Incidence and Progression to Cirrhosis of HCV Superinfection in Persons Living with HIV (PLHIV)
Italian
Cohort
I.
Naive
Antiretrovirals
N.
# 638
Massimo Puoti*1, Patrizia Lorenzini2, Enrico Girardi2, Alessandro Cozzi-Lepri3, Andrea Gori4, Claudio Mastroianni5, Giuliano Rizzardini6, Giovanni Mazzarello7, Andrea Antinori2, Antonella d'Arminio
Monforte8, and Icona Foundation Study Group1
O.
C
A.
Niguarda Ca` Granda Hosp, Milano, Italy; 2National Inst. Infectious Dis. "Lazzaro Spallanzani", Rome, Italy; 3University College London, London, UK; 4San Gerardo de` Tintori Hosp, Monza, Italy; 5"La Sapienza" Rome University Polo Pontino, Latina, Italy; 6Luigi Sacco
Hosp, Milano, Italy; 7San Martino Hosp., Genova, Italy; and 8University of Milano, San Paolo Hospital, Milano Italy
Abstract
BACKGROUND There are controversial data about the course of liver fibrosis development following Hepatitis C
superinfection in persons living with HIV (PLHIV).
AIM AND METHODS We analyzed HCV seroconverters of PLHIV enrolled in the ICONA Foundation Study in order to
estimate the incidence and predictors of HCV superinfection and the risk of progression to cirrhosis. We selected all the
subjects with a first negative anti HCV test who performed at least a second anti HCV test and estimated the incidence of
HCV seroconvertion and determined predictors by Poisson regression. We selected patients who experienced HCV
superinfection and defined the probability of progression to cirrhosis as the occurrence of liver related death, liver
decompensation, clinical diagnosis of cirrhosis or a FIB4 > 3.25 whatever occurred first using Kaplan Meier method.
RESULTS. We identified 2517 patients with a negative anti HCV test who performed at least a second test; in 207 people
this second test was positive (seroconverters) over a total of 17378 patients years; the estimated Incidence rate (IR) of
HCV superinfection was 1.2 per 100 person years of follow-up (PYFU) (95% CI 1.0-1.4). IDU (AIR vs. heterosexuals
4.58; 95% CI 1.44-14.59 p=0.010), being a MSM (AIR 2.53 vs. heterosexuals 95% 1.07-6.02 p=0.035) lower level of
education (primary school) (AOR vs. high school or degree 2,47 95% CI 0.99-6.17 p=0.052), place of residence (central
Italy (AOR vs north Italy 1.98 95% CI 1.1-3.56 p=0.023) were significantly associated with an increased risk of
seroconversion in multivariable analysis. Incidence of seroconversion significantly decreased over time from 1997 to 2010
in all risk groups except MSM (IR in 1997-2001 vs 2009-2012: 1.8 vs 1.7 in MSM p=0.346; 18.4 vs 2.4 in IDU p<0.001;
2.1 vs 0.1 in heterosexual p<0.001). We observed occurrence of cirrhosis in 16 seroconverters over 1254 PYFU for an
estimated rate of 12.8 per
PYFU (95%CI 7.8-20.8).
CONCLUSIONS The incidence of HCV superinfection in Icona cohort was high but declined over time in all groups
except MSM probably because of recent sexually transmitted infections. After HCV superinfection the probability of
progression to cirrhosis of was 11% by 9 years, which is similar to that observed in historical controls of HCV+/HIVnegative individuals which should reassure patients and caregivers regarding the risk of early cirrhosis in these patients.
We identified 2517 patients with a negative anti HCV test who
performed at least a second test; in 207 people this second test was
positive (seroconverters) over a total of 17378 patients years; the
estimated Incidence rate (IR) of HCV superinfection was 1.2 per 100
person years of follow-up (PYFU) (95% CI 1.0-1.4).
Results 2 - Table 1
Incidence Rate (IR) of anti-HCV seroconversion according
to mode of HIV transmission
Mode of HIV
transmission
Aims
We analyzed HCV seroconverters of PLHIV enrolled in the ICONA
Foundation Study in order to estimate the incidence and predictors
of HCV superinfection and the risk of progression to cirrhosis.
Methods
We selected all the subjects with a first negative anti HCV test who
performed at least a second anti HCV test and estimated the incidence
of HCV seroconvertion and determined predictors by Poisson
regression. We defined the time of occurrence of seroconversion as
the mid point of the time interval between the last negative and the
first positive anti-HCV assay.
