Pietro Lampertico
1
, Mauro Viganò
2
, Roberta Soffredini
1
, Floriana Facchetti
1
, Eliseo Minola
3
, Giuliana Cologni
4
, Marco Rizzi
4
, Osvaldo Fracassetti
4
, Fredy Suter
4
, Serena Zaltron
5
, Andrea Vavassori
5
, Giampiero Carosi
5
, M. Puoti
5
, Elena Angeli
6
, Guido A. Gubertini
6
, Carlo Magni
6
,
Angela Testa
7
, Pasquale Narciso
7
, Giorgio Antonucci
7
, Maria Vinci
8
, Giovambattista Pinzello
8
, Erika Fatta
9
, Silvia Fargion
9
, Paolo Del Poggio
10
, Barbara Coco
11
, Maurizia R. Brunetto
11
, Marco Andreoletti
12
, Agostino Colli
12
, Massimo Fasano
14
, Teresa Santantonio
13
, Guido
Colloredo
15
, Luisa Pasulo
16
, Stefano Fagiuoli
16
, Alberto Eraldo Colombo
17
, Giorgio Bellati
17
, Francesco Fumagalli Maldini
18
, Maria Milanese
18
, Massimo Pozzi
19
, Natalia M. Terreni
20
, Giancarlo Spinzi
20
, Michela Quagliuolo
21
, Mauro Borzio
21
, Giovanna Lunghi
22
, Massimo Colombo
1
Maintained viral suppression and excellent safety profile of entecavir monotherapy in 418 NUC-
naïve patients with chronic hepatitis B : a 4-year field practice, multicenter study
1. 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. 2. U.O.Epatologia, Ospedale San Giuseppe,Università degli Studi di Milano, Milan, Italy. 3. Servizio Malattie Epatiche e Infettive, Humanitas Gavazzeni, Bergamo, Italy. 4. Infectious Diseases,
Ospedali Riuniti di Bergamo, Bergamo, Italy. 5. II Divisione Malattie Infettive, Azienda Ospedaliera Spedali Civili, Brescia, Italy. 6. I and II Division Infectious Diseases, Ospedale Luigi Sacco, Milan, Italy. 7. INMI, IRCCS L. Spallanzani, Roma, Italy. 8. SC Epatologia e Gastroenterologia, Ospedale Niguarda Cà Granda, Milan, Italy. 9.
Internal Medicine 1b, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. 10. U.O. Epatologia, Ospedale di Treviglio, Treviglio, Italy. 11. U.O. Epatologia, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 12. S.C. Medicina Generale, Ospedale A. Manzoni, Lecco, Italy. 13. Clinic
of Infectious Diseases, Università di Foggia, Foggia, Italy. 14. Clinic of Infectious Diseases, Università di Bari, Bari, Italy. 15. Division of Medicine, Policlinico San Pietro, Ponte San Pietro, Italy. 16. Gastroenterology Unit, Liver and Lung Transplantation Center, Ospedali Riuniti di Bergamo, Bergamo, Italy. 17. Unità Operativa di Medicina,
Servizio di Epatologia, Ospedale Sant'Anna, Como, Italy. 18. Liver Center, Clinica Medica, Azienda Ospedaliera San Gerardo, Università Milano Bicocca, Monza, Italy. 19. U.O. Medicina, Ospedale Fatebenefratelli, Erba, Italy. 20. U.O. Gastroenterologia, Ospedale Valduce , Como, Italy. 21. U.O. Gastroenterologia, Azienda Ospedaliera
di Melegnano, Melegnano, Italy. 22. Istituto di Medicina Preventiva, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
Background and Aim
Registration trials showed Entecavir (ETV) to be a safe and
effectiv e therapy for NUC-naïv e, HBeAg positiv e and negativ e
patients with chronic hepatitis B. Data beyond year 1 are
available for a subset of patients, only
Preliminary, short-term field practice studies suggest that
most patients on ETV monotherapy achiev ed HBV
suppression with few treatment failures, only.
The risk of HCC in cirrhotic patients under long-term
suppressive therapy with ETV, is still unknown.
