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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