Advances in the all oral HCV DAA to treat HCV/HIV: “No...

Advances in the all oral HCV DAA to treat HCV/HIV: “No longer a special population?” Josep Mallolas Hospital Clínic-University of Barcelona

2

HCV in HIV/HCV: No longer a special population?

HIV/HCV co-infected patients

HIV/HCV epidemiology HIV/HCV natural history

Drug-drug interactions Treatment guidelines

Treatment Co-morbidities

3






4

Estimated worldwide numbers of HIV/HCV co-infected individuals

Clausen LN et al. World J Gastroenterol 2014; 20:12132–12143.

HIV 33 million

HCV 130–180 million

HIV/HCV co-

infection up to 10 million

5

South: 41%

North: 23%

East: 47%

Center: 20%

Prevalence 1960/5957 patients: 33%1

Prevalence of HCV/HIV co-infection in Europe

1. Rockstroh, JK., et al. Influence of Hepatitis C Virus Infection on HIV-1 Disease Progression and Response to Highly Active Antiretroviral Therapy. J Infect Dis. 2005; 192:992–1002 2. Castro Iglesisas, MA. Epidemiología de la coinfección por VHC y VIH. GH Continuada. enero-febrero 2011. Vol. 10 N.º 1. 3. González García, J., et al. Estudio multicéntrico sobre prevalencia de las coinfecciones por virus de hepatitis, indicación de tratamiento de hepatitis crónica C y necesidad de trasplante hepático en pacientes infectados por el VIH en España. Estudio GESIDA 29/02-FIPSE 12185/01Enferm Infecc Microbiol Clin 2005;23(6):340-8.

6

HCV 450,000

HIV 150,000

HIV/HCV 50,000

Prevalence of HCV-HIV co-infection in Spain

1. Encuesta Hospitalaria de pacientes con VIH/sida. 2000-2013. Ministerio Sanidad.

7

Parallel decrease in prevalence if injection drug use and HIV/HCV co-infection in Spain

Cachafeiro SP, et al. CID 2009; 48:1467–1470.

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Year of entry at CoRIS/CoRIS-MD

Seria

l Pre

vale

nce,

%

100

80

60

40

20

0

+

+ + +

+ +

+ + + +

8

Changes in patterns of risk behaviors for acquisition of HIV infection in Spain: what is changing?

Serrano-Villar S, et al. J Viral Hep 2014; 22:496–503.

CoRis cohort includijng 7,045 HIV+ patients

2004-05 2007-07 2008-09 2010-11

Risk

Cat

egor

y (%

)

100

80

60

40

20

0

40.6% 68.6%

9

• HCV incidence in MSM reached 4.1 cases per 100 PY in 2011 (18-fold increase since 1998)

• HCV incidence in intravenous drug users (IDU) decreased from 13.9 to 2.2 cases per 100 PY

• HCV incidence in heterosexuals remained <1 per 100 PY throughout the study period

Swiss HIV Cohort Study: HCV yearly incidence rate by transmission group*

Incidence of acute hep C sexually transmitted is increasing among HIV + MSM

Wandeler G et al. Clin Infect Dis. 2012;55:1408-1416

10







11







13

• We observed an exponential increase in the incidence of AHC • The main route of infection was sexual

Num

ber o

f AHC

cas

es

05

10152025303540

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Diagnosis of acute hepatitis C (AHC) in HIV–infected MSM from 2003 to 2014

Martínez-Rebollar et al. Enferm Infec Microbiol Clin, 2015

14

Results (I)

January 2003-March 2014

• n: 140 cases in 130 patients

– 126 M (MSM)

– 1 M (Drug addict)

– 3 F (1 het, 1 nos, 1 Drug Addict)

• 8 spontaneous clearance: Rate 5.4%

• 9 re-infections (1 patient with 3 episodes)

– Re-infection rate: 7.1%


15

Results (I)



– 126 M (MSM)







16

Results (I)



