Management of HIV / HCV Coinfection - Albany Medical … · 2015-07-23 · Management of HIV / HCV...

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Advances in HCV 2015Albany Medical College & Erie County Medical Center

Buffalo, New York

24 June 2015

Management of HIV / HCV Coinfection

Norbert Bräu, MD, MBA

Prof. of Medicine, Icahn School of Medicine at Mount Sinai, New York NYDivisions of Infectious Diseases & Liver Diseases

Director, Viral Hepatitis Program, James J Peters VA Medical Center, Bronx NY

Bronx VA Medical Center Mount Sinai School of Medicine

HIV / HCV coinfectionOverview

(1)Natural History of HCV Disease in HIV / HCV

(2) HCC in HIV

(3) Antiviral Therapy with DAAs for HIV / HCV

2

34 years ago …

5 June 1981

5 June 1981

3

HIV History

5 June 1981 MMWR: Los Angeles, Pneumocystis carinii pneumonia in 5 homosexual men.

1983 HTLV-III discovered (renamed HIV)1989 Zidovudine (AZT) first antiretroviral drug1996 HIV protease inihibitors, beginning of HAART

Since 2000 liver disease increasing cause of mortality in HIV0-uinfected patients

Effect of HAART on Survival

4

Rising rate of liver-related deathsand of HCC

France: Mortalité 2000 & 2005

2000 2005N ~64,000 78,000

Deaths 964 1,042

Liver deaths: 13.4% 15.4%

HCC deaths: 15% 25% p=0.03

Salmon-Ceron D, J Hepatol, April 2009

HIV and HCV CoinfectionEpidemiology

HCV or HBV within HIV+ pts:

HCV strongly depends on mode of transmission of HIV itself:

Anti-HCV[+], total 42.5% HBsAg[+], total 6.9%IDU 91 %

blood transfusion 71 %

sexual transmission 7.1 %

N=1,935

Saillour F et al., Brit Med J, 1996

5

Natural History of HCV Infection

Acute Infection

Resolved Chronic

CirrhosisStable

SlowlyProgressive

Liver failure, HCCTransplant

Death

20% (15)

25% (25) 75% (75)

25% (4)

80% (60)

75% (11)

HIV and Alcohol

100% (100)

HIV + HCV coinfectionEffect of HIV on HCV-related liver disease

Does HIV accelerate

HCV-induced liver disease ?

YES, if …

6

HIV + HCV coinfection:Liver Fibrosis Progression Rate

Benhamou Y, Hepatology, Oct 1999

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

HCV - infection duration (years)

Fibr

osis

Gra

des

(MET

AVR

scor

ing

syst

em) 4

3

2

1

00 10 20 30 40

Fibrosis Progression Rate by HIV Viral Load

Bräu N, J Hepatol, Jan 2006

7

Fibrosis progression in HIV/HCV coinfeciton- paired liver biopsies -

Spain, multicenter: N=135 HIV/HCV with paired Bx (median 3.3 yrs)

Factors independently correlated with Fibrosis Progression Rate (FPR)

risk ratio 95% CI p

HIV RNA undetectable (>70% dur F/U) 0.61 0.39 – 0.93 0.028

HAART during F/U 0.94 0.72

Baseline necroinflammation 1.77 1.16 – 2.7 0.009

EOT response to anti-HCV therapy 0.41 0.19 – 0.88 0.023

Macias J, Hepatology, Oct 2009

50

Fattovich G et al. Gastroenterology. 1997;112:463.

