HIV and Hepatitis Workshop

1
HIV and Hepatitis Workshop

• Kathleen Clanon, MD
• Kclanon_at_jba-cht.com
• 8/06

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Treatment of HCV in Coinfected Patients
3
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.

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Epidemiology
HIV/HCV Coinfection

• 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

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Rapid Progression of Cirrhosis with Co-infection
HIV/HCV Coinfection

• 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)

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Hepatic Illnesses HIV Patients
Palella FJ et al. Presented at 11th Conference
on Retroviruses and Opportunistic Infections,
2004 Abstract 872.
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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?

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Are we treating HCV in our patients?
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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.

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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 couldnt benefit
from IFN/RBV therapy.
Falck-Ytter Ann Intern Med 2002 136288-92.
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Is this similar to your experience?

• What provider barriers have you experienced?
• What system barriers?
• What patient barriers?
• What other barriers have we missed?

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HIV Clinics Know How to Support Adherence

• Can we do better than traditional HCV treatment
  models in other care settings?

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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?

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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.
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Counseling and HCM

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

NIH Consensus Statement 2002.
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Counseling and HCM

• Health Care Maintenance
• Alcohol drug treatment referral.
• Referral to peer support resources.
• Hep A and B vaccines

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Prognosis Effect of HAART on HCV
HIV/HCV Coinfection

• PIs have no activity against HCV
• Control of HIV to lt 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)

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Phase III Evaluating for Treatment
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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

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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

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When to Delay or Avoid Treatment
HIV/HCV Coinfection

• CD4 cells lt 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

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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

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Utility of Liver Biopsy
Confirm presence of chronic hepatitis
Assess severity of necroinflammation
Role of Liver Biopsy
Evaluate possible concomitant disease processes
Assess therapeutic intervention
Assessfibrosis
Brunt et al. Hepatology. 200031241-246.
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Progression of Fibrosis on Biopsy
Stage 4 Fibrous expansion of portal areas with
marked bridging (portal to portal and portal to
central)
No Fibrosis
Stage 1 Fibrous expansion of some portal areas
Stage 5,6 Cirrhosis, probable or defined
Stage 3 Fibrous expansion of most portal areas
with occasional portal to portal bridging
Cirrhotic liver Gross anatomy of cadaver
Courtesy of Gregory Everson, MD.
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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

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Does HCV Treatment Work In Coinfected Patients?

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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.

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Coinfection peg-IFN/RBV Treatment Studies Summary
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Coinfection Treatment Studies Consensus Lessons

• Peg-IFN/RBV is best current treatment
• RBV full dose is critical early in Rx
• Lack of early response predicts no SVR
• AZT RBV anemia
• ddI RBV lactate

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Side Effects of Therapy

• Peg-IFN
• Neuropsychiatric
• Depression
• Anxiety
• Irritability
• Neutropenia
• Thrombocytopenia
• Anorexia

Núñez. JAIDS. 200127426.PDR.
200155472,551,1365,2932.
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(No Transcript)
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How Long to Treat

• HCV clears more slowly in coinfected pts
• Usual duration
• 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 AbsMoPplB0103

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Low and High HCV RNAAPRICOT
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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,
  7/02 Aos TuPel.1C21

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Coinfection Algorithm
Adapted from Chung, R Topics in HIV Medicine,
July 2006
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Management of HCV/HIV in 2006

• Select ART with lower potential for toxicity
• Avoid
• 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 (lt5
  X normal) and avoid switching or discontinuing
  regimens if possible

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Practical Lessons HCV Rx in the HIV Clinic

• Severe anemia is common, start epo early, monitor
  often.
• Monitor closely for depression. SSRIs 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.

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Open questions for HIV/HCV patients
HIV/HCV Coinfection

• Will weight-based RBV improve SVR?
• Should coinfected patients be treated for
  extended periods gt48 weeks?
• Can fibrotests replace liver biopsy? (Not looking
  good as of CROI 2006.)

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HIV/HCV Co-InfectionCases
K. Clanon, MD Kclanon_at_jba-cht.com
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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).

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Sheila E. Questions

• Will you recommend starting HAART, HCV Treatment,
  or both for Ms. E at this time?
• Any specific HAART drugs to use or avoid if she
  does start HAART?

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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.

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Jorge X. Questions

• 1. Differential Dx for complaint of fatigue?
• 2. Next steps to address Jorges 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?)

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Yolanda R.

• 35 yo being treated with simultaneous HAART and
  pegIFN/RBV. You are afraid she is failing Tx.
• CD4 250, HIV VL lt75
• 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.

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Yolanda R. Questions

• 1. What are the pro and con arguments of stopping
  Yolandas HCV Tx?
• 2. Will you recommend changes in HAART if Yolanda
  continues on HCV Tx?

