Professor Vincent Soriano · Professor Vincent Soriano. in partnership with. Hospital Carlos III,...
Transcript of Professor Vincent Soriano · Professor Vincent Soriano. in partnership with. Hospital Carlos III,...
in partnership
with
Hospital Carlos III, Madrid, Spain
Professor Vincent Soriano
Five Nations Conference on
HIV and Hepatitis
in partnership
with
COMPETING INTEREST OF FINANCIAL VALUE > £1,000
Statement
None
Date: December 2015
Hospital Carlos III, Madrid, Spain
Professor Vincent Soriano
What’s new in
HIV & HBV Co-Infection ?
Vicente Soriano
Infectious Diseases Unit
La Paz University Hospital & IdiPAZ,
Madrid, Spain
HIV/HBV Outline
� Epidemiology & natural history re-visited
� Treatment issues
� Flares, acute-on-chronic, co-infections
Hepatitis B in 2014
� 240 million chronic carriers worldwide (WHO)
� Hyper-endemic areas in Southeast Asia and Sub-Saharan
Africa
� Oral nucleos(t)ide therapy is effective in most pts, but viral
eradication is not feasible.
� When tenofovir is not available, prevention and
management of LAM resistance requires expertise.
� Given the long asymptomatic period, late diagnosis is
common.
� Despite effective vaccine for 30 years, there is continuous
flow of incident cases (immigrants, non-responders, etc)
� Favorable outcome following liver transplantation
HBV genotypes (8)
Genotype Region Comments
A Northern America More sensitive to IFN
Northern Europe ↑ALT more frequently
India, Africa More rapid 3TC resistance
B Asia More benign
More sensitive to IFN
C Asia More HCC; more resistance
D Southern Europe Less response to IFN
Middle East, India
E West & South Africa
F Central & South America
G USA and Europe
H Central America, California
Kramvis et al. J Viral Hepat 2005; 12: 456-64.
Schaefer et al. Hepatol Res 2007; 37 (suppl): 20-6.
HIV
Acute
hepatitis B
Anti-HBs
Anti-HBcChronic
HBsAg
Anti-HBe HBeAg
HBV-DNAneg
HBV-DNApos
Cirrhosis
Liver decompensation
Liver cancer
Immune response Progressive disease
Natural history of HBV infection & effect of HIV
HIV enhances chronic HBV disease
� Higher serum HBV-DNA (∼1 log on average)
� More rapid liver fibrosis progression.
� More frequent selection of drug resistance.
� Less frequent spontaneous HBsAg or HBeAg
seroconversion
� More frequent coinfection with HCV and/or HDV.
� Increased mortality.
HBV Negatively Impacts on HIV Disease Progression
• Thio et al. Lancet 2002; 360: 1921-6.
• 2672 MSM from the MACS cohort
• 213 HIV+/HBsAg+, 113 HIV-/HBsAg+ & 2346 HIV+/HBsAg-
• Liver-related mortality was greater in coinfected patients
than in HIV alone (>8-fold) or HBsAg alone (>16-fold)
• Non-liver deaths more frequent in HBsAg+ with low nadir CD4
• Chun et al. JID 2012; 205: 185-93.
• 2352 HIV seroconverters in the United States
• Hazard ratio of 1.8 for AIDS/death in HBsAg+ vs HBsAg-
• Dore et al. AIDS 2010; 24: 857-65.
• 114 HIV+/HBsAg+ patients from the SMART study
• HBV-DNA rebound following ART interruption is associated
with faster CD4 decline
Time to antiretroviral therapy re-initiation in the DC arm
SMART. AIDS 2010; 24: 857-65.
Among 5472 participants, 930 (17%) were hepatitis co-infected
[HBsAg+ (n=120, 2.2%); and HCVAb+ (n=796, 14.5%).
Non-HBV/HCV:
Therapeutic Agents Available for HBV
� PEG-Interferon
� Lamivudine
� (Adefovir)
� Entecavir
� Telbivudine
� Emtricitabine
� Tenofovir
Incidence of HBV Resistance
Lamivudine (rtL180M+rtM204V/I)
Adefovir (rtN236T/rtA181V)
Lai C et al. Clin Infect Dis 2003; 36: 687-94.
0%
10%
20%
30%
40%
50%
60%
70%
80%
year 1 year 2 year 3 year 4
0%
24%
3%
42%
11%
53%
70%
Incid
en
ce o
f R
esis
tan
ce
18%
29%
75%
year 5
Telbivudine
Consequences of selecting
HBV drug resistance
� Loss of clinical benefit.
� Cross-resistance with other antivirals.
� Transmission of HBV resistant variants.
� Selection of HBV vaccine escape mutants
(occult infections and lack of protective
effect of HBV vaccine).
Shouval & Locarnini
Gastroenterology 2012; 143: 290-3.
Transmission of HBV vaccine
escape mutants
HBV-DNA
HBsAg
M204V
HBsAg
V173L
L180M
M204V
Mutant HBsAg
sE164D, sI195M
LAM
Wild type HBV LAM-resistant HBVLAM-resistant, vaccine
escape mutant HBV
EACS guidelines
Risk of cirrhosis in HBsAg+ patients
(REVEAL, n=3582)
Iloeje et al. Gastroenterology 2006;130:678-86.
