Coinfezione HIV-HCV una sfida ancora aperta? - Massimo Puoti Infectious Diseases Dept ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA MILANO - MSD Salute
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Massimo Puoti
Infectious Diseases Dept
ASST GRANDE OSPEDALE
METROPOLITANO NIGUARDA
MILANO
Coinfezione HIV-HCV
una sfida ancora aperta?
IT-NON-00682-AV-07-2021
Disclosures • Honoraria for consulting or speaking (past 5 years): AbbVie, Beckman Coulter , BMS, Janssen, Gilead Sciences, MSD, Roche, and ViiV • Research grants (past 5 years) : Gilead Sciences, ViiV, Roche, Pfizer Astellas and Novartis
3
Coinfezione HIV-HCV una sfida ancora aperta? • Terapia anti HCV in pazienti con co-infezione da HIV: – Trials – Real life studies – Linee guida • Accesso al trattamento • Verso l’eradicazione
Coinfezione HIV-HCV una sfida ancora aperta? • Terapia anti HCV in pazienti con co-infezione da HIV: – Trials – Real life studies – Linee guida • Accesso al trattamento • Verso l’eradicazione
High SVR in adult patients with HIV/HCV
co-infection treated with 1st gen. DAAs
ALLY-2:1 TURQUOISE-1, part 2:3
ION-4:2
GT 1–4, TN & TE GT 1 or 4, TN and TE
GT 1 or 4, TE & TN
SOF + DCV OMV/PTV/RTV
LDV/SOF
+ DSV ± RBV
100 97 98 97
100 96 100
80 80 80
SVR12 (%)
60 60 60
40 40 40
322/33
20 98/101 51/52 20 5 20
TN 217/223
0 TE 0 12 weeks 0
12 weeks 12 or 24 weeks
1. Wyles D, et al. N Engl J Med 2015;373:714–25; NOT HEAD-TO-HEAD COMPARISONS
2. Naggie S, et al. N Engl J Med 2015;373:705–13; • Studies included non-cirrhotic and cirrhotic patients.
3. Rockstroh JK, et al. IAS 2016; Abstract # 10333; • TE: treatment-experienced
4. Rockstroh JK, et al. Lancet HIV 2015;2:e319–27
Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6
C-EDGE CO-INFECTION: Results by HCV Genotype
100
96 97 96 96
Patients with SVR12 (%)
80
60
40
20
0
All GT1a GT1b GT4
Genotype
Overall SVR12 results includes the 2 patients with GT 6, who both achieved SVR12.
7
Rockstroh JK, et al. Lancet HIV. 2015 . http://dx.doi.org/10.1016/S2352-3018(15)00114-9
ASTRAL-5: high SVR across all patient
types in adult HIV/HCV co-infected
patients treated with 12 weeks’ SOF/VEL
ASTRAL-5: HIV/HCV co-infected
Treatment-naïve and -experienced, non-cirrhotic and cirrhotic GT 1–4 adults
95 94 100 93 97
100
80
SVR12 (%)
60
40
20
101/106 82/87 19/19 71/75 30/31
0
Total No Yes Naïve Experienced
Cirrhosis status Treatment history
Wyles D, et al. Clin Infect Dis. 2017 Jul 1;65(1):6-12. Error bars represent 95% confidence intervals
EXPEDITION-2 Study: efficacy
100
98 99
Non-
• One patient with
inferiority GT3 infection and
% Patients with SVR12
80 threshold
cirrhosis had on-
60 treatment
virologic failure at
40 150
153
150
151
ITT week 8; the
20
mITT
patient was 85%
compliant with
0
Breakthrough
SVR12
Relapse
1
0
treatment
Missing Data 1*
Discounted 1
*Patient returned at post-treatment week 24 and had achieved SVR
Rockstroh J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAB0303.
Coinfezione HIV-HCV una sfida ancora aperta? • Terapia anti HCV in pazienti con co-infezione da HIV: – Trials – Real life studies – Linee guida • Accesso al trattamento • Verso l’eradicazione
Similar Sustained Virologic Response in Real-World and Clinical Trial
Studies of Hepatitis C/Human Immunodeficiency Virus Coinfection
• Comparison of patient demographics between clinical trials and real-world data
Sikavi C et al Digestive Diseases and Sciences (2018) 63:2829–2839Similar Sustained Virologic Response in Real-World and Clinical Trial
Studies of Hepatitis C/Human Immunodeficiency Virus Coinfection
• Sustained viral response for clinical trial versus realworld data by direct-acting agent regimen.
