Treatment of Chronic Hepatitis C in HCV-HIV

Infected Patients

J Mallolas

Infectious Diseases ServiceHospital Clínic

Barcelona

1. Why to treatHCV in HIV patients ?

Why to treat HCV in HIV patients ?

1. Longer survival

2. Faster progression to cirrhosis

3. Higher mortality due to ESLD

4. Higher risk of antiretroviral hepatotoxicity

5. Faster progression of HIV disease

Incidence of Mortality in HIV-Infected Patients at the Hosp. Clinic (Barcelona, Spain) between 1984-1998

HAART: Highly Actibe Antiretroviral Therapy ( 2NRTI plus 1PI/NNRTI)

Effect of HIV on HCV Liver Fibrosis Progression Rate

Benhamou et al. Hepatology 1999;30:1054.

4

3

2

1

0

403020100

Duration of HCV Infection (years)

Fib

ros

is G

rad

es

(ME

TA

VIR

Sc

ore

)

HIV+ (n = 122)

Matched controls (n = 122)

Simulated controls (n = 122)

Increase with CD4 <200/mm3, ETOH, age

Causes of death per year in HIV patientsHospital Clínic. Barcelona

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1997 1998 1999 2000 2001

Cardiovascular causes

Accidental causes

Neoplasias

End-stage liver disease

AIDS-related illnesses

Risk factors of Hepatotoxicity in HCV-HIVcoinfected patients:

Author No. ART HCV CD4 Rate Predictors

Rodriguez1 132 PI-based 62% 324 11% HCV Alc.

Sulkowski2 211 PI-based 51% 109 12% HCV

CD4

Saves3 1249 2 NRTIs 44% 234 6% HCV HBV

den Brinker4 394 PI-based 22% 150 18% HCV HBV

Martínez5 610 NVP-based 51% 279 9.7% HCV ALT

Núñez6 222 ART 40% 337 9% HCV age,

Alc.

1. Rodriguez-Rosado et al. AIDS 1998;12:1256. 2. Sulkowski et al. JAMA 2000;283:74. 3. Saves et al. AIDS 1999;13:F115. 4. den Brinker et al. AIDS 2000;14:2895. 5. Martínez et al. AIDS 2001;15:1261. 6. Núñez et al. J AIDS 2001;27:426.

2. How to treat HCV in HIV patients ?

Sustained Response to HCV Therapy

HIV-neg HIV-pos

IFN monotherapy 20% 10%

IFN + ribavirin 45% 20%

Peg-IFN + ribavirin 55% ?

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus

ribavirin for treatment of HIV/HCV co-infected

patients

AIDS 2004, 18:F27–F36

Methods

• Randomized, single-centre, open-label clinical trial including patients with:

• HCV:– detectable HCV-RNA,

– alanine aminotransferase >1.5-fold upper limit of normal

– abnormal liver histology

• HIV:– CD4 cell count >250 x106 cell/L

– HIV- RNA , <10,000 copies/ml

AIDS 2004, 18:F27–F36

Response by Treatment Group, ITT

52

30

44

21

0

20

40

60

80

100

% o

f p

atie

nts

VR SVR

PEG + RBV (n=52) IFN + RBV (n=43)

P=0.033P=0.017

AIDS 2004, 18:F27–F36

Response by Genotype 1-4, ITT

41

11

38

7

0

20

40

60

80

100

% o

f p

atie

nts

VR SVR

PEG + RBV (n=52) IFN + RBV (n=43)

P=0.011

P=0.007

AIDS 2004, 18:F27–F36

Response by Genotype 2-3, ITT

68 67

5347

0

20

40

60

80

100

% o

f p

atie

nts

VR SVR

PEG + RBV (n=19) IFN + RBV (n=15)

P=0.914

P=0.730

AIDS 2004, 18:F27–F36

0

20

40

60

80

100

Adverse Events

% o

f pat

ient

sSide effects (I)

• 92% of patients developed adverse events.

Side effects (II)

• Premature discontinuation: 19% (Peg 23 vs 14%); 15% due to side effects (17 vs 12%)

– Severity of the adverse events not shown differences between two arms. PEG+RBV INF+RBV TOTAL p-value

Grade 1-2 290 (84%) 189 (85%) 479 (84,4%) NS

Grade 3-4 56 (16%) 33 (15%) 89 (15.6%) NS

0

5

10

15

20

Pre

ma

ture

c

um

ula

tiv

e

dis

co

nti

nu

ati

on

%

2 4 8 12 16 40

PEG+RBV

INF+RBV

Conclusions

• PEG-INF 2b + RBV was significantly more effective than IFN 2b + RBV for the treatment of chronic hepatitis C in HIV co-infected patients, mainly of genotype 1 or 4.