– 126 M (MSM)







17

Results (II)

• Co-infection with other STD (40.8%) : (n: 93 cases)

– 17 Syphilis

– 3 Syphilis + LGV

– 3 Syphilis + Gonococcal urethritis + Chlamydia

– 5 LGV

– 3 Gonococcal urethritis +Chlamydia

– 1 Herpes

– 1 Inespecific proctitis

– 5 HIV primary infection

• SVR: 56%


18

Results (II)


– 17 Syphilis



– 5 LGV


– 1 Herpes



• SVR: 56%


19

Results (II)


– 17 Syphilis



– 5 LGV


– 1 Herpes



• SVR: 56%


20

N=38 SVR: 47%

21

Phylogenetic analysis of an epidemic outbreak of acute hepatitis C in HIV-infected

patients by massive sequencing

Noelia Caro-Pérez (1) , María Martínez-Rebollar (2), Josep Gregori (3),(4) , Josep Quer (3), Patricia González (1), Martina Gambato (1), Hanna Visser (2), Juan I. Esteban (3), Josep Mallolas (2), Xavier Forns (1),

Sofía Pérez-del-Pulgar (1), Montse Laguno (2).

Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain (1). Infectious Diseases Unit, Hospital Clínic, IDIBAPS (2). Liver Unit, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall) d'Hebron , CIBERehd, Barcelona, (3) Roche Diagnostics SL. ,

Sant Cugat del Vallès, Barcelona, Spain (4)

Suggest this slide is deleted and the reference

placed on subsequent slides

22

Phylogenetic analysis

Caro-Pérez N, et al. EASL-ILC 2015; Abstract P1287.

4d

3a

1b

1a

Local controls Coinfected Patients

23

Clusters identified by genotype

4d 1b 1a

1 CLUSTER

8 CLUSTERS 5 CLUSTERS


24

Genetic distance analysis

Genetic distance p

dA(4d) < dA(1a) < 2.2e-16

dA(4d) < dA(1b) 0.039

dA(1b) < dA(1a) 0.0086


25

Hypothetical network of infection in genotype 4d patients

• Monitoring common mutations in the quasispecies

• Date of acute hepatitis C diagnosis

p75

03/11/2008

p67

27/07/2010

p4

07/04/2011

p17

14/09/2012

p29

04/06/2012

p62

28/01/2009

p45

03/04/2013

p51

04/06/2013

p38

04/01/2013

p16

14/03/2012

p57

16/10/2013


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27

HCV/HIV Coinfection: Natural History Considerations

• Accelerated rates of fibrosis progression – Possible weak cellular immune response to HCV antigens – HIV-associated immune activation may influence progression of liver disease – Activation of hepatic stellate cells – HCV-associated proinflammatory cytokines may impact HIV disease

• HCV coinfection is associated with higher rates of morbidity and mortality related to end-stage liver disease – Lower rates of spontaneous HCV clearance in HIV patients – Faster progression to cirrhosis and decompensated liver disease – HCC occurs at a younger age and associated with shorter survival

Lin W, et al. J Infect Dis. 2013;207(suppl 1):S13-S18. Weber R, et al. Arch Intern Med. 2006;166:1632-1641. Ioannou GN, et al. Hepatology. 2013;57:249-257. Weber R, et al. HIV Med. 2013;14:195-207. Macias J, et al. Clin Infect Dis. 2013;57:1401-1408. Curry MP. J Infect Dis. 2013(suppl 1):S40-S44. Chen TY, et al. Clin Infect Dis. 2009;49:1605-1615.

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Increase with CD4 <200/mm3, ETOH, age

Fibr

osis

Gra

des

(MET

AVIR

Sco

re)

Duration of HCV Infection (years)

HIV+ (n = 122) Matched controls (n = 122) Simulated controls (n = 122)

4

3

2

1

0 40 30 20 10 0

Effect of HIV on HCV Liver Fibrosis Progression Rate

Benhamou et al. Hepatology 1999;30:1054.