We selected patients who experienced HCV superinfection and
defined the probability of progression to cirrhosis as the occurrence of
liver related death, liver decompensation, clinical diagnosis of
cirrhosis or a FIB4 > 3.25 whatever occurred first. We estimated the
risk of progression to cirrhosis using Kaplan Meier method and Cox
regression to determine predictors.
Incidence
Rate per 100
PYFU
N of anti HCV
seroconv.
PYFU
Heterosexuals
73
9735
0.7
0.6-0.9
IDU
MSM
41
85
466
6020
8.8
1.4
6.5-11.9
1.1-1.7
Other/unknown
8
1157
0.7
0.3-1.4
Background
Liver failure and Hepatocellular Carcinoma due to hepatitis C virus
(HCV) infection are among the leading causes of death in HIVinfected patients [1].
Nevertheless, HCV infection leads to cirrhosis in a minority of
patients and only over a period of decades, even in those co-infected
with HIV [2]. Historically, most co-infected patients acquired both
HCV and HIV parenterally, and due to the higher infectivity of
HCV parenterally, that infection was acquired first [3].
Recently, an international epidemic of HCV infection among HIVinfected men-who have-sex-with-men (MSM) has occurred [4, 5].
These men acquired both HIV and HCV sexually, and partly due to
the higher infectivity of HIV through a sexual route, that infection
was acquired first.
A rapid progression of fibrosis was reported in most of the MSM
PLHIV with acute HCV superinfection (newly acquired infection
in a setting of chronic HIV infection) from two series in US and
Belgium [6,7] by liver biopsy and elastometry with some patients
developing liver decompensation within 6 years after infection [8]
but these series were small and the incidence of such a rapid course
of HCV infection in PLHIV has not be determined in large series.
Results 4- Figure 1
IR of anti-HCV seroconversion according to calendar
year and mode of HIV transmission
Results 1- Incidence of anti HCV seroconversion
95%CI
P<0.001
Variable
HIVRNA <50 after SC
(time-dep)
P=0.346
P<0.001
2001-2004
2005-2008
P=0.640
2009-2012
Results 5- Incidence of Liver Related Events in AntiHCV seroconverters
Variable
RR
Male gender vs female
0.56
0.24
1.30
0.175
Age (per 10 yrs older)
Mode of HIV transmission
0.77
0.54
1.10
0.146
Heterosexual
1.00
IDU
4.58
1.44
14.59
0.010
MSM
2.53
1.07
6.02
0.035
Other/unknown
0.29
0.04
2.29
0.243
CDC stage C vs A/B
1.05
0.39
2.83
0.919
cd4, per 100 cells higher (tine-dependent)
1.00
0.99
1.01
0.867
log HIV-RNA, per 1 log higher (time-dependent)
1.13
0.83
1.53
0.452
p
HBsAg reactivity (time-dependent)
1.38
0.48
4.00
0.550
History of STD
0.35
0.10
1.24
0.103
Anti-TP Ab reactivity
1.12
0.39
3.21
0.835
status ARV (time-dependent)
Instruction level
0.81
0.33
1.98
0.647
High school/university
1.00
Primary
2.47
0.99
6.17
0.052
Intermediate
0.95
0.48
1.88
0.878
Missing data
Country area
3.63
1.22
10.79
0.020
Northern Italy
1.00
Central Italy
2.00
1.11
3.60
0.021
Southern Italy - Islands
0.43
0.06
3.24
0.413
HR
CD4 at SC
<500
500-699
>=700
1997-2000
Results 3- Table 2
Variables associated with anti-HCV seroconversion by
multivariable analysis
95% CI
20,0
18,0
16,0
14,0
12,0
10,0
8,0
6,0
4,0
2,0
0,0
Results 7- Table 3
HR of liver related events according to CD4 and HIVRNA at HCV seroconversion (SC)
We observed occurrence of liver related mortality, diagnosis of
decompensated or compensated cirrhosis or occurrence of a FIB-4 > 3.25
in 16/205 seroconverters over 1254 PYFU for an estimated rate of 1.3
per 100 PYFU (95%CI 0.8-2.1).
13 patients had fib-4>3.25 and 3 developed cirrhosis.
5 years probability of the progression to cirrhosis was 5.2% and 9 years
was 11%.
