Diapositiva 1

Epidemiologia coinfezione HCV-HIV
Giuliano Rizzardini
Dipartimento Malattie Infettive Ospedale Luigi Sacco, Milano
School of Clinical Medicine, Faculty of Health Science,
University of the Witwatersrand, Johannesburg
Hepatitis C: A Worldwide Epidemic
Estimated ~ 170 million (3.1%) globally (2003)
Canada
242,000
(0.7%)
Europe
8.9 million
(1.03%)
1, 2, 3
The Americas
13.1 million
(1.7%)
4
4
1
Most Common Genotype
1
Africa
31.9 million
(5.3%)
4
4,5
3
3
Eastern
Mediterranean
21.3 million
(4.6%)
Asia: 6
1,3
Western Pacific
62.2 million
1, 3
(3.9%)
Southeast Asia
32.3 million
(2.15%)
Worldwide: 6
World Health Organization. Hepatitis C: global prevalence: update. 2003.
Farci P, et al. Semin Liver Dis. 2000. Wasley A, et al. Semin Liver Dis. 2000.
Remis, for the Public Health Agency of Canada. Modeling the Incidence and Prevalence of Hepatitis C
Infection and its Sequelae in Canada, 2007. Unpublished data, 2009.
HCV: A Global Public Health Concern
Log10 Global Death Rate
7
5
HIV
HBV + HCV
Measles
RSV, Rota
Flu
Dengue
4
HPV
6
3
2
1
Tobacco
Malaria
Road accidents
Non-HIV TB
Hospital infection
Suicide
West Nile
SARS
Ebola
Polio
Hanta
vCJD
Caused by Viruses
Other Causes
Global Death Rate
Adapted by permission from Macmillan Publishers Ltd: Nature Medicine.
Weiss RA, et al; copyright 2004.
Morbidity and Mortality for the top 20
pathogens in ON, ranked by disease burden
Hepatitis C virus
Streptococcus pneumoriae
Human papillomavirus
Hepatitis B virus
Escherichia coli
HIV/AIDS
Staphylococcus aureus
Influenza
Clostridium difficile
Rhinovirus
Respiratory syncytial virus
Parainfluenza virus
Group B steptococcus
Group A steptococcus
Haemophilus influenza
Tuberculosis
Legionella
Chlamydia
Adenovirus
Gonorrhea
Years of Life Lost (YLL)
Year-Equivalents of Reduced Functioning
(YERF)
0
2,000
4,000
6,000
8,000
Health Adjusted Life Years
10,000
OnBOIDS, Dec 2010
Estimated numbers of Co-infected
persons (worldwide)
New HCV /HIV epidemiological data.
Center for Disease Analysis 2013 (2)
Prevalence of hepatitis C in the HIV population
North: 23.2%
(n=359)
East: 47.0%
(n=613)
Central: 20.5%
(n=293)
South: 41.4% (n=695)
Regions:
South
Central
North
East
Rockstroh J, et al. J Inf Dis 2005;192:992–1002
Distribution of hepatitis C virus genotypes in the
distinct EuroSIDA regions
• The most highly
represented Genotypes are
1 and 3 in all areas.
• Genotype 2 is low or
absent in all areas
Soriano V. et.al. JID 2008
10
Dati aggiornati a Gennaio 2013 come fonte, la percentuale
del 34% sono pazienti coinfetti HIV HCV considerando il
100% dei pazienti sieropositivi.