29

ALIVE Study: HIV, Age, and Severity of HCV-Related Liver Diseases

Prospective cohort of HCV-infected IDUs (2006-2011) (n=1176) • HIV co-infected (n=394) • Baseline and semi-annual

elastography

Fibrosis was significantly greater in HCV/HIV co-infected versus HCV monoinfection (P<0.001) • No cirrhosis (12.9% versus 9.5%) • With cirrhosis (19.5% versus 11.0%) • Independently associated with

increasing age and HIV infection

HCV/HIV patients have liver fibrosis similar to HCV mono-infected patients who are nearly 10 years older

ALIVE: AIDS Linked to the IntraVenous Experience. Kirk GD, et al. Ann Intern Med. 2013;158:658-666.

Liver Fibrosis and Age: HCV/HIV Versus HCV Infection

Pred

icte

d Fi

broS

can

Scor

e (k

Pa)

Age (years)

HCV/HIV

HCV

9.2 years 6

8

10

12

14

30 35 40 45 50 55 60

30

Risk of Liver Decompensation in HCV/HIV Patients With Advanced Fibrosis

Retrospective Spanish study (11 tertiary centers (1990-2002) (n=892) • HCV treatment-naïve or no SVR • Biopsy (n=317) or LSM (n=575)

proven advanced fibrosis

Liver decompensation rate (events/100 patient-years): • Biopsy: 2.3 (1.7-3.1) • LSM: 3.98 (3.04-5.21)

Risk of decompensation increased by baseline fibrosis stage (for both biopsy and LSM) • Implications for immediate HCV

therapy

LSM: liver stiffness measurement. Macias J, et al. Clin Infect Dis. 2013;57:1401-1408.

Probability of Decompensation

Patie

nts W

ith D

ecom

pens

atio

n (%

)

Time (years)

0

10

20

30

40

50

60

1% 2% 5%

20%

4%

13%

23%

44%

1 (n=149/168)

3 (n=128/150)

5 (n=112/116)

>5 (n=81/77)

P=0.023 for trend

Baseline Fibrosis (biopsy) F3 F4

31

GESIDA HIV/HCV Cohort: HCV Eradication Reduces Liver-Related Outcomes

Berenguer J, et al. J Hepatol. 2013;58:1104-1112.

Liver Decompensation

Follow-Up (months)

Liver-Related Events

Patie

nts (

%)

Follow-Up (months)

Patie

nts (

%)

HCC Mortality

Follow-Up (months)

Patie

nts (

%)

Follow-Up (months)

80

85

90

95

100

96 0 12 24 36 48 60 72 84

SVR*†

Relapse†

NR

*P<0.05 versus NR and relapse; †P<0.05 versus NR.

Patie

nts (

%)

80

85

90

95

100 SVR†

Relapse†

NR

96 0 12 24 36 48 60 72 84 80

85

90

95

100 SVR†

Relapse†

NR

96 0 12 24 36 48 60 72 84

80

85

90

95

100SVR*†

Relapse†

NR

96 0 12 24 36 48 60 72 84

32






33

P/R = PegIFN/RBV.

SVR12/24 rates over time in HCV GT1 subjects co-infected with HIV — from IFN/RBV to single DAAs ± P/R

7 14

29

63 74 74

89 85

0

20

40

60

80

100

IFN + RBV PegIFN PegIFN/RBV BOC + P/R TVR + P/R SMV + P/R SOF + P/R SOF + RBV

SVR

(%)

Torriani FJ, et al. N Engl J Med 2004; 351:438–450; Sulkowski M, et al. Lancet Infect Dis 2013; 13:597–605;

Sulkowski M, et al. Ann Intern Med 2013; 159:86–96; Dieterich D, et al. EACS 2013. Abstract LBPS9/5;

Rodriguez-Torres M, et al. ID Week 2013; Poster 714; Molina JM, et al. AIDS 2014, Abs 105LB.

