New Paradigms in the management of HIV/HCV

co-infected patientsSanjay Bhagani

Royal Free HospitalLondon

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 Hep C

Prevalence of Hepatitis C (1685/4957 patients = 33.9%)

South: 623 = 44,9 %

North: 346 = 24,5 %

Central: 280 = 22,9 %

East: 412 = 47,7 %

Rockstroh J et al.,

EACS 2003; F12/4

Significant increase in new acute HCV infections amongst HIV+MSM

since 2001

• Test for trend p-value using Poisson regression p<0.001

• Error bars = 95% CI

Incid

en

ce o

f acu

te H

CV

in

fecti

on

/1000 p

t yrs

0

5

10

15

20

25

30

1997 1998 1999 2000 2001 2002 2003

Browne RE, et al. 2nd IAS 2003; Abstract 972

Acute HCV among HIV+ - beyond Europe....

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

:

( ) Germany, ( ) France, ( ) Australia. Australian MSM with reported IDU are marked IDU*

Cluster 1

Cluster 4

Cluster 3

Cluster 5

Cluster 7

Cluster 10

0.02

Genotype 1a

Genotype 4d

Cluster 1

Cluster 4

Cluster 3

Cluster 5

Cluster 7

Figure 1: NS5B phylogeentic tree of HCV genotypes 1a (left) and 4d (right) Monophyletic clusters are shaded, country of origin:( ) England, ( ) The Netherlands

0.020.02

Cluster 2

Cluster 6

0.02

Cluster 8

Cluster 2

Cluster 6

0.020.02

Genotype 4d

IDU*

IDU* IDU*

IDU*

IDU*

IDU*

Pair A

Pair C

Pair B

IDU* IDU*

Van der Laas et al. Gastroenterology 2009

Summary

Group SexSexual practice

Drug practice

High-risk practices

Internet

Shared implements

‘Club drugs’

STIDanta et al, AIDS 2007

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

gra

de

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

Physiology of hepatic fibrosis

Liver cellinjury

Chronicnecroinflammatory

responseHSC

(activated)

HSC(quiescent)

PDGFTGF-

ECM

HSC proliferationProgressive fibrosis

HCV

TNF-IL-1

KCKC

HIV & Hepatic Stellate Cells: implications for fibrosis in HIV/HCV

co-infected patients

Friedman SL and Arthur, Science and Medicine 2002; Tuyama AC, et al., Hepatology 2010; 52: 612-622.

Hypothesis: Hepatic Stellate Cellsare a cellular target of HIV

Activated HSC with fibrosisNormal liver

HIV/HCV – complex immune interactions

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

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

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

Hepatotoxicity 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

atie

nts

wit

h L

EE

All Patients HCV Coinf HIV Only

Reduced risk of ART-induced hepatotoxicity after HCV clearance

Labarga P et al. JID 2007;196:670–6

0 25 50 75 100 125 150

Follow-up (months)

8943

3825

115

74

64

34

01

Number of patientsNo:Yes:

0

20

40

60

80

100

Cu

mu

lati

ve i

nci

den

ceo

f h

epat

ic e

ven

ts (

%) Sustained HCV clearance

NoYes

Log Rank: 14.01 (p <0.001)

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/NASH and hepatic fibrosis in HIV/HCV co-infected patients

Merchante N, et al., Gut 2009 Sterling R, at al. Hepatology 2008

Main reasons to treat chronic HCV in HIV-infected patients

• HAART treated HIV patients live longer

• Faster progression to liver cirrhosis

• Increased mortality due to end stage liver disease

• Higher risk of hepatotoxicity following treatment with ART drugs

HCV/HIV HCV/HIV TREATMENT OUTCOMES

SVR 14-38% SVR 44-73%

Genotype 1 Genotype 3

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

Acute HCV in HIV: finding the balance

• Waiting long enough to reliably identify those that will clear virus spontaneously

• Not delaying treatment for those going on to develop ‘chronic’ infection

Acute HCV in HIV+ patients management: NEAT consensus

2010 (1)1) HCV RNA levels should be measured at initial presentation

and 4 weeks later. (BII)

2) Treatment should be offered to

a) Patients without a decrease of 2 log of HCV RNA at 4 weeks when compared with HCV RNA at diagnosis . (BII)

b) Patients with persistent serum HCV RNA 12 weeks after diagnosis of acute hepatitis C. (AII)