HCVRNA + 2257 out of 3177 tested: 71%
11%
29%
58%
2%
HCV-G1
HCV-G2
HCV-G3
HCV-G4
Distribution of HCV G1 subtypes:
HCV Genotype 1a 59%
HCV Genotype 1b 27%
HCV G1 not subtyped or mixed: 13%
HBsAg and HCVAb positivity in 12.030
patients enrolled in ICONA
35%
28.3%
30%
HCVAb+/HBsAg+: 2,3% (n=282)
25%
20%
15%
10%
6.3%
5%
0%
HBsAg+
n=762
HCVAb+
n=3405
Jun 2015 Report
Proportion of HCVAb positive ICONA patients
according to calendar year of enrolment
60%
55.3%
51.2%
50%
42.3%
40%
35.1%
30%
25.6%
22.9%
22.9%
20%
14.2%
12.4%
10%
8.9%
9.8%
9.8%
2009 n=45
2011 n=98
2013 n=75
7.1%
0%
1997
n=1325
for 2015, first
6 months
1999 n=55
2001 n=57
2003 n=50
2005 n=35
2007 n=27
2015 n=27
Jun 2015 Report
HBsAg and HCVAb positivity according to gender in
12.030 patients from ICONA
35%
3000
29.1%
30%
25%
28.0%
HCVAb+/HBsAg+
M: 2,6% (n=244)
F: 1,2% (n=38)
2500
2000
20%
1500
15%
F-%
M-%
1000
10%
7.0%
5%
4.3%
127
500
635
871
2534
0%
0
HBsAg+
HCVAb+
Jun 2015 Report
HCVAb status according to mode of HIV
transmission in ICONA
100%
92.5%
90%
80%
70%
60%
50%
40%
30%
18.5%
20%
11.4%
10%
7.9%
0%
Heterosexual contacts
n=4545
Homo/Bisexual contacts
n=3959
IDU
n=2598
Other/Unknown
n=928
Jun 2015 Report
Prevalence of HCV-RNA pos in 1515 HCVAb pos
patients tested for HCV-RNA in ICONA
214, 14%
Neg
Pos
1301, 86%
Jun 2015 Report
Proportion of HCV genotypes for 1.321 HCVRNA+ patients in ICONA
47
4%
641
49%
166
26%
479
36%
41
7%
15
8 2%
1%
411
64%
139
10%
15
1…
1 2
3
4
Others
1a
1b
1
1a/1b
1c
Jun 2015 Report
HCV genotypes according to mode of HIV
transmission in ICONA patients
70%
64.3%
60%
50%
40%
47.6%
44.6%
46.3%
1
38.6%
35.7%
35.4%
3
30%
4
19.1%
20%
Others
12.2%
10%
2
7.8%
6.6%
0.9%
10.8%
7.8%
0.9%
7.3%
2.0%
1.0%
7.3%
3.7%
0%
Heterosexual contacts
N=213
Homo/Bisexual
contacts
N=115
IDU
N=911
Other/Unknown
N=82
Jun 2015 Report
Last Fib4 values for HCVAb positive patients in HepaICONA and
ICONA, naive or failed at any anti-HCV therapy
45%
800
42.1%
37.4%
40%
700
35%
600
30%
500
25%
20.5%
400
20%
300
15%
200
10%
100
5%
722
643
0%
<=1.45
1.45-3.25
352
0
>3.25
Oct 2015
Proportion of hepatic decompensation occurred at any time in patients with last
Fib4>3,25 in ICONA and HepaICONA
Decompensated cirrhosis
n=352
24.4%
0%
5%
10%
15%
20%
25%
30%
Proportion of individual events of hepatic decompensation occurred at any time
in patients with last Fib4>3,25 in ICONA and HepaICONA
0%
2%
4%
6%
8%
10%
Esophageal Varices/ Bleeding
10.2%
Ascites / Portal Hypertension
8.5%
HCC
Hepatic Encephalopaty
12%
3.4%
2.3%
Oct 2015
Proportion of HCV-RNA positive patients starting any antiHCV treatment in ICONA till December 2012
356, 25%
Treated
Not treated
1057,
75%
Jun 2015 Report
Proportion of HCV-RNA+ patients starting any anti-HCV treatment
for the first time, according to period of starting in ICONA till
December 2012
12%
10.9%
10%
10.6%
8.8%
8%
7.0%
6.6%
%IFN
%IFN+RBV
6%
%TEL
4.3%
4%
2%
1.1%
1.0%
0%
1997-1999…
2000-2002…
2003-2005…
2006-2008…
0.4%
0.2%
2009-2012…
Jun 2015 Report
Distribution of anti-HCV treatment regimens in HepaICONA
andIicona patients, after Jan 2013 (n=312 in 306 patients)
3D+RBV
49
PR
40
SOF+RBV
35
SIM+SOF+RBV
34
SIM+SOF
34
DCL+SOF+RBV
22
3D
21
TEL+PR
17
SOF+PR
17
DCL+SOF
14
LED/SOF+RBV
11
LED/SOF
8
BOC+PR
3
DCL+PR
3
Other
2
SIM+PR
1
2D+RBV
1
0
10
20
30
40
50
60
Oct 2015
Acute HCV Definition
(1)Positive anti-HCV immunoglobulin G (IgG) in the presence or absence
of a positive HCV-RNA and a documented negative anti-HCV IgG in the
previous 12 months.
(2) Positive HCV-RNA and a documented negative HCV-RNA and negative
anti-HCV IgG in the previous 12 months.
