Do We Need A Roadmap or GPS?, Dr. Robert Gish - Hepatitis B ...

GPS, Road Map or Seeing EyeDog?

The map you use dependsupon where your are! Andwhere you are going• The road and travel method to NewYork• Approach also depends:–Budget–Willingness to take risks–How fast one wishes to get there

Basics• For any person at risk for HBV one must test :• HBsAg = infection• Anti-HBc = exposure• Anti-HBs = immunity• Liver panel

Second level testing• For all patients who are HBsAg (+)– To determine prognosis: risk of cirrhosis, cancer, deathand transplant• HBV DNA quant– To determine wild type vs. pre core mutant• HBeAg• Anti HBe

All patients: consider• Documenting immunity to HAV or performvaccination• Screening for HCV• Testing for delta virus• HCC screening

Liver tests• Liver enzymes– ALT– AST These liver enzymes are not liver function tests– GGT– Alk Phos• Liver Function:– Albumin– INR (coagulation test)– Bilirubin

Should the roadmap include“healthy” ALT in treatmentdecisions?•Patients should be treated if:–DNA positive, and–ALT elevated•Women >19•Men >25

Significant Histological Findingsin Patients with Normal ALT• Study compared liver histology in CHBpts with persistently normal (n=139) andabnormal (n=135) ALT• Normal ALT group:– 24% significantfibrosis–9.4% cirrhosis• Within normal ALT range, fibrosis ratehigher in ptswith higher ALT• Age >40 years significant risk forfibrosis• No correlation with HBeAg status orHBV DNA level50403020100Risk of Fibrosis by ALT Level43.519.8Percent

Should our roadmapinterpret HBV DNA?•Is there any level of HBVDNA which is “safe” forHBV patients?–No risk for HCC or cirrhosis

Multivariate Cox RegressionAnalysis: REVEAL, part 2HBsAg / HBV DNA level, copies/mLduring follow-upAdjusted hazard ratiop value(time-dependent variable)

One Idea for aRoadmap•DNA +Treat

The Roadmap must also includefinancial considerations

$$Financial GradientDNA >2,000 IULam first for allThen addADFOrTDFIf ALT incFew medication resourcesLimited lab testingLimited NATDNA >2,000 IU“Roadmap”3m Lam6m LdT12m ADF3 yr ETVAddSecond agentNRAt low DNAPre-ALT flareLimited medication resourcesNAT lab testingAll DNA +RxETVorTDFR ptscomboAll DNA +RxETVAndTDFInfinite MedicationAnd laboratory resourcesRobust medication resourcesExtensive NAT lab testing

Real World: Insurance and costrestraints, part 1• Use the most powerful oral single medication with thelowest rate of resistance– Monotherapy with ETV appropriate for >90% oftreatment naïve• Expect comparable TDF data: approval in US pending– Lamivudine as primary Rx?• up to 80% of patients will need combination therapy• ADF + LAM = ETV costs in most countries– Adefovir: 40-60% will need add-on therapy due to risk(or presence) of resistance or lack of 1 year primaryresponse

Real World: Insurance and costrestraints, part 2• ETV: 5 years of data: profound suppression, 1%resistance at 5 years• TDF: 1.5 year of data: Profound suppression,0% resistance at 1 year• ETV + TDF in US is $13,000/year– Much less expensive in other parts of theworld

If you are going to use lamivudine, useonly in special settings• Naive: Patient– Low level of virus– Financial restrictions– Active monitoring and management• No alternative therapies• Pregnancy• Combination therapy• Historical and ongoing use and on treatment HBVDNA negative on multiple tests

HBeAg seroconversion is considered apoor therapeutic end pointTreatment-inducedseroconversionn = 116Spontaneousseroconversionn = 182P valueRemission of ALT (months) 14.13 22.44 0.0370Remission of ALT Less robust More robust -HBeAg(-) reactivation rateat 96 months* 44% 25% 0.0460HBeAg reversion at 48 months* 24.09% 11.29% < 0.0094* Adjusted for age, gender and ALT with Cox regressionLim SG, et al. Hepatol Int 2008;2:A217–A218(Abstract PE1049), and poster presentation at APASL 2008.20

