is depicted, in blue the Placebo/E1 group. In the E1/E1 group, significant proliferative responses were induced in over half of the patients after the first course of injections. These responses were remarkably sustained throughout the injection-free period between wk26 and wk50. Almost all patients showed strong immune responses after the second course of immunizations, including the Placebo/E1 group. It should be noted that these infrequent responses seen at baseline were only borderline positive, while the stimulation indexes at wk 69 were very strong (E1/E1 group median SI 9.6 (1.0-51.9); Pl/E1 group median SI 17.6 (3.4-27.4)).On this slide, you see the relative change from baseline in serum ALT over the 2 courses in both treatment groups. In the E1/E1 patients, serum ALT decreased significantly from baseline from week 16 onwards. This sustained decline continued during the second course and during the treatment interruption period between the 2 E1 courses. No significant changes could be seen in the smaller placebo/E1 treatment group with only 9 patients and large 95% confidence intervals for the mean.On average, our patient population showed no progression to fibrosis as evidenced by a change of -0.04 points (95% CI: -0.68 to +0.60) on the Ishak fibrosis scale. As there was no control group in this study extension, we based ourselves on the literature to determine the expected natural evolution of fibrosis progression. For the Ishak fibrosis score, a 0.47 point mean progression would be expected during the course of our 17-month study based on a 0.33 points/year progression rate as recently reported in an analysis of 221 repeat liver biopsies in patients with predominantly mild untreated hepatitis C, as reported by Ryder et al (ref 1). An identical Ishak fibrosis progression rate of 0.33 points per year was recently reported by Ghany et al (ref 2), for a subgroup of twenty-three untreated patients aged 46 to 59 as well.Lets first look at the bottom of the figure, where you see the relation between the percentage change in ALT as described in the previous slide, and the change in Ishak fibrosis score . Patients on or above plus 1 point score have fibrosis progression. We will now concentrate on those patients who are on or below -1 fibrosis score change. They all have decreased ALT, mostly more than 25%.If we now also look at the third dimension in the figure, showing the change in anti-E1 antibody level, you will see that most patients with fibrosis regression and decreased ALT also have greater increases in antibody level

Date post:	31-Dec-2015
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