34

SVR12/24 rates over time in HCV GT1 subjects co-infected with HIV — from IFN/RBV to single DAAs ± P/R

P/R = PegIFN/RBV.

7 14

29

63 74 74

89 85

0

20

40

60

80

100

IFN + RBV PegIFN PegIFN/RBV BOC + P/R TVR + P/R SMV + P/R SOF + P/R SOF + RBV

SVR

(%)

Torriani FJ, et al. N Engl J Med 2004; 351:438–450; Sulkowski M, et al. Lancet Infect Dis 2013; 13:597–605;

Sulkowski M, et al. Ann Intern Med 2013; 159:86–96; Dieterich D, et al. EACS 2013. Abstract LBPS9/5;

Rodriguez-Torres M, et al. ID Week 2013; Poster 714; Molina JM, et al. AIDS 2014, Abs 105LB.

But now we have emerging data with all oral DAAs

35

PHOTON-2: Sofosbuvir + Ribavirin in GT1-4 HCV Pts Coinfected With HIV

• Ongoing, nonrandomized, open-label phase III study

– Stable ART (HIV-1 RNA < 50 copies/mL for ≥ 8 wks before enrollment); CD4: > 200 cells/mm3 if ART treated; > 500 cells/mm3 if ART naive – 97% on ART: TDF/FTC, 100%; EFV: 25%; ATV/RTV: 17%; DRV/RTV: 21%; RAL:

23%; RPV: 5%

• 20% of pts with compensated cirrhosis

• Primary endpoint: SVR12

Molina JM, et al. AIDS 2014. Abstract MOAB0105LB.

Wk 24

Sofosbuvir + Ribavirin (n = 200)



Wk 12

Tx-naive GT1, 3, 4

Tx-naive GT2

Tx-exp’d GT2, 3

Sofosbuvir 400 mg QD; weight-based ribavirin 1000 or 1200 mg/day

36

PHOTON-2 Study: Overall SVR12 Rates and Virologic Failure

HCV treatment-naïve genotypes 1, 3, 4 and HCV treatment-experienced genotypes 2,3: 24 weeks of therapy. HCV treatment-naïve genotypes 2, 3: 12 weeks of therapy. Molina J-M, et al. 20th IAC. Melbourne, 2014. Abstract MOAB0105LB.

85% 88% 89% 84%

0

20

40

60

80

100

Genotype 1 Genotype 2 Genotype 3 Genotype 4

95/112 22/25 94/106 26/31

14 (13%) 2 (8%) 10 (9%) 5 (16%) 0 0 1 (0.9%) 0

Relapse: Breakthrough:

SVR1

2 (%

)

37

*HCV G1b only. Grazoprevir (MK-5172) is an NS3/4A PI and Elbasvir (MK-8742), an NS5A inhibitor. *** All patients receiving Raltegravir.

INF-free Regimen: On-treatment Viral Response to MK-5172/MK-8742 ± RBV for 12 Weeks in HCV/HIV-Coinfected Patients: The C-WORTHY Study

Sulkowsky M, Mallolas J, EASLD (London)-2014

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INF-free Regimen: On-treatment Viral Response to MK-5172/MK-8742 ± RBV for 12 Weeks in HCV/HIV-Coinfected Patients: The C-WORTHY Study

Sulkowsky M, Mallolas J, EASLD (London)-2014

Virologic responses (per-protocol population)

39

C-EDGE Coinfection: Grazoprevir/Elbasvir for Pts Coinfected With HCV/HIV

• Multicenter, single-arm, open-label phase III trial

Rockstroh JK, et al. EASL 2015. Abstract P0887.

