Epatite C, fertilità ed aspetti terapeutici nelle donne · Epatite C, fertilità ed aspetti...

Erica Villa

Azienda Ospedaliero-Universitaria di Modena, Università di Modena e Reggio Emilia

Epatite C, fertilità ed aspetti terapeutici nelle

donne

Cagliari, 16 settembre 2017

Courtesy of

Anne Schreivogl

Summary

Fertility in CLD

The HCV model: reproductive factors and

fertility

Clinical study

Epidemiological studies

Therapeutic options

Fertility in women with chronic liver disease

Sex hormone disturbances are common in women with CLD

They are mainly due to the abnormality of the physiology of the

hypothalamic-pituitary-gonadal axis and to the etiology of liver

disease.

In women with cirrhosis, chronic anovulation is a common problem,

and it is manifested as secondary amenorrhea, oligomenorrhea, or

irregular episodes of metrorrhagia.

LT leads to partial improvements in both sex hormone levels and

sexual function.

Women achieve normal menstruation and fertility a few months after

transplantation

Gavaler JS.. Recent Dev Alcohol 1995;12:199–208.Mass K, et al. Transplantation 1996;62:476–479; Madersbacher S et al. Clin

Endocrinol (Oxf) 1996;44:461–466; Parolin M et al Transpl Proc 2004;36:943–944.; Burra et al. Liver Ttanspl 2013; 19: 122-131; Burra

P. Liver Transpl 2009;15:S50–S56.

Reproductive factors and liver disease in HCV+

women

Response to antiviral therapy with IFN-based therapies is

much lower in menopausal women

Progression of fibrosis in slower in women in fertile age

Course of CLD is greatly accelerated by menopause

HCC risk after menopause becomes equivalent to that found

in males

Shimizu et al Liver 2001 ; Di Martino et al. Hepatology 2004; Codes et al. Gut 2007; Villa et al. Plos1

2012; Villa et al Gastroenterology 2011; Villa et al. JMV 2012

Mean serum levels of Anti-Mullerian Hormone levels in

HCV-positive women divided according to reproductive

phases

Plos1 2012, Karampatou et al. J Hep 2017

Reproductive Pre-menopausal Early Menop Late Menop

P<0001

Controls HCV+

< 40 anni

> 40 anni

No

Yes Menopause

Controls HCV+

HCV-positive women

Patients

Study groups:

Clinical group:

100 Hepatitis C Virus-positive women with CLD

50 Hepatitis B Virus-positive women CLD

100 healthy women without CLD matched by age

Two external validation group,

the Italian Platform for the Study of Viral Hepatitis

Therapies (PITER) cohort

a US insurance database

Age,

reproductive status,

serum levels of AMH were collected for all 3 groups.

The following additional data were collected for the HCV+ and HBV+ groups:

• virus genotype (HCV),

• body mass index (BMI),

• estrogen level,

• insulin-like growth factor-1 (IGF-1) level,

• presence of steatosis on ultrasound,

• liver stiffness

• histologic features,

• antiviral treatment and response,

• parity,

• age at first full-term pregnancy,

• and occurrence and number of spontaneous miscarriage(s)

Clinical group

Clinical and Laboratory Assessments

Characteristic HCV+

group (n = 100)

HBV+ group

(n = 50)

