Treatment of Chronic Hepatitis C in HCVHIV Infected Patients

1
Treatment of Chronic Hepatitis C in HCV-HIV
Infected Patients

• J Mallolas
• Infectious Diseases Service
• Hospital Clínic
• Barcelona

2

• Why to treatHCV in HIV patients ?

3
Why to treat HCV in HIV patients ?

• Longer survival
• Faster progression to cirrhosis
• Higher mortality due to ESLD
• Higher risk of antiretroviral hepatotoxicity
• Faster progression of HIV disease

4
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)
5
Effect of HIV on HCV Liver Fibrosis Progression
Rate
Fibrosis Grades (METAVIR Score)
HIV (n 122)
Matched controls (n 122)
Simulated controls (n 122)
Duration of HCV Infection (years)
Increase with CD4 lt200/mm3, ETOH, age
Benhamou et al. Hepatology 1999301054.
6
Causes of death per year in HIV patientsHospital
Clínic. Barcelona
7
Risk factors of Hepatotoxicity in
HCV-HIVcoinfected patients

• Author No. ART HCV CD4 Rate Predicto
  rs
• 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 1998121256. 2.
Sulkowski et al. JAMA 200028374. 3. Saves et
al. AIDS 199913F115. 4. den Brinker et al.
AIDS 2000142895. 5. Martínez et al. AIDS
2001151261. 6. Núñez et al. J AIDS 200127426.
8

• How to treat HCV in HIV patients ?

9
Sustained Response to HCV Therapy
10
Peginterferon alfa-2b plus ribavirin compared
with interferon alfa-2b plus ribavirin for
treatment of HIV/HCV co-infected patients
AIDS 2004, 18F27F36
11
Methods

• Randomized, single-centre, open-label clinical
  trial including patients with
• HCV
• detectable HCV-RNA,
• alanine aminotransferase gt1.5-fold upper limit of
  normal
• abnormal liver histology
• HIV
• CD4 cell count gt250 x106 cell/L
• HIV- RNA , lt10,000 copies/ml

AIDS 2004, 18F27F36
12
Response by Treatment Group, ITT
P0.033
P0.017
AIDS 2004, 18F27F36
13
Response by Genotype 1-4, ITT
P0.011
P0.007
AIDS 2004, 18F27F36
14
Response by Genotype 2-3, ITT
P0.914
P0.730
AIDS 2004, 18F27F36
15
Side effects (I)

• 92 of patients developed adverse events.

16
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.

17
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, 18F27F36
18
Superiority of Peg IFN-Ribavirin (Sustained
Virological Response)

• 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

19
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

20
Sustained Response to HCV Therapy

• HIV-neg HIV-pos
• IFN monotherapy 20 lt10
• IFN ribavirin 45 12-21
• Peg-IFN ribavirin 55 27-55

21
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

Bani-Sadr F, et al. 14th CROI, Los Angeles, CA,
February 25-28, 2007. Abst. 897.
22
Abacavir Decreases SVR Rates with HCV Treatment
Possible Intracellular Competition Between
Abacavir and Ribavirin (Guanosine Analogs)

• 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 lt0.001)
• GT 1/4 (4.76 2.78-8.33 lt0.001)
• ABC use (OR 2.04 1.08-3.85 0.03)
• ABC not associated with lower SVR if higher RBV
  levels
• RBV level gt2 µg/ml 53.3 with ABC vs 38.5
  without ABC, p0.32
• ABC associated with a lower SVR rates possibly
  due to an inhibitory competition between RBV and
  ABC which are both guanosine analogs

ABV
RBV
Adenosine kinase
ABV-MP
Cytosolic deaminase
RBV-MP
CBV-MP
Guanylate kinase
RBV-DP
CBV-DP
Nucleoside diphospho kinase
RBV-TP
CBV-TP
Vispo E, et al. 47th ICAAC Chicago, IL
September 17-20, 2007. Abstract H-1731.
23
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)

