24 giugno 2014 Roma Il paziente coinfetto HIV-HCV non più “special population?” La gestione...

24 giugno 2014 Roma

Il paziente coinfetto HIV-HCV non più “special population?”La gestione clinica nell’era dei DAA di II generazione

Giustino Parruti

UOC Malattie Infettive - AUSL Pescara

24 giugno 2014 Roma

Agenda

• Interazioni tra cART e DAA - Telaprevir, Boceprevir, Daclatasvir, Simeprevir, Sofosbuvir, Ledipasvir, MK drugs

• Gestione della cART nel paziente candidato a DAA: switch a Inibitori Integrasi o Rilpivirina

• Considerazioni farmaco-economiche e strategiche nel medio-lungo termine

• Possibili scenari futuri nei coinfetti

24 giugno 2014 Roma

French real life cohorts – telaprevir(n=69)

- Patients with relapse, breakthrough and partial non-response to IFN/RBV- Patients with non-response and cirrhosis not permitted

Cotte CROI 2014 abstract 668

24 giugno 2014 Roma

French real life cohorts - boceprevir

- Patients with relapse, breakthrough and partial non-response to IFN/RBV- Patients with non-response and cirrhosis not permitted

Poizot-Martin CROI 2014 abstract LB659

24 giugno 2014 Roma

Drug CYP 3A4 TransportersNon-CYP

metabolism

Telaprevir Substrate Inhibitor

Substrate P-gp Inhibitor P-gp;

OATP1B1/2–

Boceprevir Substrate Inhibitor

Substrate P-gp; BCRP

Inhibitor P-gp; OCT1/2

AKR Substrate

Metabolic pathways of Telaprevir & Boceprevir

P-gp: P-glycoprotein; AKR: aldo-keto reductase

CYP 3A isozymes are The most abundant CYP enzymes in the liver Involved in the metabolism of many drugs

Kessara C et al 18th CROI, Abs 118; Garg V et al 18th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: 1620-1628; Kunze A et al Biochem Pharmacol 2012; 84: 1096-1102.

Also note other interaction mechanisms (eg protein binding)

24 giugno 2014 Roma

24 giugno 2014 Roma

Anemia nella casistica Pescara-Chieti(Pescara: 8 pz - Chieti: 5 pz)

avvio 1° sett

2° sett

3° sett

4° sett

6° sett

8° sett

10° sett

12° sett

16° sett

20° sett

6.0

8.0

10.0

12.0

14.0

16.0

18.0

CEIFMVGMNBAMRAMZAMMPLLADCNRNLPMEDIA

24 giugno 2014 Roma

Iperuricemia nella casistica Pescara-Chieti

avvio 2s 4s 6s 8s 10s 12s0

2

4

6

8

10

12

14

16

CEIFMMNVGBAMRAMMMZAPLLADCNRNLPMEDIA

24 giugno 2014 Roma

24 giugno 2014 Roma

In seconda giornata…

• Un paziente riferisce vomito nella notte e tachicardia notturna non aveva sospeso manidipina

• Riduzione di dose non funziona, controllo PA con modifica terapeutica

24 giugno 2014 Roma

24 giugno 2014 Roma

Simeprevir in HIV/HCV-coinfection - C212 Study: SVR12 – Primary Endpoint

Dieterich EACS 2013 abstract LBPS9/5

24 giugno 2014 Roma

Simeprevir in HIV/HCV-coinfection - C212 Study: SVR12 – Primary Endpoint

16

SVR1

2, %

78/106 42/53 13/15 7/10 16/28

SVR12, sustained virologic response 12 weeks after end of treatment

Dieterich EACS 2013 abstract LBPS9/5

24 giugno 2014 Roma

Recently Approved DAAs

Drug CYP Activity Transporters Interaction Potential

Simeprevir CYP3A4 substrate Mild inhibition of

intestinal CYP3A4 No hepatic inhibition of

CYP3A4

P-gp substrate Mild inhibition of

intestinal P-gp Inhibits OATP1B1,

MRP2

Moderate

Sofosbuvir Metabolised by cathepsin A; CES1 and is phosphorylated.