P value Age (y) 37.2 ± 8.5 35.1 ± 8.0 .209

Duration of HCV infection (y) 12 ± 7 12 ± 8 .972

Platelet count (×103/mm

3) 219 ± 70 202 ± 65 .144

Alanine aminotransferase (IU/L) 79 ± 30 89 ± 65 .305

Gamma-glutamyl transferase (IU/L) 35 ± 21 29 ± 22 .113

Cholesterol (mg/dL) 179 ± 50 189 ± 45 .219

Triglyceride (mg/dL) 99 ± 35 85 ± 55 .105

Ferritin (ng/mL) 89 ± 30 77 ± 54 .148

Blood glucose (mg/dL) 75 ± 22 80 ± 25 .233

HOMA 1.7 ± 1.5 1.5 ± 1.0 .715

Mean BMI (kg/m2) 23.6 ± 5.0 23.2 ± 4.6 .637

HCV genotype 1/2/3/4, n 56/15/21/8 NA

Grade of inflammation 3.6 ± 1.5 5.2 ± 0.5 .001

Stage 1.8 ± 1.3 2.4 ± 1.1 .043

Presence of steatosis, n (%) 40 (40) 10 (20) .014

Stiffness (kPa) 6.0 ± 3.0 5.7 ± 2.0 .468

Data are reported as the mean ± SD, unless otherwise noted. NA, not available.

Baseline Characteristics of Study Participants

Karampatou et al J Hep 2017

Hormonal and Reproductive Characteristics of Study

Participants

Characteristic HCV+

(n =

100)

HBV+

(n = 50)

Controls

(n = 100)

P, I vs. II P, I vs. III P, II vs. III

AMH, all women (ng/ml) 3.2 ± 3.1 2.8 ± 1.7 4.3 ± 2.5 .548 .0009 <.0001

AMH, 20–30 y (ng/ml) 3.4 ± 2.2 3.6 ± 1.4 5.5 ± 1.3 .271 <.0001 <.0001

AMH < 0.16 ng/ml, n (%) 34 (34) 2 (4)

6 (6) <.0001 <.0001 .6073

Estradiol (ng/ml) 77 ± 58 87 ± 33 86 ± 49 .219 .410 .8827

IGF-1 (ng/ml) 110 ± 58 126 ± 60 NA .145 - -

Parity, n (%) 52 (52) 21 (42) NA .248 - -

Age at first pregnancy (y) 30 ± 6 27 ± 7 NA .235 - -

History of miscarriage, n

(%)