Sikavi C et al Digestive Diseases and Sciences (2018) 63:2829–2839Similar Sustained Virologic Response in Real-World and Clinical Trial
Studies of Hepatitis C/Human Immunodeficiency Virus Coinfection
• Comparison of efficacy and effectiveness of various subgroups
Sikavi C et al Digestive Diseases and Sciences (2018) 63:2829–2839Clin Infect Dis. 2019 Feb 1;68(4):569-576. doi: 10.1093/cid/ciy547.
HEPAVIR
REALLIFERESULTSOF
GRAZOPREVIR/ELBASVIRINHCV-INFECTED
PWID:THEZEPALIVESTUDY
Juan Macías1, Pilar Rincón1, Luis E. Morano-Amado2, Francisco Téllez3,
María J. Ríos-Villegas4, Rafael Granados5, Antonio Collado6, Carlos
Galera7, Francisco Vera8, Dolores Merino9, Oscar Rincón10, Juan A.
Pineda1, for the HEPAVIR and GEHEP study groups
1Hospital Universitario de Valme, Seville, 2Hospital Universitario Alvaro Cunqueiro, Vigo,
3Hospital Universitario de Puerto Real, Cadiz, 4Hospital Universitario Virgen Macarena,
Sevilla, 5Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas, Gran Canaria,
6Hospital Universitario Torrecárdenas, Almeria, 7Hospital Clínico Universitario Virgen de la
Arrixaca, Murcia, 8Hospital General Universitario Santa Lucía, Cartagena, 9Hospital Juan
Ramón Jiménez, Huelva, 10Medical Department MSD-Spain, Spain.
ZepaLive Study, presented at GEHEP 2017 2Results: ZEPALIVE STUDY GZR/EBR in PWID
Response to GZR/EBR according to PWID and OAT status
(n=171 patients with evaluable response)
100% 95% 94% 97%
Non PWID (n =87)
80% PWID w/o OAT (n=52)
PWID with OAT (n=32)
60%
40%
20%
0%
n/N= 83/87 49/52
31/32
SVR12 9
ZepaLive Study, presented at GEHEP 2017 2HIV-coinfected patients respond worse to direct-acting antiviral
based therapy against chronic hepatitis C in real life than HCV
monoinfected individuals: a prospective cohort study
• In a prospective multicohort study, patients who initiated DAA-based therapy at
the Infectious Disease Units of 33 hospitals throughout Spain were included.
• Relaps after end-of-treatment response to IFN-free therapy was observed in 3/208
(1.4%) HCV monoinfected subjects and 10/231 (4.4%) HIV/HCV-coinfected
individuals (p = 0.075).
• In a multivariate analysis adjusted for age, sex, transmission route, body-mass
index, HCV genotype, and cirrhosis, the absence of HIV-coinfection (adjusted odds
ratio: 3.367; 95% confidence interval: 1.15-9.854; p = 0.027) was independently
associated with SVR12 to IFN-free therapy.
Neukam K et al HIV Clin Trials 2017; 18: 1126-34DAA Really Similarly Effective in HIV Coinfection?
• GECCO Cohort SVR12 According to CD4 and Cirrhosis Status
(9 German centres) 100
• n=1505 90 97,2
90,9 88,4
80
• 1156 mono-, 70
82,8
SVR 12(%)
349 coinfected 60
50
• Liver cirrhosis 29% 40
(31% vs. 22%) 30
• Overall-SVR 95%, 20
10
95% monoinfected, 0
94% coinfected CD4 ≥350 CD4Berenguer J et al CROI 2018;#607
Berenguer J et al CROI 2018;#607
Berenguer J et al CROI 2018;#607
Rates of SVR12 according to the presence of cirrhosis, decompensated
cirrhosis , history of previous interferon treatment and HCV genotype in
5464 HCV infected patients treated in Lombardy with EASL recommended
treatment schedules stratified according to HIV co-infection
Study ALL Cirrhotics Decompensated PEGIFN Exp. Genotype 3
Group
HIV+ 4444/4564 2512/2588 71/75 1434/1472 413/435
(97,4%) (97,1%) (94,7%) (97,4%) (94,9%)
HIV- 872/900 557/576 46/50 150/157 213/225
(96,9%) (96,7%) (92%) ( 95,5%) (94,7%)
Multivariate logistic regression identified two predictors of lack of SVR12 HCV G3 infection (OR 2.25 95%
CI 1.5-3.66 pCoinfezione HIV-HCV una sfida ancora aperta? • Terapia anti HCV in pazienti con co-infezione da HIV: – Trials – Real life studies – Linee guida • Accesso al trattamento • Verso l’eradicazione
EACS Coinfection guidelines 2017 Seite 27 EACS guidelines version 9.0
EACS Guidelines October 2018. Version 9.1 28
• All (HCV) patients should be tested for human immunodeficiency virus (HIV) • Drug-drug interactions are a key consideration in treating HIV-HCV coinfected patients, and close attention must be paid to anti-HIV drugs that are contraindicated, not recommended or require dose adjustment with particular DAA regimens (A1). • The same IFN-free, ribavirin-free treatment regimens should be used in HIV-coinfected patients as in patients without HIV infection, as the virological results of therapy are identical. Treatment alterations or dose adjustments should be performed in case of interactions with antiretroviral drugs (A1).
