Global Prevalence of HBV, HCV , HIV - American College of ...s3.gi.org/acgmeetings/2016/pgsyllabus/2016PG_0037.pdf · HIV=human immunodeficiency virus; ... Serum samples from patients

Paul Y. Kwo, MD, FACG

Paul Y. Kwo, MD, FACGProfessor of Medicine

Stanford Universityemail: [email protected]

HCV and HBV and/or HIV

Global Prevalence of HBV, HCV , HIV

Journal of Clinical Virology

240 m

ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology

Page 1 of 19


Hepatitis C is Underdiagnosed in U.S.

Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C; 2010.

Nu

mb

er

infe

cted

4,000,000

3,000,000

2,000,000

1,000,000

0

~21%

HIV

~65%

HBV

~75%

HCV

UndiagnosedDiagnosed

HIV=human immunodeficiency virus; HBV=hepatitis B virus; HCV=hepatitis C virus

HEPATOLOGY2015;62:1353–1363)

5,000,000

Ly KN, et al. Ann Intern Med. 2012;156(4):271-278.

Mortality Rates from HBV, HCV, and HIV in United States, 1999-2007


Page 2 of 19


Host DNA

Hepatitis C Differs from HIV and HBV No long-term or Latent Reservoir

Host cell

Nucleus

HBV HIV HCV

cccDNA Proviral DNA

Viral RNA

TREATMENTTREATMENT TREATMENTLong-term suppression of viral replication

Long-term suppression of viral replication2,3

Viral Eradication = Cure

1. Pawlotsky JM. J Hepatol 2006;44:S10-S13; 2. Siliciano JD, Siliciano RF. J Antimicrob Chemother 2004;54:6-9;3. Lucas GM. J Antimicrob Chemother 2005;55:413-416

cccDNA = covalently closed circular DNA

Author population # cases % HBV/HCV infected

Prevalence of hepatitis B virus/hepatitis C virus dual infection worldwide

World J Gastroenterol 2014 October 28; 20(40): 14559-14567


Page 3 of 19


U.S. Veterans Among veterans with HCV, exposure to HBV is common

(35%) as defined by anti-HBc(+)

HBV co-infection is relatively low (1.4%) defined by HBsAg(+) and anti-HCV(+) with HCV RNA PCR (+)

Risk factors for coinfection: age 50< years, male sex, positive HIV status, history of hemophilia, sickle cell anemia or thalassemia, history of blood transfusion, cocaine and other drug use

Those with documented HBV viremia were at a significantly higher risk for cirrhosis, HCC, and overall death than HCV monoinfected patients.

HEPATOLOGY 2013;58:538–545, HEPATOLOGY 2014;60:1870-1877

Clinical Presentation of co-infection

Higher rates of cirrhosis, decompensation have been reported in some studies with HBV/HCV coinfection

Superinfection may occur with either virus

Occult hepatitis B: presence of HBV DNA, in serum and/or the liver tissue without detectable HBsAg with or without Anti-HBc

– Reports vary on prevalence, higher in Europe

– General estimates are 7-15%


Page 4 of 19


•9

U.S. FDA dates of Approved Therapies for CHB

Nucleosides/Nucleotides

Tenofovir* VIREAD® Gilead Sciences 2008

Telbivudine TYZEKA™ Idenix / Novartis 2006

Entecavir* BARACLUDE™ Bristol-Myers Squibb 2005

Adefovir dipivoxil HEPSERA™ Gilead Sciences 2002

Lamivudine EPIVIR-HBV® GlaxoSmithKline 1998

Interferons

Peginterferon alfa-2a* PEGASYS® RocheLaboratories 2005

Interferon alfa-2b, recombinant INTRON® A Schering / Merck 1992

•Preferred therapies – AASLD Guidelines

Candidates forHBV Treatment

APASL(2008)

EASL(2012)

Martin et al(2015)

AASLD(2016)

HBV DNA threshold (IU/L)

HBeAg positiveHBeAg negative

20,0002000

20002000

20,0002000

20,0002000

ALT:Normal range

- -(M: 30 U/L; F: 19 U/L)