Not metabolised by CYPs

No inhibition of CYP

P-gp and BCRP substrate

Inhibition (weak) of intestinal P-gp and BCRP

Weak

FDA Antiviral Drugs Advisory Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir USPI; Sekar V et al; EASL 2010; Abstract 1076; Mathias A 14 th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.

24 giugno 2014 Roma

24 giugno 2014 Roma

Daclatasvir Clinical Pharmacology

Single dose of 60 mg QD; Half life of 12-15h

DDIs

ATV/r – decrease dose to 30 mg QD

EFV – increase dose to 90 mg QD

No effect of gastric acid modifiers

No effect on Midazolam or Oral Contraceptives

Bifano M et al, 2013, 8th Int Workshop on Clin Pharm of Hep Ther, Abs O-15; Bifano M et al AVT 2014; In Press; Bifano M et al 2013; EASL; Abs 794.

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24 giugno 2014 Roma

Effect of ARVs on Simeprevir: Victim

Drug Effect on Simeprevir AUC (exposure)

Mechanism/Recommendation

Darunavir/r2.6-fold increase (DRV

increased 18%)

RTV Inhibits CYP3A4Not recommended

Rilpivirine No effect No dose adjustment

Efavirenz 70% decreaseEFV induces CYP3A4

Not recommended

Raltegravir 11% decreaseNo dose adjustment

Tenofovir14% decrease (TFV

increased 18%)

Intestine or renal transportNo dose adjustment

Ouwerkerk-Mahadevan S et al, IDSA 2012; Abs 1618; Ouwerkerk-Mahadevan S et al, CROI 2012; Abs 49 ; Simeprevir (Olysio) USPI

24 giugno 2014 Roma

Effect of Simeprevir on Statins: Perpetrator

DrugEffect of Simeprevir on

Statin AUCMechanism/

Recommendation

Atorvastatin 2.1-fold increase

CYP3A & OATP1B1 inhibition

Use lowest dose

Rosuvastatin 3.2-fold increase OATP1B1 inhibitionInitiate with 5mg

Simvastatin 40% increase CYP3A inhibitionTitrate dose carefully

Simprevir (Olysio) USPi 2013

24 giugno 2014 Roma

Sofosbuvir

Not metabolised by CYPNo inhibition of CYPWeak interaction with intestinal P-gp & BCRP

24 giugno 2014 Roma

Effect of ARVs on Sofosbuvir: Victim

Drug Effect on Sofosbuvir and GS-331007 AUC (exposure)

Recommendation

Darunavir/r SOF increased 34%; GS-331007 – no effect

No dose adjustment

Rilpivirine No effect on SOF or GS-331007 No dose adjustment

Efavirenz No effect on SOF or GS-331007 No dose adjustment

RaltegravirNo effect on SOF or GS-331007:

RAL decreased 27%No dose adjustment

Tenofovir No effect on SOF or GS-331007No dose adjustment

Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013

24 giugno 2014 Roma

Effect of Co-administered Drugs on Sofosbuvir: Victim

DrugEffect on Sofosbuvir and GS-

331007 AUC (exposure) Recommendation

Methadone(multiple dose)

SOF increased 30%; no effect on GS-331007

No dose adjustment

Cyclosporine SOF increased 4-fold but no effect on GS-331007

No dose adjustment

Tacrolimus No effect on SOF or GS-331007

No dose adjustment

Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013

24 giugno 2014 Roma

PegIFN + RBV + SOF in HIV/HCV CoinfectionSVR12

Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714

GT 1 GT 2 GT 3 GT 4GT 1a GT 1b

87

17/19 13/15

89

4/4 1/1 2/2 1/1

100100100100

0

10

20

30

40

50

60

70

80

90

100

HC

V R

NA

<L

LO

Q (

%)