Grazoprevir/Elbasvir (n = 218)

HCV treatment-naive pts coinfected with HIV and

GT1, 4, or 6 HCV (N = 218)

Wk 12

Coformulated grazoprevir/elbasvir dosed orally 100/50 mg once daily

Baseline ART

Undetectable HIV-1 RNA on ART (%) 96.8

• Abacavir containing 21.6

• Tenofovir DF containing 75.2

• Raltegravir 51.8

• Dolutegravir 27.1

• Rilpivirine 17.4

• 66% with GT1a HCV, 60% had HCV RNA > 800,000 IU/mL, 16% cirrhotic

40

C-EDGE Coinfection: Key Findings

• No subgroup provided an efficacy advantage or disadvantage

• New NS3, NS5A RAVs detected at failure in 5 of 6 pts who relapsed

• Short-lived HIV-1 RNA increases occurred in 2 pts on ART during grazoprevir/elbasvir treatment: both resuppressed HIV-1 RNA without change of ART

• During 12 wks of treatment, no significant changes in CD4+ cell count (n = 207)

• Grazoprevir/elbasvir well tolerated: no pt discontinued for AEs and no serious treatment-related AEs

Rockstroh JK, et al. EASL 2015. Abstract P0887.

SVR12 With 12 Wks GZR/EBV According to Genotype

LTFU or DC* 4 3 1 0

Breakthrough 0 0 0 0

Relapse 6 4 1 1

Reinfection 1 1 0 0

*Unrelated to virologic failure.

SVR1

2 (%

)

136/ 144

42/ 44

27/ 28

All Pts GT1a GT1b GT4

95.0 94.4 95.5 96.4

207/ 218

0

100

80

60

20 n/N =

40

41

TURQUOISE-I: SVR12 rates in HIV/HCV co-infected patients treated with OBV/PTV/r + DSV + RBV

Sulkowski MS, et al. JAMA 2015; 313:1223–1231.

OBV/PTV/r + DSV + RBV for 12 or 24 weeks in GT1 treatment-naive and -experienced patients, all with HIV/HCV co-infection

OBV/PTV/r + DSV + RBV

(n=31)

0 24 12

Study weeks

OBV/PTV/r + DSV + RBV (n=32)

HCV GT1, naive or

experienced, (N=63)*

* Including 6 (19%) patients with cirrhosis (F4) in the 12 week arm and 6 (19%) patients with cirrhosis (F4) in the 24 week arm. DSV = dasabuvir; OBV = ombitasvir; PTV/r = paritaprevir/ritonavir.

94 91

0

20

40

60

80

100

SVR1

2 (%

) 12 weeks 24 weeks OBV/PTV/r + DSV + RBV 2 patients in the 24-week arm had recurrence of HCV believed to be

due to re-infection

n N

29 32

29 31

42

TURQUOISE-I: high SVR12 rates in patients receiving either atazanavir or raltegravir

ART = anti-retroviral therapy. Eron JJ, et al. J Int AIDS Soc. 2014; 17(Suppl 3):19500.

Atazanavir ART: • 1 patient withdrew consent

Raltegravir ART: • 1 patient in the 12-week

arm relapsed • 1 patient in the 24-week arm

experienced viral breakthrough • 2 patients in the 24-week arm had

recurrence of HCV believed to be due to re-infection

94 93 100 85

Atazanavir Raltegravir0

20

40

60

80

100

SVR1

2 (%

)

12 weeks 24 weeks

15 16

14 15

12 12

17 20

n N

Response in patients on HIV ART Reasons for non-response

43

Time to HCV RNA <25 IU/mL in HCV mono-infected and HIV/HCV co-infected patients and SVR12 by time to HCV RNA Suppression

Wyles D, et al. CROI 2015. Abstract 147

<25 IU/mL (LLOQ)

Treatment Week

Cum

ulat

ive

%

0 2 40

20

40

60

80

100

1 6+

<15 IU/mL (LLOD)

