Treatment of HCV in HIV Disease: New Challenges, New Promise

1
Douglas T. DIETRICH
2
Treatment of HCV in HIV Disease New Challenges,
New Promise

• Douglas T. Dieterich, M.D
• Professor of MedicineDivision of Liver Diseases,
• Gastroenterology and Infectious Diseases
• Director of CME
• Department of Medicine
• Mt. Sinai School of MedicineNew York, New York

3
Hospital Admissions for Liver Complications
Increased 5-Fold (19952000)
Opportunistic infections IDU-related
complications Liver-related complications
Hospitalizations per Patient-Years Follow-Up
1995 1996 1997
1998 1999 2000
Gebo KA, et al. JAIDS. 200334165-173.
4
Liver disease is a major cause of death in the
ART era
Death from end-stage liver disease (ESLD) as a
of all deaths among HIV patients
60
50
Pre-HAART era
50
45
HAART era
40
35
Mortality ()
30
20
13
12
10
5
0
Italy (Brescia)
Spain (Madrid)
USA (Boston)
Bica et al. Clin Infect Dis 2001
32492497Puoti et al. JAIDS 2000
24211217Soriano et al. Eur J Epidemiol 1999
1514Soriano et al. PRN Notebook 2002
71015Martin-Carbonero et al. AIDS Res Human
Retrovirus 2001 1714671471
5
Causes of Liver Disease in HIV Infection
6
Ishak fibrosis stage on second biopsy among
persons with little or no fibrosis on first
biopsy
n 51
60
Median (IQR) time between bxs, 2.84 yrs
(2.053.41) 28 with more than 2 stage progression
45
40
Patients ()
23
20
14
10
8
0
0
1
2
3 or 4
5 or 6
Fibrosis stage at second biopsy
Sulkowski MS et al. 12th Conference on
Retroviruses and Opportunistic Infections
(Abstract P-172). Boston, MA USA, February
2225, 2005
7
FibroScan
The probe induces an elastic wave through the
liver
The velocity of the wave is evaluated in a region
located from 2.5 to 6.5 cm below the skin surface
Explored volume
2.5 cm
1 cm ?
4 cm
LB 1/50,000 of the liver FibroScan 1/500 of the
liver
8
Transient Elastography in HIV HCV Co-infected
Patients

• 72 patients with simultaneous liver biopsy and
  Fibroscan
• Liver stiffness 3.0 to 46.4 kilopascal
• Liver stiffness correlated signficantly to
  fibrosis stage p lt 0.0001
• AUROC(area under receiver operating curve) was
  .72 for Fgt2 and .97 for F4.
• F4 was gt plt count, AST/ALT ratio, APRI, and
  FIB 4

De Ledinghen et al J Acquir Immune Defic Syndr
41 175-179
9
Liver Biopsy

• Gold standard for grading and staging disease
• Invasive, expensive
• Needle liver biopsy samples lt 1/50,000th of the
  liver
• Incorrect staging of 1 stage in 10 to 20 of
  cases
• Dependent on
• Length of biopsy25 mm optimal (16)
• Number of biopsies performed
• Type of biopsy needle used
• Etiology of liver disease

10
The Importance of Liver Biopsy
11
Conflicting Data on the Effects of HCV Upon HIV
Disease

• Meta-analysis involving 6216 patients from 8
  trials
• Mean increase in CD4 cell count among HIV/HCV
  coinfected patients was 33.4 cells/mm3 less than
  that observed in HIV-monoinfected patients
• EuroSIDA
• After adjusting for baseline factors,
  investigators concluded that HIV/HCV-coinfected
  patients do not have a greater risk of
  progressing to AIDS

Miller et al. Clin Inf Dis. 200541713-720.
Rockstroh et al. J Inf Dis. 2005192992-1002
12
Significant increase in new acute HCV infections
in 2003
30
25
20
15
Incidence of acute HCV infection/1000 pt yrs
10
5
0
1997
1998
1999
2000
2001
2002
2003

• Test for trend p-value using Poisson regression
  plt0.001
• Error bars 95 CI

Browne RE, et al. 2nd IAS 2003 Abstract 972
13
HCV A new epidemic among MSM?