FTC/TDF + Protease Inhibitor

8/9 7/8 6/6

89 88100

0

1020

3040

50

6070

8090

100

SV

R12

(%

)

FTC/TDF + NNRTI

FTC/TDF + Raltegravir

24 giugno 2014 Roma

Study Design

¨ Broad inclusion criteria– Cirrhosis permitted with no platelet cutoff

– Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)

¨ Wide range of ART regimens allowed – Undetectable HIV RNA for >8 weeks on stable ART regimen

¨ Baseline CD4 count– ART treated: CD4 T-cell count >200 cells/mm3 and HIV RNA < 50 c/mL

– ART untreated: CD4 T-cell count >500 cells/mm3

Wk 0 Wk 12 Wk 24 Wk 36

SOF + RBV, n=114 GT 1 TN

SOF + RBV, n=41GT 2/3 TE

SOF + RBV, n=68 GT 2/3 TN

Wk 48

SVR 12SVR 24

24 giugno 2014 Roma

Antiretroviral Regimens

Regimen, n (%)

Treatment Naive Treatment Experienced

GT 1 n=114

GT 2/3n=68

GT 2/3n=41

On ART 112 (98) 61 (90) 39 (95)

Tenofovir DF/emtricitabine plus

Efavirenz 42 (37) 20 (33) 16 (41)

Atazanavir/ritonavir 24 (21) 7 (11) 8 (21)

Darunavir/ritonavir 15 (13) 17 (28) 2 (5)

Raltegravir 21 (18) 8 (13) 7 (18)

Rilpivirine 7 (6) 5 (8) 2 (5)

Other 3 (3) 4 (7) 4 (10)

24 giugno 2014 Roma

Patient Disposition

*Three GT1 subjects inadvertently discontinued after 12 weeks; One GT 1 subject did not adhere to study visits

Regimen, n (%)

Treatment Naive Treatment Experienced

GT 1 n=114

GT 2/3n=68

GT 2/3n=41

Completed 103 (90) 62 (91) 40 (98)

Discontinued 11 (10) 6 (9) 1 (2)

Reason for discontinuation

AE 3 (3) 3 (4) 1 (2)

Withdrew consent 2 (2) 1 (1) 0

Protocol violation* 4 (4) 0 0

Investigator decision 1 (<1) 1 (1) 0

Efficacy failure 1 (<1) 0 0

Lost to follow-up 0 1 (1) 0

24 giugno 2014 Roma

Virologic Response: Genotype 1P

atie

nts

with

HC

V R

NA

<LL

OQ

(%

)

Series10

20

40

60

80

100 96 100

76 75*

86/114110/114 103/103 87/114

Week 4 EOT SVR12 SVR24

24 giugno 2014 Roma


atie

nts

with

HC

V R

NA

<LL

OQ

(%

)

Series10

20

40

60

80

100 96100

96100

8892

8892

25/26 22/23

Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24

Treatment Naïve12 Weeks SOF + RBV

Treatment Experienced24 Weeks SOF + RBV

23/26 23/26 24/24 23/23 22/24 22/2425/26 22/23 23/26 23/26 24/24 23/23 22/24 22/24

24 giugno 2014 Roma


atie

nts

with

HC

V R

NA

<LL

OQ

(%

)

Series10

20

40

60

80

100100 10098 100

67

94

67

88

41/41 39/40

Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24

Treatment Naïve12 Weeks SOF + RBV

Treatment Experienced24 Weeks SOF + RBV

28/42 28/42 17/17 17/17 16/17 15/1741/41 39/40 28/42 28/42 17/17 17/17 16/17 15/17

24 giugno 2014 Roma

Safety Summary

*Weight loss, insomnia/agitation, pneumonia, suicide attempt, foreign body sensation in throat, increased anxiety, dyspnea.†Suicide 9 days after completing study treatment; patient had history of depression and was being treated for ADHD and insomnia before entering study.

