HIV and Hepatitis Workshop Kathleen Clanon, MD [email protected] 8/06.

HIV and Hepatitis Workshop

Kathleen Clanon, MDKathleen Clanon, [email protected]@jba-cht.com

8/068/06

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.About 400,000 HIV/HCV + in U.S.● overall 30-50% of HIV+ are co-infected

Prevalence of HCV in HIV+ individuals:Prevalence of HCV in HIV+ individuals:● approx. 90% in IVDU● 60-85% in hemophiliacs● 4-8% in HIV+ MSM

HIV/HCV Coinfection

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)

HIV/HCV Coinfection

Hepatic Illnesses HIV Patients

Palella FJ et al. Presented at: 11th Conference on Retroviruses and Opportunistic Infections, 2004; Abstract 872.

45.7

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Proportion (%) of Deaths Due to Nonopportunistic Causes

Nonopportunistic Illnesses Contributing to Death as a Percentage (%) of All Deaths Between 2000 and 2002

P<.0001 for trend

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

Elements of HCV/HIV ManagementPhase 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, 1999.1. USPHS Guidelines for Preventing OI in PWHIV, 1999.2. Boyle B and Vaamonde C. DDW, May 2002, San Francisco, Abs 106665.2. 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.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 HCVPIs have no activity against HCV Control of HIV to < 400 copies/ml does Control of HIV to < 400 copies/ml does

not affect HCV RNA levelsnot affect HCV RNA levels May see transient elevation of ALT after May see transient elevation of ALT after

initiationinitiation PI vs NNRTI, no difference in rate of PI vs NNRTI, no difference in rate of

liver fibrosis liver fibrosis (Deitrich, CROI 2005)(Deitrich, CROI 2005)

HIV/HCV Coinfection

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

HIV/HCV Coinfection

Whom Do We Treat?

Liver Biopsy evaluation: Stage 1/Grade 1: treatment optionalStage 2-4/Grade 2-4: treatment indicated

Persistently elevated AST Compliance with follow-up appointments

Utility of Liver Biopsy

Role of Role of Liver BiopsyLiver Biopsy

Confirm presence of chronic hepatitis

Brunt et al. Hepatology. 2000;31:241-246..

Assess severity of necroinflammation

Evaluate possible concomitant

disease processes

Assess therapeutic intervention

Assessfibrosis

Progression of Fibrosis on BiopsyNo Fibrosis

Stage 1: Fibrous Stage 1: Fibrous expansion of expansion of some portal areassome portal areas

Stage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging

Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central)

Stage 5,6: Cirrhosis, probable or defined

Cirrhotic liver: Gross anatomy of cadaver

Courtesy of Gregory Everson, MD.

Elements of HCV/HIV ManagementPhase I: Phase I: Screening and diagnosisScreening and diagnosis

Phase II:Phase II: Counseling and health care Counseling and health care maintenancemaintenance

Phase III:Phase III: Evaluation for treatmentEvaluation for treatment

Phase IV:Phase IV: Monitoring treatmentMonitoring treatment

Phase V:Phase V: Managing progressive liver Managing progressive liver diseasedisease

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.

Coinfection peg-IFN/RBV Treatment Studies: Summary

StudyStudy ACTG ACTG A5071A5071

APRICOTAPRICOT RIBAVICRIBAVIC

SVR % for SVR % for GT 1GT 1

27%27% 40%40% 27%27%

D/C Rate D/C Rate due to AEsdue to AEs

12%12% 15%15% 31%31%

Coinfection Treatment Studies Consensus Lessons Peg-IFN/RBV is best current treatmentPeg-IFN/RBV is best current treatment RBV full dose is critical early in RxRBV full dose is critical early in Rx Lack of early response predicts no SVRLack of early response predicts no SVR AZT + RBV = anemiaAZT + RBV = anemia ddI + RBV = lactateddI + RBV = lactate

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

Low and High HCV RNA:APRICOT%SVR%SVR Low HCV RNA Low HCV RNA

(< 800,000)(< 800,000)High HCV RNA High HCV RNA (>800,000)(>800,000)

Gentoype 1Gentoype 1 62%62% 18%18%

Genotype 2,3Genotype 2,3 62%62% 65%65%

Does Rx Improve Liver Health if No SVR?

