current treatment of hepatitis c in hiv co-infected patients dominique salmon internal medicine...

Current treatment of hepatitis C in HIV co-infected patients

Current treatment of hepatitis C in HIV co-infected patients

Dominique SALMONDominique SALMON

Internal Medicine Department, COCHIN HospitalInternal Medicine Department, COCHIN Hospital

Paris, FRANCEParis, FRANCE

12th ISVHLD - ANRS Co-infection day, July 5, 200612th ISVHLD - ANRS Co-infection day, July 5, 2006

Main points

Chronic HCV infection Candidates Pre therapeutic assessementPeg IFN and RBV dosesTreatment durationManagement of adverse events

Acute HCV infection

Candidates and Pretherapeutic assessement

Candidates to therapy

• All HCV chronically infected patients should be offered treatment if the benefits outweigh the risks

• CD4 < 200/mm3 : treat HIV first

• Alcoholics : - same efficacy of PegIFN + RBV - Pb of adherence to treatment

• Active drug users: - opiate substitution priority - case by case evaluation

Alberti et al, 1st ECC, J Hepatol 2005Alberti et al, 1st ECC, J Hepatol 2005

Pretherapeutic liver evaluation

• HCV genotype

• HCV viral load

• Liver biopsy: useful, but not mandatory when a decision to treat has been taken

• New markers of fibrosis

Impact of genotype and HCV-RNA on SVR

% pts with SVR in APRICOT

Torriani et al NEJM 2004,

0

10

20

30

40

50

60

70

geno 1 geno 2-3

> 5,9 logUI/ml

< 5,9 logUI/ml

Liver biopsy in HIV/HCV co-infected patients

Genotype 1 and 4, and high

HCV load (>800,000 IU/ml)

Presence of co-morbidities :

- Excessive alcohol

consumption

- HBV and/or delta co-infection

- Medication hepatotoxicity

Genotype 2 and 3

Genotype 1 and 4 , and

low HCV load (≤800,000

IU/ml)

Required for treatment decision

Not required for treatment decision


New tests of fibrosis

FibroScan + seric markers

Discordance Concordance

Liver biopsy

Treatment or

follow-up

Follow-up

Minimal fibrosis < F2

Moderate or severe

fibrosis F >2

Treatment

Castera et al. Gastroenterology 2005; 128: 343-50.

Doses of Peg IFN and ribavirin

Doses of Peg-IFN

ACTG 5071ACTG 5071 RIBAVICRIBAVIC LAGUNOLAGUNOAPRICOTAPRICOT

Peg-IFN 2a Peg-IFN 2b

• Peg-IFN 2a 180 g/w• Peg-IFN 2b 1.5 g/kg/w

40

27 27

44

0

20

40

60

80

100

SV

R (

%)

SVR SVR with PegIFN + RBV in with PegIFN + RBV in HIV/HCV patientsHIV/HCV patients

38%

(1 and 4)

14%17%

(1 and 4)

29%Genotype 1

53%27%44%62%Genotype 2-3

44%27%27%40%Gobal

LAGUNORIBAVICACTG5071

APRICOT

Genotype 2 or 3Genotype 2 or 3 Genotype 1 or 4Genotype 1 or 4

Low ARN HCVLow ARN HCV< 800 000 UI/ml< 800 000 UI/ml

High ARN HCV High ARN HCV > 800 000 UI/ml> 800 000 UI/ml

Ribavirin 800 mgRibavirin 800 mg Ribavirin 1000-1200 mgRibavirin 1000-1200 mg


Dose of ribavirin is criticalDose of ribavirin is critical

Genotype 2 or 3Genotype 2 or 3 Genotype 1 or 4Genotype 1 or 4

Whatever Whatever HIV-RNAHIV-RNA

Ribavirin 800 mgRibavirin 800 mg Ribavirin 1000-1200 mgRibavirin 1000-1200 mg


Dose of ribavirinin 2006Dose of ribavirinin 2006

Increased ribavirine dose useful in genotype 1 with high viral

load (WIN-R)

Jacobson et al. LB3, AASLD 2005

Genotype 2, 3

6558

6860

0

70

24 weeks 48 weeks

SV

R

(%)27

3432

39

0

10

20

30

40

Viral load> 600 000 Ul/ml

Viral load < 600 000 Ul/ml

SV

R

(%)

Genotype 1 p = 0.173

Group A: PEG-IFNα-2b + ribavirin 800 mg/dvs.