Patients, %

SOF + RBV

24 Weeks (n=155) 12 Weeks (n=68)

AEs 92 84

AEs in ≥10% of patients

Fatigue 39 35

Insomnia 15 21

Headache 14 13

Nausea 15 18

Diarrhea 11 9

Irritability 10 10

URI 12 12

Grade 3-4 AEs 12 10

Serious AEs 6 7

Treatment D/C due to AEs* 3 4

Death 0 1†

24 giugno 2014 Roma

Laboratory Abnormalities

n (%)

SOF + RBV

24 Weeks (n=155)

12 Weeks (n=68)

Any Grade ≥3 33 (21) 8 (12)

Grade ≥3 hyperbilirubinemia (indirect) 28 (18) 4 (6)

Taking atazanavir* 26 (17) 4 (6)

Not taking atazanavir 2 (1) 0

Grade ≥3 elevated lipase† 3 (2) 0

Hemoglobin††

<10 mg/dL 27 (17) 7 (10)

<8.5 mg/dL 2 (1) 1 (1)

*4 patients changed ARV regimens from atazanavir to darunavir due to hyperbilirubinemia;

†Lipase elevations were not associated with clinical signs/symptoms and resolved ††43 (19%) required ribavirin dose reduction during study; epoetin alfa was not permitted.

24 giugno 2014 Roma

HIV Safety

¨ Eleven patients were not on ARVs during the study¨ No clinically significant variation in HIV RNA occurred

during HCV treatment dosing

¨ Two patients with transient HIV viral breakthrough– Both with documented nonadherance to ART

• No decrease in CD4 T-cell % with treatment– Decrease in absolute CD4 T-cells consistent with

known ribavirin-mediated decrease in lymphocytes

24 giugno 2014 Roma

Conclusions• The interferon-free regimen of SOF + RBV resulted in high SVR12 and

SVR24 rates in HIV-infected patients with HCV genotype 1, 2 and 3 co-infection– SVR12 rates were similar to those observed in patients with HCV

monoinfection • SOF + RBV was effectively co-administered with multiple antiretroviral

regimens including inhibitors of HIV-1 protease, reverse transcriptase (non-nucleoside/nucleoside) and integrase– HIV viral breakthrough seen exclusively in the setting of poor ART

adherence– No effect on CD4 T-cell percent

• No resistance (deep sequencing) was observed in virologic failures

• SOF was well tolerated, with a low rate of treatment discontinuations due to adverse events

24 giugno 2014 RomaSulkowski et al, EASL 2014 abstract O63

C-WORTHY HCV-PI + NS5A for HIV/HCV coinfection

24 giugno 2014 RomaSulkowski et al, EASL 2014 abstract O63

C-WORTHY HCV-PI + NS5A for HIV/HCV co-infection

24 giugno 2014 Roma

DAAs in Development

Drug CYP Activity Transporters Interaction Potential

Asunaprevir CYP3A4 substrate Inducer of CYP3A4

(weak) Inhibition of

CYP2D6 (weak)

P-gp, OATP1B1/3 substrate

Inhibition of P-gp (weak), OATP1B1/3

Moderate

Ledipasvir Little metabolism Not Inhibitor of CYP

or UGT Not Inducer of CYP

or UGT

P-gp substrate (likely) Inhibition of intestinal

P-gp (weak) Inhibition of

OATP1B1/3 (weak)

Weak

Eley T et al, 2013, 8th Int Workshop on Clin Pharm of Hep Ther; Abs O-13; Eley T et al, 2011, 62nd AASLD Abs 381; Eley T et al 2012, 7th Int Workshop on Clin Pharm of Hep Ther; Abs O-4; Kirby B et al 2013, 8 th Int Workshop on Clin Pharm of Hep Ther; Abs O-20; Mathias A, 14th Int Workshop on Clin Pharm of HIV Ther, Session 5