3) Patients showing spontaneous HCV RNA clearance before and after 12 weeks should be followed with serial HCVRNA assay until 48 weeks after onset in order to confirm resolution of acute hepatitis C. (AIII)

Acute HCV in HIV+ patients management: NEAT consensus

2010 (2)I) Pegylated-interferon and weight-based ribavirin is

recommended for the treatment of acute HCV in HIV-infected patients. (AII)

II) Duration of treatment should be based on RVR (negative HCV RNA at week 4).

a) In patients with RVR treatment duration should be limited to 24 weeks. (AII)

b) In patients without RVR treatment duration of 48 weeks should be considered. (BIII)

c) In non-RVR patients who do not show a 2log drop in HCV RNA at week 12 treatment can be discontinued. (BIII)

APRICOT – Peg IFN 2a + Ribavirin APRICOT – Peg IFN 2a + Ribavirin arm SVR by genotype and viral arm SVR by genotype and viral

loadload

40

29

62 61

18

61

0

10

20

30

40

50

60

70

Overall G1 G2/3 low G1 High G1 Low

High > 800 000 iu/l Low < 800 000 iu/lTorriani et al, NEJM 2004

APRICOT: SVR rates according APRICOT: SVR rates according to exposureto exposure

Genotype 1 recipients of peginterferon alfa-2a plus ribavirin

39%

SV

R r

ate

(%

)S

VR

rate

(%

)

≥80/80/80exposure

0

10

20

30

40

50

11%

<80/80/80exposure*

62

29%

Allpatients

n = 176

114

*Patients violated the rule if ≥1 of the three targets were not achieved Opravil M, et al. 45th ICAAC 2005; Abstract

2038

Gt 1 (n = 150)

34

162729

Gt 2/3 (n = 78)

47

7362 69

APRICOT: Baseline CD4+ Count and Efficacy of Peg-IFN alpha-

2a Plus RBV• Retrospective analysis of HIV/HCV-coinfected patients treated with

peg-IFN alpha-2a + RBV in APRICOT

• SVR rates analyzed in overall population and within genotypes according to baseline CD4+ cell count quartiles (Q1-Q4)

• Rate of SVR varied according to CD4+ cell percentage quartile in genotype 1 but not in genotypes 2/3

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%)

Predictors of response

Host

Acute infectionYounger ageLack of stage 3/4 fibrosisEthnicity – genetic??Low BMILack of hepatic steatosisHigh CD4 %Lack of insulin

resistance?

Virus

Genotypes 2/3Low viral loads

Thio C, Thomas D. Gastroenterology 2010

IL28B SNPs and SVR in HIV/HCV

Pineda, et al. CID 2010 (in Press)

Chromosome 20 SNPs and Ribivirin associated Anaemia

Viral Dynamic response to interferon and Viral Dynamic response to interferon and ribavirinribavirin

Pawlotsky Hepatology 2002; 32(4)

APRICOT: week 12 – genotype 1 ≥2 log10 drop HCV RNA

● Genotype 1 patients (n=176)

SVR: n=50

PPV=45%

No SVR: n=60 (55%)

SVR: n=1 (2%)

No SVR: n=65

NPV=98%

n=66(37%)

n=110(63%)

Yes

No

Torriani F, et al. 45th ICAAC 2005; Abstract 1024

≥2 log10 drop or undetectable

HCV RNA

Does RVR predict response?(week 4 undetectable HCV

RNA)• APRICOT

– PPV 82%– NPV 79%

• RIBAVIC– PPV 97.5%– NPV 81.3%

• PRESCO– Lack of RVR independent

predictor of relapse

• Crespo M et al.– G3 patients with RVR low

rates of relapse with 24 weeks of therapy

• ROMANCE– G2/3 patients without RVR

need longer Rx (48 weeks)

How can we maximise How can we maximise response to therapy?response to therapy?

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

29

45

20

52

31

38

0

10

20

30

40

50

60

% p

atie

nts

ach

ievi

ng

SV

R

ITT RBV <13.2mg/kg/day

RBV ≥13.2mg/kg/day

Patients (n=256) taking 1 PI or 1 NNRTI and ABC plus LDV or TDF plus LDV or FTC as

N(t)RTI backbone during HCV therapy

ABC TDF

Mira JA, et al. J Antimicrob Chemother 2008; 62(6): 1365–1373 Medscape® www.medscape.com

ABC

ABV-MP

Adenylosuccinatesynthase-lyase

RBV

RBV-MPCBV-MP

Adenylate kinase

Guanylate kinase

RBV-DPCBV-DP

Nucleoside diphospho-kinase

RBV-TPCBV-TP

p=0.02p=0.02 p=0.03p=0.03 p=0.4p=0.4

Dose of Ribavirin?Dose of Ribavirin?

