esperienze con daa nella coinfezione hcv/hiv · 2017. 12. 9. · esperienze con daa nella...
TRANSCRIPT
Esperienze con DAA nella coinfezioneHCV/HIV
Raffaele Bruno, MD
University of Pavia
Division of Infectious Diseases
Fondazione IRCCS Policlinico San Matteo
Pavia, Italy
Disclosure
Advisory board a speaker:
• Abbvie
• BMS
• Gilead
• MSD
Outline
Efficacy of DAA’s in HIV- HCV coinfected patients
Drug – Drug interactions
The Possible Association Between DAA Treatment for HCV Infection and HCC
Occurence/Recurrence
HBV reactivation during DAA’s treatment
Reinfection
Outline
Efficacy of DAA’s in HIV- HCV coinfected patients
Drug – Drug interactions
The Possible Association Between DAA Treatment for HCV Infection and HCC
Occurence/Recurrence
HBV reactivation during DAA’s treatment
Reinfection
SVR
rat
e (%
)
Improved SVR12/24 rates over time in HCV GT1 patients co-infected with HIV1–10
• IFN, interferon; RBV, ribavirin; PEG, pegylated interferon; BOC, boceprevir; TVR, telaprevir; SMV, simeprevir; OMV, ombitasvir; DSV, dasabuvir; PTV, paritaprevir
• 1. Torriani FJ et al. N Engl J Med 2004;351:438–450; 2. Sulkowski M et al. Lancet Infect Dis 2013;13:597–605; 3. Sulkowski M et al. Ann InternMed 2013;159:86–96; 4. Dieterich D et al. CROI 2014. P#24; 5. Sulkowski M et al. AASLD 2013; 6. Rodriguez-Torres M et al. IDWeek 2013. P#714; 7. Sulkowski M IAC 2014, Melbourne, Australia; 8. Naggie S et al. CROI 2015. Seattle, WA. #LB-152; 9. Osinusi A et al. JAMA 2015;313:1232–1239; 10. AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed July 2015
IFN+RBV6 mo1
PEG12 mo1
PEG+RBV12 mo1
BOC+PEG+RBV6-12 mo2
TVR+PEG+RBV6-12 mo3
SMV+PEG+RBV6-12 mo4
SOF+PEG+RBV
3 moStudy 19106
SOF+RBV6 mo
PHOTON-15
LDV/SOF3 mo
ION-48, ERADICATE9
OMV/PTV/RTV+DSV+RBV
3-6 moTURQUOISE-17
SVR Rates From Clinical Trials Investigating the Efficacy of DAAs in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection
Wyles DL, et al. Clin Infect Dis, 2016
SVR Rates From Clinical Trials Investigating the Efficacyof DAAs in Human Immunodeficiency Virus/Hepatitis C
Virus Coinfection - II
Wyles DL, et al. Clin Infect Dis, 2016
12 Week Regimen HCV Mono-Infection HCV/HIV Co-infection
LDV/SOF 99% (211/214) 96% (332/355)DCV+SOF 100% (41/41) 97% (123/127)
OBV/PTV/RTV+DSV 96% (455/473) 94% (29/31)+RBV (PrOD)
EBR/GZP 95% (273/288) 95% (179/189)
Hepatology 2017
COMPASSIONATE PROGRAM IN CO-INFECTED PATIENTS
Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir combination
treatment in co-infected HIV-HCV patients:
results of a Italian compassionate use program
Andreoni M et. al.Clin Infect Dis. 2017 Mar 1;64(5):680-683
SIMIT Compassionate Use Program
Torino
Roma (5 centri)
Milano(5 centri)
Siena
Bari
Catania
Salerno
Napoli
GenovaAncona
Pescara
Bergamo
Brescia
Pavia
Modena
Ferrara
Padova
Monza
26 sites involved
26,2%
73,8%
F
M
Adapted by poster SAT-147 – EASL Barcellona 2016Andreoni M et. al.Clin Infect Dis. 2017 Mar 1;64(5):680-683
SVR
85,1
99,0 98,6 96,7
0
20
40
60
80
100
SVR4 EOT SVR4 SVR12
172202
202204
140142
188193
Adapted by poster SAT-147 – EASL Barcellona 2016Andreoni M et. al.Clin Infect Dis. 2017 Mar 1;64(5):680-683
•Optimal duration of SOF/LDV for acute HCV infection in HIV-coinfected pts not known; previous study showed SVR12 rate of 77% with 6 wks of therapy[1]
• SWIFT-C: single-arm study[2]
• Baseline HIV regimens: boosted PI, 26%; NNRTI, 30%; INSTI, 52%; TDF/FTC, 85%; ABC/3TC, 15%
SWIFT-C: 8-Wk SOF/LDV for Pts With HIV and Acute GT1/4 HCV Coinfection
1. Rockstroh JK, et al. Lancet Gastroenterol Hepatol. 2017;2:347-353.
2. Naggie S, et al. AASLD 2017. Abstract 196.
Pts with acute GT1/4 HCV
infection and HIV coinfection
(N = 27; n = 26 GT1)
SOF/LDV QD
(N = 27)
Wk 8 SVR12
100%
Icona Foundation and HepaIcona Study Group PLOS ONE May 17, 2017
Only 35.3% had access to HCV treatment. Despite excellent rates of
SVR12 rates (91.6%), only 21% (545/2,607) of our HIV-HCV co-
infected patients are cured.