Treatment Week

Cum

ulat

ive

%

0 2 40

20

40

60

80

100

1 6+

HCV Mono-infectedHCV/HIV-1 Co-infected

SVR1

2, %

Pat

ient

s

Week 1 Week 2 Week 4 Week 6+0

20

40

60

80

10097 9698 10097 98

617628

2930

9921024

55

2425

355362

HCV Mono-infected HCV/HIV-1 Co-infected

NA92

1213


44

96 95 97 96 94

0

20

40

60

80

100

Overall Naive Exp Nocirrhosis

Cirrhosis

SVR1

2 (%

)

n N

321 335

179 185

142 150

258 268

63 67

ION-4: LDV/SOF in HCV GT1 or 4 patients with HIV co-infection — SVR12 rates

* Including 8 (2.4%) patient with GT4 and 67 (20%) patients with cirrhosis. Exp = experienced. Cooper E, et al. EASL-ILC 2015; Poster presentation P1353.

LDV/SOF (N=335)

0 12 Study weeks

Study design: GT1 and 4 with

HIV/HCV co-infection*

Efficacy results: GT1 and 4 with

HIV/HCV co-infection

ION-4: LDV/SOF Effective Across All Pt Demographic and Disease Subgroups

10 relapses all in black pts

No pt with HIV virologic rebound

No discontinuation of therapy due to adverse events

4 pts experienced increase in creatinine > 0.4 mg/dL

– 2 completed treatment without change in ART

– 1 pt changed TDF to new NRTI

– TDF dose reduced in 1 pt

Black Nonblack 1a 1b 4 < 800,000 ≥ 800,000 < 30 ≥ 30 CC CT TT TDF/FTC/EFV TDF/FTC + RAL TDF/FTC/RPV < 350 ≥ 350

HCV Genotype

Baseline HCV RNA (IU/mL)

Baseline BMI (kg/m2)

Race

IL28B

ARV Regimen

Baseline CD4 (cells/mm³)

Overall

60 70 80 90 100

SVR12, % (95% CI)

Statistically significant in multivariate analysis

Naggie S, et al. CROI 2015. Abstract 152LB. Cooper C et al. EASL 2015. Reproduced with permission.

ION-4: Resistance Analysis and LDV/SOF Drug–Drug Interactions With bPIs

Deep sequencing at BL identified 67 (20%) pts with NS5A RAVs[1]

– 63 (94%) of these pts achieved SVR12

RAVs in NS5A found in 10/12 pts with virologic failure

No S282T mutation in NS5B found in any pt at BL or virologic failure

In drug–drug interaction studies with LDV/SOF and boosted PIs and TFV[2]

– LDV/SOF increases ATV, RTV, and TFV exposure

– ATV/RTV + TDF/FTC increases LDV

– DRV/RTV + TDF/FTC decreases SOF

Staggered administration did not mitigate interactions but interactions not deemed clinically relevant

1. Naggie S, et al. CROI 2015. Abstract 152LB. Cooper C et al. EASL 2015. 2. German P, et al. CROI 2015. Abstract 82.

ALLY-2: SOF + DCV in GT1-6 HCV/HIV-Coinfected Pts

Phase III open-label study

– Non GT1 < 20% in each cohort; compensated cirrhosis < 50% overall; HIV-1 RNA < 50 c/mL and CD4+ ≥ 100 in pts on ART; CD4 ≥ 350 in pts not on ART

– ART allowed: PI/RTV, NRTIs, NNRTIs, INSTIs, MVC, ENF

Primary endpoint: SVR12 in GT1 naive pts treated for 12 wks

Wyles DL, et al. CROI 2015. Abstract 151LB. EASL 2015. Abstract LP01

Treatment-naive pts (N = 151)

SOF 400 mg QD + DCV 30/60/90* mg QD

(n = 101)


(n = 52)

Treatment-experienced pts (N = 52)

Wk 12

Pts followed to Wk 36


(n = 50)

Wk 8

*Standard dose of 60 mg adjusted for ART: 30 mg with RTV; 90 mg with NNRTIs except RPV.