Retrospective analysis of APRICOTRetrospective analysis of APRICOT N = 64 pts with paired pre – and post -Rx bxN = 64 pts with paired pre – and post -Rx bx Histologic response defined as Histologic response defined as ↓ at least 2 pts ↓ at least 2 pts

in indexin index 1/3 of pts without SVR had + histologic 1/3 of pts without SVR had + histologic

responseresponse

Lissen, E. et al, 3Lissen, E. et al, 3rdrd IAS Conf., Rio de Janeiro, 7/02 Aos IAS Conf., Rio de Janeiro, 7/02 Aos TuPel.1C21TuPel.1C21

Coinfection AlgorithmA F T E R H IV D isea se S tab iliza tion

T re a t w ith p e g IF N /R B V4 8 w e e ks

G e no typ e 2 ,3O R

G e no typ e 1 , L o w V L

T re a t w ith p e g IF N /R B V4 8 w e e ks

C o n s id e r d /c if no E V R

G e no typ e 1H ig h V L

M ild to M o d L ive r D ise a seG o a l: E ra d ica te H C V

C o n s id e r:p e g IFN /R B V 2 4 w e e ks

O Rm a in te na n ce IFN

C irrh o s is o r B rid g in g F ib ro s isG o a l: D e la y p ro g re ss ion

H C V T re a tm e nt G o a ls

Adapted from: Chung, R Topics in HIV Medicine, July 2006

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 (<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

Will weight-based RBV improve SVR? Should coinfected patients be treated for

extended periods >48 weeks? Can fibrotests replace liver biopsy? (Not

looking good as of CROI 2006.)

HIV/HCV Coinfection

HIV/HCV Co-Infection

CasesK. Clanon, MDK. Clanon, MD

[email protected]@jba-cht.com

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?

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?1. Differential Dx for complaint of fatigue?

2. Next steps to address Jorge’s complaint?2. Next steps to address Jorge’s complaint?

3. For future reference, how would you discuss the 3. For future reference, how would you discuss the issue of biopsy before therapy for patients like issue of biopsy before therapy for patients like Jorge (and what if Jorge had genotype 1?)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 1. What are the pro and con arguments of stopping Yolanda’s HCV Tx?Yolanda’s HCV Tx?

2. Will you recommend changes in HAART if 2. Will you recommend changes in HAART if Yolanda continues on HCV Tx?Yolanda continues on HCV Tx?

HCV WebsitesFor 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

Relative needlestick and sexual exposure risk

Place in order – highest>>lowestPlace in order – highest>>lowest Hepatitis B, C, and HIV??Hepatitis B, C, and HIV??

Needlestick:Needlestick:

Sexual transmission:Sexual transmission:

Relative Risk of Infection: “Rule of Three” HBV contaminated needle:HBV contaminated needle:

eAg+ 30% risk of transmissioneAg+ 30% risk of transmission eAg- 10% riskeAg- 10% risk

HCV contaminated needle:HCV contaminated needle: 3% risk3% risk

HIV contaminated needle:HIV contaminated needle: 0.3% risk0.3% risk

Sexual transmission: HBV>HIV>HCVSexual transmission: HBV>HIV>HCV

HBV-HIV Coinfection Common and more rapidly progressiveCommon and more rapidly progressive HBV DNA levels higher and spontaneous HBV DNA levels higher and spontaneous

seroconversion less frequentseroconversion less frequent ALT lower and histology worseALT lower and histology worse HAART may induce severe exacerbationHAART may induce severe exacerbation Interferon Interferon αα minimally effective (<10% loss of minimally effective (<10% loss of

HBeAg)HBeAg) 3TC induces rapid fall in HBV DNA but few have 3TC induces rapid fall in HBV DNA but few have

sustained loss of HBeAg (YMDD variants)sustained loss of HBeAg (YMDD variants) Nuc analog combinations under study Nuc analog combinations under study

Evaluation and monitoring“should” include: HBsAg, HBeAg, anti-HBe, anti-HDVHBsAg, HBeAg, anti-HBe, anti-HDV

HBV DNAHBV DNA

Liver enzymesLiver enzymes

Liver synthetic testsLiver synthetic tests

Abdominal ultrasoundAbdominal ultrasound

Consider Liver biopsy if abnormal ALTConsider Liver biopsy if abnormal ALT

Minimum - every 6 monthsMinimum - every 6 months ALTALT HBV DNAHBV DNA HBeAgHBeAg

HCC screen every 6 months if :HCC screen every 6 months if : CirrhosisCirrhosis Strong family historyStrong family history > 45 years of disease> 45 years of disease High AFP >20 ?High AFP >20 ?

Evaluation and monitoring

Goals of Therapy for HIV/HBV

Induce sustained suppression of HBV replication.

Slow liver disease progressionAvoid 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.

