HIV/HCV co-infectioncurrent and future

management

Sanjay BhaganiConsultant Physician/Senior Lecturer

Dept of Infectious Diseases/HIV MedicineRoyal Free Hospital/University College London

Mortality of HIV-infected patients in France (GERMIVIC

Study Group)

0

5

10

15

20

Per

cen

tag

e

1995(n=17,487)

1997(n=26,497)

2001(n=25,178)

2003(n=20,940)

Overall mortality AIDS-assoc. Mortality Liver disease assoc. mortality

Rosenthal et al. AASLD 2004; Abstract 572.

Overlapping HCV & HIV epidemics

40 million 175

million

10 million

HIV HCV

Epidemic of Acute HCV among HIV+ MSM-beyond Europe...and

continuing.....

1. Luetkemeyer JAIDS 2006; 2. Danta AASLD 2008; 3. Jones 4th Works. HIV & Hep. Coinf. 2008; 4. Fisher CROI 2007;5. Stand 01/2009; 6.Gambotti Euro Surveill 2005; 7. Larsen AASLD 2007; 8. van de Laar JID 2007;

9. Rauch CID 2005; 10. Gallotta 4th Works. HIV & Hep. Coinf. 2008; 11. pers.com.; 12. Matthews , CID 2009

Europe:– UK2,3,4 – Germany5 – France6,7 – Netherlands8 – Switzerland9 – Italy10

– Belgium11

Australia12:

USA1,2:

HCV-seroconversion may be delayed

• Median time from HCV RNA to Ab(+) = 91 days (0-1206)

• 10% Ab(-) after 9 months

• 5% Ab(-) after 12 months

• Low ALT/low nadir CD4 associated with delayed/null AB response

Thomson E, et al. AIDS 2009; 23: 89-93

Natural course of acute HCV infection

1. Acute Hepatitis C takes a chronic course more frequently in HIV infected individuals (II)

2. Spontaneous clearance of acute HCV in HIV patients occurs in 0 – 40% (III) and is associated with

a) Host genetic factors (IL28b-CC genotype) and stronger adaptive immune responses. (II)

b) Female sex, exposure group (sexual transmission vs. IVDU), HBsAg+, jaundice and higher peak ALT (II)

c) Early decline of HCV-RNA 4-8 weeks after presentation (III)

Natural Course AHC in HIV-positiveC.NEAT Cohort, 92 untreated patients

Vogel et al. CROI 2010, Poster 640

Week 4 HCV-RNA may be predictive for negative HCV-RNA at week 24 (=spontaneous clearance)

Sensitivity analysis classifying missing = failure reduced NPV of a pRVC to 78%

pRVC partial rapid virological control 2 log drop of HCV-RNA at week 4

cRVC complete rapid virological control HCV-RNA < 615 IU/ml at week 4

cEVC complete early virological control HCV-RNA < 615 IU/ml at week 12

Clearance HCV-RNA < 615 IU/ml week 24

4842

66

40

0

10

20

30

40

50

60

70

pRVC cRVC cEVC Clearance

Pe

rce

nt

of

Pa

tien

tsClearance

chronic HCV

predictive value

pRVC 22 3 PPV 88%

no pRVC 4 23 NPV 85%

cEVC 32 4 PPV 89%

no cEVC 2 23 NPV 92%

Managing Acute HCV in HIV+The NEAT consensus

Decay HCV-RNADecay HCV-RNA

HCV-RNA HCV-RNA

wait: cont´d controls

throughout week 48

wait: cont´d controls

throughout week 48

Initial presentation

acute HCV

Initial presentation

acute HCV

2 log10

negative

< 2 log10

positive

TreatmentTreatment

TreatmentTreatment

Week 4Week 4

Week 12Week 12

EACS Guidelines 2011Screening and counselling

• All HIV+ patients should be screened for HCV at diagnosis, and then on an annual basis– HCV RNA in those with a high index of suspicion and a negative

HCV-AB test

• Those at high risk of HCV-infection (ongoing IVDU, unprotected mucosal traumatic sex, unprotected anal intercourse, recent STD) with unexplained rise in hepatic serum aminotransferases– HCV-Ab– If HCV-Ab negative – test for HCV RNA for early identification

• Since HIV and HBV and occasionally HCV are sexually transmitted counselling regarding safe-sex practices should be provided

Consideration for treatment with anti-HCV therapy in HIV/HCV co-infected

patientsPertinent issues:

• Natural history of liver disease and liver associated mortality

• Effect of HAART• Response rates to PegIFN-alpha and

ribavirin• Predictors of response• Current guidelines – who to treat and

when to start?• Future…..

