HCV in the HIV infected Patient

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HCV in the HIV infected Patient

• David L. Thomas, MD

Advisory Board Merck Co.
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HCV Treatment Future is Bright
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HCV Treatment Present is Challenging for HIV/HCV
Coinfected Patients
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2008 Management of HIV/HCV Coinfected Patients

• Whom to treat
• How to treat
• When to stop

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56 year old Caucasian male with HIV and HCV
infection

• HIV and HCV diagnoses early 1990s exposures late
  1970s
• No ART CD4 lymphocyte 782/mm3, HIV RNA lt400c/ml
• HCV genotype 1a HCV RNA 6.4 log IU/ml
• ALT 77 INR 1, TB 1.9 creat 1 plts 219K
• Liver biopsy 2001 mild fat no fibrosis

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Which would you do next?

• Repeat liver biopsy
• Check FibroSure
• Peg IFN and RBV, check HCV RNA 4 and 12 wks
• Compliment him on his DNA and follow
• Check CD4 lymphocyte percent

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Which would you do next?

• Repeat liver biopsy
• Could be progression
• Could be an error

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Three Year Predictive Value of Liver Biopsy
Represents Error and Natural History

• 175 HIV/HCV coinfected persons biopsied twice,
  median 2.9 yrs
• 41 (24) had 2pt increase
• Must repeat test

Sulkowski et al AIDS 2007
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Courtesy of M. Pinzani, Florence
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Liver Biopsy Readings Have Limited Validity

• Sampling error (metavir 2-4 fibrosis)
• 161 gt 3cm biopsies reduced 1.5cm and 1cm and
  re-scored1
• mild 3cm 59 1.5 cm 68 1cm 80
• Specimen diameter reduced
• 63 mild increased to 87
• sampling error underestimates fibrosis

1 Colloredo J Hepatol 2003
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Which would you do next?

• Check FibroSure
• Reasonable validity in HIV/HCV coinfected
  persons, especially considering lack of
  sensitivity and specificity of biopsy

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Validity of Noninvasive Methods of Detecting
Significant Liver Fibrosis
Test Prev Sens Spec AUROC
Fibrotest1, 130 45 66 92 0.856
SHASTA2, 95 27 62 84 0.878
FIB43, 830 21 67 71 0.737
APRI4, 263 58 51 91 0.73
Forns4, 263 58 43 96 0.71
Metavir 2-4, MHAI 3-6 (except FIB 4 Metavir
3-4) 1Myers AIDS 2003 2Kellener J Hepatol 2005
3Sterling Hepatology 2006- MHAI 0-3 vs. 4-6
4Maciás Gut 2007
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Which would you do next?

• Peg IFN and RBV, check HCV RNA 4 and 12 wks
• Liver disease staging is inaccurate
• Therapeutic trial provides information on adverse
  events and response for this patient

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FibroSure0.9 repeat liver biopsy (gt2 cm) shows
metavir 3 (of 4) fibrosis mild macro-vesicular
fat, moderate activity. Now what?

1. Peg IFN and RBV
2. Wait for new HCV drugs
3. AZT-based ART
4. ABC-based ART
5. TDF-based ART

Peg IFN and RBV after
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HAART and Treatment of HCV

• ART should be given if indicated by HIV stage
• Insufficient evidence that PegIFN/RBV response is
  improved
• By ART
• By higher CD4
• Many recommend it anyway, especially with high
  HIV RNA or CD4 350-500/mm3

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NRTI Choice and RBV

• Dont use ddI and RBV
• Avoid AZT and RBV
• ? ABC and RBV
• 1493 HIV/HCV coinfected getting PegRBV
• 62 No SVR associated with GT 1/4 viral load
  low RBV trough ABC (OR 2.22, 0.91-5.40)
• 2No difference in SVR in 238 TDF versus 52 ABC2

Effect Bani Sadr J AIDS 2007 1Vispo Antivir
Ther 2008 Mira et al CROI 2008 ABST 1074 No
effect 2Gonzales-Garcia CROI 2008 ABST 1076
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Peg and RBV 1.2 g/d was started without ART.
Treatment is well tolerated. HCV RNA drops 6.4 to
4.99 log IU at 30 days. Which is best?