40

30

20

10

0 2 4 6 8 10

100

80

60

40

20

0 2 4 6 8 10

Years Years

HCV Cirrhosis -- Natural HistoryMorbidity and Mortality

HCC Cirrhosis Decompensation

Cumulative decomp. and HCC(%) Cumulative mortality(%)

8

Effect of HIV on HCV-related cirrhosis

Cumulative incidence of liver failure in HIV/HCV pts. with cirrhosis (N=154)

6.40 cases / 100 person-yrs

Est. 3-yr incid. 48 %

Est. 5-yr incid. 53 %

Pineda JA, Clin Infect Dis, 15 Oct 2009

Effect of HIV on HCV-related end-stage liver disease

Shorter survival after decompensation in HIV/HCV vs. HCV (N=1,837)

median HIV/HCV 16 mo

HCV 48 mo

Independent risk factors for death:HIV+, age, MELD score, HE 1st Sx

Pineda JA, Hepatology, Apr 2005

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HCC in HIV – Rising IncidenceAndalucia (Spain) 1999 – 2010

n = 14,300 (2010)

Merchante N. et al., Clin Infect Dis, Jan 2013

HIV / HCV

All HIV patients 0.1 0.2 0.5 0.7 1.0 0.9

HCC in HIV – Rising Prevalence

VA System (USA) 1996 – 2009

n = 24,000 (2009)

Ioannou GN. et al., Hepatology, Jan 2013

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HCC in HIV - Outcome

Case Series

2001 n= 7 García-Samaniego J et al. (Madrid), Am J Gastro


Case Series


2004 n=41 Puoti M et al. (Italy), AIDS

2007 n=63 North American Liver Cancer in HIV Study GroupBräu N et al., J Hepatol

2011 n=102 Berretta M et al. (Italy), Oncologist

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Case Series


2004 n=41 Puoti M et al. (Italy), AIDS

2007 n=63 North American Liver Cancer in HIV Study GroupBräu N et al., J Hepatol

2011 n=102 Berretta M et al. (Italy), Oncologist

2012 n=26 Yopp AC et al. (Dallas), Clin Gastroent Hepatol2012 n=23 Lim C at al. (Paris), JAIDS2013 n=48 Pavoni M et al. (Bologna, Italy), Dig Liver Dis

Puoti M et al., AIDS, Nov-2004

1st Italian HCC in HIV study (2004)

Median survival:

HIV-pos. (n=41) 5.9 mo

HIV-neg. (n=701) 18.0 mo


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****

*

*

**

*

*

*

12 sites (US, Canada) HIV-pos. HCC (n=63)

4 sites HIV-pos. + HIV–neg. HCC (n=226)

North American Liver Cancer in HIV Study Group

* *

*

*

*

*

*

Bräu N et al., J Hepatol, Oct 2007

At risk HIV[-] 226 64 29 14 7 2 1 median survival: 7.5 moAt risk HIV[+] 63 11 3 1 1 0 0 median survival: 6.9 mo

N American HCC in HIV Study: Survival All Patients

Bräu N et al., J Hepatol, Oct 2007

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Berretta M et al., Oncologist, 2011

2nd Italian HCC in HIV study (2011)

Median survival:

HIV-pos. 35 mo

HIV-neg. 59 mo

Comparison Survival HIV(+) vs. HIV(-)

NMedian survival (mo)

Study HIV(+) HIV(‐) HIV(+) HIV(‐) pItaly (2004) 41 701 5.9 18.0 0.045North America (2007) 63 226 6.9 7.5 0.44Italy (2011) 104 484 35 59 0.048

Dallas (2012) 26 164 9.6 5.2 0.85Paris (2012) 23 46 18 26 0.2Bologna (2013) 48 234 16 30 0.035

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••

•••

• ••••

••

• ••••••• •

•••

• NAn=281

SAn=24

EURn=59

Liver Cancer in HIV Study GroupN=365 as of 05-May-2014

•AUSn=1

•

Does Screening for HCC in HIV/HCV Patients Improve Survival ?

