HIV-HCV Coinfection Workshop

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HIV and Hepatitis
Workshop

Kathleen Clanon, MD
Kclanon@jba-cht.com
3/06
Treatment of HCV in
Coinfected Patients
Why Do We Need to Treat HIV/HCV
Coinfected Patients?

• HCV is common in HIV patients (approx 25-40%
in U.S.)
• HCV is a more serious disease in coinfected
patients than in monoinfected.
• HCV has become one of the leading causes of
death in the HIV population.
• HCV coinfection carries significant morbidity,
limits ARV options, decreases QOL.
Epidemiology
• About 400,000 HIV/HCV + in U.S.
● overall 30-50% of HIV+ are co-infected
• Prevalence of HCV in HIV+ individuals:
● approx. 90% in IVDU
● 60-85% in hemophiliacs
● 4-8% in HIV+ MSM
Rapid Progression of Cirrhosis
with Co-infection
• Cross-sectional study - (Soto, J Hepat 1997)
● 547 patients with 116 HIV+/HCV+
● injection drug users
• Results
● HIV+ 14.9% with cirrhosis (mean HCV
duration, 6.9 years)
● HIV- 2.6% (mean duration, 23.2 years)
Hepatic Illnesses HIV Patients
Proportion (%) of Deaths Due to Nonopportunistic Illnesses Contributing to
Nonopportunistic Causes Death as a Percentage (%) of All Deaths
Between 2000 and 2002
80
71.7
70

50 45.7

0
1996 2002

P<.0001 for trend

Palella FJ et al. Presented at: 11th Conference on Retroviruses and Opportunistic Infections, 2004; Abstract 872.
Potential Benefits of HCV Therapy
in Patients Infected With HIV
• Viral eradication
• Delay fibrosis progression
• Prevent/delay bad clinical outcomes
– Liver decompensation
– Hepatocellular carcinoma
– Death
• Improve tolerance and effectiveness of
HAART
– Permit aggressive antiretroviral drug therapy
– Enhance immune reconstitution?
Are we treating HCV
in our patients?
HIV ACCESS
Alameda County, CA
Chart survey done of 1021 HIV patients in care in
2000.

• Most patients screened for HCV.
• 36% co-infected (271)
• Counseling: ETOH use rarely documented.
• Hep A & B vaccinations approx. 42%.
• Only 5 pts (1.8%) ever received IFN treatment
with one SVR.
Who Chooses Who Gets
Treated?
• Chart review study of monoinfected HCV pts in
an urban GI specialty clinic.
• 293 patients evaluated for HCV, only 83 (28%)
were treated. Reasons for not treating were:
1. Nonadherence to visits 37%
2. Medical contraindication 34%
3. Active substance use 13%
4. Patient preference 11%
Authors concluded most patients couldn’t benefit from IFN/RBV therapy.

Falck-Ytter Ann Intern Med 2002; 136:288-92.
Is this similar to your experience?

• What provider barriers have you
experienced?
• What system barriers?
• What patient barriers?
• What other barriers have we missed?
HIV Clinics Know How to
Support Adherence

Can we do better than traditional HCV
treatment models in other care settings?
Elements of HCV/HIV
Management
Phase I: Screening and diagnosis
Phase II: Counseling and health care
maintenance
Phase III: Evaluation for treatment
Phase IV: Monitoring treatment
Phase V: Managing progressive liver disease

How far are you going in your practice?
Screening and Diagnosis
• Test all HIV patients for anti-HCV EIA ab.1
• If IDU and neg HCV ab, check HCV PCR.
(False-neg ab has been reported, 3.4% in one
HIV cohort).2
• If HCV pos., check PCR to confirm active
infection (10-15% spontaneous clearance in
monoinfected).
1. USPHS Guidelines for Preventing OI in PWHIV, 1999.
2. Boyle B and Vaamonde C. DDW, May 2002, San Francisco, Abs 106665.
Counseling and HCM
Counseling Topics:

• Prognosis & treatment basics.
• Avoid EtOH, hepatotoxic meds.
• Limit acetaminophen < 2 gm/day.
• Limit Vitamin A and complementary meds.
• Prevent transmission (sex, drugs, needle
exchange).