2X ULN(M: 30 U/L; F: 19 U/L)

When to treat:key factors

HBV DNAand ALT

HBV DNAand ALT

HBV DNAand ALT

HBV DNAand ALT

Biopsy Consider in certain groups

Consider incertain groups

Consider in certain groups

Consider incertain groups

Lok AS, et al. Hepatology 63.1 (2016): 284-306.Martin P, et al. Clinical Gastroenterology and Hepatology 2015;13:2071–2087.EASL. J Hepatol 2012 vol. 57 j 167–185.Liaw Y-F, et al. Hepatol Int. 2008;2:263-283.Terrault NA, et al. Hepatology 63.1 (2016): 261-283.


Page 5 of 19


New Polymerase inhibitor Coming

Evaluation of those with HCV/HBV infection Anti-HCV with HCV RNA if antibody detected

HBsAg, anti-HBs, Anti-HBc

– HBeAg, anti-HBe, HBV DNA if HBsAg detected

Fibrosis assessment

Assess for therapy for hepatitis B

Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies

HCV Guidelines.org


Page 6 of 19


Reactivation of HBV with treatment of HCV

Reported with the use of interferon

Multiple case reports in the DAA era in HBsAg+ and HBsAg(-)/anti-HBc(+) HCV infected individuals

– Sofosbuvir/simeprevir

– Asunaprevir/daclatasvir

– Ledipasvir/sofosbuvir in HIV/HCV coinfection

J Med Case Rep 2015;9:164 Clin Infect Dis 2015;61:1302–130 Hepatology Research. 2015 Jan 1

Clinical Gastroenterology and Hepatology (2016)...

Three Hepatitis B Reactivation Cases Among 327 CHC Patients Treated With Pan-oral DAAs

Wang, Cheng, et al. "Hepatitis due to Reactivation of Hepatitis B Virus in Endemic Areas Among Patients With Hepatitis C Treated With Direct-acting Antiviral Agents."

Clinical Gastroenterology and Hepatology (2016).


Page 7 of 19


Other reports suggest the risk is low for HBV reactivation

Serum samples from patients in a clinical trial of ledipasvir-sofosbuvir in Taiwan and Korea

Of 173 patients enrolled, 103 (60%) had been previously infected with HBV defined by anti-HBc(+)

Serum samples analyzed for HBV DNA by PCR during treatment with DAAs

None showed evidence of HBV reactivation during HCV therapy

•Sulkowski, Mark S., et al. "No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for

• Hepatitis C Virus Infection." Clinical Infectious Diseases (2016): ciw507.

So what to do in HBV/HCV infected individuals Evaluate for therapy for HBV in addition to HCV and if appropriate treat

HBV with tenofovir/entecavir if treatment guidelines are met

If advanced fibrosis (F3/F4) and/or patient would not tolerate reactivation of hepatitis B, suppress HBV virus regardless even if viral level is < 2,000IU/L with tenofovir/entecavir

– If HBV treatment deferred, then follow HBV DNA and liver chemistries every 4 weeks during therapy for up to 12-24 weeks post DAA therapy

HBsAg negative/anti-HBc+ should be followed with liver tests every 4 weeks during HCV therapy for the rare but real phenomenon of reactivation

– If ALT and AST do not normalize with clearance of HCV RNA on DAAs, check HBV DNA in anti-HBc +/HBsAg - individuals in addition to other causes

Ongoing surveillance for HBV reactivation by EMA and PMDA in Japan during HCV treatment with DAAs


Page 8 of 19


Liv

er r

elat

ed m

ort

alit

y ra

te/1

00 p

y

02468

10121416

HBV HIV HIV/HBV

Mortality of HIV/HBV co-infection pre HAART

Thio et al Lancet 2002; 360:1921;

Treatment options for HIV-HBV

Drug HBV HIV

3TC / FTC ++ ++

Tenofovir +++ +++

Adefovir ++ ?