• Newly infected male, MSM, HCV patients at a
  London clinic, January 1997 May 2003 n44
• Reasons for testing ?ALT (35), sexual contact
  with HCV person (3), jaundice (3), HIV screening
  (2), H/O IVDU (1)
• Risk factors identified IVDU (1), sexual contact
  (39), none (4)

Browne RE, et al. 2nd IAS 2003 Abstract 972
14
HIV-positive MSM with acute HCV infection in 3
hospital wards in Paris, France (n29)
4
3
Number of patients
2
1
0
Jan
Apr
Jul
Oct
Jan
Apr
Jul
Oct
Jan
Apr
Jul
Oct
Jan
Apr
Jul
Oct
2001
2002
2003
2004
Year
Gambotti L. Eurosurveillance 2005 10 115
15
Possible transmission risk factorsResults of
anonymous questionnaire (n11)
Met sex partner at gay venue or via internet
(n11)
Tattoos or piercing within 6 months prior to
hepatitis C (n3)
Unprotected anal sex with casual partner within
six months prior to hepatitis (n11)
Hard sex (n8)-fisting (n5) -bleeding (n6)

• STI reported (n10)
• syphilis (n6)
• gonorrhoea (n3)
• genital herpes (n3)
• chlamydia (n3)
• warts (n3)
• anal/genital infection (n3)

Inhaled poppers during sex (n11) Used
psychoactive drugs during sex (n5)
Gambotti L. Eurosurveillance 2005 10 115
16
German acute Hepatitis C Trial I (19982000)
interferon alfa-2b monotherapy for 6 months
100
98
80
60
HCV RNA negative
n44
40
20
0
48(F/up Wk 24)
0
4
8
12
16
20
24
Weeks
Jaeckel E, et al. N Engl J Med 2001 345 1452
17
Acute HCV in IVDU Swiss Association for the
Study of the Liver Study (SASL 18)
5 spontaneous clearance
27 patients
6 refused therapy 2 patients lost to observation
22 patients treatment indicated
6 premature stop due to side-effects (1 SVR)
14 patients Peg-IFN treatment started
8 patients adherent to therapy
7 patients with SVR
Broers, B et al. J Hepatol 2005 42 323
18
Hep-Net Acute HCV Study HCV-II
100
94
89
82
80
71
60
Patients ()
40
20
0
ETR
SVR
ETR
SVR
ITT n89
Pts. adherent to therapy n65
Adherent to therapy 80 of pegylated interferon
dose, 80 of treatment duration
Wiegand et al. (Submitted)
19
Response to treatment acute HCV infection in
HIV patients
Pegylated interferon alfa-2b (1.5 ?g/kg/wk)
ribavirin (8001200 mg/day) for 24 weeks
ETR
SVR
100
100
100
80
67
65
59
60
55
Virological response ()
40
20
0
All Patients(n27)
Genotype 1(n20)
Genotype non-1(n4)
Nelson M, et al. 3rd IAS 2005 Abstract TuPe1.1C10
20
Hôpital Pitié-Salpêtrière, Paris, France (n14)
Peg-IFN alfa-2a (40KD) 180 µg/wk plus ribavirin
800 mg/day for 24 weeks
100
86
90
79
80
71
70
60
HCV RNA lt50 IU/mL ( patients)
50
40
30
20
10
0
Week 48 (SVR)
Week 12
Week 24
Dominguez S, et al. 10th EACS 2005 Oral
presentation PS7/6
21
Acute HCV at Mount Sinai Liver Biopsy Series of
7 Risk Factors
22
The Biopsy of Case 1 Had Fibrosis Typical of
Damage Caused by Chronic HCV
Mild portal inflammation, interface hepatitis,
and lobular necroinflammatory activity. Portal
fibrosis with occasional fibrous septum formation
on trichrome stain (panel C). Immunostains for
HBsAg and HBcAg were negative (not shown).
Arrows in panel B identify a region of focal
interface hepatitis arrows in panel C indicate
fibrous septae (blue).
23
Case 2 Also Had Evidence of Chronic Injury
Marked expansion of portal tracts by fibrosis and
inflammation. Lymphoid aggregates. Moderate
interface hepatitis and lobular necroinflammatory
activity. Mild steatosis. Trichrome stain reveals
portal and periportal fibrosis with rare fibrous
septum formation. HBsAg and HBcAg were not
detectable by IHC (not shown). Arrow in B marks
an expanded portal tract with a lymphoid
aggregate arrows in C indicate portal and
periportal fibrosis.
24
Fat In The Wrong Places And Insulin Resistance
HOMA-IR
8
6
4
2
2
R
0.7938