35 (35) 4 (8) NA .0004 - -

History of miscarriage and AMH < 2.47 ng/ml, n

24 1 NA .0076 - -

History of multiple miscarriages

8 1 NA .1447 - -


0

10

20

30

40

50

60

Pregnancies Miscarriages

HCV

HBV

Relative proportion of pregnancies and miscarriage in

HCV+ and HBV+ women

%

52 21 35 4

P=.001


0

5

10

15

20

25

30

<2.47 ng/ml >2.47 ng/ml

HCV

HBV

Occurrence of miscarriages and median AMH level among

HCV+ and HBV+ women

P = .0049

24 111 3


Relationship between circulating IGF-1 levels and AMH levels (A),

liver stiffness (B), grade of inflammation (C), and degree of fibrosis

(D) in HCV+ and HBV+ women

Data from the PITER HCV Cohort Study

273 women (42.0%) had a history of miscarriage

122/273 (44.6%) had a history of multiple

miscarriages: 71 women (26.0%) had 2 miscarriages,

26 women (0.9%) had 3 miscarriages,





1 woman (0.36%) had 8 miscarriages

Data on miscarriage available in 650 HCV+ women




590 HCV+ women

between 15 and 49 years of age

HCV+ women

Total fertility rate

Whole Italian population

of the same age range 1.37

0.7


Data from the US Insurance Cohort Study

HCV/HIV Infection No HCV/HIV Infection

Women with HCV and /or HIV diagnosisN=111,043

Women without HCV or HIV diagnosisN=30,733,127

Continuous plan ≥1 year post-index dateN=76,264

Continuous plan ≥1 year post-index date N=11,560,535

Continuous plan ≥9 months pre-index date N=35,570

Continuous plan ≥9 months pre-index date N=6,967,045

Women aged 18–45N=16,895

Women aged 18–45N=3,041,048

Cases: 13,264 Controls: 39,792

Only HCVN=9,010

HIV/HCVN=398

1:3 match

Only HIVN=7,487

Sample Selection: Infertility Analysis

0,2

0,3

1,4

3,3

2,4

2,5

6,2

8,7

15,8

27,2

1,4

1,9

2,9

5,3

5,5

11,3

11,9

20,5

26,3

35,3

2,3

1

7,9

2,3

3,6

5,3

9,5

23,3

30,8

28,9

0 5 10 15 20 25 30 35 40

Renal diseases

Alcohol abuse

Ovary dysfunction

Obesity

Diabetes

Drug abuse

Hypertension

Hematologic diseases

Metabolic diseases and immunity disorders

Diseases of the circulatory system

Patients, %

HIV/HCV HCV No HCV

Comorbidities of Women in Infertility Analysis

ProbabilityofInfer lityWithHCV/HIVCo-infec on,HCVMono-infec on,orHIVMono-infec on(vsnoHCVorHIVinfec on)

*p<0.0001;referencegroup:noHCV/HIV

4.52.8 7.2

3.02.5 3.4

2.52.2 3.0

0 1 2 3 4 5 6 7 8

HCV

HCV/HIV

HIV

*

*

*

OddsRa os,95%ConfidenceIntervals

Pregnant Women (N=2,647,993)

Women with continuous plan ≥6 months before and ≥1 year after index date N=880,058

Women without HIVN=875,975

HCV-infected womenN=3,198

Women without HCVN=872,777

Aged 18–45N=1,226

Cases: 1,225 Controls: 12,2501:10 match

HCV diagnosis before pregnancyN=1,512

Aged 18–45N=822,046

Sample Selection: Pregnancy Outcomes Analysis

Adjusted results- pregnancy outcomes

Outcomes Odds ratio Confidence Interval

Premature birth 1.336 1.059 1.685

Live birth 0.754 0.622 0.913

Stillbirth 1.252 0.491 3.188

Gestational diabetes 1.240 1.019 1.510

Pre-eclampsia 1.206 0.935 1.556

Miscarriage 1.106 0.885 1.383

• Adjusted results are consistent with unadjusted results.

• Premature and live birth results are significant.

Data from the US Insurance Cohort Study

Therapeutic options

AMH Levels and Response to IFN-based Antiviral Therapy

75 HCV+ women (36 ± 8 years) underwent antiviral treatment, all

with Peg IFN/R, associated with Telaprevir (n=2) or Boceprevir (n=6).

Mean age at therapy was 36±8 years.

SVR was achieved in 53 women (70.6%).

0

10

20

30

40

50

60

70

80

AMH<0.16ngml AMH>0.16 ng/ml

SVR

%

10/19 44/56

P = .030


Predictive factors for SVR in HCV+ women

Genotype

OR 2.309, 95% CI 1.119 – 1-190, p=0.023

AMH (normal vs. abnormal)

OR 3.649 , 95% CI 1.123–11.904, p=0.012


0

10

20

30

40

50

60

70

Miscarriage rate

SVR

No SVR

%

Response to Antiviral Therapy and Rate of

Miscarriage

17/53 14/22

P= .0102


Prospective study of 3D in F0-F3 young (<35

years) HCV+ gt 1 or 4 women

Primary objective

The modification of AMH levels before and after successful

antiviral therapy in comparison with age-matched HCV-

positive women not undergoing antiviral treatment is the

primary endpoint.

Secondary objective

• Modification of the Estradiol (E2) levels

• Occurrene of miscarriage during the observation period

post-therapy.

Summary

In women with Hepatitis C infection, ovarian

senescence occurs early and negatively influences

reproductive function and response to therapy

Both prospective and cohort-based data indicate that

HCV+ women have strikingly impaired fertility and high

rate of miscarriages.

The role of antiviral therapy with DAA in reversing

ovarian senescence and improving fertility should be

explored.