Entecavir +++ +

Telbivudine +++ -/+

IFN / PEG-IFN +++ +


Page 9 of 19


Treat HIV in any HBV/HIV coinfectedperson at any CD4 count: WHO 2009

Start ART in all HIV/HBV co-infected individuals who require treatment for their HBV infection, irrespective of CD4 cell count or WHO clinical stage.

– (Strong recommendation, low quality of evidence)

Start TDF and 3TC or FTC containing antiretroviral regimens in all HIV/HBV co-infected individuals needing treatment.

– (Strong recommendation, moderate quality of evidence)DHHS guidelines Dec 2009; IAS guidelines JAMA 2008; 300: 555

HIV v HCVHIV HCV

Virus Retrovirus Flavivirus

Transmission Sex > Blood Blood > Sex

Viremia High (109 virons/day) Higher (1012 virons/day)

Target Cells Lymphoid (CD4) Hepatocytes

Mutations Frequent Reverse transcriptase (RNA-

DNA)

FrequentRNA polymerase

(RNA-RNA)

Time to Clinical Illness Years Decades

Nuclear Reservoir Yes No (cytoplasmic)

Curable 1 cure after BMT >95%


Page 10 of 19


HCV/HIV Co-Infection Outbreak in Indiana

84% Co-infected with HCV


Page 11 of 19


HCV Co-Infection in HIV+ MSM

CD4

Viral Load

Crystal methamphet

amines

Multiple Partners

Sexual Practices

Other STDs

SEXDRUGS

HIV

•Martinello CROI 2016

•Lachowsky CROI 2016

Enhanced fibrosis in HCV/HIV Co-Infection

•Chen Nat Rev Gastroenerol Hepatol. 2014


Page 12 of 19


HCV Treatment and Incidenceof ESLD, HCC, and Death

Prospective U.S. cohort (1993-2011) (n=638)

– Liver biopsy at baseline– 35% underwent HCV treatment with

PR Baseline >F2 versus <F2 fibrosis

– Higher treatment rates: 54% versus 28% (P<0.001)

– Similar SVR rates: 17% versus 16% No clinical events (ESLD, HCC, and

death) among patients achieving SVR

•Cu

mu

lati

ve S

urv

ival

•0 2 4 6 8 10

•Survival Free of

•ESLD, HCC, or Death

Time Since Biopsy (years)

•Log-rank P=0.005

•No HCV treatment

•SVR

•Relapse

•Nonresponse

•Limketkai BN, et al. JAMA. 2012;308:370-378.

Check for drug-drug interactions (DDI) between HCV and HIV drugs!• Drug interactions

http://www.drugs.com/drug_interactions.html

http://www.medscape.com/druginfo/druginterchecker

http://www.drugstore.com/pharmacy/drugchecker/

http://drugchecker.aol.com

http://hcvdruginfo.ca

• List of CYP substrates, inhibitors, inducers

http://medicine.iupui.edu/clinpharm/ddIs

• HIV drug interactions

http://www.hiv-druginteractions.org

http://www.hep-druginteractions.org Khoo S. 15th International Workshop on Clinical Pharmacologyof HIV & Hepatitis Therapy, May 2014 [oral presentation].CYP, cytochrome


Page 13 of 19


Drug Interactions Between Select ARTs and HCV Therapies

•27

DCV LED/SOF

OBV/PTV/r

OBV/PTV/r+DSV

EBV/GZR

SOF/VEL

SMV SOF

Integrase Inhibitors

Raltegravir D≈20% E20% E134% ↓11%E8%

↓5%D27%

Dolutegravir E38%

Elvitegravir/cobicistat ↑ ↑36/78E

↑ ↑ ↑

These drugs should not be coadministered

Potential interaction – may require dosage adjustment or close monitoring

No clinically significant interaction expected

NRTIs

Abacavir

Emtricitabine ↓6%

Lamivudine

Tenofovir ↑10%E10%

E ↓14%E18%

↓6%

Zidovudine

↓ = potential decreased exposure of DAA; ↑ = potential increased exposure of DAA;

D = potential decreased exposure of ARV; E = potential elevated exposure of ARV.