24 giugno 2014 Roma

ARV Treated (n=37)- CD4 count > 100 cells/mm3

- HIV RNA < 40 copies

- Current ARVs ≥ 8 weeks

Fifty HIV/HCV genotype 1, treatment-naive subjects HAI fibrosis stage 0 – 3

SOF/Ledipasvir for HIV/HCV-coinfectionERADICATE

SVR 12

SVR 4

ARV Untreated (n=13)CD4 count stable + HIV RNA <500 copies

OR- CD4 count > 500 cells/mm3

ARVs: tenofovir, emtricitabine, efavirenz, rilpivirine and raltegravir

Wk 0 Wk 1248 week follow up

SOF/LDV (400/90mg)

Osinusi A, EASL, 2014, O14

24 giugno 2014 Roma

ARV Untreatedn = 13

ARV Treatedn = 37

Median age (range) 59 (48 - 63) 58 (34 - 75)

Male, n (%) 7 (54) 30 (81)

African American, n (%) 10 (77) 32 (86)

Median BMI (range) 26 (22 - 35) 26 (19 - 41)

Genotype 1a, n (%) 9 (75) 30 (81)

Median HCV RNA log10 IU/mL (range)

6.07 (4.05 – 7.29)

5.97(4.80 – 7.05)

HAI Fibrosis Stage 3 , n (%) 5 (38) 8 (22)

Median CD4 T-cell count (range) 687 (319 – 1287)

576 (113 – 1612)


SOF/Ledipasvir for HIV/HCV-coinfection ERADICATE

24 giugno 2014 Roma

RegimenARV Treated

n = 37

ARVs n (%) 37 (100)

Tenofovir/Emtricitabine plus

Efavirenz (EFV) 15 (41)

Raltegravir (RAL) 10 (27)

Rilpivirine (RPV) 8 (21)

RPV/RAL 3 (8)

EFV/RAL 1 (3)



24 giugno 2014 Roma

Med

ian

HC

V V

iral D

ecay

106

104

102

ARVUntreated

Clearance of infectiousvirus (c)

9.05/day 10.3/day p=0.68

ARVTreated



24 giugno 2014 Roma

ARV - 13/ 13 13/13 13/ 13 12/12 10/10 10/10

ARV + 37/37 37/37 30/30 22/22


SOF/Ledipasvir for HIV/HCV-coinfectionERADICATE

24 giugno 2014 Roma

24 giugno 2014 Roma

SOFOSBUVIR/LEDIPASVIR IN RETREATMENT OF HCV GENOTYPE-1 PATIENTS WHO PREVIOUSLY FAILED SOFOSBUVIR/RIBAVIRIN THERAPY

Anu Osinusi1,2, Miriam Marti1, Anita Kohli3,4, Eric Meissner 1, Kerry Townsend1, Amy Nelson1, Rachel Silk3, Xiaozhen Zhang 1, William T.

Symonds5, John McHutchison5, Michael Polis 1, Henry Masur4, Shyam Kottilil 1 for the NIAID/CC Hepatitis C SYNERGY team1,3,4

1Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland, 2Dept of Infectious Diseases, University of Maryland, Baltimore, 3CMRP, SAIC–Frederick Inc, Frederick National Laboratory for Cancer Research,

Frederick, Maryland , 4Critical Care Medicine Department, NIH, Bethesda, Maryland , 5Gilead Sciences, Foster City, California

24 giugno 2014 Roma

Disclosures No financial disclosures

Investigator initiated study conducted by NIAID/CC, NIH

This presentation includes discussion of investigational use of Sofosbuvir (SOF)/Ledipasvir (LDV) fixed dose combination

Fuding Statement: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

This research was supported by the National Institute of Allergy and Infectious Diseases

24 giugno 2014 Roma

Background The IFN-free regimen of sofosbuvir (SOF) + RBV for

24 weeks has recently been approved for use in GT-1 IFN ineligible subjects (SVR12 rates: 68 – 76%)