WomenInHepatology

Courtesy of Anne Shreivogl

GENDER-C Project

Gastroenterology, Modena

Barbara Lei Mariagrazia Del Buono Veronica Bernabucci Filippo Schepis Anna Ferrari

Stefano Gitto Ranka Vukotic Aimilia Karampatou

Lab

Rosina Critelli Elena Turola Fabiola Milosa Francesca Faillaci, Rosario Condello

Pathology, AOU, Modena

Luisa Losi, Livia Maccio

Clinical Pathology, NOCSAE, Modena

Tommaso Trenti Enrica Baraldi Simonetta Tagliavini Annamaria Cenci

Istituto Superiore di Sanità

Loreta Kondili, Stefano Rosato, Stefano Vella and Piter Investigators: A. Craxi, S.Petta, V. Calvaruso (University Paolo Gioaccone Palermo); L. Chessa, M.C.Pasetto (University of Cagliari); E. Bigliotti, F. Tamburini (Sapienza University of

Rome); G. Montalto, A.R. Capitano (University Paolo Giaccone Palermo); D. Ieluzzi, G.Fattovich, S, Storato (University of Verona); A. L. Zignego ; M. Monti, L. Gragnani

(University of Florence); M. Zuin, E. Finati, A.Giorgini ( San Paolo Hospital Milano); G Angarano, M. Milella (University of Bari); F.Alessandro, M Dallio, C. Loguercio (2

nd University of Naples);G. Mazzella, G.Lazzarini, M Di Fine (University S. Orsola Malpighi, Bologna); F.P.Russo, I. Franceschet (Padua Hospital); F.Castelli, S. Zaltron

(Spedali Civili Brescia); G.Raimondo, R. Filomia , G.Martino University, Messina); M Puoti, E. Danieli (Niguarda Cà-Granda Hospital, Milano) M.Strazzabosco, M Gemma

(S. Gerardo, Hospital, Monza); M. Angelico, F. De Leonardis (Tor Vergata University, Rome); A. Gori, E. Cappelletti (S.Gerardo Hospital, Monza); R. Bruno S.Cima (S.

Matteo IRCCS, Pavia); C.Coppola, D.C Amoruso (Gragnano Hospital Napoli); P. Andreone, G.Simonetti (Sant’Orsola Malpighi University , Bologna); GB. Gaeta, V.Rizzo

(2 nd University Napoles); P. Toniutto, D.Dissegna (University of Udine); M.Mondelli S.Ludovisi (S. Matteo IRCCS, Pavia); M Persico, M.Masarone (G.da Procida

Hospital Salerno); C.Torti, A.Strazzulla (University Hospital Mater Domini, Catanzaro); F.Rosina,L.Framarin (Local Health District, Gradenigo, Torino); Maria Giovanna

Quaranta, Loredana Falzano, Alessandra Mallano (Istituto Superiore di Sanità).

★

The two meetings were held in Modena during the Women in Hepatology Meeting in May 2014 and in Naples during the AISF

Monothematic Conference in October 2014.

The Position Paper was generated by the Gender Committee of the Italian Association for the Study of the Liver (AISF) to provide an

official position paper in a setting characterized by uncertain clinical behavior and lack of uniform approach.

Digestive and Liver Disease 48 (2016) 120–137

★ Filomena Morisco, Raffaele Bruno, Elisabetta Bugianesi, Patrizia Burra,Vincenza Calvaruso, Alice Cannoni, Nicola Caporaso, Gian Paolo Caviglia,Alessia

Ciancio, Silvia Fargion, Alessandro Federico, Annarosa Floreani,Giovanni Battista Gaeta, Maria Guarino, Pietro Invernizzi, Anna Licata,Carmela Loguercio,

Giuseppe Mazzella, Felice Petraglia, Massimo Primignani,Kryssia Rodriguez-Castro, Antonina Smedile, Luca Valenti, Ester Vanni, SilviaVannuccini, Chiara

Voltolini,

★

Malattie Infettive, Università La Sapienza Gloria Taliani

Epatite C, fertilità ed aspetti terapeutici nelle donne · Epatite C, fertilità ed aspetti...

Documents

Transcript of Epatite C, fertilità ed aspetti terapeutici nelle donne · Epatite C, fertilità ed aspetti...