NIH Consensus Statement 2002.
Counseling and HCM

Health Care Maintenance:

• Alcohol & drug treatment referral.
• Referral to peer support resources.
• Hep A and B vaccines
Prognosis: Effect of HAART
on HCV
• PIs have no activity against HCV
• Control of HIV to < 400 copies/ml
does not affect HCV RNA levels
• May see transient elevation of ALT
after initiation
• PI vs NNRTI, no difference in rate of
liver fibrosis (Deitrich, CROI 2005)
Phase III: Evaluating for
Treatment
Whom Do We Treat?
• HIV stable (No AZT/ ddI in regimen.)
• If HIV not stable, needs to be addressed
first (judgment call!)
• Treatment/follow-up adherence
• Mostly drug & alcohol free (methadone
okay)
• Willing to undergo treatment
• Pre-treatment liver biopsy necessary
Whom Do We Treat (2)
• Depression under control
• No other contraindications for treatment
(renal failure, severe cardiac disease,
severe
anemia/neutropenia/thrombocytopenia,
uncontrolled diabetes, autoimmune
diseases)
• Compensated liver disease
• Pretreatment vaccine for Hep A/Hep B
When to Delay or Avoid
Treatment
• CD4+ cells < 100/mm³, active opportunistic infections
• Uncontrolled HIV viral load
• Decompensated liver disease
• Untreated depression
• Ongoing substance abuse
• Nonadherence
• Active ischemic heart disease
• Untreatable malignancy
• Severe autoimmune disease
• Pregnancy plans
Whom Do We Treat?
• Liver Biopsy evaluation:
– Stage 1/Grade 1: treatment optional
– Stage 2-4/Grade 2-4: treatment indicated
• Persistently elevated AST
• Compliance with follow-up appointments
Utility of Liver Biopsy
Confirm presence Assess severity of
of chronic hepatitis necroinflammation

Role of
Liver Biopsy

Evaluate possible Assess
concomitant Assess therapeutic
disease processes fibrosis intervention

Brunt et al. Hepatology. 2000;31:241-246.
Progression of Fibrosis on Biopsy
Stage 4: Fibrous
No Fibrosis expansion of portal
areas with marked
bridging (portal to
portal and portal to
central)
Stage 1: Fibrous
expansion of Stage 5,6: Cirrhosis,
some portal areas probable or defined

Stage 3: Fibrous Cirrhotic liver:
expansion of Gross anatomy of
most portal areas cadaver
with occasional
portal to portal
bridging
Courtesy of Gregory Everson, MD.
Elements of HCV/HIV
Management
Phase I: Screening and diagnosis
Phase II: Counseling and health care
maintenance
Phase III: Evaluation for treatment
Phase IV:Monitoring treatment
Phase V: Managing progressive liver
disease
Does HCV Treatment Work In
Coinfected Patients?
Defining Success
EVR = Early viral response, 12 week viral
load is undetectable or decreased by 2
logs.
ETR = End of treatment response,
undetectable viral load at end of
treatment.
SVR = Sustained viral response,
undetectable
6 or more months after therapy.
APRICOT Study Design
PEG (40 kDa) IFN alfa-2a (180 µg, QW)
Follow-up
plus RBV placebo (800 mg, QD)

PEG (40 kDa) IFN alfa-2a(180 µg, QW)
plus RBV (800 mg, QD) Follow-up

Interferon alfa-2a(3 MIU, TIW)
Follow-up
plus RBV (800 mg, QD)

0 24 48 72
Study Weeks

Torriani et al. Retroviruses and Opportunistic Infections; February 27, 2002; Seattle, WA. Abstract 121.
PEG-IFN alfa-2a plus RBV
Sustained Virologic Response: Genotype
70%

60%
50%
40% Roferon+RBV
30% Pegasys+plac
Pegasys+RBV
20%
10%
0%
gt1 gt2,3
Results: AEs
Interferon Peg-IFN+ Peg-IFN+
alpha+ placebo ribavirin
ribavirin
ANC < 500 1% 13% 11%

Plat < 20K 0% <1% <1%

HB < 6.5 -- 2% 1%

CD4 / % -131 (+1.3%) -135 (1.4%) -157 (3%)