Sexual Transmission of HCV Among
HIV+ MSM: An Emerging Population
• Reports of epidemic of sexually transmitted HCV among HIV+ MSM
– United States: 6-fold higher incidence rate in HIV+ vs HIVMSM[1]
– Swiss HIV Cohort Study: HCV incidence increased 18-fold from
1998 to 2011[2]
– Sydney, Australia: 9% of HIV+ MSM coinfected with HCV vs
1.9% HIV- MSM[3]
– Amsterdam, Netherlands: HIV/HCV coinfection prevalence
increased from 14.6% to 20.9% from 2000-2007[4]
• Phylogenic analysis indicates HCV transmission clusters in some
areas[5]
1. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 2. Wandeler G, et al. Clin Infect Dis. 2012;55:1408-1416.
3. Lea T, et al. Sexual Health. 2013;10:448-451. 4. Urbanus AT, et al. AIDS. 2009;23:F1-F7.
5. MMWR. 2011;60:945-950.
Acute HCV:
Importance of Transmission networks
 IDU in 73%
 Sexual transmission in
18% of whom 92% were
HIV+.
Matthews. Clin Inf Dis, 2011
Hepatitis C reinfection occurs
frequently among gay men living
with HIV in London
The investigators designed a retrospective
study involving gay men with HIV and HCV
co-infection who received care between
2004 and 2012. A total of 858 gay men with
this co-infection received care at the hospital
in this period, and 191 of them cleared HCV
infection but were subsequently reinfected
with the virus
Overall reinfection rate of 7.8/100 py [95%
confidence interval (CI) 5.8-10.5]. Eight individuals
were subsequently reinfected a second time at a
rate of 15.5/100 py (95% CI 7.7-31.0).
Among 145 individuals with a documented primary
infection, the reinfection rate was 8.0 per 100 py
(95% CI 5.7-11.3) overall, 9.6/100 py (95% CI 6.614.1) among those successfully treated and
4.2/100 py (95% CI 1.7-10.0) among those who
spontaneously cleared. The secondary reinfection
rate was 23.2/100 py (95% CI 11.6-46.4).
HCV reinfections in HIV+ MSM
553 patients from 7 NEAT centers
with cured acute HCV since 6/2001
141 with at least one reinfection (25.5%)
1509 patient-years of FU, median 2.1
years
Incidence rate: 7.82/100 patient-years
Treated patients: 7.9/100 patient years
Spontaneous clearers: 3.3/100 patientyears
1st episode
(n=141)
2nd episode
(n=141)
3rd episode
(n=26)
4th episode
(n=5)
Ingiliz et al., EASL 2014, Martin et al., AIDS 2013
Coinfezioni HIV/HCV: ieri e oggi
Coinfezioni di lunga durata in
HIV +
 In Italia si stima che il 60% delle
persone con HIV sia anche
portatrice del virus dell’epatite C
(HCV)
 La maggioranza di queste vivono
con entrambe le infezioni da molti
anni
 La maggioranza di queste hanno
contratto entrambi i virus
attraverso siringhe infette o per
trasfusioni e/o uso di emoderivati
infetti
Coinfezioni recenti in HIV+
 Nuove diagnosi di infezione acuta
HCV in persone omosessuali HIV+
Fattori correlati









HIV+
Rapporti anali non protetti
Scambio di sex toys
Rapporti molto prolungati/energici
Fisting
Sesso di gruppo – sex party
Elevato numero di patner sessuali
Presenza di altre MTS (sifilide)
Incontri in chat
HIV-HCV:
siamo certi che non sia più
una special population?
HIV/HCV co-infection
HIV accelerates HCV disease
progression1
HCV effect on HIV is less
characterised but results in2
Increased:
• Degree of fibrosis and
progression to cirrhosis
• Rate of progression to
hepatocellular carcinoma
• Hepatocyte apoptosis with
HIV/HCV co-infection
• Steatosis severity
• Higher HCV RNA levels
• Pro-inflammatory cytokines
Increased:
• Immune activation
• Sensitization of CD4+ T-cells
towards apoptosis
• Rates of chronic kidney disease
and mortality
1. Rockstroh JK, Spengler U. Lancet Infect Dis 2004;4:437–44
2. Andreoni M et al, Eur Rev Med Pharmacol Sci 2012;16:1473–83
Impact of HCV Exposure/ Coinfection on HIV disease
Issue
HCV exposure
( HCVAb+ vs
HCVAb-)
Faster HIV disease progression
Yes1
Impaired CD4 recovery on cART
Yes2
Impaired HIVRNA suppression on cART
Yes 4
Worsened renal function