Treatment Endpoints for HBV

Biochemical (AST) normalizationVirological (serum HBV-DNA

suppression)Histological improvementRare: Serological (HBeAg &/or

HBsAg seroconversion)

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

Medications with anti-HBV Activity

FDA ApprovedFDA Approved 3TC 100mg/d3TC 100mg/d IFN alpha-2b 5 mIU IFN alpha-2b 5 mIU

sq qdsq qd pegIFN alfa-2a 180 pegIFN alfa-2a 180

mcg/week for 48 wksmcg/week for 48 wks Adefovir 10 mg/dAdefovir 10 mg/d Entecavir 0.5-1.0 mg/d Entecavir 0.5-1.0 mg/d

NOT Approved for HBVNOT Approved for HBV TenofovirTenofovir EmtricitabineEmtricitabine

HIV/HBV: Initiating HBV TherapyThe 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(+).

QuestionHow would you approach treatment of HBV infection in these 3 patients?

DHS/HIV/PP

CD4 >350, no HAART required

Biopsy Nl ALT, F0 or F1 No HBV therapyNo HBV therapy

HBeAg negHBeAg neg

F4 = CirrhosisF4 = CirrhosisAny viremiaAny viremiaAbnormal ALT or F2-F4

A.A. Adefovir 10 mg/dAdefovir 10 mg/d

A.A. Peg-IFN 180 ug 48 wkPeg-IFN 180 ug 48 wk

B.B. Adefovir 10 mg/dAdefovir 10 mg/d

WT, no WT, no cirrhosiscirrhosis

A.A. Adefovir 10 mg/dAdefovir 10 mg/d

B.B. Peg-IFNPeg-IFN

CD4 >350, on HAART

Biopsy Nl ALT, F0 or F1 Keep current Keep current HAARTHAART

HBeAg HBeAg negneg

CirrhosisCirrhosisAny viremiaAny viremia

Abnormal ALT or F2-F4

A.A. Include TDFInclude TDF

B.B. Include FTC-TDFInclude FTC-TDF

C.C. Add Adefovir 10 Add Adefovir 10 mg/dmg/d

A.A. Peg-IFN 180 ug 48 wkPeg-IFN 180 ug 48 wkB.B. a. Incorporate 1 (or 2) HBV-active NAsa. Incorporate 1 (or 2) HBV-active NAs b. if YMDD mutant, include TDFb. if YMDD mutant, include TDF

WT, no WT, no cirrhosiscirrhosis

CD4 <350, HAART-experienced

ALT, DNA, Biopsy

Low ALT, DNA < 105 Low activity or fibrosis

No HAART No HAART changeschanges

HBeAg HBeAg negneg

CirrhosisCirrhosisAny viremiaAny viremia

A.A. Incorporate TDFIncorporate TDF

B.B. Add Adefovir 10 Add Adefovir 10 mg/dmg/d

A.A. Incorporate 1 or 2 HBV-active NAsIncorporate 1 or 2 HBV-active NAs

B.B. If YMDD mutant Add TDF or ADVIf YMDD mutant Add TDF or ADV

C.C. ? Peg-IFN? Peg-IFN

WT, no WT, no cirrhosiscirrhosis

ALT>100, DNA > 105 High activity or fibrosis

Any CD4, HAART-naive

ALT, DNA, Biopsy

Low ALT, DNA < 105 Low activity or fibrosis

A.A. Any HAARTAny HAART

B.B. Include Lam or FTCInclude Lam or FTC

HBeAg HBeAg negneg

CirrhosisCirrhosisAny viremiaAny viremia

A.A. Incorporate TDFIncorporate TDF

A.A. Include 1 or 2 HBV active NAsInclude 1 or 2 HBV active NAs

B.B. Incorporate TDFIncorporate TDF

C.C. ? Peg-IFN? Peg-IFN

WT, no WT, no cirrhosiscirrhosis

ALT>100, DNA > 105 High activity or fibrosis

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

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End-of-Follow-up Combined Response*

*HBeAg loss, HBV DNA < 500,000 c/mL, ALT normalization*HBeAg loss, HBV DNA < 500,000 c/mL, ALT normalization

4.5 MIU4.5 MIUIFN IFN -2a-2a

90 90 μgμg PEG-IFN PEG-IFN-2a (40KD)-2a (40KD)

180 180 μgμg PEG-IFN PEG-IFN-2a (40KD)-2a (40KD)

270 270 μgμg PEG-IFN PEG-IFN-2a (40KD)-2a (40KD)

12%

26% 28%

19%

n = 51 n = 49 n = 46 n = 48

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: 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?