Group B: PEG-IFNα-2b. + ribavirin 13 + 2 mg/kg

G1: 48 week G2-3 : 24 sem. vs. 48 week

p = 0.047

725 776 446 391 322 316 588 602

n= n=

PRESCO trial

Study weeks

0 96724824 60 84

Peg

-IF

N +

RB

V

1000

-120

0 m

g/d

ay

12 36

Follow-up

G2,3

G1,4

G1,4

G2,3

Follow-up

Follow-up

Follow-up

Only patients who achieved EVR (>2 log drop in HCV-RNA at week 12) continued treatment.

n=389

APRICOT (800mg/d) vs PRESCO and FRIED (1000-1200 mg/d) : genotype 1

response

Soriano, ICAAC 2006, acceptedOn-treatment analysis

31%

Per

cen

tag

e o

f p

atie

nts

34%

29%

36%46%

13%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

<50UI/ml W4 SVR

Apricot

Presco

Fried

Breilh D., Abstract 928, CROI 2005 Breilh D., Abstract 928, CROI 2005

RB

V C

once

ntra

tion

(mg/

L)R

BV

Con

cent

ratio

n (m

g/L)

00

00

0,50,5

11

1,51,5

22

2,52,5

33

3,53,5

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414

Time (hours)Time (hours)

D4D4 W2W2 W3W3

Virologic failureVirologic failure Virologic succes Virologic succes

Relation between RBV concentration Relation between RBV concentration and sustained virologic response in and sustained virologic response in

Co-infected patientsCo-infected patients

Recommended treatment duration

= 48 weeks

Positive predictive value of early virological response

(EVR) on SVR

74 %

94%

58 %

82%

66 %

83%

EVR at W4> 2 log drop HCV RNA

undetectable

HCV-RNA

70 %45 %56 %

EVR at W12

> 2 log drop HCV RNA

Genotype 2/3

Genotype 1

All genotypes

Torriani, NEJM, 2004, 292;

Probability of success is evaluable as early as W4

>2 log HCV-RNAdecrease

HCV-RNA undetectable

SVR probability60%

geno 1 58%

SVR probability83%

geno 2/3 74%

Negative predictive value of early virological

response (EVR)

84 %90 %88 %

No EVR at W4< 2 log drop HCV RNA

100 %98 %-

No EVR at W12

< 2 log drop HCV RNA

Genotype 2/3

Genotype 1

All genotypes

Torriani, NEJM, 2004, 292;

Early viral Kinetics in RIBAVIC trial

82

94

71

99

0

20

40

60

80

100

W4 W12

VPP VPN

Carrat et al. JAMA 2004

Duration of treatment

Evaluate at week 12

early virological response

HCV-RNA

> 2 log

Treatment

for 48 weeks

If HCV-RNA neg at W24

TTT should be

stopped

HCV-RNA

< 2 log


Optimal duration for genotype 2,3 in HIV co-

infected patients ?

Keep patients on the optimal dose of peg-IFN and ribavirin

Proactive management of adverse events and antiretroviral treatment

23%31%39%25%Tx interruption

31%

pegIFN RBV

10% 25%

34% 18%16%

20%

25%

18%

dose

AE

Lab abnormality

LagunoACTG

5071

RibavicApricot

Torriani NEJM 2004;Carrat Jama 2004; Chung,NEJM 2004; Laguno AIDS 2004

Impact of adherence on SVR withPegIFNa/ribavirin bitherapy

SVR depends on RBV doses within the 12 first weeks

Reddy et al. EASL 2005

p=0.01 66

57

45

00

10

20

30

40

50

60

70

>97% 80 -97% 60 -80% <60%

Prevention and proactive management of adverse

events

betablockers

levothyroxin

Hyper or hyothyroidism

No ddI (d4t) : RR X 2.3

Mitochondrial toxicity (1-3%) Liver decompensation

avoid AZT

Use EPO

Use G-CSF

Anemia

Hb < 8 g/dl : 3.8%

Neutropenia

Manage depressive mood changes

Depression

paracetamol

+/- NSAID

Influenza-like syndrome

keep > 95% of the dose mainly for the first 3 months

RIBAVIC – Mitochondrial toxicity (pancreatitis –

hyperlactatemia)• Incidence– 27,5 / 1000 pat./year (all)– 34,1 / 1000 pat./year (with ARV)– 0 / 1000 pat./year (without ARV)