• Side effects were very frequent, the majority of them were mild or moderate.

• Total CD4 fell in both arms but no evidence of deleterius effect on HIV control were seen.

AIDS 2004, 18:F27–F36

IFN type n. IFN/RBV PEG IFN/RBV

ACTG 2a 133 12% 27%

APRICOT 2a 868 12% 40%

RIBAVIC 2b 400 19% 27%

Laguno 2b 95 21% 44%

Crespo 2b 121 26% 55%

Superiority of Peg IFN-Ribavirin (Sustained Virological Response)

Differences in Baseline Characteristics Make Difficult a Comparison Face to Face

Fibrosis 3-4 IVDU h ALT Geno1

ACTG 10% 50% 67% 78%

APRICOT 12% 65% 87% 60%

RIBAVIC 40% 80% 83% 66%

Laguno 30% 85% 100% 63%

Crespo ? 79% 100% 48%

Sustained Response to HCV Therapy

HIV-neg HIV-pos

IFN monotherapy 20% <10%

IFN + ribavirin 45% 12-21%

Peg-IFN + ribavirin 55% 27-55%

Risk Factors for Failure of HCV Tx

• Study of risk factors for failure to achieve EVR to PEG-IFN + RBV

– 154 HIV/HCV co-infected patients

– EVR: ≥ 2 log10 c/mL ↓HCV RNA

• Increased risk of failure with:– Serum HIV RNA

– HCV genotypes 1 and 4

– Abacavir use

– Increased bilirubin levels

• Potential drug interaction between RBV and ABC may be impacting outcomes

Univariate OR

Multivariate OR

P value

Serum HCV RNA

2.12 2.11 0.022

HCV GT 2/3 1

HCV GT 1/4 9.82 12.13 <0.0001

d4T 0.55

ABC 3.62 4.92 0.0083

GGT (x ULN) 1.21

Bilirubin (x ULN)

2.52 4.52 0.0064

Bani-Sadr F, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 897.

Abacavir Decreases SVR Rates with HCV Treatment

• Retrospective study of 426 HIV/HCV patients (80% on HAART) starting pegIFN + RBV

• 72% did not achieve SVR

• Lack of SVR associated with:

– Higher HCV-RNA (1.92 [1.33-2.78] <0.001)

– GT 1/4 (4.76 [2.78-8.33] <0.001)

– ABC use (OR 2.04 [1.08-3.85] 0.03)

• ABC not associated with lower SVR if higher RBV levels

– RBV level >2 µg/ml: 53.3% with ABC vs 38.5% without ABC, p=0.32

• ABC associated with a lower SVR rates possibly due to an inhibitory competition between RBV and ABC which are both guanosine analogs

Vispo E, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract H-1731.

Possible Intracellular Competition Between Abacavir and Ribavirin (Guanosine

Analogs)

Possible Intracellular Competition Between Abacavir and Ribavirin (Guanosine

Analogs)

RBVRBV

RBV-MPRBV-MP

RBV-DPRBV-DP

RBV-TPRBV-TP

CBV-MPCBV-MP

CBV-DPCBV-DP

CBV-TPCBV-TP

ABVABV

ABV-MPABV-MP

Guanylate kinaseGuanylate kinase

Nucleoside diphospho kinase

Nucleoside diphospho kinase

Cytosolic deaminaseCytosolic deaminase

Adenosine kinaseAdenosine kinase

Abacavir does not influence the rate of sustained virological

response in HIV-HCV co-infected patients treated with pegylated interferon and weight

adjusted ribavirin

Authors: Laufer N1, Laguno M1, Perez I2, Cifuentes C3, Murillas J4, Vidal F5, Bonet L4, Veloso S5,

Gatell JM1; Mallolas J1.