• Liver (Sutinen AIDS 2002)
• Significantly higher liver fat in HIV LD vs.
  HIV no LD and HIV-
• Severity of insulin resistance related to liver
  fat but not VAT

P lt 0.01
0
0
2
4
6
8
10
Intramuscular fat in HIV men (Sakkas, unpubl,
2003)
25
NAFLD the hepatic manifestation of the
metabolic syndrome
47 million have metabolic syndrome 80 have
NAFLD 15 of US population has a fatty liver 3-4
have NASH
Obesity
Hyper- triglyceridemia
Diabetes
NAFLD
Hypertension
26
NASH is associated with mitochondrial
paracrystalline inclusions
Sanyal et al, Gastro, 2001, 1201183-1192
27
NASH pre vs post treatment with pioglitazone
vitamin E
Pre treatment (10 X)
Post treatment (10 X)
Sanyal et al, Clin Gastroenterol and Hepatol, Dec
2004
28
Insulin Resistance and HCVEffect on Response
to PegIFN/RBV Therapy
SVR in Genotype 1
Homa Homeostasis model of assessment HOMA of
insulin resistance Romero-Gomez, M et al.
Gastroenterology 2005128636-641.
29
Does steatosis affect response to treatment?
No steatosis
98
Steatosis
89
59
Percent SVR
59
57
51
41
39
40
35
24
21
Geno 2 F0-1
F2,3,4
High Viral Load
Geno 1,4.5.6
Geno 1,4.5.6 High V Load
Geno 1,4.5.6 High V Load F2,3,4
Poynard et al. Hepatology 2003.
30
Insulin resistance and NAFLD in co-infection

• Results
• In univariate analyses global and
  semi-quantitative measures of steatosis strongly
  associated with HOMA-IR (plt0.0001) -see plot
• ALT (p0.003) AST (p0.003)
• genotype (p0.049) negative once genotype 3
  excluded
• ethnicity (p0.024)
• Significant correlation between HOMA-IR and HAI
  fibrosis stage (p0.011) and steatohepatitis
  stage (p0.005)
• BMI correlated with HOMA-IR (p0.0085) but not
  histological parameters
• In logistic regression analyses only IR
  positively associated (p0.015 OR1.08 95CI
  1.01-1.14) with moderate/severe steatosis

31
Insulin resistance and NAFLD in co-infection

Baseline Insulin Resistance by EVR
60
r -0.282
p 0.031
50
40
30
20
Baseline IR
10
0
No
Y
es
EVR
32
RIBAVIC- ANRS HC02mitochondrial toxicity event 
(MTE)

• 6 acute pancreatitis (one with hyperlactatemia)
• 7 hyperlactatemia (hospitalization)
• 4 suspicions of hyperlactatemia
• Association with Didanosine treatment

Odds-ratio for ddi 23 95 CI 5-105
33
Occurrence of Hepatic DecompensationAPRICOT
12
10.5
10
8
6
Patients ()
4
1.6
2
0
n 14
n 14
0
All Patients
Cirrhotic Patients(non-decompensated)
Non-cirrhotic Patients
(n 735)
(N 868)
(n 133)
34
Risk Factors

• Total bilirubin ? (OR 1.12, Plt0.001)
• Alkaline phosphatase ? (OR 1.02, Plt0.001)
• Albumin ? (OR 0.83, Plt0.002)
• Platelets ? (OR 0.96, Plt0.001)
• Hemoglobin ? (OR 0.53, P0.001)
• Didanosine treatment (OR 4.06, P0.03)
• Lamivudine treatment (OR 0.30, P0.04)
• PT INR, efavirenz, saquinavir and non-nucleoside
  inhibitor treatments (Plt0.20)

35
Ribavirin and ddI dont do it
ddI ddI-MP ddA-MP ddA-DP ddA-TP RT g-Pol
IMP dehydrogenase
Inositol IMP XMP GTP
(-)
Ribavirin-MP Ribavirin
Adenosine kinase

• Ribavirin increases IMP
• Increases ddATP
• Increases inhibition of HIV RT
• Increases inhibition of host g-pol