Outline
Efficacy of DAA’s in HIV- HCV coinfected patients
Drug – Drug interactions
The Possible Association Between DAA Treatment for HCV Infection and HCC
Occurence/Recurrence
HBV reactivation during DAA’s treatment
Reinfection
DAA Victim of DDI Perpetrator of DDI DDI
Potential
Glicaprevir / Pibrentasvir
Simeprevir
Grazoprevir/elbasvir
Substrate for
CYP3A4,
OATP1B1/3, P-gp,
BCRP
Substrate for
CYP3A4, P-gp &
OATP1B1
Substrate for
CYP3A4, P-gp &
OATP1B1
Inhibits CYP3A4,
OATP1B1/3, OCT1,
BCRP, P-gp, UGT1A1,
.
Inhibits gut CYP3A4,
CYP1A2, OATP1B1 &
P-gp
Inhibits P-gp & BCRP
Moderate
Moderate
Moderate
Inhibits OATP1B1, P-gp
& BCRP.
Inhibits P-gp & BCRP
Inhibits P-gp & BCRP
Daclatasvir
Ledipasvir/sofosbuvir
Velpatasvir/sofosbuvir
Sofosbuvir
Substrate for
CYP3A4, P-gp
Substrate for P-gp &
BCRP
Gut pH
Substrate for P-gp &
BCRP
Gut pH
Substrate for P-gp &
BCRP
Moderate
Moderate/
Low
Moderate/
Low
Low
Mechanisms of Drug Interactions of DAAs
Available at www.hep-druginteractions.org and relevant SmPCs ie Incivo (telaprevir), updated 27th July 2015; Victrelis (boceprevir), updated 5th March 2015; Viekirax (2D), updated 2nd
Oct 2015; Exviera (dasabuvir) updated 2nd Oct 2015; Olysio (Simeprevir), updated 25th Aug 2015; Daklinza (daclatasvir), updated 30th Sept 2015; Sovaldi (sofosbuvir), updated 27th Aug2015; Harvoni (LDV/SOF), updated 27th Nov 2015
EBR/GZR= Elbasvir/Grazoprevir
GLE/ PIB= Glecaprevir/ Pibrentasvir
LED/SOF = Ledipasvir/ Sofosbuvir
Outline
Efficacy of DAA’s in HIV- HCV coinfected patients
Drug – Drug interactions
The Possible Association Between DAA Treatment for HCV Infection and HCC
Occurence/Recurrence
HBV reactivation during DAA’s treatment
Reinfection
RECURRENCE: Reappearance of HCC in a subject (with or
without liver disease) with a previous HCC judged to be
radically cured by any technique (TACE, RFTA, resection)
OCCURRENCE: De novo appearance of HCC in a subject (with or
without liver disease) with no history or previous evidence of a
liver tumor
Semantics of Hepatocellular Carcinoma (HCC)
HCV clearance on DAAs and RECURRENCE of HCC
Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy
HCC recurrence rate was 27.6%,
3 pts died and 16 developed radiologic tumor recurrence.
Overall median follow-up time after DAA was 5.7 months (0.4-14.6).
Median time between HCC treatment and start of DAA was 11.2 months
Median time from DAA start to recurrence was 3.5 months
27.5% 72.4%
Reig M. J Hepatol. 2016
Cammà C, Cabibbo G, Craxì A. J Hepatology 2016
“ by reanalyzing the Reig’s data, asignificant difference in recurrence wasfound between patients wich obtained acomplete HCC response > 6 months beforestarting DAA’s therapy ”
The recurrence of HCC is not correlated to treatment but depends on the time of assessment of response to ablative or resective therapy for HCC
HCV clearance on DAAs and occurrence of HCC
“Antiviral therapy in patients with decompensated cirrhosis led to prolonged improvement in liver function, with no evidence of paradoxical adverseimpact nor increase in liver malignancy.”
Cheung MCM et al, Journal of Hepatology 2016: 65, 741–747
SVR by DAAs reduces the incidence of HCC in patientswith HCV infection
77 pts SVR by DAA regimens vs 528 pts by PEG-IFN + RIBA
Follow-up of 4.0 years
2.6% of DAA-treated pts developed HCC
The HCC risk rate after SVR is similar independently from DAA or IFN-based regimens.
Kobayashi M. J. Med. Virol. 2017
Sustained HCV clearance (SVR) by either IFN-based or DAA regimens
minimizes the rate of progression of CHC to cirrhosis and hence
reduces indirecty the risk of HCC.
