THE 6 TH NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS Hepatitis B and Hepatitis C Co-infections with HIV in Vietnam: Now – And Tomorrow’s Cures Siobhán O’Connor,

THE 6TH NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS

Hepatitis B and Hepatitis C Co-infections with HIV in Vietnam:

Now – And Tomorrow’s Cures

Siobhán O’Connor, MD, MPHSenior Medical Officer for Global Health

Division of Viral Hepatitis U.S. Centers for Disease Control and Prevention

The 6th National Scientific Conference on HIV/AIDS

Outline

1. Background and importance, Vietnam context

2. Burden, Vietnam context

3. Interventions: Integrated HIV programs and treatment as prevention

4. Current and pipeline treatments for hepatitis C virus and hepatitis B virus

5. Conclusions


Factor EffectHBV endemic country▬Early infection, before HIV

HIV/HBV co-infection rates ≥ population rates

HIV risk behaviors Risk for new HBV infection the20-40% of adults still susceptible to HBV

HIV infection Hepatitis B disease progression, with HBV replication1-14

1/2 as likely to clear new, acute HBV infection3

Tenofovir/lamivudine ART HBV load, ± fibrosis15-16 – NOT cured

Hepatitis B Virus Co-infection with HIV Factors and Effect

1Thio, AIDS 2012. 2Thio, Lancet 2002. 3Konopnicki, AIDS 2005. 4Hoffmann, AIDS 2009. 5The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group, AIDS 2010. 6Dore, AIDS.2010. 7Chun, J Infect Dis, 2012. 8De Vries-Sluijs, Gastroenterology 2010. 9Mendes-Correa, BMC Infect Dis 2011. 10Martín-Carbonero, AIDS 2011. 11Avihingsanon, AIDS Res Ther 2012. 12Zoutendijk, J Infect Dis 2012. 13De Vries-Sluijs, Gastroenterology 2010. 14Tsuchiuya, Epidemiol Infect 2013. 15Stockdale, Clin Infect Dis 2015. 16Soriano, AIDS 2015.


Factor EffectHCV rates vary in general population1

Behavioral risk, blood supply, universal precautions influence HIV/HCV rates

HIV risk behaviors Risk for HIV/HCV▬Injection drugs > sexual transmission▬HCV may precede HIV

HIV infection2 Hepatitis C disease progression

HCV therapy with approved Peg-interferon-Ribavirin

Response rates low, substantial side effects

Hepatitis C Virus Co-infection with HIVFactors and Effect

1Sereno L, J Int Assoc Physicians AIDS Care 2012. 2Sulkowski M. Hepatology 2014.

Hepatitis B VirusPopulation Prevalence Influences Risk

Vietnam Population

~10-12% HBV-infected+

~48-75% immune to HBVI

~15-40% Susceptible to HBVS

High Risk

GroupsHIV+

HIV–


Hepatitis B VirusPopulation Prevalence Influences Risk

Vietnam Population

~10-12% HBV-infected+

~48-75% immune to HBVI

~15-40% Susceptible to HBVS

High Risk

GroupsHIV+

HIV–

+SSIIII


Hepatitis C VirusInfluences on Risk Group Prevalence

X% Susceptible to HCVS

~1-4% HCV+

Vietnam PopulationHigh Risk

GroupsHIV+

HIV–


Hepatitis C VirusInfluences on Risk Group Prevalence

X% Susceptible to HCVS

~1-4% HCV+

Vietnam PopulationHigh Risk

GroupsHIV+

HIV–+

SSS


Hepatitis B Virus and Hepatitis C VirusTransmission in High Risk Groups

– Vietnam: people who inject/injected drugs (PWID), men who have sex with men (MSM), female sex workers

– HCV transmission – Internal >>> External– HBV transmission – External & Internal

HBVHCV

HBV

PWID

MSM

FSW HCV



HIV, HBV and HCV Among Male IDU Vietnam, 2009-10 IBBS*1, 10 provinces

*Integrated Behavioral and Biologic Survey, conducted by NIHE. 1Nadol PJ, PLoS ONE 2015.