Effect of HIV/HCV co-infection on fibrosis rateEffect of HIV/HCV co-infection on fibrosis rate(Benhamou et al 1999)

0

0.5

1

1.5

2

2.5

3

3.5

4

10 20 30 40

HIV + Matched controls Simulated controls

Fibrosis progression influenced by• CD4 cell count (< 200 cells/microlitre)• Age at infection ( > 25 years)• Male sex• Alcohol consumption ( > 50g/d)

Fibro

sis

Sco

re

Impact of HIV RNA, CD4, or Both on Liver Fibrosis

Progression Rate

0.08

0.1

0.12

0.14

0.16

0.18

0.2

HIV RNAHIV RNA(copies/mL)(copies/mL)

0.1220.122

Ish

ak F

ibro

sis

Un

its/Y

ear

Ish

ak F

ibro

sis

Un

its/Y

ear

Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.

0.1450.145

0.1960.196

0.1210.121

0.1550.155

0.1230.123

0.1620.162

PP=0.53=0.53

PP=0.04=0.04

PP=0.005=0.005

PP=0.005=0.005 PP=0.005=0.005

<400 400-99K <400 400-99K >>100K 100K >>350 <350 <400 350 <350 <400 >>400400

CD4CD4(cells/mm(cells/mm33))

HIV RNA HIV RNA (copies/mL)(copies/mL) + +<500 CD4 cells/mm<500 CD4 cells/mm33

HIV/HCV – complex immune interactions

Klenerman P, Kim A. PLOS Med 2007; 4: 1608-1614

Immune activation and liver disease

HIV -> GIT CD4+ T-cell depletion

Immune activation

IL-1TNF-IFN-IL-12

Hepatic fibrosisHSC activation

Microbial translocation LPS

DCs

macrophage

CirrhosisHCVAlcohol

Altered portal vein circulation

Mathurin et al., Hepatology 2000; 32:1008-1017; Paik et al., Hepatology 2003; 37:1043-1055; Balagopal et al., Gastroenterology 2008; 135:226-233.. Slide Courtesy Prof S Lewin

HIV-HCV

Alcohol

HBV

Haemochromatosis

HCV

Steatosis BMI>25

2PBC0.00

0.17

0.33

0.50

0.67

0.83

1.00

0 20 40 60 80

Haza

rd f

un

ctio

n

4682 patients

Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265

Age in years

Progression to cirrhosis

HIV/HCV - Cirrhosis and survival

Pineda et al. Hepatology 2005

So what effect does HAART have?

A) Overall-Mortality

Observation time[days]]

500040003000200010000

Cu

mu

lati

ve s

urv

ival

1,1

,9

,7

,5

,3

P<0.0001

Patients with HAART

Patients with ART

untreated Patients

6000

Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 13794 49 37 32 27

6000500040003000200010000

1,1

,9

,7

,5

,3

B) Liver-related-Mortality

P<0.018

Patients with HAART

Patients with ART untreated Patients

Overall and Liver-related Mortality - effect of HAART

Qurishi N et al. Lancet, 2004

Cu

mu

lati

ve s

urv

ival

Observation time[days]]

Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 13794 49 37 32 27

Effect of HAART on progression to ESLD – a meta-analysis

PRE-HAART POST-HAART

Thien, H et al. AIDS 2008; 22: 1979-1991

Hepatotoxicty by co-infection status

1. Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88

Interactions were not significant between drug CLASS and CO (p=0.800)

N arms 11 7 4 12 9 3 14 10 4 11 6 5 5 3 2 53 35 18 N patients 581 1242 2705 2038 1055 7621 244 737 2321 630 572 4504 337 505 384 1408 483 3117

0

10

20

30

40

NNRTI PI Mixed BPI NRTI Overall

Drug Class

% P

ati

en

ts w

ith

LEE

All Patients HCV Coinf HIV Only

Lipohypertrophy (fat accumulation)•Dorsocervical fat pad enlargement (buffalo

hump)