•28

DCV LED/SOF

OBV/PTV/r

OBV/PTV/r+DSV

EBR/GZR

SOF/VEL

SMV SOF

NNRTIs

Efavirenz ↓32% ↓-/34% Severe* Severe* ↓71%↓6%D4%

Etravirine ↓E? ↓E? ↓

Nevirapine ↓ ↓E? ↓E? ↓

Rilpivirine E E ↑6%E12%

↑9%E6%

Entry Inhibitor

Maraviroc E? E E

ART = antiretroviral therapy; BOC = boceprevir; DCV = daclatasvir; LED = ledipasvir; OBV/PTV/r + DSV = ombitasvir/paritaprevir/ritonavir + dasabuvir; SMV = simeprevir; SOF = sofosbuvir; TVR = telaprevir; Peg IFN = pegylated interferon; RBV = ribavirin.

1. European AIDS Clinical Society (EACS) Guidelines Version 8.0, Updated October 2015. Available at: http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html. Accessed October 25, 2015.

•↓ = potential decreased exposure of DAA; ↑ = potential increased exposure of DAA; •D = potential decreased exposure of ARV; E = potential elevated exposure of ARV.





Page 14 of 19



ART = antiretroviral therapy; BOC = boceprevir; DCV = daclatasvir; LED = ledipasvir; OBV/PTV/r + DSV = ombitasvir/paritaprevir/ritonavir + dasabuvir; SMV = simeprevir; SOF = sofosbuvir; TVR = telaprevir; Peg IFN = pegylated interferon; RBV = ribavirin.

•29

DCVLED/SOF

OBV/PTV/r

OBV/PTV/r+DSV

EBR/GZR

SOF/VEL

SMV SOF

Protease Inhibitors

Atazanavir/ritonavir ↑110% ↑8/113% ↑94% ↑ ↑

Darunavir/cobicistat ↑ ↑ E ↑ ↑ ↑ ↑

Darunavir/ritonavir ↑40% ↑34/39% D ↑ ↑ ↑34%

Lopinavir/ritonavir ↑15% ↑ ↑ ↑

•↓ = potential decreased exposure of DAA; ↑ = potential increased exposure of DAA; •D = potential decreased exposure of ARV; E = potential elevated exposure of ARV.




TURQUOISE-I: Paritaprevir/r + Ombitasvir+ Dasabuvir + RBV (3D + RBV)

Wyles D et al.Hepatology. 2014;60(suppl): Abstract 1939

•3D + RBV

•3D + RBV

3D: Co-formulated Paritaprevir/ritonavir/ombitasvir, 150 mg/ 100 mg/ 25 mg + dasabuvir, 250 mgRBV: 1000-1200 mg daily, weight-basedPatients on atazanvir for HIV were instructed to discontinue their stand-alone ritonavir during 3D therapy

HCV Genotype 1HIV-1Included HCV treatment-naïve, treatment-experienced, cirrhotic and non-cirrhotic patients

Phase 2/3SVR12

SVR12

93.5 90.6

0

20

40

60

80

100

12 Weeks

SV

R12

, % P

atie

nts

24 Weeks

n=31 32

•2 patients in the 24‐week group had re‐infection, not relapse.


Page 15 of 19


SV

R12

(%

)

•321/335 •265/276 •56/59 •103/115•215/217•239/250 •74/77 •8/8

96% 96% 95% 100% 96% 96% 96%100% 99%

90%

Overall Male Female Non-black •BlackGT 1a GT 1b GT 4BL HCV RNA

< 800K

BL HCV RNA ≥ 800K

•36/36 •285/299

•Statistically significantin multivariate analysis

Naggie et al, CROI 2015, Oral #LB-152

ION-4: LDV/SOF in HIV/HCV for 12 weeks SVR12 by Subgroup

•All relapsers in the Black cohort had cirrhosis

ALLY-2 Study: SVR12 Rates for Daclatasvir + Sofosbuvir for 8 or 12 weeks in HIV/HCV Coinfection

0

20

40

60

80

100

SV

R12

(%

)

97%

76%

Overall

(n=101/52/50)

12-Week Regimen

HCV treatment-naïve

HCV treatment-experienced98%

Genotype 1

(n=83/44/41)

Genotype 2

(n=11/2/6)

Genotype 3

(n=6/4/3)

96%

76%

98% 100%

83%

100% 100%

67%

100%

8-Week Regimen

HCV treatment-naïve

•Relapse

•(n=10)

•Relapse

•(n=1)

Relapse

(n=1)

•12-week regimen: no impact of race, baseline HCV RNA, cirrhosis, baseline NS5A RAVs, or ART regimens on SVR12.