Importance of weight-based Ribavirin(1000mg <75kg/1200mg >75kg)

Soriano, et al. AIDS 2007. 21: 1073-89

Extended duration of Extended duration of therapy?therapy?

• Retrospective analysis of genotype 1 patients receiving 48 weeks of pegIFN alfa-2a + RBV (N = 453)

Longer Duration of Undetectability on Treatment Increases Chance

for SVR

HCV RNA Positive

at Week 24

4 12 24Week Became HCV RNA Negative

91

66

45

2

Ferenci P, et al. J Hepatol. 2005;43:425-433.

20

40

60

80

100

SV

R (

%)

0

Treatment of Chronic Treatment of Chronic HCVHCV

Extending TherapyExtending Therapy

6152

32

45

0

20

40

60

80

48 72

Weeks of Treatment

% H

CV

RN

A (

-)

EOT

SVR

Extending the duration of therapy reduced relapse from 47% to 13%

Sanchez-Tapias et al. AASLD 2004. Abstract 126.

Results (On Treatment analysis)

56

15(8%)

36(80%)

9(16%)

Voluntary withdrawals (64) 4(4%)

Short arm

Extended arm

PRESCO

192 45 96No. of patients (389)

31%

53%

67%

82%

G 1/4

G 2/3

5924

4664

p=0.004

p=0.04

Induction or higher Induction or higher doses of Peg-IFN?doses of Peg-IFN?

• 270 mcg vs. 180 mcg PegIFN – alpha 2a + R (1000mg/1200mg) for 4 weeks followed by 180mcg + R

• No difference in RVR or EVR

Untreated Follow-up

SLAM-C trial in HIV–HCV co-infected non-responders (Sherman)

Peg-IFNα-2a 180 µg plus

RBV 800–1200

mg

HCV RNA 2 log dropNR and

naïve n=200

HCV RNA

<2 log drop12 weeks

Peg-IFNα-2a 180 µg plus

RBV 800–1200 mg

Peg-IFNα-2a 180 µg

Stop treatment, observation period

60 weeks

72 weeks

24 weeks

Randomisation

Slam-C results

• Interim analysis April 2007– 45 patients with paired liver biopsies in the non-

EVR arm

• Insufficient fibrosis progression to determine a difference between the groups

• BUT – HALT-C results– No sig. reduction in fibrosis or diff between arms– No reduction in primary end-points

Sherman et al, CROI 2008

Anti-HCV drugs in development

Slide courtesy Tracy Swann 2010

Slide courtesy Tracy Swann 2010

NS5A inhibitors

Slide courtesy Tracy Swann 2010

Nitazoxinide

Slide courtesy Tracy Swann 2010

New Interferons

Slide courtesy Tracy Swann 2010

Even the best are only human……

Pertinent issues with the Stat-Cs

• NS3/NS4 PIs – cytochrome P450 metabolised – anti-HIV PIs/NNRTIs

• NS5b – Nucleosides – potential interaction with anti-HIV NAs

• NS5b – Non-nucleosides – Cyp450 interactions?

• Very high HCV mutation rates – rapid emergence of drug resistance

• Potential for X-resistance amongst classes• Mutations not archived but continued

circulation dependent on fitness

Take home messages:• HIV/HCV co-infection is common• Increasing incidence of acute HCV• ESLD major cause of morbidity/mortality• Early HAART beneficial

– Avoid d-thymidine analogues/AZT

• Treat HCV with PegIFN and Ribavirin– Best results if HCV treated in the acute phase– Maximal doses of Ribavirin (1000/1200mg)– Avoid AZT, d4T and DDI, – ?Avoid Abcavir– EPO and G-CSF – avoid dose reductions

Take home messages:• Duration of therapy individualised

– Genotype– Pre-Rx viral load– Fibrosis stage– RVR/EVR

• No role for maintenance low-dose IFN• Give some thought to hepatic steatosis

• New anti-HCV drugs (STAT-Cs!) will be available in the future…

• …be careful out there….!!!

Proposed optimal duration of HCV therapy in 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, Bhagani, Bruno et al, EACS Guidelines 2008