•Central or abdominal obesity

•Breast enlargement

Lipoatrophy (fat wasting or loss)•Arms and/or legs ( prominence of veins)

•Face

•Buttocks

Insulin Resistance and Hyperlipidaemia•Diabetes and impaired GTT

•Hypercholesterolaemia and hyperlipidaemia

John M, Nolan D, Mallal S. Antiviral Therapy 2001; 6: 9-20.JIAPAC Supplement, Winter 2001.Behrens GMN, Stoll M, Schmidt RE. Drug Safety 2000; 23(1): 57-76.

Lipodystrophy

Insulin Resistance and hepatic fibrosis in HIV/HCV co-infected patients

Merchante N, et al. Gut 2009

What about response to anti-HCV therapy?

HCV/HIV treatment outcomes

0

25

50

75

100

G1 G2/3

Monoinfection

APRICOTACTGRIBAVIC

Laguno et al.PRESCO

Genotype 1SVR 14–38%

Genotype 3SVR 44–73%

Genotype

SV

R (

%)

Fried et al, NEJM 2002, 347: 975-982, Torriani et al, NEJM 2004; 351: 438-50, Chung R, et al, NEJM 2004: 351; 451-9, Carrat F, et al, JAMA 2004: 292: 2839-42, Laguno et al, AIDS 2004; 18: F27-F36, Nunez et al, JAIDS 2007: 45: 439-44

Acute HCV/HIV: Overall virological responses:

64%

74%71%

66%

42%

RVR w12(pcr- ) w12(EVR) EOT SVR

133 = 56 89 95 99 85Bhagani et al. 3rd Int HIV/Hepatitis co-infection meeting, Paris 2007,

Vogel et al Antiviral Therapy (in press) 2010

Predictors of response to PegIFN and Ribavirin in co-infected

patientsHost Factors Viral Factors Younger Age Non-Genotype 1 and 4

Ethnic Group (Caucasian) HCV viral load <400000 –800000 IU/ml IL28b SNP (CC at rs12979860)

Low Body Mass Index Treatment Associated Factors Minimal hepatic fibrosis Weight-based ribavirin Lack of hepatic steatosis RVR

Lack of previous or current IDU Lack of dose reduction ?CD4 count (%) ?ribavirin trough concentration at week 4

?lack of Insulin Resistance

Gt 1 (n = 150)

34

162729

Gt 2/3 (n = 78)

47

73

62 69

CD4+ Count and Efficacy of Peg-IFN alpha and RBV

APRICOT: Dieterich D, et al. ICAAC 2006. Abstract H-1888.

0

20

40

60

80

100

Pts

Wit

h S

VR

(%

)

Q4 (32.1% to 69.3%)

Q1 (2.5% to 19%)

Q2 (19.1% to 25.0%)

Q3 (25.0% to 32.1%)

Avidal, et al. JAIDS 2009

Ribavirin-Related Anaemia:HIV Coinfection

Torriani F, et al, N Engl J Med. 2004;351:438.

PEG-IFN 2a (180 µg/wk) + RBV (800 mg/d)

40%

25%

3.80%

16% 16%

10%

0%

20%

40%

60%

SVR Early D/C All

Severe Anemia (Hb < 8.5 g/dL)

Early D/CAnemia

RBV Dose Reduction For Anemia

EPO

Interactions between RBV & nucleoside analogues

AZT ddI d4T

anemia hepatic pancreatitis weight

decomp. & lactic acidosis loss

mitochondrial DNA synthesis lactate

Blanco et al. NEJM 2002; 347: 1287

Abacavir and SVR

• SVR predicted by– Genotype– Viral load– RBV trough

concentrations

• Abcavir use associated with NR/NSR in patients with low rbavirin trough concentrations

Vispo et al, 3rd Int. HIV/hepatitis Conference, Paris 2007. Abs 46

EACS 2011 - HCV treatment • Patients with acute HCV – treat if HCV RNA

persistently detectable 12 weeks after putative time of infection

• Chronic HCV – offer treatment to ALL (biopsy/staging/grading NOT essential)– Those with CD4 <350 – reasonable to give HAART

first– Use HAART with low potential for hepatotoxicity– Manage insulin resistance actively

• Those with F0/F1 fibrosis, especially if G1/G4– If CD4 <500 – early HAART

– reasonable to wait in terms of Anti-HCV Rx – but frequent monitoring

Proposed optimal duration of HCV therapy in chronic HCV/HIV-coinfected patients.