Once HCV cirrhosis has developed, the risk of HCC is reduced but not
canceled altogether. HCV patients with cirrhosis in SVR still need
regular US surveillance for HCC
HCV clearance and HCC: the take-home message
Outline
Efficacy of DAA’s in HIV- HCV coinfected patients
Drug – Drug interactions
The Possible Association Between DAA Treatment for HCV Infection and HCC
Occurence/Recurrence
HBV reactivation during DAA’s treatment
Reinfection
Bersoff-Matcha SJ, Cao K, Jason M, et al. Ann Intern Med. 2017;166(11):792-798
Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of
cases reported to the U.S. Food and Drug Administration Adverse Event Reporting System
…..immune reconstitution occurs with HCV removal, host recognition of HBV DNA probably occurs followedby vigorous host immune responses leading to liver injury (HBV flare)
LDV/SOF 12 weeks was safe and achieved 100% SVR in HCV GT 1 and GT 2 patients co-infected with HBV
LDV/SOF for 12 Weeks in HBV/HCV Co-Infection
Liu, EASL 2017, PS-098
Open-label, Phase 3 study of LDV/SOF for 12 weeks in 111 Taiwanese patients with HCV GT 1 or 2 co-infected with HBV
111/111
LDV/SOF 12 weeksN=111
HCV
Mean age, y (range) 55 (32–76)
Male, n (%) 42 (38)
GT 1 / GT 2, n (%) 68 (61) / 43 (39)
HCV treatment experienced, n (%) 37 (33)
Mean baseline HCV RNA, log10 IU/mL (range) 5.9 (3.8–7.1)
Cirrhosis, n (%) 18 (16)
Mean ALT, U/L (range) 68 (17–281)
HBV
HBsAg positive, n (%) 110* (99)
HBeAg positive, n (%) 1 (<1)
HBV treatment experienced, n (%)‡ 5 (4)
Mean baseline HBV DNA, log10 IU/mL (range) 2.1 (1.3–5.8)
Baseline HBV DNA <LLOQ, n (%) 37 (33)
*1 patient changed HBsAg status between screening and baseline; ‡ No patients currently on HBV treatment (>6 months)
SVR
12
, %
67/67
57/59†
100
0
20
40
60
80
100
111111
111111
4343
Overall
SafetyLDV/SOF 12 weeks
N=111
Overall Safety
Any AE 66 (60)Grade 3‒4 AE 1 (<1)Serious AE 4 (4)DC due to AE 0
LaboratoryAbnormalities
Grade 3–4 1† (<1)
Baseline Demographics SVR12
†44 year old male with transient, asymptomatic G4 lipase at Week 4 unrelated to treatment.
LDV/SOF for 12 Weeks in HBV/HCV Co-Infection
n, %OverallN=111
BL HBV DNA <LLOQn=37
BL HBV DNA ≥LLOQn=74
Increase to ≥LLOQ 31 (28) 31 (84) —
+ ALT >2x ULN 0 0 —
Increase >1 – <2 log10 IU/mL 37 (33) 11 (30) 26 (35)
+ ALT >2x ULN 1 (<1) 0 1 (1)
Increase ≥2 log10 IU/mL (any visit) 24 (22) 11 (30) 13 (18)
+ ALT >2x ULN 4 (4) 0 4 (5)
HBV Reactivation, Criteria
ULN: male 43 U/L; female 34 U/L.
No patient had AEs of jaundice, liver decompensation, liver failure or liver transplant
Treatment with LDV/SOF for 12 weeks was associated with “silent” HBV viral reactivation in 63% of
patients (70/111)
No patient experienced clinical signs or symptoms of HBV reactivation
5 (5%) patients had concomitant increase in ALT; 2 (2%) patients started HBV therapy
Higher baseline HBV DNA and ALT were associated with asymptomatic clinical HBV
reactivation
No patient experienced clinical signs or symptoms of HBV reactivation
Liu, EASL 2017, PS-098
Management of HCV/HBV coinfected patients
EASL 2017 CPG HBV, J Hepatol 2017
Recommendations:
1) Treatment of HCV with direct-acting antivirals (DAAs) may cause
reactivation of HBV. Patients fulfilling the standard criteria for HBV
treatment should receive NA treatment. (Evidence level II, grade of
recommendation 1)
2) HBsAg-positive patients undergoing DAA therapy should be considered
for concomitant NA prophylaxis until week 12 post DAA, and monitored
closely. (Evidence level II-2, grade of recommendation 2)
3) HBsAg-negative, anti-HBc positive patients undergoing DAA should be
monitored and tested for HBV reactivation in case of ALT elevation.
(Evidence level II, grade of recommendation 1)
NA= Nucleoside/Nucleotide Analogues
Outline
Efficacy of DAA’s in HIV- HCV coinfected patients
Drug – Drug interactions
The Possible Association Between DAA Treatment for HCV Infection and HCC
Occurence/Recurrence
HBV reactivation during DAA’s treatment
Reinfection
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