2 %NoNon

0 %YesNo

7 %NoYes

24 %YesYes

% with mitochondrial

toxicityd4TddI

Multivariate analysis : odds-ratio for ddI = 23 [95 % CI : 5-105]Carrat et al. JAMA 2004; 292: 2839-2848

AZT: impact on anemia and RBV doses

52 %

20 %

0 %

20 %

40 %

60 %

AZT No AZTPati

ents

w

ith R

BV

dose

decr

ease

Hb decrease at W4

Hb decrease at W4

3,14

1,96

0

1

2

3

AZT No AZT

Hb

(g/d

l)

RBV dose decrease at W4

RBV dose decrease at W4

Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

*p = 0,009 ; †p < 0,001 ; ‡p < 0,03 ; §p = 0,003 ; Epoetin alfa vs. Placebo.

Physical Mental Vitality

†‡*

§

Afdhal et al. Gastroenterology 2004Afdhal et al. Gastroenterology 2004

Impact of Epoetin alfa

9%

5%

12%14%

11%

-1%

8% 9%

22%

6%

23%25%

-5

0

5

10

15

20

25

30

35

40

% C

han

ge f

rom

Stu

dy E

ntr

y

Week 9 Week 17 Week 9 Week 17 Week 9 Week 17

Epoetin alfa/Epoetin alfa

Placebo/Epoetin alfa

Management of non responders

Was the treatment adequate ?

No Adherence Pb,

side effects, low doses

Yes100% of the dose

during the first 12 W

Retreatment

Partial response or relapse

No response= true

non responder

Approach dependent on histology :

• Minimal disease => wait new drugs

• Significant disease (F3-F4) => – Monitor ESLD and HCC– Consider alternative strategies

Maintenance therapy

HAART

RetreatmentHigh dose peg-IFN?

New drugs ?

Acute HCV treatment

Treatment of acute HCV hepatitis

• 168 HCV monoinfected: ALT (5-10x), PCR and/or sero-conversion

• Egypt, USA, Germany• Geno 1, 4: 60%• 1.5g/kg/wk PEG 2b for 12 weeks • Initiation from 1st positive RNA result either at :

SVR (%)

Time of Rx onset Intent to Rx Treated

8 weeks (n=43) 95% 95%

12 weeks (n=43) 93% 91%

20 weeks (n=82) 77% 70%

Kamal et al Gastroenterology 2006;130:632-8

Treatment of acute HCV

Kamal et al Gastroenterology 2006;130:632-8

Geno 1 Geno 2+3 Geno 4

Comparison of the 2 largest studies of acute HCV infection

Kamal et alWiegard et al

N° patients 168 89

Rx duration 12 weeks 24 weeks

SVR 95% (early Rx) 89%

Main group Occ exposure: 56%IDU, sex: 44%

+ve factors Geno non-1ALT >500

Kamal et al Gastroenterology 2006;130:632-8; Wiegand et al Hepatology 2006; 43: 250-6

•PEG alone 12 weeks as good as 24 weeks •Delay up to 12 weeks max from diagnosis•Max chance of SVR for geno 2 or 3

Treatment of acute HCV hepatitis in HIV infection

N° Regimen Duration

(weeks)

genotype % SVR

Vogel M

et al

11 Variable 23-48 GT 1/4 : 10

Other: 1

91%

Gilleece YC

et al

27 PegIFN +RBV 24 GT 1: 20

Other : 4

55%

100%

Dominguez S

et al

14 PegIFN + RBV 24 GT 1/4 : 8

Other: 3

71.4%

Vogel et al, J Viral Hepatitis, 2005; Gilleece et al, J AIDS 2005;Dominguez S et al, submitted

Initiation from PCR/seroconversion at 12 weeks

Conclusion (1)

• As eradication is possible, hepatitis C treatment discussed for all patients, except if minimal liver disease

• Histological evaluation crucial: liver biopsy should

not be an obstacle new tools available.

• Improved success rates with HCV therapy due to:– proactive management side effects– increased ribavirine dose (1000-1200mg

genotype 1)

Conclusion (2)• Duration of treatment (48 weeks) depends on EVR:

– at 12 weeks : stop if no significant response– at 24 weeks : stop if viral load remains positive.

• Fields of research :

– Geno1, high VL : higher doses RBV and/or Peg IFN ?

– Slow responders : longer duration of therapy ?

– True non responders: maintenance therapy ?– New molecules.

current treatment of hepatitis c in hiv co-infected patients dominique salmon internal medicine...

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