W4 W12 W24 W48 W72

HCV-RNAneg

HCV-RNApos

> 2 log dropin HCV-RNA

< 2 log dropin HCV-RNA

HCV-RNAneg

HCV-RNApos

G2/3

G1/4

Stop

Stop

G2/3

G1/4

24 weekstherapy *

48 weekstherapy

72 weekstherapy

* In patients with baseline low viral load and minimal liver fibrosis.

Rockstroh, et al, EACS Guidelines 2011

Rx algorithm for acute HCV in HIV+

NEAT Consensus 2010

*evidence based on using a 615 IU/ml cut-off to define negative HCV-RNA

HCV-RNA

negative*

HCV-RNA

negative*

Stop TherapyStop Therapy

Peg-IFN +

RBV (AII)

Peg-IFN +

RBV (AII)

< 2 log10

24 weeks of therapy24 weeks of therapy

Drop HCV-RNA

2 log10

Drop HCV-RNA

2 log10

Week 4Week 4 Week 12Week 12

HCV-RNA

positive*

HCV-RNA

positive*

48 weeks of therapy48 weeks of therapy

HIV/HCV 2011

HIV/HCV co-infection

•Early reversal of Immune suppression

•Use non-toxic agents

Address Co-factors:•Alcohol

•Hepatic Steatosis•Insulin Resistance

•Identify early• Rx – ‘early’/acute

Chronic HCV- Rx:•Max dose Ribavirin

•Interactions•Avoid dose-reductions

•Kinetics based Rx length

Patient Education – avoid infection

Ge D et al. Nature 2009; 461(7262):399-401

DL Thomas et al. Nature 461, 798-801 (2009) doi:10.1038/nature08463

Sampling locations, allele frequencies and degree of regional differentiation of the rs12979860 C allele.

Pineda et al, CROI 2010

IL28B SNPs and HIV/HCV co-infection

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation andpolyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotideNonnucleoside

*Role in HCV life cycle not well defined

NS5A* inhibitors

Select DAAs in Clinical Development

Phase I Phase II Phase III

Protease Inhibitors ABT-450ACH-1625GS 9451MK-5172VX-985

BMS-650032CTS-1027DanoprevirGS 9256IDX320Vaniprevir

BI 201335BoceprevirTelaprevirTMC435

Nonnucleoside polymerase inhibitors

BI 207127IDX375

ABT-333ABT-072ANA598BMS-791325FilibuvirTegobuvirVX-759VX-222

Nucleoside polymerase inhibitors

IDX184PSI-7977RG7128

NS5A inhibitors A-831PPI-461

BMS-790052BMS-824393CF102

SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Experienced

mono-infected Pts

0

20

40

60

80

100

SV

R (

%)

Treatment-Naive Pts

Treatment-Experienced

38-44[1-2]

17-21[3-4]

Current Standard of Care

0

20

40

60

80

100

SV

R (

%)

63-75[1-2]

59-66[3-4]

SOC + Protease Inhibitors (Approved in 2011)

1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3. Bacon BR, et al. AASLD 2010. Abstract 216. 4. Foster GR, et al. APASL 2011. Abstract 1529.

Treatment-Naive Pts

Treatment-Experienced

RESPOND-2: SVR Rates According to Treatment Arm and Prior Response

0

20

40

60

80

100

Overall

SV

R (

%)[1

]

4-wk PR + 44-wk BOC + PR (n = 161)

59*

PriorNonresponders

PriorRelapsers

48-wk PR (n = 80)

4-wk PR + response-guided BOC + PR (n = 162)

66

21

40

52

7

75

29

69

P < .0001 vs control

(both arms)

*46% of patients inresponse-guided arm

eligible for shorter duration of therapy, with 86% SVR rate.[2]

Bacon BR, et al. AASLD 2010. Abstract 216.

Study 107: TVR Re-treatment of Pts With PegIFN/RBV Failure in PROVE

1/2/3 Trials

Berg T, et al. EASL 2010. Abstract 4.