Results 6- Figure 2
Kaplan Meier Estimate of the probability of liver
related events in PLHIV with HCV superinfection in
the Icona cohort
95% CI
P
1
0.78
1.09
0.23
0.34
2.69
3.52
0.694
0.889
0.66
0.19
2.25
0.508
Summary of results
The estimated incidence of anti-HCV SC in the Icona cohort
was 1.2 per 100 person years of follow-up (PYFU) (95% CI 1.01.4).
Incidence of anti-HCV seroconversion was higher in MSM and
IDU, in those living in central Italy and in those with lower level
of education.
Incidence of anti-HCV seroconversion remained stable in MSM
and significantly declined over time in all other risk groups.
The occurrence of liver cirrhosis or liver decompensation or
liver related death in seroconverters was 12.8 per 1000 PYFU
(95%CI 7.8-20.8).
Immune status at SC was not related to a higher risk of
occurrence of liver related events
Conclusions
Incidence of new HCV infection was low in PLHIV in Italy.
Epidemic of HCV among MSM in Italy seems to be limited even if
it seems able to maintain stable the number of new cases in this risk
group
Progression to cirrhosis in PLHIV with HCV superinfection does
not seem to be so dramatic as in small series observed in US and
Belgian MSM.
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BOARD OF DIRECTORS
M. Moroni (Chair), G. Angarano, A. Antinori, , O. Armignacco, A. d’Arminio Monforte, F. Castelli, R. Cauda, , G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, C.F. Perno, F. von Schloesser, P. Viale.
SCIENTIFIC SECRETARY
A. d’Arminio Monforte
A. Antinori, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, E. Girardi, S. Lo Caputo, C. Mussini, M. Puoti
STEERING COMMITTEE
A. Ammassari, M. Andreoni, A. Antinori, C. Balotta, P. Bonfanti, S. Bonora, M. Borderi, M.R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, P. Cinque, A. Cozzi-Lepri, A. d’Arminio Monforte, A. De Luca, M. Gargiulo, C. Gervasoni, E. Girardi, A. Gori, G. Guaraldi, M. Lichtner, S. Lo Caputo, G. Madeddu, F. Maggiolo, G. Marchetti, S.
Marcotullio, L. Monno, R. Murri, C. Mussini, M. Puoti, C. Torti
STATISTICAL AND MONITORING TEAM
A. Cozzi-Lepri, P. Cicconi, I. Fanti, T. Formenti, L. Galli, P. Lorenzini
PARTICIPATING PHYSICIANS AND CENTERS
Italy A. Giacometti, A. Costantini, O. Cirioni, F. Frontini (Ancona); G. Angarano, L. Monno, C. Carrisa (Bari); F. Maggiolo, C. Suardi (Bergamo); P. Viale, E. Vanino, G. Verucchi (Bologna); F. Castelli, E. Quiros Roldan, C. Minardi (Brescia); T. Quirino, C. Abeli (Busto Arsizio); P.E. Manconi, P. Piano (Cagliari); J. Vecchiet, K. Falasca (Chieti); L.
Sighinolfi, D. Segala (Ferrara); F. Mazzotta, S. Lo Caputo (Firenze); G. Cassola, G. Viscoli, A. Alessandrini, R. Piscopo, G. Mazzarello (Genova); C. Mastroianni, V. Belvisi (Latina); P. Bonfanti, I. Caramma (Lecco); A. Chiodera, P. Castelli (Macerata); M. Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. d’Arminio Monforte, A.L. Ridolfo, R. Piolini, A.
Castagna, S. Salpietro, L. Carenzi, M.C. Moioli, P. Cicconi, G. Marchetti (Milano); C. Mussini, C. Puzzolante (Modena); A. Gori, G. Lapadula (Monza); N. Abrescia, A. Chirianni, M.G. Guida, M. Gargiulo (Napoli); F. Baldelli, B. Belfiori (Perugia); G. Parruti, T. Ursini (Pescara); G. Magnani, M.A. Ursitti (Reggio Emilia); R. Cauda, M. Andreoni, A.
Antinori, V. Vullo, A. Cingolani, A. d’Avino, A. Ammassari, L. Gallo, E. Nicastri, R. Acinapura, M. Capozzi, R. Libertone, G. Tebano (Roma); A. Cattelan (Rovigo); M.S. Mura, G. Madeddu (Sassari); P. Caramello, G. Di Perri, G.C. Orofino, S. Bonora, M. Sciandra (Torino); G. Pellizzer, V. Manfrin (Vicenza).