Check for DDIs between HCV and HIV drugs!
• Drug interactions
▪ http://www.drugs.com/drug_interactions.html
▪ http://www.medscape.com/druginfo/druginterchecker
▪ http://www.drugstore.com/pharmacy/drugchecker/
▪ http://drugchecker.aol.com
▪ http://hcvdruginfo.ca
• List of CYP substrates, inhibitors, inducers
▪ http://medicine.iupui.edu/clinpharm/ddIs
• HIV drug interactions
▪ http://www.hiv-druginteractions.org
▪ http://www.hep-druginteractions.org
Khoo S. 15th International Workshop on Clinical Pharmacology
of HIV & Hepatitis Therapy, May 2014 [oral presentation].
CYP, cytochrome❖ Prospective, observational study of all
antiretroviral experienced patients who
initiated raltegravir from 3 years in IDD
Hospital Carlos
❖ Laboratory parameters, liver stiffness, liver
enzyme elevations (LEEs) were evaluated
Conclusions:
“our results demonstrate the hepatic safety
profile of raltegravir in HIV-infected patients,
including those with chronic hepatitis C”
32
Vispo E. et al. J Antimicrob Chemother 2010; 65: 543–547,
32J Antimicrob Chemother. 2014 33 Feb;69(2):471-5
34
J. Macias et al., CID 2017 Sep 15;65(6):1012-1019.
Coinfezione HIV-HCV una sfida ancora aperta? • Terapia anti HCV in pazienti con co-infezione da HIV: – Trials – Real life studies – Linee guida • Accesso al trattamento • Verso l’eradicazione
Trends in HCV treatment uptake, efficacy and impact on liver
fibrosis in the Swiss HIV Cohort Study.
• We compared treatment incidence, sustained virological response (SVR)12 and liver fibrosis
stages between three time periods: period 1, 01/2009-08/2011 (prior to the availability of
DAAs); period 2, 09/2011-03/2014 (first generation DAAs); period 3, 04/2014- 12/2015
(second generation DAAs).
• At the beginning of the third period, 876 SHCS participants had a chronic HCV infection of
whom 180 (20%) started treatment with a second-generation DAA. Three-quarters of them
had advanced liver fibrosis (Metavir ≥ F3) of whom 80% were cirrhotics.
• SVR12 was achieved in 173/180 (96%) patients, three patients died and four experienced a
virological failure.
• Over the three time periods, treatment uptake (4.5/100 py, 5.7/100 py, 22.4/100 py) and
efficacy (54%, 70%, 96% SVR12) continuously increased.
• The proportion of cirrhotic patients with replicating HCV infection in the SHCS declined
from 25% at the beginning to 12% at the end of the last period.
Beguelin C et al Liver Int 2018: 38:424-3112(5): e0177402. https://doi.
ICONA + HepaIcona cohorts: Rate of access to DAA Older age, HIV-RNA< 50 copies/mL were associated to faster DAA initiation, higher CD4 count and HCV-genotype 3 with delayed DAA initiation in those eligible to DAA reimbursement.
Coinfezione HIV-HCV una sfida ancora aperta? • Terapia anti HCV in pazienti con co-infezione da HIV: – Trials – Real life studies – Linee guida • Accesso al trattamento • Verso l’eradicazione
Popolazioni difficili da raggiungere
• Necessità di strategie dedicate
– Dipendenza
• SERT
• TD di strada
– Prigioni
– Immigrati
– TransgenderAcute outbreaks of HCV have been reported in HIV+
MSM across the world
UK4,5 589 cases Belgium10 69 cases
Germany6 157 cases Swiss11 14 cases
Canada1 51 cases France7 29 cases 12
Denmark 13 cases
8,9
The Netherlands 127 cases
Japan14 21 cases
USA2,3 44 cases Korea15 3 cases
Lebanon13 1 case Taiwan16 28 cases
Hong Kong17 14 cases
Australia18 27 cases
Total number of cases reported in the literature from these countries
1. Burchell AN, et al. Can J Infect Dis Med Microbiol 2015;26:17‒22; 2. Luetkemeyer A, et al. J Acquir Immune Defic Syndr 2006;41:31‒6; 3. Cox A, et al. Gastroenterology 2009;136:26–31; 4.