1. Stop, no chance of SVR
2. Increase Peg dose
3. Continue current therapy
4. Start pioglitazone
5. Start ART

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Baseline HCV RNA was retested with assay with
high upper range7.5 log IU/ml (vs 6.2).
Treatment continued. HCV RNA drops to 3.7 log IU
at 12 weeks. Which is best?

1. Stop
2. Reduce Peg IFN dose, stop RBV
3. Continue current therapy

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Treatment continued. HCV RNA drops to 3.42 log IU
at 24 weeks. ALT 58. Which is best?

1. Stop
2. Reduce Peg IFN dose, stop RBV
3. Continue current therapy for 18 months
4. Stop, start pioglitazone and ART and restart ART
   in 6 months

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Forms of Virologic Response
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PEG/RBV
Log IU HCV RNA
Weeks of HCV Treatment
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HCV Therapy Generally Should be Stopped Unless gt2
logs at 12 wks and undetectable at 24 wks

• No cure
• No control

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Rare SVR Without Early Virologic Response in
HIV/HCV Coinfected Patients
Study Peg RBV Rx No EVR SVR
ACTG 5071 106 63 0
APRICOT 289 85 2
RIBAVIC 205 68 1
Chung NEJM 2004 Torriani NEJM 2004 Carrat JAMA
2004
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No Control of HCV Infection in ACTG 5178 (SLAM C)
PegIFN 2a
EVR
RANDOMIZE
_
PegIFN 2a RBV 1-1.2g/d
OBSERVE

CONTINUE
72 Weeks
Bx1
Bx2
Bx3
Sherman and 5178 team CROI 2008
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ACTG 5178 SLAM C EVR Was Common
112 44.4
PegIFN 2a
EVR
RANDOMIZE
_
PegIFN 2a RBV 1-1.2g/d
OBSERVE

CONTINUE
183 55.6
72 Weeks
Bx2
Bx3
Bx1
Sherman and 5178 team CROI 2008
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ACTG 5178 SLAM C Maintenance Versus Observation
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112 44.4
PegIFN 2a
EVR
RANDOMIZE
_
PegIFN 2a RBV 1-1.2g/d
OBSERVE

CONTINUE
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183 55.6
72 Weeks
Bx2
Bx3
Bx1
Sherman and 5178 team CROI 2008
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ACTG 5178 No Benefit of Maintenance

• No benefit of 18 months of maintenance
• DSMB stopped study
• Cirrhosis 18 and 21 of maintenance and
  observation arms

Sherman and 5178 team CROI 2008
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Maintenance Therapy Does Not Reduce Clinical
Outcomes in HIV-negative Non-responders

• RCT PegIFN 2a 90 mcg/wk versus observation for
  Ishak 3-6 fibrosis
• Biopsy 1.5 and 3.5 yrs, clinical evaluation
• 517 treated versus 533 controls
• Lower ALT, HCV RNA, and inflammation
• Outcome 34.1 vs 33.8 (P0.91)

DeBisceglie Hepatology supp Oct 2007 LB1 AASLD
Boston 2007
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Longer Treatment May Increase SVR in Slow
Responders (HIV NEG)

• HCV genotype 1 RNA wk 4 randomized to 48
  (n149) versus 72 wk (n142)1
• SVR 44 72 wks versus 28 48 wks
• HCV genotype 1 2 log drop at 12 wks, not neg
  until 24 wks.
• SVR 48 18 lt SVR 72 38 (p0.026)2

1Sanchez Tapias Gatro 2006 2Pearlman Hepatol
2007.
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Treatment stopped. Creat 1.0 ALT 74 IU INR 1.0
which is best?

1. Refer to Dr. Sulkowski for investigational HCV
   drug
2. Refer to Dr. Fierer for counseling to prevent
   secondary transmission
3. Refer to Dr. Afdhal for management of cirrhosis
   and transplant evaluation
4. All of the above

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Virologic Response Predicts SVR in HIV Infected
Persons
Rodrigues-Torres and APRICOT team CROI 2008
ABST 1073