•Genotype 4 results not shown (n=3). Wyles D, et al. NEJM 2015.


Page 16 of 19


C-EDGE: SVR12 Rates With Grazoprevir/Elbasvir in HCV Patients With HIV Coinfection

0

20

40

60

80

100

SV

R12

(%

)

93.1% 93.2% 92.9% 94%

Overall

(n=218)

93.1%

1a

(n=144)

1b

(n=44)

Genotype

Yes

(n=35)

No

(n=183)Baseline Cirrhosis

4

(n=28)

100%

SVR12 by ART containing: abacavir (95.7%), tenofovir DF (97.5%), raltegravir (96.4%), dolutegravir (100%), rilpivirine (94.6%).

Rockstroh JK, et al. J Hepatol. 2015;62(suppl 2):S675. Abstract P0887.

95 95 92 100 92 100

0

20

40

60

80

100

SV

R12

(%

)

ASTRAL-5 HIV/HCV Coinfection Study12 weeks of Sofosbuvir/Velpatasvir

LTFU, lost to follow-up. Error bars represent 95% confidence intervals.

99

104

•62

•65

•11

•12

•11

•11

•11

•12

•2 relapse

•1 LTFU

•4

•4Total 1a 1b 2 3 4

Genotype

•1 LTFU•1 withdrew

• consent


Page 17 of 19


RegimenGeno‐type

Weeks Study SVR12

Velpatasvir + Sofosbuvir all 12 ASTRAL‐1 19/19 (100%)

Sofosbuvir + ledipasvir 1 12 ION 4 63/67 (94%)

Elbasvir/grazoprevir 1,4 12 C‐Edge coinfection 35/35 (100%)

Paritaprevir/Ombitasvir/RBV 1 12 Turquoise‐1 5/6 (83%)

Daclatasvir + Sofosbuvir /RBV 1‐4 12 ALLY‐2 39/40 (98%)

NOT HEAD TO HEAD TRIALS

HIV/HCV: Compensated Cirrhosis

Recommendation

HIV/HCV‐coinfected persons should be treated and retreated the same as persons without HIV infection, after recognizing and managing interactions with antiretroviral medications

Rating: Class I, Level B

• Treatment should be prioritized in patients at high risk for liver‐related complications which includes patients with HCV/HIV coinfection, regardless of fibrosis stage

• Treating patients at high risk for transmitting HCV to others may decrease transmission and HCV disease prevalence which includes MSM with high‐risk sexual practices and active injection drug users

Guidelines from EASL and AASLD/IDSA: Prioritize HCV Treatment for Persons with HIV

Coinfection

•36

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org.


Page 18 of 19


Persons with HIV infection may be a greater risk for HCV re-infection following curative treatment

Risk of HCV reinfection following SVR: meta-analysis of 66 studies in 11,071 patients

HIV-infected male partners with re-infection

with telaprevir resistant HCV (V36M)

Franco et al. Gastroenterology 2014; Hill et al CROI 2015 (#654)

HCV Management and treatment: HIV/HCV coinfection

Are there clinically important drug-drug interactions?

– Expert consideration of HIV and HCV disease

Treatment should not be shortened to 8 weeks for most HIV coinfected patients

Risk of re-infection may be high among HIV-infected MSM

– Harm-reduction after SVR


Page 19 of 19

Documents

Global Prevalence of HBV, HCV , HIV - American College of ...s3.gi.org/acgmeetings/2016/pgsyllabus/2016PG_0037.pdf · HIV=human immunodeficiency virus; ... Serum samples from patients