*** Antiviral Therapy (submitted for publication)

Figure 1.Impact of Abacavir use on virologic response to pegylated interferon plus ribavirin in HCV/HIV-coinfected patients

50,42

56,41

68,89

42,86

35,14

18,18 16,67

48,28

57,14

7,69

31,58

66,04

38,1

11,11

0

10

20

30

40

50

60

70

80

90

100

% o

f p

atie

nts

wit

h l

ack

of

resp

on

se Without ABC

With ABC

4 12 24 36 48 60 72

159

45

168

42

152

47

52

11

90

24

119

29

195

49

Without ABC

With ABC

Comparison of Pegylated Interferons

• Cohort study of PEG2A (n=315) and PEG2B (n=242) with RBV in HIV/HCV+, HCV Tx naïve pts (2000-2005)

– Well matched except more F3-F4 in PEG2B (32.8% vs 42.0%; p < 0.05)

– No differences dose RBV or duration Tx

• No differences in efficacy or safety PEG2A vs. PEG2B

• Factors independently associated with SVR

– CDC clinical category (A/B vs C: 3.30 95%CI: 1.38 - 7.89, p = 0.007)

– HCV genotype (GT 2/3 vs 1/4: 3.05 95%CI: 1.67 - 5.56, p<0.001)

SVR by HCV Genotypes

Pat

ient

Per

cent

Berenguer J, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract V-1897.

14

46

19

45

05

101520253035404550

G1-4 G2-3PEG2B-RBVPEG2A-RBV

A randomized trial to compare the efficacy and safety of PEG-interferon (PEG) alfa-2b plus ribavirin (RBV) vs PEG alfa-2a plus RBV for treatment

of chronic hepatitis C in HIV co-infected patients.

Laguno M1, Cifuentes C2, Murillas J3, Vidal F4, Bonet L3, Veloso S4, Tural C5, Perez I1, Gatell JM1, Mallolas J1.

1Hospital Clínic. Barcelona. Spain. 2Hospital Son Llàtzer. Mallorca. Spain. 3Hospital Son Dureta. Mallorca. Spain. 4Hospital Joan XXIII. Tarragona. Spain.

5Hospital Germans Trias i Pujol. Badalona. Spain.

E-mail: mallolas@clinic.ub.esTel. +34-93-2275574

FAX. + 34-93-4514438

CROI-2008. Boston. USA

Poster: 1018 b

METHODS

• Prospective, randomized, multi-centre, open-label clinical trial

• Inclusion criteria: – Detectable HCV-RNA

– Alanine aminotransferase >1.5-fold upper normal limit

– Abnormal liver histology

– CD4 counts >250 cells/mm3 and HIV-RNA <50000 copies/mL.

• Treatment arms:PEG 2b (80-150 µg/wk adjusted to body weight)

orPEG 2a (180µg/wk)

+ RBV (800-1200 mg/d adjusted to body weight) in both arms

• Duration of treatment: 48 weeks.

METHODS

• Primary endpoint: – Sustained Virological Response

• (SVR= HCV-RNA negative at week 72).

• Sample size was calculated to detect, with 80% power, differences above 20 percentual points if they exist.

Demographics and Baseline Characteristics

• Baseline Characteristics of 182 included patients:

Both groups were well balanced:

– 72,5% males

– 76% former drug users

– 63% HCV genotype 1 or 4

– 29% bridging fibrosis or cirrhosis

– 56% HCV viral load > 800000 IU/mL.

* Mean (Std Desv); # Number (%)

Interferon (nº patients)

PEG 2b (86) PEG 2a (96) All (182)

Male gender # 68 (79.1) 64 (66.7) 132 (72.5)

Age (years)* 40,7 (5,0) 40,6 (5,4) 40,7 (5,2)

Age at HCV infection time (years) * 23,3 (6,9) 22,2 (6,6) 22,8 (6,8)

Baseline weight (Kg) * 69.4 (12,3) 67.3 (10,8) 68.3 (11,5)

Time with HCV infection (years) * 17.3 (6,4) 18.3 (6,0) 17.8 (6,2)

HCV Genotype # 1 32 (39,5) 47 (50,5) 79 (45,4)

2 3 (3,7) 3(3,2) 6(3,4)

3 31 (38,3) 28(30,1) 59 (33,9)

4 15 (18,5) 15 (16,3) 30 (17,2)

Baseline HCV-RNA >600.000 IU/ml # 50 (60,2) 54 (58,1) 104 (59,1)

Baseline HCV-RNA >800.000 IU/ml # 48 (57,8) 50 (53,7) 98 (55,7)

Fibrosis score # 0-2 51 (70,8) 64 (71,1) 115 (70,9)

3-4 21 (29,2) 26 (28,9) 47 (29,1)

Baseline ALT (IU/mL)* 111.2 (75,3) 89.1 (47,4) 99.4 (62,9)

HIV risk group # IDU 69 (81,2) 68 (70,8) 137 (75,7)

HMX 4 (4,7) 7 (7,3) 11 (6,1)

HTX 9 (10,6) 20 (20,8) 29 (16)

Others 3 (3,5) 1 (1) 4 (2,1)