The ideal regimen for retreatment of SOF failures in GT-1 infections is unclear

Single reported case of a GT-1 patient who failed 8 weeks of SOF/LDV therapy and was successfully retreated with SOF/LDV/RBV for 24 weeks (Lonestar, AASLD 2013)

Lawitz E et al AASLD 2013 #215, Osinusi A et al JAMA 2013 (310)

24 giugno 2014 Roma

Background

Sofosbuvir (HCV NS5B RNA polymerase inhibitor)

- Potent antiviral activity against HCV GT 1 - 6

Ledipasvir (HCV NS5A inhibitor)

- Activity against HCV GT1a and 1b, 4 - 6

- Effective against variants with the NS5B resistance mutation S282T

Sofosbuvir/Ledipasvir Fixed dose combination- Once daily, oral (400/90mg) combination pill

24 giugno 2014 Roma

Objective

To evaluate the efficacy of SOF/LDV in HCV monoinfected, GT- 1 patients who relapsed with prior SOF/RBV therapy.

24 giugno 2014 Roma

Sofosbuvir 400mg + RBV 600mgn = 25

Sofosbuvir 400mg + RBV 1000 -1200mg n = 25

Sofosbuvir 400mg + RBV 1000 -1200mg n = 10

Part 1

Sixty HCV genotype 1, treatment-naive subjects Part 1: HAI fibrosis stage 0-2 Part 2: HAI fibrosis stage 0-4

Design: NIAID SPARE Study (SOF/RBV)

Part 2

SVR 48 : 90%

24 weeks

SVR 48 : 68%

SVR 48: 48%

Osinusi A, et al JAMA 2013, 310

ITT analysis

24 giugno 2014 Roma

Despite Rapid and Prolonged Viral Suppression, 17 of 55 Patients Relapsed After the End of Treatment

Vir

al L

oad

(lo

g 10)

Relapse is the cause of treatment failure in other DAA trials using sofosbuvir and ribavirin, although mechanisms are unknown

Gane EJ et al, NEJM 2013 (368), Osinusi A et al, JAMA 2013 (310)Jacobson IM et al, NEJM 2013 (368), Lawitz E et al, NEJM 2013 (368).

24 giugno 2014 Roma

SOF/LDV (400/90mg) NIAID SYNERGY STUDY

Study Design: SOF/LDV

n = 14 SVR 12

Wk 0 Wk 1248 week follow up

Hypothesis: combining SOF with a second DAA may effectively suppress HCV replication and improve odds of achieving SVR

3 participants did not participate- 1 developed hepatocellular cancer- 1 opted for telaprevir triple therapy- 1 declined participation

SOF/RBV (SPARE Study)

17 relapsers

24 giugno 2014 Roma

Study Endpoints Primary endpoint: Efficacy (SVR 12)

- All patients who received one dose of study drug (ITT analysis)

Safety and tolerability

- Adverse events and discontinuations

NS5B S282T resistance mutations- Population sequencing (Sanger methodology)

- Sensitivity cut-off: 20% - 25%

24 giugno 2014 Roma

SOF/LDVn= 14

Median age (range) 59.5 (48-70)

Male, n (%) 13 (93)

African American, n (%) 13 (93)

IL28B CT/TT, n (%) 12 (86)

Median BMI (range) 28.5 (20 - 41)

Genotype 1a, n (%) 8 (57)Median HCV RNA log10 IU/mL (range)

6.45 (5.5 - 6.8)

HAI Stage 3 - 4 Fibrosis, n (%) * 7 (50)

Profile of Participants

* Fibrosis staging prior to enrollment in NIAID SPARE study

24 giugno 2014 Roma

Population Sequencing For S282T Mutation

PTSOF/RBV

Day 0 EOTWk 26SVR2

Wk 28SVR4

Wk 32SVR8

Wk 36SVR12

Weeks between regimens

1 WT ND ND WT WT 532 WT ND ND ND WT WT 573 WT ND WT 534 WT ND ND ND WT WT 595 WT ND WT WT 536 WT ND WT WT 577 WT ND WT WT 578 WT ND S282T WT 579 WT ND ND WT WT WT 54