High SVR12 rates with 12 wks SOF + DCV

– Large decline in SVR rate with shortening to 8 wks

12-Wk 12-Wk 8-Wk 12-Wk 12-Wk 8-Wk

ALLY-2: Virologic Outcomes With SOF + DCV in HIV/HCV-Coinfected Pts

In 12-wk groups analyzed by GT, 100% with SVR12 except GT1a

– GT1a naive: 96%; exp’d: 97%

Similar SVR12 rates in pts with or without baseline NS5A RAVs

12 pts with relapse, 10 in 8-wk arm

– 1 in 8-wk arm had emergent NS5A RAVs

No NS5B RAVs at BL or time of failure

No discontinuation of therapy due to AEs

10 pts with HIV-1 RNA > 50 at EOT

– 8 with repeat testing; 7 with suppression without change in ART; 1 with HIV-1 RNA of 59; 2 LTFU

2 with HIV VF = HIV-1 RNA ≥ 400 c/mL

SVR

12, %

96

0

20

40

60

80

98

76

97 98

n/N = 80/ 83

43/ 44

100

31/ 41

98/ 101

51/ 52

76

38/ 50

Wyles DL, et al. CROI 2015. Abstract 151LB. EASL 2015. Abstract LP01.

Naive Exp’d Naive Exp’d

GT1 Overall

DACLATASVIR PLUS SOFOSBUVIR WITH OR WITHOUT RIBAVIRIN IN PATIENTS WITH HIV-HCV COINFECTION: INTERIM ANALYSIS OF A

FRENCH MULTICENTER COMPASSIONATE USE PROGRAM

Hélène Fontaine, Karine Lacombe, Catherine Dhiver et al.

EASL 2015 April 22-26 Vienna Austria

50

Interim analysis of DCV + SOF ± RBV in patients with HIV/HCV co-infection from a French compassionate use program: Baseline characteristics

aIncludes F3 and F3/F4. b66 patients had missing data. c115 patients had missing data. Fontaine H, et al. ILC 2015. Abstract LP23

51

Interim analysis of DCV + SOF ± RBV in patients with HIV/HCV co-infection from a French compassionate use program: Efficacy

Treatment discontinuations occurred in 14 patients (1.9%) and were related to an adverse event (n=4), death (n=3), patient decision (n=3), contra-indication (n=3) and unknown reason (n=1).

Fontaine H, et al. ILC 2015. Abstract LP23

52






53

Co-morbidities among HIV/HCV co-infected patients

• Among 8,039 HIV infected veterans, 5251 (65.3%) had HCV co-infection

• All cause mortality rate was:

• 74.1 (70.4 to 77.9) per 1000 person years among veterans with HIV/HCV co-infection

• 39.8 (36.3 to 43.6) per 1000 person years among veterans with HIV mono-infection

• Positive predictors of mortality included:

• Decompensated liver disease (2.33 (1.98 to 2.74))

• Coronary artery disease (1.74 (1.32 to 2.28))

• Chronic kidney disease (1.62 (1.36 to 1.92))

• Anemia (1.58 (1.31 to 1.89))

Erqou S, et al. ISRN Gastroenterol. 2014 Apr 7;2014:764540. doi: 10.1155/2014/764540.

54

RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV — design

Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01.

Day 1 Week 12

Open-label Treatment

OBV/PTV/r + DSV


SVR12

Week 24

GT1b

GT1a

• For GT1a: RBV 200 mg QD • For GT1b: No RBV

SVR4

55

RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV — efficacy

Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01.

All patients completing treatment to date had virologic response

Virologic response has been sustained in all patients who have reached post-treatment weeks 4 and 12

Time-point N Virologic

Response (n) Percent

End of Treatment 14 14 100

Post-treatment Week 4 10 10 100

Post-treatment Week 12 2 2 100

56

C-SURFER: Grazoprevir/Elbasvir in Pts With GT1 HCV and Stage 4 or 5 CKD

• Multicenter, part-randomized, parallel-group, placebo-controlled, phase III trial

Roth D, et al. EASL 2015. Abstract LP02.