HIV VL * + 0.02 - 0.79 - 0.7

* Only those w/ detectable virus
Does Rx Improve Liver Health
if No SVR?
• Retrospective analysis of APRICOT
• N = 64 pts with paired pre – and post -Rx
bx
• Histologic response defined as ↓ at least 2
pts in index
• 1/3 of pts without SVR had + histologic
response
Lissen, E. et al, 3rd IAS Conf., Rio de Janeiro, 7/05 Abstract TuPel1C21
Coinfection Program Structure:
Alameda County Medical
Center
• 80% RN dedicated to program
• Weekly support and education group.
• Monthly coinfection session in HIV Clinic
• Biopsies done by GI in HIV clinic
• Approx 40 people treated in past 2 years.
How Do We Treat?
• Educate about treatment risks
• Start Peg-Interferon & Ribavirin
• Close monitoring of labs (CBC&Diff, Liver
Panel every 2 weeks for 2 months, TSH
every 3 months, Uric Acid every month)
• Viral loads (HIV/HCV) at 8 and 12 weeks,
then every 3 months
How Do We Treat?
• If hemoglobin drops below 10-11 gm/dl,
start erythropoietin treatment
• If absolute neutrophil count drops below
750, dose reduction of interferon. If not
sufficient, start G-CSF
• Monitor depression with standardized
scale every month, adjust antidepressants
prn
When Do We Treat?
• If early HIV, consider HCV therapy prior to
HIV treatment
• If progressive HIV, optimize HIV control
first
• When on stable HIV regimen, consider
HCV therapy
• Control any substance abuse/psychiatric
disease
How Long to Treat?
• HCV clears more slowly in coinfected pts
• Usual duration of RX in monoinfected:
● GT 1, 4 = 48 weeks
● GT 2, 3 = 24 weeks

• Randomized Trial in Coinfected of GT 2 or 3
● N = 74, all suppressed at wk 24
● Randomized to no further Rx or continue to 48 weeks
● SVR in 24 wk group = 60%
● SVR in 48 wk group = 90%

Zannini, B. et al: 3rd IAS Conf , Rio de Janeiro 7/05, Abstract
MoPplB0103
Management of HCV/HIV in 2006
• In early weeks of Rx, it’s all about the ribavirin
dose.
• Avoid ART with higher risk for toxicity
– High-dose ritonavir, nevirapine
– ddI (in advanced liver disease), d4T, ZDV in
patients on RBV
• Monitor CBC and AST/ALT closely, q 2 weeks
initially
• Treat through “minor” elevations of serum ALT
(<5 X normal) and avoid “switching” or
discontinuing regimens if possible
Practical Lessons: HCV Rx
in the HIV Clinic
• Severe anemia is common, start epo early,
monitor often.
• Monitor closely for depression. SSRI’s for
everyone!
• Warn pts that abs CD4 will fall due to IFN (%CD4
is preserved).
– HIV VL decreased in non-HAART pts.
• Water (2-3 liters per day) is the best side effect
management tool.
Open questions for HIV/HCV
patients

• Should GT 1 coinfected patients be
treated for extended periods >48 weeks?
• Will weight-based RBV improve SVR?
• Can fibrotests replace liver biopsy? (Not
looking good as of CROI 2006.)
HIV/HCV
Co-Infection
Cases
K. Clanon, MD
Kclanon@jba-cht.com

April 12, 2005
Sheila E.
38 yo with CD4 280, VL 20K, both
worsening over the past 6 months.

• Never on HAART.
• Persistent elevation of ALT/AST.
• HCV genotype 1.
• Biopsy last month shows bridging
fibrosis and moderate inflammation
(Stage 2, Grade 3).
Sheila E. ~ Questions
1. Will you recommend starting HAART,
HCV Treatment, or both for Ms. E at
this time?

2. Any specific HAART drugs to use or
avoid if she does start HAART?
Ali S.
50 yo with CD4 400, VL 3K, on AZT/3TC/EfV. He
has been reluctant to change, saying “if it ain’t
broke, don’t fix it”.

• HCV genotype 1, HCV VL 5M. Biopsy done 3
months ago was Stage 2, Grade 2.
• Started pegIFN/RBV 3 weeks ago, now complains
of fatigue and SOB.
• CBC now shows, Hgb 6gm (down from 12.0) and
WBC 1.1 (baseline 3.4.)
Ali S. ~ Questions

1. Likely causes of the anemia and leukopenia?
2. Possible interventions, with pro’s and con’s? -
For Anemia?
- For Leukopenia?
3. What could be done differently with the next
patient to prevent or mitigate these complications?
4. Will you recommend changes in ARVs?
Jorge X.
41 yo being treated with pegIFN/RBV.