To assess the long-term effectiveness and safety of ETV in a
large cohort of NUC-naïv e patients w ith CHB
Patients and Methods
Study retrospective/prospective cohort, multicenter
Patients 418 consecutive NUC-naiv e patients with CHB
(19 Italian centers)
Enrolment: 2007-2008
Treatment ETV 0.5 mg
Follow -up 48 months (2-62)
Assays: HBV-DNA (PCR-based assays)
ETV-resistance (INNO-LiPA HBV DR V2-3)
Monitoring: ev ery 3-6 months
Baseline clinical and virological
characteristics
Num ber 418
Age, yr* 58 (18-82)
Male 316 (76%)
HBe Ag neg 347 (83%)
HBV-DNA, log IU/ml* 6.0 (1.5-9)
ALT, U/ml* 92 (11-2241)
Genotype D 84/93 (90%)
Cirrhosis 202 (49%)
BMI > 25 Kg/m
2
168/365 (46%)
Concomitant diseases 228 (56%)
* Median (range)
0
20
40
60
80
100
0%
6
67%
Patients %
85%
12
Virological response through month 52
(undetectable HBV DNA)
Baseline
405 418 391
Patients
on f-up
95%
344
Months 24
96%
288
36
98%
188
48
100%
81
54
Virological response by HBeAg status
(undetectable HBV DNA)
0
20
40
60
80
100
6
41%
Patients %
66%
12
67 66
88%
48
Months 24
0
20
40
60
80
100
6
74%
Patients %
90%
12
338 327 Patients on f-up
96%
296
24
HBeAg positive HBeAg negative
87%
35
36
98%
260
36
94%
29
48
99%
167
48
100%
12
54
100%
58
54
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 Months
Patients :
- at risk
HBeAg seroconversion rates*
71 67 54
56%
45
- on f-up 71 67 64 55 47
38
43
27
HBeAg seroconversion: 27 patients
* Kaplan-Meier estimates
35
17
20
9
10
4
0
10
20
30
40
50
0 6 12 18 24 30 36 42 48 Months
Patients :
- at risk
HBsAg loss in HBeAg-positive patients*
21%
HBsAg loss: 12 patients
* Kaplan-Meier estimates
71 70 65 54
- on f-up 71 67 64 55 47
48
43
38
35
25
20
13
10
6
0
1
2
3
4
5
6
0 6 12 18 24 30 36 42 48
HBV-DNA log UI/ml
Months of treatment
ETV 0.5 mg/die
TDF 245 mg
LLQ < 6 UI/ml
L180M
M204V
S202G
One patient developed ETV resistance*
*Innolipa assay
0
20
40
60
80
100
16%
6
69%
Patients %
81%
24 12
Biochemical response
(normal ALT)
86%
Baseline
401 418 390 347
Patients
on fup
88%
301
Months 36
89%
188
48
93%
81
54
0
10
20
30
40
50
0 6 12 18 24 30 36 42 48 Months
Patients
at risk
HCC rates in cirrhotic patients*
10%
HCC: 12 patients
* Kaplan-Meier estimates
164 161 154 148 136 117 84 41 13
*2 (0.2%) patients had to reduce ETV dose due to eGFR decline: a 78-year old women with AH;
a 48-year olt renal-transplanted woman with compensate dcirrhosis
** median (range)
***one patient only
Renal safety*
Variables Baseline Month 12 Month 24 Month 36 Month 48
Creatinine**, mg/dl 0.90
(0.6-9.0)
0.90
(0.5-2.2)
0.90
(0.5-2.0)
0.90
(0.5-2.0)
0.90
(0.5-2.0)
Serum creatinine >1.5
mg/dl
2% 2% 1% 1% 3%
***
Phosphorus* *, mg/dl Na 3.4
(2.4-4.3)
3.2
(2.2-4.4)
3.1
(1.9-4.5)
3.1
(2.4-4.2)
Phosphorus <2.0
mg/dl
Na 0% 0% 2% 0%
Proteinuria (≥30 mg
by dip stick)
Na 0% 2% 0% 3%
***
0
20
40
60
80
100
18
33%
% Patients with TmPO4/GFR ratio
24
TmPO4/GFR ratio over time*
months 30 36
20%
36%
18%
37%
20%
51%
21%
TmPO4/GFR < 0.80 mmol/L
TmPO4/GFR < 0.70 mmol/L
No. patients studied
42
43%
21%
15 39 54 42 53
*No data available from baseline to month 12 Patients withdrawing from the study
OUTCOME No. (%) REASON (No. patients)
Dead 28 (7%) HCC (16) decom (2), extraheaptic (9)
unclassified (1)
OLT 11 (3%) HCC* (10), ESLD (1)
Lost to follow-up 39 (9%) na
TDF* rescue 20 (5%) HBV DNA positive at week 48-96
Peg-IFN 8 (2%) 3 HBeAg pos, 5 HBeAg negative
Stop ETV 12 (3%) HBsAg loss
Overall 118 (28%)
* HCC was diagnosed before ETV in 9 patients
** TDF+ETV
Summary
Virological responses increased over time in both HBeAg
positive and negative patients, with more than 90% achieving
undetectable HBV DNA
HBeAg and HBsAg seroconversion rates increased over time.
Twelve patients stopped ETV successfully.
One patient (0.2%) developed ETV resistance at month 42
Most patients achieved persistently normal ALT levels
HCC developed at 2.5% yearly rates in cirrhotics
No safety issues were recorded, none of the patients had to stop
the medication. Two patients (<1%) had to reduce the dose
Conclusions
ETV monotherapy was safe and effective up to 4
years in clinical practice, as it provided high
rates of virological suppression and increasing
rates of HBeAg and HBsAg seroconversion