10 WT ND WT WT WT WT 5611 WT ND WT WT WT WT 5912 WT ND ND ND ND WT 5913 WT ND ND WT WT WT 6014 WT ND WT WT WT WT 61

24 giugno 2014 Roma

Treatment Response On SOF/LDV

n / N 14/14 14/14 14/14 14/14 14/14 14/14

24 giugno 2014 Roma

No Significant Hemoglobin Decline Occurred During Treatment With SOF/LDV

Mean hemoglobin drop from baseline at 12 weeks with SOF/LDV was 0.3g/dL vs. 1.2 g/dL with SOF/RBV

24 giugno 2014 Roma

Adverse events All Adverse events SOF/LDV

n = 14Deaths, grade 3 or 4 AEs or discontinuations 0

Headache 1

Myalgia 2

Congestion 1

Constipation 1

Diarrhea 1

Rash 1

24 giugno 2014 Roma

Laboratory Abnormalities (≥ Grade 2)

4 Grade 3 events: hypophosphatemia (2), hypercholesterolemia (1), elevated creatinine (1)

Laboratory Abnormalities ≥ Grade 2

SOF/LDV n = 14

Elevated creatinine 1

Hypophosphatemia 2

Hypoglycemia 1

Neutropenia 1

Hyperbilirubinemia 1

24 giugno 2014 Roma

No Changes Observed In Renal Parameters On Treatment

Serum Creatinine Estimated Glomerular Filtration Rate

24 giugno 2014 Roma

Conclusions

The IFN/RBV free regimen of SOF/LDV resulted in 100% SVR12 rates in patients who had relapsed post completion of SOF/RBV 24 week therapy

One patient with detectable S282T mutation after relapse to SOF/RBV achieved SVR

SOF/LDV was well tolerated with no discontinuations

These results suggest that patients who fail SOF/RBV therapy can be successfully retreated with SOF/LDV for 12 weeks

24 giugno 2014 Roma

Combination Oral, Hepatitis C Antiviral Therapy for 6 or 12

Weeks:Results of the SYNERGY Trial

Anita Kohli, Zayani Sims, Miriam Marti, Amy Nelson, Anu Osinusi, Dimitra Bon, Eva Hermann, Colleen Kotb, Rachel

Silk, Gebeyehu Teferi, William T. Symonds, Phil S Pang, John McHutchison, G. Mani Subramanian, Michael A. Polis,

Henry Masur, Shyam Kottilil

National Institute of Allergy and Infectious DiseasesNational Institutes of Health

Department of Health and Human ServicesBethesda, MD

24 giugno 2014 Roma

Study Design• Sofosbuvir (nucleotide NS5B inhibitor) 400 mg / ledipasvir (NS5A

inhibitor) 90 mg once daily

• GS-9669 (non-nucleoside NS5B inhibitor) 500 mg once daily

• GS-9451 (a protease/ NS3/4 inhibitor) 80 mg once daily

Treatment naïveAll stages

fibrosisTreatment naïve

Cirrhosisexcluded

Treatment naïveCirrhosisexcluded

0 6 12Week

SVR12

SVR12

SVR12

Sofosbuvir + Ledipasvir (n=20)

Sofosbuvir + Ledipasvir+ GS-9669 (n=20)

Sofosbuvir + Ledipasvir+ GS-9451 (n=20)

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Profile of ParticipantsSofosbuvir +Ledipasvir

12 weeks(n=20)

Sofosbuvir +Ledipasvir +

GS-96696 weeks(n=20)



p-value

Age – mean ± standard deviation 57 ± 8 54 ± 7 54 ± 9 0.28

Male – n (%) 14 (70) 13 (65) 16 (80) 0.56

Race – n (%)