Method:N=198 HIV/HCV patients with HCC

Diagnosis of HCC via Screening vs. Symptoms

Compare:* Staging* Therapy* Survival (adjust for lead-time bias)

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Screening for HCC in HIV/HCV Patients

Patient Characteristics

Screenedn=117(59%)

Not Screenedn=81(41%)

P

Age (yrs), Mean 52 54 0.082

Female Sex 4% 10% 0.162

Alcohol abuse 30% 50% 0.003

CTP Score: 6.6 7.7 <0.001

HIV parameters Median CD4+ cells (per mm3)

HIV RNA <400 copies/mL

344

79%

274

54%

0.027

<0.001

Fox RK, AASLD, Washington DC, Nov 2013


Screenedn=117

Not Screened

n=81P

Hepatic LesionsMultiple Tumors 42% 58% 0.035

Median Size Largest Tumor (cm)

3.0 5.2 <0.001

Portal Vein ThrombosisExtrahepatic Metastases

12%9%

31%28%

0.001<0.001

Meets Milan criteria for OLT

64% 29% <0.001

Tumor Characteristics

Screenedn=117

Not Screened

n=81

P

BCLC Stage, n (%)ABC } Advanced,D } Incurable

BCLC Stages C and D

44%17%27%11%

39%

7%20%43%30%

73%

<0.001

<0.001

HCC Tumor Staging


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Screenedn=117

Unscreenedn=81

P

Potentially Curative, n (%)Radiofrequency AblationPercutaneous Ethanol InjectionSurgical ResectionLiver Transplantation

Effective, Non-Curative, n (%)ChemoembolizationSorafenibSorafenib & Chemoembolization

No Therapy, n (%)

53 (46%)198

179

35 (30%)2843

28 (24%)

10 (12%)5221

17 (21%)1430

54 (67%)

<0.001

Any HCC Therapy 88 (76%) 27 (33%)


HCC Therapy


Screening for HCC in HIV/HCV Patients Survival – adjusted for lead-time bias (8.6 mo)

Median survivalScreened 19.2 moUnscreened 3.5 mo


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Screening for HCC in HIV/HCV Patients Cox Proportional Hazard Analysis


Risk FactorUnivariate

Hazard Ratiofor Death

Univar.P

Multi-Variable

H.R.for death

95% confid. Interval

Multi-var.P

Effective HCC Therapy 0.13 <0.001 0.21 0.13 – 0.35 <0.001

HCC Screening 0.22 <0.001 0.38 0.24 – 0.58 <0.001

BCLC stages A&B vs. C&D 0.36 <0.001 0.58 0.38 – 0.89 0.012

AFP (per 1000 ng/ml) 1.004 0.061

Alcohol abuse 1.84 0.001

CD4+ cells (per 100/mm3) 0.89 0.014

HIV RNA (per log10 copies/ml) 1.31 <0.001

Screening for HCC in HIV/HCV Patients Screening over Time

52% 49%

77%

0%

20%

40%

60%

80%

100%

1995 - 2004 2005 - 2008 2009 - 2013

p=0.002


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HIV Viral Load & Natural History of HCC

Hypothesis: HIV viremia negatively influences course of HCC

In HIV/HCV: More rapid progression of hepatic fibrosiswith HIV RNA 400+ Copies/ml

Fibrosis Progression Rate by HIV Viral Loadin chronic hepatitis C

Bräu N, J Hepatol, Jan 2006

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HIV Viremia: Influence on HCC Survival

HIV RNA <400 c/ml

n=254

HIV RNA400+ c/ml

n=93P

Age (yrs), Mean 53.8 52.0 0.078

Male Sex 234 (92%) 85 (91%) 0.83

Etiology of HCCHepatitic CHepatitis BNon-Viral (NASH, Alcohol)

201 (79%)49 (19%)4 (2%)

71 (76%)21 (23%)1 (1%)

0.78

Alcohol Abuse 57 (23%) 36 (41%) 0.001

Platelet count (1000/mm), Mean 146 163 0.16

Child-Pugh Score, Mean 6.6 7.5 <0.001

HCC Diagnosis via Screening 174 (69%) 41 (44%) <0.001

CD4+ Cells (per mm3), Median 347 244 <0.001

Citti, AASLD 2014, Boston MA



Median survival

HIV RNA <400 c/ml 19.8 monthsHIV RNA 400+ c/ml 5.4 months

At Risk

HIV RNA <400 254 107 60 35 23 10 4 3 2 1 1

HIV RNA 400+ 93 22 13 7 7 4 4 4 3 1 0

Survival at 1 yr 2 yrs

HIV RNA <400 c/ml 61% 46%HIV RNA 400+ c/ml 36% 27%

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Factor Univar.