Relapse SVRRVR

0

20

40

60

80

100

Prior Null Responders*

(n = 51)

Pat

ien

ts (

%)

41

Prior Partial Responders†

(n = 29)

Prior Virologic Breakthrough

(n = 8)

37

24

86

55

26

88

0

75

93

3 (1/29)

97

Prior Relapsers(n = 29)

*Null responders: Wk 4 HCV RNA reduced by < 1 log10 IU/mL; Wk 12 HCV RNA reduced by < 2 log10 IU/mL.†Partial responders: HCV RNA reduced by ≥ 2 log10 IU/mL at Wk 12, but HCV RNA detectable at Wk 24.

n= 21 196/25 25 16

6/23 7 6 27 28

Complex Kinetic Guided Rx lengths with TVR and BOC

• Stopping Rules– Week 4 or week 12 HCV RNA >1000 U/l– ?week 12 detectable

W4 W8 W12 W24 W48

RxNaïve/Relapsers

PartialResponders/Non-Responders(and HIV+)

PIFN + Ribavirin + TVR

PIFN + Ribavirin + TVR

P + R

P + R

P + R

eRVR+

eRVR-

BOV- kinetic guided Rx length

• Stopping Rules– Week 4 HCV RNA <1 log drop– week 12 >100 U/l

W4 W8 W12 W28 W36 W48

RxNaïve

PartialResponders/Relapsers

P + R

P + R

PIFN + Ribavirin + BOV

PIFN + Ribavirin + BOV P + R

PIFN + Ribavirin + BOV

PIFN + Ribavirin + BOV P + R

eRVR+

eRVR-

eRVR- (and ?HIV+)

eRVR+

Other issues with NS3/4 inhibitors

• Side-effect profiles– TVR – rash– BOC - anaemia

• Potential for drug-drug interactions with anti-HIV drugs– TVR – ONLY use with Atazanir/R and EFV– BOC – significant interaction with EFV, ?interaction with

boosted-PIs

• Genotype 1 specific activity

• Resistance

Activity of PIs by HCV Genotype

Agent Potential Activity

Protease InhibitorsBoceprevir[1,2] 1, 2

Telaprevir[3,4] 1, 2

BI 201335[5] 1, 2?

Danoprevir[6] 1, 2?

MK-5172[7] 1-6

TMC435[8] 1, 2, 4, 5, 6

Vaniprevir[9] 1, 2?

1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Pawlotsky JM, et al. Gastroenterology. 2011[epub ahead of print]. Abstract 820. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Foster G, et al. EASL 2010. Abstract 57. 5. Sulkowski M, et al. EASL 2010. Abstract 1190. 6. Terrault N, et al. AASLD 2010. Abstract 32. 7. Petry A, et al. AASLD 2010. Abstract 807. 8. Fried M, et al. AASLD 2010. Abstract LB-5. 9. Manns MP, et al. AASLD 2010. Abstract 82.

Resistance to DAAs - summary

Class GeneticBarrier

CrossResistance

Persistence

NS3/4 Low (1b>>1a) yes Yes but at low level

NS5b Nucs high Prob. no unlikely

NS5b Non-nuc Low No Yes - ?high level

NS5a High (1b>1a) yes ??

Cyclophilininhibitors

high yes unlikely

What do we need to think about in the coming months

• Treat now with PegIFN and Ribavirin or wait?

• Who should we prioritise for Rx with available DAAs?

• Characterisation of drug-drug interactions• Predictors of response to triple therapy• What is the significance of HCV resistance

mutations• How can we encourage Pharma to prioritise

trials in HIV/HCV and patients to take part in clinical trials

HCV Rx landscape – the future?

2011 2013 2015 2018

pIFN + R + PIpIFN + R(g3/g2 + acute HCV)

Use of IL28BP/R lead-in phaseResponse guided therapy

DAA + P + R2DAAs + P2DAAs + R2DAAs + P+R

2012 2014 2016 2017

HCV resistance testing - Rx failure/rebound - baselineUse of other SNPs to Predict side-effectsIFN-lambda – IFN of choice?

3 or more DAAsInduction/consolidationRegimensShort duration of Rx

IFN-alphaHistorical therapy!