Baseline CD4 cell count (cell/mL) * 592.5 (269,2) 602.3 (279,6) 597.7 (274,0)

Baseline CD4 cell count >300 # 78(91,8) 88 (91,7) 166 (91,7)

HIV viral load < 200copies/mL # 63 (74,1) 70 (72,9) 133 (73,5)

Demographics and Baseline Characteristics

• HCV Genotypes

5.81

37.21

4.6536.05

16.283.13

48.96

3.13

29.17

15.63

Not typ Genot. 1 Genot. 2 Genot. 3 Genot. 4

PEG 2b PEG 2a

RESULTS

• Global vEVR, EVR and SVR:

35,06

80,49

45,83

69,01

34,7241,86

0102030405060708090

100

vEVR (week 4) EVR (week 12) SRV (week 72)

PEG 2b PEG 2a

(Primary endpoint)

% o

f r

esp

on

se

n. 72 77 71 82 86 96

32

RESULTS (EVR)

SVR

n=71

n=32 (65%)

n=17 (35%)

n=22 (31%)

n=0

n=22 (100%)

EVR

No EVR

No SVRSVR

No SVR

N=49(69%)

PEG 2b

n=82

n=42 (64%)

n=24 (36%)

n=16(20%)

n=0

n=16 (100%)

EVR

No EVR

SVR

No SVRSVR

No SVR

N=66(80%)

PEG 2a

• Global PPV and NPV of EVR:

RESULTS

• vEVR, EVR and SVR by genotype:

71.15

32.26

78.26

96.3

70.9761.76

55.17

27.6620.51

56.76

83.33

15.69

0

10

20

30

4050

60

70

80

90

100

vEVR (week4) EVR (week 12) SRV (week 72) vEVR (week 4) EVR (week 12) SRV (week 72)

PEG 2b

PEG 2a

Genotype 1 or 4 Genotype 2 or 3

% o

f r

esp

on

se

n: 39 51 38 52 47 62 29 23 30 27 34 31

RESULTS

• The independent factors related with SVR in the multivariate analysis were:– HCV genotype 2 or 3

– male gender

– age ≤40 years

Effect Odds Ratio Estimate

Lower 95% Confidence

Limit for Odds Ratio

Upper 95% Confidence

Limit for Odds Ratio variable Pr > Chi-Square

Age: <= 40 years vs > 40 years 2.637 1.308 5.317 age 0.0067

PEG 2a vs PEG 2b 1.606 0.813 3.171 Interferon 0.1725

Gender: male vs female 2.828 1.241 6.447 gender 0.0134

HCV Genotype: 2+3 vs 1+4 4.618 2.317 9.202 genotype <.0001

0

10

20

30

40

50

60

70

80

90

100

Genera

l Diso

rders

Phychi

atric d

isorde

rs

alope

cia

diges

tive dis

orders

Anemia

Leuc

open

ia

Thrombo

penia

Loca

l reac

tion

Hyperla

ctatem

iaOthe

rs

% o

f p

ati

en

ts

PEG 2b PEG 2a

RESULTS (AEs)

• 96% of patients presented ≥ 1 side effect.

* *

* p<0.05

• Adverse effects Grade III or IV.

• 10% (n=19) of patients discontinuated the treatment due to adverse effects

8% (n=7) in PEG 2b and 13% (n=12) in PEG 2a arm, (p=0.56)

0

10

20

30

40

50

60

70

80

90

100

AE ≥ 1 AE= grade III ≥ 1 AE= grade IV ≥ 1 AE= grade III or IV

PEG 2bPEG 2a

RESULTS (AEs)

**

* p<0.05

% o

f p

atie

nts

RESULTS

• Cumulative and number of patients with adverse events leading to treatment discontinuation.

02468

101214161820

2 4 8 12 16 20 24 28 32 36 40 44 48

n patients

cumulative

Nu

mb

er o

f p

atie

nts

Weeks

CONCLUSION

• In HIV infected patients, treatment of chronic HCV with RBV plus PEG 2b or PEG 2a had no statistically significant differences in tolerance and efficacy.

Acknowledments

Infections Diseases Service:Laguno MMurillas JLeón ABlanco JLGarcía-Gasalla MMartínez EMilinkovic ALoncá MCallau PMiró JMPoal MRodriguez ACasadesus CGarcía FGatell JMMallolas J

Radiology Service:Bianchi LVilana RGilabert RGarcía-Criado ABargalló X

Hepatology Service:Sánchez-Tapias JM

Pathology Service:Miquel R

Biostatistics:de Lazzari EPérez I

Phyquiatry Service:Blanch J

*** To the Patients