Black 16 (80) 19 (95) 18 (90)0.32

White 4 (20) 1 (5) 2 (10)

HCV genotype – n (%)

1a 11 (55) 14 (70) 17 (85)0.12

1b 9 (45) 6 (30) 3 (15)

HCV RNA >800,000 IU/mL – n (%) 15 (75) 13 (65) 14 (70) 0.79

IL28B genotype – n (%)

CC 5 (25) 2 (10) 5 (25)0.66

CT/TT 15 (75) 18 (90) 15 (75)

Knodell HAI Fibrosis Score – n (%)

0–2 12 (60) 15 (75) 15 (75)

0.163 5 (25) 5 (25) 5 (25)

4 3 (15) 0 0

24 giugno 2014 Roma

Treatment Response (ITT)Sofosbuvir + Ledipasvir (n=20)Sofosbuvir + Ledipasvir + GS-9669( n=20)Sofosbuvir + Ledipasvir + GS-9451 (n=20)

0

Week 4

10

20

30

40

50

60

70

80

90

100

EOT SVR 4 SVR 12

% o

f p

atie

nts

wit

hH

CV

RN

A <

LL

OQ

(IT

T)

90

100 100 100 100 100 10095

100 10095

100

24 giugno 2014 Roma

HCV Viral Kinetic Fitted Model

0

Med

ian

HC

V R

NA

dec

lin

e

102

103

104

105

106

107

Time (days)7 14 21 28

Sofosbuvir + LedipasvirSofosbuvir + Ledipasvir + GS-9669Sofosbuvir + Ledipasvir + GS-9451

24 giugno 2014 Roma

Early Normalization of ALT and AST

● Alanine aminotransferase (ALT) levels declined to normal by day 14 in 90%, 100% and 95% of patients treated with sofosbuvir + ledipasvir, sofosbuvir + ledipasvir + GS-9669 and sofosbuvir + ledipasvir + GS-9451, respectively

0

Ala

nin

e am

inot

ran

sfer

ase

(U/L

)

0

Day

Sofosbuvir + Ledipasvir(n=20)Sofosbuvir + Ledipasvir +GS-9669 (n=20)Sofosbuvir + Ledipasvir +GS-9451 (n=20)

20

40

60

80

100

7 2 3 4 6 8 10 12 14 16 18 20 24

Week

00

Day

20

40

60

80

100

7 2 3 4 6 8 10 12 14 16 18 20 24

Week

Asp

arta

te a

min

otra

nsf

eras

e (U

/L)

24 giugno 2014 Roma

Sofosbuvir +Ledipasvir

12 weeks(n=20)





Any Grade 4 abnormality during treatment* – n (%) 0 0 0

Any Grade 3 abnormality during treatment* – n (%) 3 (15) 2 (10) 4 (20)

Hypophosphatemia 0 2 (10) 0

Elevated serum creatinine 0 0 3 (15)

Decreased hemoglobin 0 0 1 (5)

Elevated ALT 1 (5) 0 0

Elevated AST 1 (5) 0 0

Elevated LDL 1 (5) 0 0

Hyperglycemia 1 (5) 0 0

Hypoglycemia 1 (5) 0 0

Safety Profiles

• Elevated creatinine occurred in two patients with baseline renal insufficiency and in third patient who initiated 1600 mg/day ibuprofen

* From Day 0 to 30 days post-treatment

24 giugno 2014 Roma

Conclusions

• Hepatitis C can be successfully and safely treated in six weeks using three direct acting agents with different mechanisms of acting

• Addition of a third DAA enabled a shorter duration of therapy

• This short duration, simple therapy for HCV may prove relevant for the global elimination of hepatitis C, where uncomplicated, well-tolerated therapy is required to ensure adherence and minimize health care expenditures

24 giugno 2014 Roma

24 giugno 2014 Roma Il paziente coinfetto HIV-HCV non più “special population?” La gestione...

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