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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

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HBV/HIV Coinfection
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Relative needlestick and sexual exposure risk

• Place in order highestgtgtlowest
• Hepatitis B, C, and HIV??
• Needlestick
• Sexual transmission

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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 HBVgtHIVgtHCV

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HBV-HIV Coinfection

• Common and more rapidly progressive
• HBV DNA levels higher and spontaneous
  seroconversion less frequent
• ALT lower and histology worse
• HAART may induce severe exacerbation
• Interferon a minimally effective (lt10 loss of
  HBeAg)
• 3TC induces rapid fall in HBV DNA but few have
  sustained loss of HBeAg (YMDD variants)
• Nuc analog combinations under study

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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

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Evaluation and monitoring

• Minimum - every 6 months
• ALT
• HBV DNA
• HBeAg
• HCC screen every 6 months if
• Cirrhosis
• Strong family history
• gt 45 years of disease
• High AFP gt20 ?

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Goals of Therapy for HIV/HBV

• Induce sustained suppression of HBV replication.
• Slow liver disease progression
• Avoid HBV flare with immune reconstitution
• Eradication is NOT a likely outcome
• Conversion to HBsAg- rare in coinfection
• Conversion to HBeAg- rare in anyone

1 Lok, et al. J Hepatology 2003 38 S90-S103.
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Treatment Endpoints for HBV

• Biochemical (AST) normalization
• Virological (serum HBV-DNA suppression)
• Histological improvement
• Rare Serological (HBeAg /or HBsAg
  seroconversion)

1 Lok, et al. J Hepatology 2003 38 S90-S103.
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Algorithm assumes detectable HBV DNA prior to
start or change anti-HBV therapygt 105
copies/ml for Wild Typegt 104 for HBeAg
negative variants
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Anti-HBV therapy if ALT gt 2X ULN (Lok
2004)ALT elevated (Keefe 2004) normal ALT
pts may have significant fibrosis ? liver biopsy
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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
• Questions1. 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
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Medications with anti-HBV Activity

• FDA Approved
• 3TC 100mg/d
• IFN alpha-2b 5 mIU sq qd
• pegIFN alfa-2a 180 mcg/week for 48 wks
• Adefovir 10 mg/d
• Entecavir 0.5-1.0 mg/d

• NOT Approved for HBV
• Tenofovir
• Emtricitabine

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HIV/HBV Initiating HBV Therapy

• The following patients are co-infected with HBV
  and HIV. All have HBsAg(), persistent
  elevations of ALT (gt 2-3x), and HBV DNA levels gt
  106. None has ever received ARV Rx or HBV Rx.
• Patient 1 CD4 490, HIV RNA23,000 HBeAg().
• Patient 2 CD4 524 HIV RNA38,000 HBeAg(-).
• Patient 3 CD4 210 HIV RNA 112,000 HBeAg().
• QuestionHow would you approach treatment of HBV
  infection in these 3 patients?

DHS/HIV/PP
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CD4 gt350, no HAART required
Biopsy
Nl ALT, F0 or F1
No HBV therapy
F4 Cirrhosis Any viremia
Abnormal ALT or F2-F4
WT, no cirrhosis
HBeAg neg

• Adefovir 10 mg/d

• Peg-IFN 180 ug 48 wk
• Adefovir 10 mg/d

• Adefovir 10 mg/d
• Peg-IFN

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CD4 gt350, on HAART
Biopsy
Keep current HAART
Nl ALT, F0 or F1
Cirrhosis Any viremia
Abnormal ALT or F2-F4
WT, no cirrhosis
HBeAg neg

• Include TDF
• Include FTC-TDF
• Add Adefovir 10 mg/d

• Peg-IFN 180 ug 48 wk
• a. Incorporate 1 (or 2) HBV-active NAs
• b. if YMDD mutant, include TDF

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CD4 lt350, HAART-experienced
Low ALT, DNA lt 105 Low activity or fibrosis
ALT, DNA, Biopsy
No HAART changes
ALTgt100, DNA gt 105 High activity or fibrosis
Cirrhosis Any viremia
WT, no cirrhosis
HBeAg neg

• Incorporate TDF
• Add Adefovir 10 mg/d

• Incorporate 1 or 2 HBV-active NAs
• If YMDD mutant Add TDF or ADV
• ? Peg-IFN

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Any CD4, HAART-naive
Low ALT, DNA lt 105 Low activity or fibrosis

• Any HAART
• Include Lam or FTC

ALT, DNA, Biopsy
ALTgt100, DNA gt 105 High activity or fibrosis
Cirrhosis Any viremia
WT, no cirrhosis
HBeAg neg

• Incorporate TDF

• Include 1 or 2 HBV active NAs
• Incorporate TDF
• ? Peg-IFN

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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
• Questions1. What are the goals of therapy?2.
  What should you monitor to determine the response
  to therapy?

DHS/HIV/PP
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End-of-Follow-up Combined Response
28
30
26
25
19
20
Patients with response()
12
15
10
n 51
n 49
n 46
n 48
5
0
4.5 MIUIFN ?-2a
90 µg PEG-IFN?-2a (40KD)
180 µg PEG-IFN?-2a (40KD)
270 µg PEG-IFN?-2a (40KD)
HBeAg loss, HBV DNA lt 500,000 c/mL, ALT
normalization
Cooksley, Venice 2002
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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

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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

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Therapy for Hepatitis B 2006Unanswered 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?