H.R. for

Death

Univar.

P

Multi‐variable

H.R. for Death

95% Conf.

Interval

Multi‐var.

P

HCC Diagnosis through Screening 0.23 <0.001 0.35 0.25 – 0.49 <0.001

BCLC stages A&B vs. C&D 0.38 <0.001 0.58 0.41 – 0.83 0.003

Alcohol abuse 1.97 <0.001 1.64 1.18 – 2.28 0.003

Extrahepatic Metastases 2.59 <0.001 1.65 1.13 – 2.41 0.009

Portal Vein Thrombosis 1.51 <0.001 1.56 1.08 – 2.24 0.016

Child‐Pugh score (per unit) 1.26 <0.001 1.15 1.06 – 1.25 0.001

HIV RNA Level (per log10 cop./ml) 1.33 <0.001 1.16 1.03 – 1.30 0.013

CD4+ cell Count (per 100/mm3) 0.89 0.001

Platelet Count (per 100,000/mm3) 1.12 0.006

Solitary Liver Tumor 0.67 0.008

Multi-Variable Cox Regression Analysis


Total Cohort N=367 (100%)

Comparison of OLT with other curative therapies:

OLT n= 27 (7.4%)

Other Curative Therapy n=108 (29.5%)

Surgical Resection 51

Radiofrequency Ablation 45

Percutaneous Ethanol Inject. 12

Liver Transplantation for HCC in HIV

Platt H, AASLD 2014, Boston MA

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OLTn=29

Other Curative Rx

n=108P

Age (yrs), Mean 50.0 53.4 0.060

Etiology of HCCChronic Hepatitis CChronic Hepatitis BNon-Viral (Alcohol, NASH)

21 (78%)6 (22%)

0

84 (78%)22 (20%)2 (2%)

0.77

Excessive Alcohol 6 (22%) 26 (26%) 0.73

Child-Pugh score, Mean 6.8 5.8 0.026

HIV RNA <400 copies/mL 18 (82%) 85 (83%) 0.94

CD4+ Cells (per mm3), Median 322 423 0.36

OLTn=27

Other Curative Rx

n=108P

Hepatic Lesions Mulitple Tumors

Size Largest Lesion (cm), Median (Range)

15 (56%)

3.0 (1.3 – 5.6)

22 (20%)

2.85 (0.5 – 11)

<0.001

0.98

AFP level (ng/ml), Median

13.0 44.5 0.022

Extrahepatic metastases 0 7 (6.5%) 0.17

Meets Milan Criteria for OLT

21 (78%) 83 (80%) 0.82




Survival at: 2 yrs 5 yrs

OLT 92% 85%Other Cur. Rx 71% 52%

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OLT 92% 85%Other Cur. Rx 71% 52%


OLT 92% 85%Radiofrequ. Abl. 71% 68%Surg. Resection 77% --Ethanol Inject. 41% --

Vibert E et al., Hepatology, Feb 2011

Other Reports of Transplantation for HCC in HIV

Single center, Paris HIV(+) 21 16 OLT HIV(-) 65 58 OLT(76%) (89%)

Survival

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HCV Antiviral Therapy in HIV/HCV Coinfection

• Ledipasvir (NS5a) + sofosbuvir (NA) (Harvoni®)

• ERADICATE (N=50) GT 1 nv F0-F3

• ION-4 (N=355) GT 1 nv/exp 20% cirrh

•AbbVie 3D + RBV (Viekira Pak®)