2010 Integrated Behavioral and Biologic Survey: Men Who Have Sex with Men1,2

1Nadol P, et al. High Hepatitis C Virus (HCV) Prevalence among Men Who Have Sex with Men (MSM) in Vietnam and Associated Risk Factors: 2010 Vietnam Integrated Behavioral and Biologic Survey [Under review]. 2Conducted by NIHE.

Hepatitis C virus (HCV) exposure (past or current infection) and active hepatitis B virus infection rates among men who have sex with men (MSM) in four provinces

Provincial HCV Ag/Ab and HBsAg rates % (range)

Marker HIV

status Median Hanoi n=398

Hai Phong n=399

HCMC n=397

Can Tho n-394

HCV Ag/Ab All 28.4 25.4 (16.8-34.0) 38.8 (31.4-46.3) 31.4 (24.0-38.9) 13.7 (8.2-19.1) Pos 84.5 --- 100 (---) 83.1 (64.2-100) 84.5 (66.6-100) Neg 21.9 25.4 (17.7-33.1) 28.3 (21.6-35.1) 18.3 (11.7-20.0) 8.9 (4.6-13.2)

HBsAg All 12.4 48.5 (30.9-66.2) 12.0 (7.7-16.3) 12.7 (8.1-17.3) 8.5 (4.9-12.2) Pos 17.2 78.6 (55.1-100) 16.6 (4.3-28.8) 17.7 (4.1-31.3) 15.2 (0.0-40.8) Neg 11.3 57.9 (46.8-69.0) 11.2 (6.7-15.8) 11.4 (6.4-16.4) 8.1 (5.0-11.2)

HCV Ag/Ab = Either antigen or antibody to hepatitis C virus (past or current HCV infection, cannot distinguish) HBsAg = Hepatitis B surface antigen (current HBV infection) Pos = positive (infected); Neg = negative (not infected)

Unpublished – Under review


HBV and HCV amongHigh Risk Groups and HIV-infected

2010 Integrated Behavioral and Biologic Survey*▬ 53% hepatitis B virus (HBV) load >20,000 IU/ml1

• Genotypes B and C▬ 71% hepatitis C virus (HCV) Ag/Ab+ were RNA+1

• Genotypes 1 >>> 6 > 3 > 2 (consistent with published convenience samples2,3) – Implications for treatment

Data in-progress– HCV among HCMC sex workers (FHI, MoH)– Tenofovir-based ART impact: HIV, HBV, HCV in HCMC

(Provincial AIDS Committee, Tropical Disease Hospital)

*Integrated Behavioral and Biologic Survey, conducted by NIHE. 1Nadol P, et al. High Hepatitis C Virus (HCV) Prevalence among Men Who Have Sex with Men (MSM) in Vietnam and Associated Risk Factors: 2010 Vietnam Integrated Behavioral and Biologic Survey [ Under review]. 2Dunford L, PLoS ONE 2012. 3Wasitthankasem R, PLoS ONE 2014.


Hepatitis B Virus and Hepatitis C Virus Surveillance: High Risk Groups

Vietnam 2012-13 Integrated Biological and Behavioral Survey (Round III)*#

▬ People who inject(ed) drugs (PWID), men who have sex with men (MSM), female sex workers (FSW)

▬ Hanoi, Hai Phong, Ho Chi Minh City▬ Active and past hepatitis B virus infection (HBV)

• Still susceptible to HBV (not immune)

▬ Active HCV infection and past HCV infection• Hepatitis C core antigen replaces HCV RNA (novel)

*Implemented by NIHE, with CDC assistance; #Analysis in-progress


Hepatitis B Virus and Hepatitis C VirusTransmission Among High Risk Groups

People who inject/injected drugs (PWID), men who have sex with men (MSM), female sex workers

HCV transmission – Mostly Internal HBV transmission – External & Internal

HBVHCV

HBV

PWID

MSM

FSW HCVXXX

XThe 6th National Scientific Conference on HIV/AIDS

INTE

RVEN

TIO

N

Interventions to Prevent HIV and HCV Among Persons Who Inject Drugs

1MacArthur GJ, Int J Drug Policy 2014.