• CD4 300, HIV VL 20K.
• Not on HAART.
• HCV genotype II.
• No liver biopsy was done before starting Tx.
• History of depression, started on SSRI just
prior to starting HCV Tx.
• Now week 8 of HCV Tx, complaint of severe
fatigue, not leaving house. Wants to quit Tx.
Jorge X. ~ Questions

1. Differential Dx for complaint of fatigue?

2. Next steps to address Jorge’s complaint?

3. For future reference, how would you discuss
the issue of biopsy before therapy for
patients like Jorge (and what if Jorge had
genotype 1?)
Yolanda R.
35 yo being treated with simultaneous HAART and
pegIFN/RBV. You are afraid she is failing Tx.

• CD4 250, HIV VL <75
• On HAART regimen of ddI/TDF/LPVr for 6 months.
• HCV genotype I, HCV VL 2.5M.
• Pretreatment liver biopsy shows Stage 2, Grade 3.
• On pegIFN/RBV and you believe she is adherent.
• Week 12, HCV viral load is still 1M.
Yolanda R. ~ Questions

1. What are the pro and con arguments of
stopping Yolanda’s HCV Tx?

2. Will you recommend changes in HAART if
Yolanda continues on HCV Tx?
HCV Websites
For providers:
• www.cdc.gov/ncidod/diseases/hepatitis

• www.hivandhepatitis.com

• www.va.gov/hepatitisc

For clients/patients:
• www.thebody.com

• www.hcvadvocate .org

• www.hivandhepatitis.com
HBV/HIV Coinfection

Cases courtesy Dr. David Spach
University of Washington
Relative needlestick and sexual
exposure risk
• Place in order – highest>>lowest
– Hepatitis B, C, and HIV??

• Needlestick:

• Sexual transmission:
Relative Risk of Infection:
“Rule of Three”
• HBV contaminated needle:
– eAg+ 30% risk of transmission
– eAg- 10% risk
• HCV contaminated needle:
– 3% risk
• HIV contaminated needle:
– 0.3% risk
• Sexual transmission: HBV>HIV>HCV
Initial workup
• HIV • HBV
– HIV VL – ALT, 1 month apart
– Bili, Albumin, PT
– CD4
– AFP
– CD8 – (Ammonia)
– (New) medications – HBeAg, Ab
– HBV DNA
– HBV genotype
– Delta Ab
– Ultrasound
– Histology
Evaluation and monitoring
“should” include:
• HBsAg, HBeAg, anti-HBe, anti-HDV
• HBV DNA
• Liver enzymes
• Liver synthetic tests
• Abdominal ultrasound
• Consider Liver biopsy if abnormal ALT
Evaluation and monitoring
• Minimum - every 6 months
– ALT
– HBV DNA
– HBeAg
• HCC screen every 6 months if :

– Cirrhosis
– Strong family history
– > 45 years of disease
– High AFP >20 ?
Goals of Therapy & Treatment
Endpoints for HBV
• Goals of therapy
– Prevent long-term clinical outcomes by inducing
sustained suppression of HBV replication.
(chronic HBV infection is currently not readily
eradicable)
- Objective is to slow liver disease progression
• Treatment endpoints
– Biochemical normalization
– Serological (HBeAg &/or HBsAg seroconversion)
– Virological (serum HBV-DNA suppression)
– Histological improvement
1 Lok, et al. J Hepatology 2003: 38; S90-S103.
Algorithm assumes detectable
HBV DNA prior to start or
change anti-HBV therapy:

> 105 copies/ml for Wild Type
> 104 “ for HBeAg negative
variants
Anti-HBV therapy if:

ALT > 2X ULN (Lok 2004)
ALT elevated (Keefe 2004) *

* normal ALT pts may have significant fibrosis 
liver biopsy
HIV/HBV: Initiating HBV Therapy
• George R: A 36-year-old man with HIV and HBV
co-infection:
• CD4 520, VL 18,000; Never on HAART.
• Persistent 3-5x increase in ALT/AST levels.
• HBsAg+; HBeAg+; HBV DNA: 6 x 108 IU/ml.
• Liver biopsy not performed

• Questions:
1. What medications are now FDA-approved for
treatment of HBV?

2. What approved medications have activity against
HBV, but do not have indications for HBV
treatment? DHS/HIV/PP
HIV/HBV: Initiating HBV Therapy
The following patients are co-infected with HBV and
HIV. All have HBsAg(+), persistent elevations of
ALT (> 2-3x), and HBV DNA levels > 106. None has
ever received ARV Rx or HBV Rx.
• Patient 1: CD4 490, HIV RNA=23,000; HBeAg(+).
• Patient 2: CD4 524; HIV RNA=38,000; HBeAg(-).
• Patient 3: CD4 210; HIV RNA = 112,000; HBeAg(+).