Pre-existing core promoter and pre-coremutants in HBV patients• In patients with HBeAg(+) disease, the presence of core promoter andpre-core mutants is common27-42% of patients with HBeAg + disease have the mutant HBV virusAll patientsHBeAg(+)HBeAg(-)80% 80Core promoter variant%707060605050404030302010 201000 A B C D AlltypesChu CJ, et al. Gastroenterology 2003;125:444–451.Pre-core variantA B C DAlltypes21

Should the new Roadmapinclude pretreatment precoreand core promoter mutationtesting in all patients who areHBV DNA positive?My recommendation is “yes”22

As we travel the road toHBV viral negativity, arewe changing outcomes?

Changes in Size of Esophageal Variceswith LAMIVUDINEADEDOVIR• EV worsened in 3% with longtermHBV suppression withLAM ADV vs.. 25% withLAM+ADV after clinicalresistance (p=0.0003)• Overall, yearly rates of developmentand progression of EV were 2.0 and2.0, respectively, both lower thanexpected in cohort of untreated virologiccirrhosis*HBV-DNA persistently < 3.3 log10 copies/ml on therapy with LAM or LAM+ADV for virological resistance**HBV DNA10 > 6 log and ALT > ULN, confirmed by molecular analysis.Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.1009080706050403020100RegressionStableProgression (p=0.0003)Response*N=81Resistance**N=42

US UNOS: Liver TransplantWaitlist Registrants with HBV500450400350300250200150100500ESLDHCCAcute4321985 1990 1995 2000 200552271128

How does the adefovirtreatment vehicle fit ourtravel plans ?

Can we change ourconvoluted travel route?•Can we change from the “flight ofthe bumble bee” to the “directroute?”•Is there a “4 wheel drive allterrainvehicle” for HBVtreatment?

ADV+LAM vs.. ADV for HBeAg- LAM-R Patients3-yr Cumulative Probability ofVirological Response (< 3 Log) by Baseline Viremia10099%806078%71%4020p

ETV Efficacy vs.. Baseline HBV DNALevelsMedian HBV DNA Levels of nucleoside naïve, HBeAg positive andnegative patients treated with ETVBaseline HBV DNA (copies/mL)Baseline≥10 1110 10n=87n=4010 9n=14910 8n=14210 7n=97n=8010 6n=2710 5n=1310 410 310 2024 36 48 72Treatment WeekColonno RJ, 41 st EASL 2006, Vienna, # 490• ETV efficacy independent ofbaseline HBV DNA levels• 348/369 (94%) patients withbaseline HBV DNA levels

Results:Projected Ten-Year Risk: Use MarkovModelingHCC Cirrhosis Any Liver EventETV 2.9% 8% 8.8%ADV 7.5% 15.7% 17.8%Iloeje et al, EASL 2006, Abstract #497

Will TDF be added to theRoadmap?• Yes, likely to replace ADF in thoseareas of the world where it is available

TenofovirHBeAg+ patients: % HBV DNA

Study 102, HBeAg- Patients: 72-WeekTDF vs. 48-Week ADV → 24-Week TDFP < .001 P = .315HBV DNA

The Resistance Route if full of canyonsand peaks

Genotype-Independent Numbering Scheme for HBV Polymerase/RTTerminalProtein1 183 349(rt1)DomainSpacer POL/RT RNaseH692 (rt 344)845 a.a.I(G)II(F)F__V__LLAQ__ YMDDA B C D ErtL80V/I rtV173L rtM204V/I/SLMVrtL180MADV rtA181T rtN236TETV Resistance rtI169T rtL180M rtT184S/A/I/L/G/C/MrtS202C/G/I rtM204V rtM250I/VTDF Resistance rtL180M rtA181T/V rtA194T/rtM204V/I rtN236TL-dT Resistance rtA181T/V rtM204IClevudine rtL180M rtM204VThe location of the major antiviral drug-resistant mutations associated with lamivudine (LMV), adefovir (ADV), and entecavir (ETV), telbivudine(LdT) tenofovir (TDF) resistance. Modified from Locarnini S. 2004. Sem in Liver Dis 24 (Suppl 1):3-10.