(-)
(-)
36
Summary of Results From Coinfection Trials
Study N Treatment SVR ()
All GT 1 GT
non-1 RIBAVIC 412 PEG IFN a-2b RBV 800 27
17 44 IFN a-2b RBV
800 20 6 43 ACTG 133 PEG IFN a
2a RBV 600 27 14 73 IFN
a -2a RBV 600 12 6
33 APRICOT 860 PEG IFN a 2a RBV 800 40
29 62 IFN a -2a RBV 800 12 7
20 LAGUNO 93 PEG IFN a-2b W/B RBV 44
38 53 IFN a-2b W/B RBV 21
7 47 PRESCO 389 PEG IFN a-2a W/B RBV
50 36 72 G1 48 w 31 72w
52 G2 24 w 67 48w 82
37
Apricot Sustained Virologic Response
60
50
40
Response
30
20
10
0
IFN alfa-2a RBV
PEG-IFN alfa-2a(40 kDa) Placebo
PEG-IFN alfa-2a(40 kDa) RBV
Defined as lt50 IU/mL HCV RNA at week 72 ITT
38
Results treatment factors predictive of an SVR

• The relationship between various treatment
  factors and SVR rates were examined
• Cumulative peginterferon-alfa-2a (40KD) dose was
  strongly correlated with cumulative ribavirin
  dose (r0.87)
• Ribavirin dose also correlated with ribavirin
  treatment duration (r0.98)

No SVR
SVR
100
80
60
Cumulative peginterferon-alfa-2a (40KD) dose
40
20
0
100
0
20
40
60
80
Cumulative ribavirin dose
39
MLR analysis impact on SVR rates
Less likely to have an SVR
More likely to have an SVR
Only factors with a significant (plt0.05) effect
are shown
Odds ratio (95 CI)
40
Histological Response in Patients with an SVR
80
IFN alfa-2a RBV
74
69
PEG-IFN alfa-2a (40KD) Placebo
PEG-IFN alfa-2a (40KD) Placebo
70
62
PEG-IFN alfa-2a (40KD) RBV
60
50
40
of Patients
30
26
30
22
20
8
10
5
4
n 19
n 1
n 3
n 4
n 11
n 6
n 51
n 23
n 20
0
Improved
No change
Worsened
No Change Change of 1, -1 or 0 in HAI
scoreWorsening 2-point increase in HAI score
41
Histological Response in Patients without an SVR
80
IFN alfa-2a RBV
PEG-IFN alfa-2a (40KD) Placebo
70
PEG-IFN alfa-2a (40KD) RBV
60
50
43
43
36
40
34
34
32
of Patients
30
30
25
23
20
10
n 21
n 26
n 33
n 14
n 35
n 45
n 26
n 29
n 34
0
Improved
No change
Worsened
No Change Change of 1, -1 or 0 in HAI
scoreWorsening 2-point increase in HAI score
42
Zidovudine impact on HCV treatment
Alvarez D et al. 12th Conference on Retroviruses
and Opportunistic Infections (Abstract
P-192). Boston, MA USA, February 2225, 2005
43
Hematologic Response
Hematologic Response
14
Epoetin alfa (n30)

 
13.7 0.4
SOC (n22)

13
12

1
1.7 0.3
11
Mean Hb (g/dL)
10
1
Baseline
2
3
4
8
12
16
T
ime (
W
eeks)
Plt.001 vs. BL
Plt.001 for epoetin alfa vs. SOC.
P.503 vs. BL
Dieterich D, et al. CROI 2004
44
Hematologic Response AZT vs. no AZT
Hematologic Response AZT vs. no AZT
 