Giraudon I, et al. Sex Transm Infect 2008;84:111–5; 5. Ruf M, et al. Euro Surveill 2008;13:1‒3; 6. Vogel M, et al. Clin Infect Dis 2009;49:317‒8; 7. Gambotti L, et al. Euro Surveill
2005;10:115‒7; 8. Urbanus A, et al. AIDS 2009;23:F1–F7; 9. Arends JE, et al. Neth J Med 2011;69:43‒9; 10. Bottieau E, et al. Euro Surveill 2010;15:1‒8; 11. Rauch A, et al. Clin Infect Dis
2005;41:395‒402; 12. Barfod TS et al. Scand J Infect Dis. 2011;43:145‒8; 13. Dionne-Odom J, et al. Lancet Infect Dis 2009;9:775‒83; 14. Nishijima T, et al. J Acquir Immune Defic Sundr
2014;65:213–7; 15. Lee S, et al. Korean J Intern Med 2016; doi: 10.3904/kjim.2015.353; 16. Sun YH, et al. J Clin Microbiol 2012;50:781–7; 17. Lin AWC, et al. J Int AIDS Soc 2014;17:19663; 18.MSM Have Highest HCV Reinfection Risk
• German multi-center cohort (GECCO
Cohort) HCV Reinfection Prevalence
• 2074 HCV patients 14.1
• 66% GT1, 24% GT3
% with Reinfection
• 37% IVDU, 12% MSM
• 23% HIV coinfected
• Median 63 weeks until
1.9
HCV reinfection 0.7
(n=41, 36 in MSM)
Overall IVDU MSM
Ingiliz P, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 612.TasP in HCV/HIV+ MSM: HCVREE Study
• 6-monthly HCV PCR Tests in the Swiss HIV Cohort (n=3722)
• 177 (4,8%) newly diagnosed HCV (Phase A) -> DAA Therapy
• After Re-Screening only 28 (0,8%) showed a renewed positive
HCV PCR (Phase C)
Newly Diagnosed HCV Infections Over Time
250 Incident infections Chronic infections
Total Number
200
150
49% decrease! 92.5% decrease!
100
50
6 n = 12
0
Phase A Phase C Phase A Phase C
Braun L, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 81LB.Acute HCV-epidemic in MSM:
DAA therapy can make a difference!
Boerekamps A et al, CID 2017Virus without Boarders: HCV in MSM
• Phylogenetic analysis
• 29 HIV patients with HCV GT1a
• 90% of viral sequences found in 5 different European transmission clusters
• 1/3 “imported” infections (25% from Germany, 40% from UK)
Phylogenetic Tree
* Incident Swiss HCV Infections in HIV+ MSM
* Chronic from Switzerland
* UK
* Germany
* The Netherlands
* Other Countries in Europe
* Outside Europe
* Unknown
Salazar-Vizcaya L, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 130.NoCo Study Flowchart
HCV: The Next STD in MSM on PrEP?
• ANRS IPERGAY PrEP Study
• HCV antibody test: High Risk MSM
(N=428)
– Baseline
– 6-monthly
Acute HCV-Infected Patients
• 25 sex partners in the last (N=14)
2 months
• 15x sex in the last 4 weeks BLIND Phase OPEN Phase
• 92% unprotected receptive At Enrollment
(N=1)
After Inclusion*
(N=1)
During Follow-Up
(N=7)
anal intercourse
• 54% chemsex
Gras J, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 585.
Gras J, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 585.Coinfezione HIV-HCV: una sfida ancora aperta?
Messaggi chiave
• Elevata efficacia delle opzioni terapeutiche disponibili in HIV+
• Dati dei trials →riscontro nei dati di real life → tassi di risposta sovrapponibili tra HIV+ ed
HIV-
• Linee guida chiare → problema più rilevante cART concomitante:
– switch pre DAA verso terapie compatibili e liver friendly specie in pz con malattia avanzata e danno epatico
residuo ((N)ASH, HBV etc)
• Accesso al tratamento riflette le regole di rimborsabilità dei singoli contesti ma attenzione a
non trascurare pz con controllo non ottimale malattia da HIV
• Verso l’ eradicazione:
– Trattamento universale anche epatite acuta e reinfezioni
– Monitoraggio reinfezioni e nuove infezioni in HIV
– Monitoraggio infezioi e reingezioni pz in PrEP
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