Resistance is badResistance is common• Lamivudine: up to 100% by year 5• Adefovir: 29-42% by year 5• Telbivudine: 10-20% by year 2• Entecavir: treatment naïve: 1% year 5– Nucleoside resistance: 50% by year 5• Tenofovir: 0% by year 1.5• Interferon: no resistance

What is the roadmap for resistance?• Complex• Based on:–Viral factors–Patient factors–medication availability

Management of HBV ResistanceLamivudine/TelbivudineResistanceAdefovir ResistanceEntecavirResistance*Adefovir/TenofovirLamivudine/Telbivudine• Add-on preferred because • Add preferred overof better viral suppression switch [5,6]and lower incidence of ADV Entecavirmutations [1-3]• Add preferredEntecavir Switch and • Or• Add TDF because of lower • Switch to entecavir (if nocross-resistance issues [4] prior lamivudine• OK to add ADFresistance) [7]Potential future approach Potential future approach• Switch to• Switch to clevudine/*With preexisting lamivudine resistance.emtricitabine/tenofovir? tenofovirAdd tenofovirAdd adefovir [8]1. Peters M, et al. Gastroenterology. 2004; 126:91-101. 2. Perrillo R, et al. Gastroenterology. 2004;126:81-90. 3. Fung S, et al. J Hepatol.2006;44:283-290. 4. Chang T, et al. Gastroenterology. 2005;129:1198-1209. 5. Villeneuve J, et al. Hepatol. 2003;31:207–210. 6. Fung S, et al. JHepatol. 2005;43:937-943. 7. Fung et al. J Hepatol. 2005;43:937-943. 8. Villet S, et al. AASLD 2005. 981.

What is the new paradigm?What is the best road map?• Treat all patients until HBsAg negative• Will need cost modeling!• Incremental cost-effectiveness ratios (ICER) perquality-adjusted life-year (QALY) key toidentifying the best road ahead

What does the roadmap say is the bestroute through “interferon” country?• Focused role– High ALT– Low to moderate HBV DNA• When patient asks for defined treatment period– A woman wishing to get pregnant in 1-2 years• Where government pays only for one year of therapy– Choose patient with• Higher ALT• Lower DNA• HBeAg negative patients– Use as first line therapy !• Especially If there is an assay for HBsAg: Architect Assay

Marcellin et al EASL 2008: PEG alfa 2aSummary of response rates4 years post-treatment30252724PEG-IFNα-2a +/– LAM (N=230)LAM (N=85)Patients (%)2015101816P=0.0421766%11% HBsAg lossP=0.021117520ALT normal*

Who is best patient for interferon?• High ALT• Low HBV DNA• Liver function: normal

It is no longer darkoutside and you havea simple map

Roadmap to manage or prevent resistance inTreatment-Naive PatientsAvailable treatmentoptionsLAM/ADV TDF ETV TelbivudineResponse andResistanceMonitoringMeasure HBV DNA with sensitive assays;monitor virologic changes every 3-6 months;monitor for breakthrough, and compliance etcOutcomeNo resistanceidentifiedwith viralnegativityResistanceidentified“Suboptimalresponse”:4-12w Lam6m: LdT1 year ADF3+years ETV/?TDFTherapeuticPlanContinue withplannedmedicationAdd secondmedicationadd secondmedication

The Future?• TDF: What will its clinical resistance profile be?• Clevudine:– Will it induce a long term, off- treatment, viralresponse? or– Will it have clinically important cross-resistance withother nucleosides ?• Will more sensitive assays be available todetermine changes in treatment when early viralresistance emerges?– Ultra deep pyrosequencing

Ultra-Deep Pyrosequencing forHIVWang, Mitsuya, et al. Submitted

Design of Nucleonics’ Multi-TargetingAnti-HBV eiRNA NUC 500-001AKan rOptimizedPol III promoterBRNAi Target Sites on HBV mRNAsABCDDPre-genomic / pre CPre-S1Pre-S2/SXOriCAll HBV RNAs are targeted for degradation

What is the best road map tomanage HBV?•HBV DNA positive = Treat•Use the therapy with thehighest response rate and thelowest rate of resistance•Pursue HBsAg seroconversion

Thank you• HBV Foundation• Tim and Joan Block• Fiona Ma• CPMC HBV Team• gishr@sutterhealth.org