14
13.8 0.5
13.6 0.7

13
12.3 0.5
12
11
1
1.0 0.4
Mean Hb (g/dL)
10
1
Baseline
2
3
4
8
12
16
T
ime (
W
eeks)
Plt.090 for epoelin alfa-treated patients
receiving AZT vs. not receiving AZT.Plt.001 for
epoetin alfa-treated patients receiving AZT vs.
SOC patients reciving AZT.P.001 for epoetin
alfa-treated patients not receiving AZT vs. SOC
patients not receiving AZT.
Dieterich D, et al. CROI 2004
45
PRESCO trial design
G1,4
Follow-up
G1,4
Follow-up
PEGASYS 180 µg plus COPEGUS 10001200 mg
n398
G2,3
Follow-up
G2,3
Follow-up
84
72
60
96
48
24
36
12
0
Study weeks
Patients who achieved EVR (gt2 log10 drop in HCV
RNA at week 12) continued treatment
46
Presco Results
47
US study in HIVHCV co-infected NR to IFN RBV
(Dieterich, Sulkowski)
Peg-IFNa-2a 90 µg
Follow-up
No treatment
Follow-up
HCV RNA pos
Peg-IFNa-2a 180 µg plus RBV 8001200 mg
NR to IFN or IFN/RBV, n100
HCV RNA neg
Peg-IFNa-2a 180 µg plus RBV 1200 mg
Follow-up
120
24
0
48
72
96
Study weeks
Randomisation
48
SLAM-C trial in HIVHCV co-infected
non-responders (Sherman)
Peg-IFNa-2a 180 µg plus RBV 8001200 mg
Untreated Follow-up
HCV RNA ?2 log drop
24 weeks
60 weeks
Peg-IFNa-2a 180 µg plus RBV 8001200 mg
NR and naïve n200
12 weeks
HCV RNA lt2 log drop
Peg-IFNa-2a 180 µg
Stop treatment, observation period
72 weeks
Randomisation
49
Approach to non-responders
Liver biopsy

• METAVIR 34
• Retreat with Peg-IFN RBV
• Antifibrotic treatment strategy
• Consider Peg 360 and wt based RBV
• Treat with insulin sensitzer

• METAVIR 23
• Retreat with Peg-IFN RBV
• Consider Peg 360 and wt based RBV
• Treat with insulin sensitizer

• METAVIR 01
• Wait for new treatment options (Helicase,
  protease inhibitors, polymerase inhibitors)

50
Orthotopic Liver Transplantation

• 23 HIV compared to UNOS (11,453 HIV -)
• HCV, 14 and HBV, 9
• CD4, 200 (range 76 506)
• MELD 16
• HCV worse than HBV
• Drug-drug interaction (tacrolimus)
• Outcome not associated with HIV RNA or CD4

Ragni M. Survival in HIV-infected Liver
Transplant Recipients. 10th CROI 155
51
Nelfinavir interaction with tacrolimus

• Mean 38-fold tacrolimus dose reduction for
  patients taking nelfinavir compared to placebo
• Mean dose for patients (n 5) on nelfinavir
  0.26mg/d
• Frequent drug level monitoring and great caution
  are necessary when introducing or withdrawing
  HAART in HIV-positive organ transplant recipients

Jain et al. Liver Transpl. 20028841-845
52
Patient Survivalcompared with OPTN
 
 
One Year Patient Survival
Three Year Patient Survival
 
All OPTN
87.6 (87.0, 88.2)  
95.6 (95.4, 95.8)
 
79.9 (79.3, 80.5)
90.8 (90.5, 91.1)
65 years OPTN
80.5 (77.9, 83.0)  
90.4 (89.4, 91.3)
 
69.6 (66.9, 72.2)
78.0 (76.6, 79.4)
HIV-infected study subjects
90.9 (73.9, 100)
93.8 (81.9, 100)
 
80.8 (56.8, 100)
93.8 (81.9, 100)
Based on OPTN data as of February 4, 2005. One
year survival is based on 1999 - 2001
transplants, and 3 year survival is based on 1996
- 1999 transplants.
53
Participating Centers(visit the study website
for updated list of centers and contact
information)
54
Conclusions

• HCV is a major, if not the major cause of
  morbidity and mortality in HIV patients today
• Successful treatment of HCV (cure) in HIV
  patients is possible and even likely with
  pegylated interferon and ribavirin
• Side effects can be effectively managed to ensure
  treatment success
• Liver (and kidney) transplant is possible and is
  being investigated in HIV patients

55
Registration Early reg. Feb. 15 - March 15,
2007 Regular reg. March 16 - April 30, 2007 Late
reg. May 1 - May 31, 2007 Abstract
submission Deadline April 30, 2007

• Acute Hepatitis C- epidemiology and treatment
• Chronic Hepatitis C- kinetics, current treatment
• and new therapies
• Hepatitis B - Treatment strategies
• Liver Transplantation- selection and management
• Steatosis in HIV and HCV
• Non invasive measures of fibrosis
• End stage of liver disease managment
• Tayloring ART therapy in Hepatitis
• Update on new drugs for HCV and HBV
• Clinical cases

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