global prevalence of hbv, hcv , hiv - american college of...
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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
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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%
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Paul Y. Kwo, MD, FACG
•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.
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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).
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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 +++ +
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Paul Y. Kwo, MD, FACG
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%
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Paul Y. Kwo, MD, FACG
HCV/HIV Co-Infection Outbreak in Indiana
84% Co-infected with HCV
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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.
Drug Interactions Between Select ARTs and HCV Therapies
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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.
These drugs should not be coadministered
Potential interaction – may require dosage adjustment or close monitoring
No clinically significant interaction expected
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Paul Y. Kwo, MD, FACG
Drug Interactions Between Select ARTs and HCV Therapies
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.
These drugs should not be coadministered
Potential interaction – may require dosage adjustment or close monitoring
No clinically significant interaction expected
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.
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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
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Paul Y. Kwo, MD, FACG
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.
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Paul Y. Kwo, MD, FACG
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
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