• Question
How would you approach treatment of HBV infection is
these 3 patients?
DHS/HIV/PP
CD4 >350, no HAART required
Biopsy No HBV therapy
Nl ALT, F0 or F1

F4 = Cirrhosis
Abnormal ALT or F2-F4 Any viremia

WT, no
cirrhosis
HBeAg neg
A. Adefovir 10 mg/d

A. Peg-IFN 180 ug 48 wk A. Adefovir 10 mg/d
B. Adefovir 10 mg/d B. Peg-IFN
CD4 >350, on HAART
Biopsy Nl ALT, F0 or F1 Keep current
HAART

Abnormal ALT or F2-F4 Cirrhosis
Any viremia

WT, no
cirrhosis HBeAg A. Include TDF
neg B. Include FTC-TDF
A. Peg-IFN 180 ug 48 wk
B. a. Incorporate 1 (or 2) HBV-active NAs C. Add Adefovir 10
b. if YMDD mutant, include TDF mg/d
CD4 <350, HAART-experienced
Low ALT, DNA < 105
ALT, DNA, Low activity or No HAART
Biopsy fibrosis changes
ALT>100, DNA > 105
High activity or Cirrhosis
Any viremia
fibrosis
WT, no
cirrhosis HBeAg
A. Incorporate TDF
neg
A. Incorporate 1 or 2 HBV-active NAs B. Add Adefovir 10
mg/d
B. If YMDD mutant Add TDF or ADV
C. ? Peg-IFN
Any CD4, HAART-naive
Low ALT, DNA < 105 A. Any HAART
ALT, DNA, Low activity or
B. Include Lam or FTC
Biopsy fibrosis

ALT>100, DNA > 105
High activity or Cirrhosis
fibrosis Any viremia
WT, no
cirrhosis HBeAg
neg A. Incorporate TDF
A. Include 1 or 2 HBV active NAs
B. Incorporate TDF
C. ? Peg-IFN
HIV/HBV: Monitoring Response

• A 41-year-old woman with HIV and HBV co-infection:
• CD4 220, VL 88,000; Never on HAART.
• Labs show 3-4x increase in ALT/AST levels.
• HBsAg(+); HBeAg(-); HBV DNA: 4 x 109 IU/ml.
• Started on Tenofovir-DF + Lamivudine + Efavirenz

• Questions:
1. What are the goals of therapy?
2. What should you monitor to determine the
response to therapy? DHS/HIV/PP
End-of-Follow-up Combined Response*
30 26% 28%
Patients with response(%)

25
19%
20

15 12%
10

5 n = 51 n = 49 n = 46 n = 48
0
4.5 MIU 90 μg PEG-IFN 180 μg PEG-IFN 270 μg PEG-IFN
IFN -2a -2a (40KD) -2a (40KD) -2a (40KD)
*HBeAg loss, HBV DNA < 500,000 c/mL, ALT normalization
Cooksley, Venice 2002
Adefovir in HBV patients with active
replication and liver disease
• Recommended treatment for HBeAg+ HBV is 12
months
• Stop adefovir after HBeAg seroconversion
documented on 2 occasions ~3 - 6 months apart
• Prolonged treatment if HBeAg seroconversion not
achieved – probably will be necessary in most
• Indicated in treatment of 3TC resistance
• Dose adjustments in renal insufficiency
• Resistance much less frequent than for 3TC, but
occurs
3TC in HBeAg positive and likely
HBeAg negative HBV disease
• Stage liver disease to determine urgency of therapy
• Recommended treatment for HBeAg+ and HBeAg –
disease is 12 months – but likely too restrictive
• Stop lamivudine after HBeAg seroconversion
documented on 2 occasions ~3-6 months apart
• Prolonged treatment if HBeAg seroconversion not
achieved (?), prolonged therapy for HBeAg - pts
• Lamivudine resistance:
– Continue lamivudine if continued benefit (clinical assessment,
ALT, HBV DNA)
– Consider switching to adefovir
Therapy for Hepatitis B: 2006
Unanswered Questions
• Optimal treatment duration?
• What will be the role of pegylated interferon?
• What will be the role of combination therapy?
– Nucleoside + nucleoside?
– Nucleoside + immunomodulator?
• What will be the long-term consequences of
YMDD mutants?
• Therapy for pre-core mutants?