24
Figure 1.Impact of Abacavir use on virologic
response to pegylated
interferon plus ribavirin in HCV/HIV-coinfected
patients
100
90
80
68,89
70
66,04
60
57,14
56,41
of patients with lack of response
50,42
48,28
50
42,86
38,1
40
35,14
31,58
30
18,18
20
16,67
11,11
10
7,69
0
4
12
24
36
48
60
72
159 45
168 42
152 47
52 11
90 24
119 29
195 49
25
Comparison of Pegylated Interferons
SVR by HCV Genotypes

• Cohort study of PEG2A (n315) and PEG2B (n242)
  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 lt 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 95CI 1.38
  - 7.89, p 0.007)
• HCV genotype (GT 2/3 vs 1/4 3.05 95CI 1.67 -
  5.56, plt0.001)

50
46
45
45
40
35
30
Patient Percent
25
19
20
14
15
10
5
0
G1-4
G2-3
PEG2B-RBV
PEG2A-RBV
Berenguer J, et al. 47th ICAAC Chicago, IL
September 17-20, 2007. Abstract V-1897.
26
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.
Poster 1018 b

• 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_at_clinic.ub.esTel. 34-93-2275574FAX.
  34-93-4514438
• CROI-2008. Boston. USA

27
METHODS

• Prospective, randomized, multi-centre, open-label
  clinical trial
• Inclusion criteria
• Detectable HCV-RNA
• Alanine aminotransferase gt1.5-fold upper normal
  limit
• Abnormal liver histology
• CD4 counts gt250 cells/mm3 and HIV-RNA lt50000
  copies/mL.
• Treatment arms
• PEG 2b (80-150 µg/wk adjusted to body weight)
• or
• PEG 2a (180µg/wk)
• RBV (800-1200 mg/d adjusted to body weight) in
  both arms
• Duration of treatment 48 weeks.

28
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.

29
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 gt 800000 IU/mL.

Mean (Std Desv) Number ()
30
Demographics and Baseline Characteristics

• HCV Genotypes

PEG 2b
PEG 2a
Not typ Genot. 1 Genot. 2 Genot. 3 Genot. 4
31
RESULTS

• Global vEVR, EVR and SVR

of response
n. 72 77 71
82 86 96
(Primary endpoint)
32
RESULTS (EVR)

• Global PPV and NPV of EVR

n32 (65)
SVR
N49 (69)
EVR
n17 (35)
No SVR
n71
n0
PEG 2b
SVR
n22 (31)
n22 (100)
No EVR
No SVR
n42 (64)
SVR
N66 (80)
EVR
n24 (36)
No SVR
n82
n0
PEG 2a
SVR
n16 (20)
n16 (100)
No EVR
No SVR
33
RESULTS

• vEVR, EVR and SVR by genotype

of response
n 39 51 38 52
47 62 29 23 30
27 34 31
Genotype 1 or 4
Genotype 2 or 3
34
RESULTS

• The independent factors related with SVR in the
  multivariate analysis were
• HCV genotype 2 or 3
• male gender
• age 40 years

35
RESULTS (AEs)

• 96 of patients presented 1 side effect.

plt0.05
36
RESULTS (AEs)

• Adverse effects Grade III or IV.
• 10 (n19) of patients discontinuated the
  treatment due to adverse effects
• 8 (n7) in PEG 2b and 13 (n12) in PEG 2a arm,
  (p0.56)

plt0.05


of patients
37
RESULTS

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

Number of patients
Weeks
38
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.

39
Acknowledments

• Infections Diseases Service
• Laguno M
• Murillas J
• León A
• Blanco JL
• García-Gasalla M
• Martínez E
• Milinkovic A
• Loncá M
• Callau P
• Miró JM
• Poal M
• Rodriguez A
• Casadesus C
• García F
• Gatell JM
• Mallolas J

• Radiology Service
• Bianchi L
• Vilana R
• Gilabert R
• García-Criado A
• Bargalló X
• Hepatology Service
• Sánchez-Tapias JM
• Pathology Service
• Miquel R
• Biostatistics
• de Lazzari E
• Pérez I
• Phyquiatry Service
• Blanch J

To the Patients