Yes5
Higher incidence of osteopor. fractures
Yes7
Higher incidence of Cardiovascular
related events
Yes 8
Higher incidence of Diabetes
Yes 9
Higher non AIDS non liver related
mortality
Yes10
HCV acyive replication
(HCVAb+ HCVRNA+ vs
HCVAb+ HCVRNA-)
Yes3
Yes6
Yes11
1. Greub, Lancet, 2000, Piroth, J Viral Hepat, 2000 De Luca et al, Arch Intern Med, 2002), Herrero Martinez E JID
2002, Dorrucci AIDS 2004; Braitsein JID 2006;
2. Lincoln, HIV Med, 2003
3. Potter M AIDS 2010
4. Pulido AIDS Review 2012; Hua L AIDS 2013
5. Izzedine AIDS 2009; Lucas JID 2013
6. Peters AIDS 2012; Mocroft A PLOS One 2012; Lucas jiD 2013
7. Lo Re Hepatology 2012; Maalouf J Bon Min Res 2013, Casado Osteopos Int 2014
8. Erqou S CROI 2014
9. Howard AA JAIDS 2014; Butt AA AIDS 2009; Jain MK HIV Med 2007; Butt AA Hepatology 2004
10. Mallet V CROI 2014
11. Grint D CROI 2014
The liver in patients with HIV/HCV co-infection
HIV/HCV co-infection can result in:
Increased frequency and speed of
progression to cirrhosis1
Hepatic decompensation1
Hepatocellular carcinoma1
Higher incidence of liver enzyme
elevation during ARV treatment2
1. Sánchez-Conde M, et al. Clin Infect Dis 2006;43:640–4
2. Vispo E, et al. J Antimicrob Chemother 2010;65:543–7
Rapid fibrosis progression among 174 HIV/HCV
co-infected non-cirrhotic adults between two liver biopsies
Median individual serum AST level (U/L) between
biopsies among HIV/HCV co-infected individuals
with and without fibrosis progression
70
No change
≥2 stage change
76
Stable or improved
Worsened >1 Ishak
fibrosis stage
increase
24
0
20
40
60
80
Median AST (IU/L
60
Ishak fibrosis stage at first and second liver
biopsy among 174 HIV/HCV-co-infected adults*
50
First biopsy
fibrosis stage
0
1
2
3
4
40
30
Second biopsy fibrosis stage
0
45
8
1
0
0
54
1
20
20
2
0
0
41
2
12
12
11
1
0
36
3
2
7
2
8
0
19
4
2
2
0
3
0
7
5
3
0
0
5
0
8
6
1
2
1
2
2
8
85
51
17
19
2
174
*Shaded
20
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Median time interval of 2.9 years
AST: aspartate aminotransferase
regions represents subjects in whom the fibrosis stage
observed at second biopsy was at least two Ishak units greater than
observed at first biopsy (two-stage progression)
Sulkowski M. AIDS 2007;21:2209–16
HCV Coinfection vs Monoinfection:
Cumulative Incidence of Decompensation
• 10-year hepatic decompensation risk 83% higher in coinfected
patients
– Adjusted HR 1.83 (95% CI: 1.54-2.18)
0.2
HIV/HCV coinfected
HCV monoinfected
0.1
0.074
0.048
P < .001
0
0
1
2
3
4
5
6
7
8
Yrs to Hepatic Decompensation
9
10
23. Lo Re V, et al. IAC 2012. Abstract WEAB0102.
A prospective study (ANRS CO13 Hepavih and CO12 Cirvir)
Primary liver cancer is more aggressive in
HIV-HCV coinfection than in HCV infection
Liver-related death: 1st cause of
death in HIV-HCV patients1
43 %
12 %
0
10
20
30
40
8%
5%
4%
4%
4%
2%
6%
7%
Cirrhotic Patients: > 50% deaths related to HCV
Non cirrhotic patients : 60% deaths non related to HCV nor HIV
1HSogni
P. Conference on French HIV-HCV Consensus Guidelines, 2012
Decompensated
cirrhosis
HCC
Post-transplantation
Causes of death in the Swiss HIV Cohort study 2005-09
Ruppik M. et al. Changing patterns of causes of death in the SHCS 2005-2009. CROI 2011.
Poster # 789. Available at: http://www.retroconference.org/2011/PDFs/789.pdf.
Mortality in HCV-infected patients with HIV
 Chronic HCV infection is independently associated with a 50% increase
in mortality among patients with a diagnosis of AIDS
Cumulative probability
0.50
Without HCV markers
Cleared
Chronic
0.25
0
0
2
4
6
Follow-up (years)
8
10
Branch A, et al. Clin Infect Dis 2012;55:137–44
Mallet V et al, Croi 2014 abstr 690
Overall, ESLD and death remain higher
in HIV-HCV patients in cART era1
Cum. I X 1,5
1Lo
Re V, WEAB0102, IAC 2012, Washington DC - USA
FUTURE CHALLENGES
Treatment as prevention concept in HCV
1
1Durier
N. Plos One 2012
35