Intervention Decrease Injection Risks

PreventHIV

PreventHCV

Syringe exchange ++ + +Pharmacy access + + *Drug preparation equipment

+ * +

Opioid substitution ++ ++ +

Education + + +Supervised injection + + +

++ sufficient data; + tentative data; +: Inconclusive; * : no data



Hepatitis C Virus (HCV) DAA*Treatment as Prevention (TasP)1

• Prevalence in many US cities falls close to 50%-65%

• Treating just 8% of active injectors per year would reduce prevalence by 50% to 90% in 15 years

*Direct Acting Antivirals

1Martin, Hepatology 2013..


Value of Comprehensive Prevention:TasP*, Syringe Access and

Opioid Substitution1

*TasP = treatment as prevention, OST = opioid substitution treatment, HCNSP = syringe access programs 1Martin, Clinical Infectious Diseases, 2013.

HCV Direct-acting Antivirals (DAA)Approved and in Clinical Trials

Black = Approved by U.S. Food and Drug Administration and the European Commission. Blue = European Commission approved. 1Asselah T, Hepatology 2015 (Suppl 2, EASL 2015).

Regimen: Focused on DAA-naïve GenotypeDaclatasvir + sofosbuvir +/- ribavirin 1 2 3 5 6

Ledipasvir + sofosbuvir 1 5 6

Ombitasvir + paritaprevir/ritonavir + dasabuvir + ribavirin 1

Ombitasvir + paritaprevir/ritonavir + ribavirin 4

Simeprevir + sofosbuvir +/- ribavirin 1

Sofosbuvir + ribavirin 2 3* 4* 5* 6*

Simeprevir + ribavirin 1 4

Sofosbuvir + velpatasvir (GS-5816)1 1 2 3 4 5 6*May require pegylated-Interferon


Hepatitis C Virus: Direct-acting Antivirals (DAAs)

Treat to “Cure” (SVR) All oral (interferon-free), well-tolerated (ribavirin-free) High sustained viral response rates (SVR) >> interferon <12-week to 24 week courses Some once daily – improves adherence New pan-genotypic combinations achieve SVR >90% in

all genotypes (e.g., 1, 6, 3, 2) No genotyping?1-5 Costs decreasing: India licensed generic cost of 4

weeks [sofosbuvir + ribavirin] may be USD150

1Universty of Washington, http://www.hepatitisc.uw.edu/. 2AASLD, http://www.hcvguidelines.org/full-report/unique-patient-populations-patients-hivhcv-coinfection). 3NIH, AIDSinfo (https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/26/hiv-hcv). 4Nelson DR, Hepatology 2015. 5Asselah T, Hepatology 2015 (Suppl 2, Abstract P1332, EASL 2015).


Key Issues: Direct-acting Antiviral (DAA) HCV Treatment in Vietnam

HCV treatment IS EFFECTIVE with HIV co-infection1-3

– Monitor ART* interactions: tenofovir toxicity (ledipasvir); other3 – Review other ART interactions

>90% genotype 1 (GT1), GT6 and GT2 responses (major GT circulating in Vietnam) – GT3 was less responsive1-3

– New pangenotypic regimens improve GT3 response: >90%1-5

Cirrhotics need longer treatment, +/- ribavirin & treatment restrictions for HIV/HCV cirrhotics1-5

*ART=HIV-suppressive antiretroviral therapy. ^SVR = sustained viral response. 1Universty of Washington, http://www.hepatitisc.uw.edu/. 2AASLD, http://www.hcvguidelines.org/full-report/unique-patient-populations-patients-hivhcv-coinfection). 3National Institutes of Health, AIDSinfo (https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/26/hiv-hcv ). 4Nelson DR, Hepatology 2015. 5Asselah T, Hepatology 2015 (Suppl 2, Abstract P1332, EASL 2015).

Early treatment is best!!!!


Care and Treatment CascadePrevents Morbidity and Transmission

(Treatment as Prevention [TasP])

Hepatitis C Cascade

InfectionEarly

diagnosis

Earlyentry

into care

EarlyDAA

treatmentCURECURE

HIV and HCV morbidity

XTransmissi

on


Medicines Patent Pool (MPP, UNITAID) includes licensed generic HCV direct-acting antivirals (DAAs)

1Adapted from Hepatitis B Foundation, Drug Watch, http://www.hepb.org/professionals/hbf_drug_watch.htm.