Grazoprevir/Elbasvir (n = 111)

Placebo (n = 113)

GT1 HCV-infected pts with

stage 4/5 CKD (n = 224) Grazoprevir/Elbasvir

(n = 113)

Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. This study also included a pharmacokinetic analysis (n = 11) in which pts were treated as in the randomized grazoprevir/elbasvir study group.

Treatment Wk 12

Follow-up Wk 4

Follow-up Wk 16

Open-label period

Randomized period

• Treatment arms well matched at baseline – Pts split evenly by GT1a and 1b infection (52% for GT1a); 6% had compensated

cirrhosis – 75% and 77% were on hemodialysis; 32% to 36% were diabetic – 81% and 82% were CKD stage 5 (eGFR < 15 mL/min/1.73 m2, or on

hemodialysis); 18% and 19% were CKD stage 4 (eGFR 15-29 mL/min/1.73 m2)

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C-SURFER: Efficacy Results

Modified analysis set: pts in pharmacokinetic substudy and pts randomized to immediate treatment who received ≥ 1 drug dose; excludes pts who died or discontinued where cause not related to study treatment. Full analysis set: all pts receiving ≥ 1 drug dose. *1 pt relapsed on each arm. †6 pts in the full analysis set discontinued unrelated to treatment: lost to follow-up (n = 2), n = 1 each for death, noncompliance, withdrawal by subject, and withdrawal by physician (owing to violent behavior). Roth D, et al. EASL 2015. Abstract LP02.

GZR/EBR 12 wks

SVR1

2 (%

)

94 99

115/ 116*

115/ 122*†

100

6/6

100

61/61

98.2

54/55

98.9

86/87

97.6

40/41

Cirrhotic GT 1a HCV

GT 1b HCV

Diabetic On hemodialysis

Modified Full Analysis Set

Full Analysis Set

20 n/N =

100

80

60

40

0

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Drug–Drug Interactions With ARVs

www.hep-druginteractions.org (March’15)

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61



62



63



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www.hep-druginteractions.org (Accessed May 2015).

But there are resources out there to help…

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AASLD/IDSA Guidance for HIV/HCV Coinfection

Same recommendations as in HCV-monoinfected patients, but consider drug–drug interactions

• Need to adjust or withhold RTV if receiving a boosted PI with OMV/PTV/RTV + DSV

• Potential for LDV-mediated increase in tenofovir levels, especially if tenofovir used with RTV

– Avoid LDV if CrCl < 60 mL/min or if receiving tenofovir with RTV-boosted PI

• OMV/PTV/RTV + DSV can be used with raltegravir (and probably dolutegravir), enfuvirtide, tenofovir, emtricitabine, lamivudine, atazanavir

• SMV can be used with: raltegravir (and probably dolutegravir), rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, abacavir

• Other interactions at aidsinfo.nih.gov/guidelines, hiv-druginteractions.org

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C.

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EASL Recomendations on Treatment of Hepatitis C in 2015

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EASL Recomendations on Treatment of Hepatitis C in 2015

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EASL recommendations for treatment prioritisation

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Summary

HIV/HCV co-infection remains

a widespread problem

associated with high morbidity and mortality

HIV/HCV epidemiology and natural

history

Updated guidelines state that HIV/HCV co-infection should be treated the same as HCV mono-infection, DDIs should always be appropriately monitored and HIV/HCV co-

infected patients should be prioritised for treatment

DDIs are relatively

common in HIV/HCV co-

infected patients but they are

typically manageable and

resources are available

Effective treatments are

now available to cure the HCV in

the great majority of patients

including those with HIV/HCV

Renal disease is more prevalent in

HIV/HCV co-infected patients than uninfected

patients but effective HCV

treatments are becoming available

Treatment Co-morbidities DDIs

Advances in the all oral HCV DAA to treat HCV/HIV: “No...

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