• TURQUOISE-I (part A N=63) GT 1 nv/exp +/- cirrh

• Daclatasvir (NS5a) + sofosbuvir

• ALLY-3 (N=203) GT 1-6 nv 13% cirrh

• Grazoprevir (PI) + elbasvir (NNI)

• C-EDGE-Coinfection GT-1 -4 -6

LDV + SOF in GT1 Treatment‐Naïve HCV/HIV Coinfection: ERADICATE: Efficacy

ARV Untreated: LDV/SOF (n = 13)

ARV Treated: LDV/SOF (n = 37)

N = 50 GT1, TN Stable HIV

Study Weeks

SVR 12

12 24

Osinusi A, et al. JAMA. 2015 Feb 23. [Epub ahead of print].

SVR 12

100% 100% 100% 100% 100% 100%100% 100% 100%97% 97% 97%

0%

20%

40%

60%

80%

100%

Week 4 Week 8 EOT SVR4 SVR8 SVR12

% Patients with HCV RNA < LLO

Q

ARV Untreated (n = 13) ARV Treated (n = 37)

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LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION‐4: Study Design

N=335 LDV/SOF

Wk 0 Wk 12

Wk 24

Phase 3, multicenter (US, Canada, New Zealand)

HCV GT 1 + 4, nv/exp, 20% cirrhosis

HIV‐1 positive, HIV RNA <50 copies/mL; CD4 cell count >100 cells/mm3

ART regimens included FTC and TDF plus EFV, RAL, or RPV, no PIs

Naggie S, et al. NEJM 2015 [in press]

SVR12

LDV/SOF 12 Weeks

Overall Naïve vs Experienced Cirrhosis Status

96 95 97 96 94

0

20

40

60

80

100

SV

R12

(%

)

321/335 179/185 258/268 63/67142/150

CirrhosisNo CirrhosisExperiencedNaïve

LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION‐4: Efficacy


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LDV/SOF 12 Weeks

Overall Naïve vs Experienced Cirrhosis Status

96 95 97 96 94

0

20

40

60

80

100

SV

R12

(%

)

321/335 179/185 258/268 63/67142/150

CirrhosisNo CirrhosisExperiencedNaïve

LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION‐4: Efficacy


Stable CD4 counts through treatment and follow‐up phase

No patient had confirmed HIV virologic rebound

Overall safety

Patients, n (%)

LDV/SOF 12 WeeksN=335

AEs 257 (77)

Grade 3‒4 AE 14 (4)

Serious AE 8 (2)*

Treatment D/C due to AE 0

Death 1 (<1)†

Grade 3‒4 laboratory abnormality

36 (11)

LDV/SOF for 12 Weeks in HIV/HCV Coinfection ION‐4: Safety

Naggie S, et al. CROI 2015.

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Overall safety

Patients, n (%)


AEs 257 (77)

Grade 3‒4 AE 14 (4)

Serious AE 8 (2)*


Death 1 (<1)†


36 (11)





Overall safety

Patients, n (%)


AEs 257 (77)

Grade 3‒4 AE 14 (4)

Serious AE 8 (2)*


Death 1 (<1)†


36 (11)



Patients, n (%)

LDV/SOF 12 WeeksN = 335

Headache 83 (25)

Fatigue 71 (21)

Diarrhea 36 (11)

Nausea 33 (10)

Arthralgia 22 (7)

Upper respiratory tract infection 18 (5)

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■ Standard DCV dose is 60 mg daily– Dose-adjusted for concomitant ARV therapy: – 30 mg with ritonavir-boosted PIs, – 90 mg with NNRTIs except RPV

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

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

12

NaiveRandomize 2:1

Experienced

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

Week 0 8

N

101

50

52

SVR12*

DCV + SOF for 8 vs.12 Weeks in GT 1‐6 HIV/HCV Coinfection ALLY‐2: Study Design

Wyles D, et al. CROI 2015.