Nucleos(t)ide analogs – DNA polymerase inhibitors1

Adefovir dipivoxil Hepsera Gilead SciencesFoster City, CA

FDA approved, 2002

Entecavir Baraclude Briston-Myers SquibbPrinceton, NJ

FDA approved 2005

Lamivudine/3TC Epivir-HBV GlaxoSmithKlinePhiladelphia, PA

FDA approved, 1998

Telbivudine Tyzeka Novartis,Switzerland

FDA approved 2006

Tenofovir disoproxil fumarate

Viread Gilead SciencesFoster City, CA

FDA approved, 2008


Hepatitis B Treatment: SuppressionU.S. Food and Drug Administration Approved

Hepatitis B Treatment: SuppressionIn Clinical Trials


Nucleos(t)ide analogs – DNA polymerase inhibitors1

AGX-1009(Tenofovir ODE)

Prodrug of tenofovir Agenix, Australia

Phase I in China

Clevudine Inhibits DNA polymerase

Bukwang, S. KoreaEisai, Japan

Approved, S. Korea

CMX157 Prodrug of tenofovir ContraVir Pharmaceuticals,Edison, NJ

Phase II

Tenofovir alafenamide (TAF)

Prodrug of tenofovir Gilead SciencesFoster City, CA

Phase III



Non-nucleoside antivirals1

Myrcludex B Entry inhibitor Hepatera, Russia with Phase II, EuropeARC-520 RNAi gene silencer Arrowhead Research Corp Phase II/IIINVR-1221 Capsid inhibitor Novira Therapeutics Phase IIaSB 9200 Small molecule nucleic

acid hybridsSpring Bank Pharma Phase II

Rep 2139 HBsAg release inhibitor REPLICor, Inc., Canada Phase IIBirinipant SMAC inhibitor TetraLogic Phase I/IIaBay 41-4109 Inhibits viral nucleocapsid AiCuris, Germany Phase I

TKM-HBV HBsAg inhibitor Tekmira, Canada Phase IAlinia (Nitazoxanide) Small molecule Romark Labs Preclinicaldd-RNAi compound Gene silencing Benitec, Australia and

Biomics, ChinaPreclinical

BSBI-25 cccDNA inhibitor Baruch S. Blumberg Inst. PreclinicalCpAMS HBV core protein Assembly Biosciences PreclinicalMore…………..


Hepatitis B Treatment PipelineProlonged Suppression, Eliminate Infection

Hepatitis B Treatment PipelineImmune Enhancers to Eliminate


Non-interferon immune enhancersABX 203 Therapeutic vaccine ABIVAX, France Phase IIb/III

GS-4774 Therapeutic vaccine Gilead Sciences with Globe Immune

Phase II

GS-9620 TLR7 agonist Gilead Sciences Phase II

CYT107 Immune modulator Cytheris, France Phase I/IIa

TG 1050 Immunotherapeutic Transgene, China Phase I

INO-1800 Therapeutic vaccine Inovio Phase I


Care and Treatment CascadePrevents Morbidity and Transmission

(Treatment as Prevention [TasP])

Pipeline

Hepatitis B Cascade

InfectionEarly

diagnosis

Earlyentry

into careManage+/- Treat

Majority Suppress HIV and HBV

morbidity

CURECURE

Transmission

X

Tran

smiss

ion


Hepatitis C virus (HCV) / Hepatitis C– Pangenotypic cure feasible now – costs declining

Hepatitis B virus (HBV) / Hepatitis B– First line tenofovir-based ART; care for HBV mono-infection Similarities with HIV 90-90-90

– EARLY test/diagnose – Early care/manage – Access treatment Treatment as Prevention + prevention programs Reduce HBV, HCV-associated HIV morbidity/mortality Reduce HBV and HCV transmission


ConclusionsHBV and HCV

Mono-infections, Co-infections with HIV

Documents

THE 6 TH NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS Hepatitis B and Hepatitis C Co-infections with HIV in Vietnam: Now – And Tomorrow’s Cures Siobhán O’Connor,