ALLY-2: SVR12

GT 1 (N = 168)

DCV + SOF for 8 vs.12 Weeks in GT 1‐6 HIV/HCV Coinfection ALLY‐2: Efficacy GT 1


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DCV + SOF for 12 Weeks in GT 1‐6 HIV/HCV Coinfection ALLY‐2: Efficacy GT 1 – 4


Event, n (%) 12-Week GroupsN = 153

8-Week GroupN = 50 Total

Deathsa 0 1 (2) 1 (0.5)

Serious AEsb 4 (3) 0 4 (2)

AEs leading to discontinuation 0 0 0

Opportunistic infections 0 0 0

Grade 3 or 4 lab abnormalities

INR > 2.0 x ULN 2 (1) 0 2 (1)

ALT > 5.0 x ULN 0 0 0

AST > 5.0 x ULN 0 1 (2) 1 (0.5)

Total bilirubin > 2.5 x ULNc 7 (5) 1 (2) 8 (4)

a One death of 52 year-old male with cardiac arrest at posttreatment Week 4 (not related to study therapy).

DCV + SOF for 12 Weeks in GT 1‐6 HIV/HCV Coinfection ALLY‐2: Efficacy GT 1 ‐ 4


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Event, n (%) 12-Week GroupsN = 153

8-Week GroupN = 50 Total

Deathsa 0 1 (2) 1 (0.5)

Serious AEsb 4 (3) 0 4 (2)

AEs leading to discontinuation 0 0 0

Opportunistic infections 0 0 0

Grade 3 or 4 lab abnormalities

INR > 2.0 x ULN 2 (1) 0 2 (1)

ALT > 5.0 x ULN 0 0 0

AST > 5.0 x ULN 0 1 (2) 1 (0.5)

Total bilirubin > 2.5 x ULNc 7 (5) 1 (2) 8 (4)

a One death of 52 year-old male with cardiac arrest at posttreatment Week 4 (not related to study therapy).

DCV + SOF for 12 Weeks in GT 1‐6 HIV/HCV Coinfection ALLY‐2: Efficacy GT 1 ‐ 4


3D + RBV in GT 1 HCV/HIV CoinfectionTURQUOISE‐I: Study Design

3D + RBV (n = 32)

3D + RBV (n = 31)

SVR12Open-label Treatment

SVR12

Day 1 Week 12 Week 24 Week 36

Key Eligibility Criteria: HCV GT1 infection, HCV treatment‐naïve or PEG/RBV‐experienced, Child‐Pugh A cirrhosis allowed, stable HIV‐1 infection on ATV or RAL‐inclusive ART regimen

Sulkowski MS, et al. JAMA. 2015 Feb 23. [Epub ahead of print].

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100%97%

94% 94%100%

97%94%

91%

0%

20%

40%

60%

80%

100%

RVR EOTR SVR4 SVR12

% P

atie

nts

3D + RBV 12-week 3D + RBV 24-week

(Week 4) (Week 12 or 24)

31/31 32/32 30/31 31/32 29/31 30/32 29/31 29/32

3D + RBV in GT 1 HCV/HIV CoinfectionTURQUOISE‐I: Efficacy

Sulkowski MS, et al. JAMA. 2015 Feb 23. [Epub ahead of print].

Summary: HIV and Hepatitis Coinfection

•HIV accelerates HCV liver disease if HIV RNA pos.

* Accelerated fibrosis progression * accel. cirrhosis liver failure * accel. liver failure death

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• HCC is on rise on HIV+ pts.

* discrepant data on survival vs. HIV- pts. * HIV viral load correlates with survival * Screening with better survival * High survival with OLT




• HCC is on rise on HIV+ pts.

* discrepant data on survival vs. HIV- pts. * HIV viral load correlates with survival * Screening with better survival * High survival with OLT

• High efficacy of DAA combinations in HIV/HCV with good tolerability

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Thank you for your kind attention

Management of HIV / HCV Coinfection - Albany Medical … · 2015-07-23 · Management of HIV / HCV...

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Transcript of Management of HIV / HCV Coinfection - Albany Medical … · 2015-07-23 · Management of HIV / HCV...