RR 1 1.4 2.5 5.9 9.8
0
4.5 5.9
9.8
23.5
36.2
HBsAg-
(18,541)
<300 300 - 104 104-105 105-106 >106
Adjusted for gender, ALT, alcohol and smoking
HBV-DNA copies/ml
% 365 cases of cirrhosis over 11 years
Risk of HCC in HBsAg+ patients(REVEAL, n=3584)
Chen et al. JAMA 2006; 245: 65-73.
0
3 3.3
14.4
3230.5
HR
184 cases of HCC over 12 years
HBsAg-
(18,541)
<300 300 - 104 104-105 105-106 >106
Adjusted for gender, ALT, alcohol and smoking
HBV-DNA copies/ml
New challenges
HBV therapeutics in 2014
� Tenofovir toxicity (kidney, bone)
� High cost of tenofovir
� Tenofovir drug interactions (HIV, HCV)
� Tenofovir failures (entecavir intensification?)
Management of tenofovir toxicity
for chronic hepatitis B
1. TDF dose reduction
2. Entecavir
3. TAF (TDF prodrug)
4. Lamivudine
Tenofovir for chronic hepatitis B
Plaza et al. AIDS 2013; 27: 2219-24.
Virological response to tenofovir in patients with detectable
HBV-DNA according to HIV and HBeAg status
Plaza et al. AIDS 2013; 27: 2219-24.
TDF for HBV - Summary
• The antiviral efficacy of tenofovir is similar in HIV/HBV-
coinfected and HBV-monoinfected patients.
• Nearly 90% of baseline viremic patients achieve
undetectable HBV-DNA on tenofovir at week 96.
• Baseline serum HBV-DNA is the major determinant of
virological response.
• There is no significant influence of HBeAg, drug
resistance mutations nor coinfection with hepatitis C or
delta.
Plaza et al. AIDS 2013; 27: 2219-24.
HIV-monoinfected (n=524)
HIV/HCV-coinfected with SVR (n=106)
HIV/HCV spontaneous clearance (n=21)
HIV/HBV-coinfected (n=85)
HIV/HCV untreated (n=258)
HIV/HCV non-responders (n=127)
HIV/delta (n=17)
Time free from liver decompensation events or
death in 1138 HIV+ patients
Months
100806040200
Patients
(%)
100
90
80
70
p=0.002
p<0.0001
p<0.001
Fernandez et al. Clin Infect Dis 2014; 58: 1549-53.
Acute-on-Chronic Liver Failure
due to HBV
Severe exacerbation of liver damage in patients with
underlying chronic hepatitis B and no cirrhosis
that may lead to liver failure and death.
• ALT >20 ULN
• Bilirubin >5 ULN
• Prothrombin time <60%
• HBeAg seroconversion
• HBsAg seroconversion
• HBV drug resistance emergence
• HBV reactivation following chemotherapy
Criteria
Etiology
Hepatitis B flares
Liver enzyme elevations in patients with
known chronic hepatitis B
• Delta super-infection
• HAV, HCV or HEV super-infection
• Drug-related hepatotoxicity
• Immune reconstitution with ARV
• Acute alcohol intake
HBV – HCV dual infections in HIV
Soriano et al. J Infect Dis 2007; 195: 346-51.
21 HIV / HBsAg+ / HCV Ab+ patients exposed to treatment
for either HBV or HCV.
Summary
� HBV markers must be tested at baseline in all HIV+ persons.
� HBV vaccination must be given to those with neg markers.
� Chronic hepatitis B progresses faster in HIV.
� It increases the risk of hepatotoxicity using ARVs.
� Treatment of HBV should be considered as a priority in HIV+ pts.
� All HBV/HIV patients should be tested for viral load, genotype and liver fibrosis generally assessed by non-invasive tools.
� Avoid 3TC (FTC) as only anti-HBV agent up front.
� HBV treatment plan should be individualized, based on the need for HIV treatment and prior 3TC therapy.
� Stop and regression of advanced liver fibrosis can be seen with prolonged sustained suppression of HBV replication.
� Exclude delta hepatitis in all HBsAg+ patients.
� Treat active replicating virus in HBV-HCV dually infected patients.
Acknowledgments
� Pablo Barreiro, IdiPAZ & La Paz University Hospital, Madrid
� Antonio Aguilera, Hospital Conxo - CHUS, Santiago
� Eva Poveda, Inibic - Complexo Hospitalario, A Coruña
� Carmen Rodríguez & Jorge del Romero, Centro Sandoval, Madrid
� Carmen de Mendoza, Puerta de Hierro Research Institute, Madrid
� Pablo Labarga, La Luz Clinic, Madrid
� Jose V. Fernandez-Montero, University Hospital Crosshouse,
Kilmarnock, Scotland, UK
Hepatocyte
HBV
DNA
RT
cccDNA
RNA
DNA
Hepatocyte
HCV
RNA
Cytosol
Pol RNA
Nucleus
CD4+
T lymphocyte
HIV
RNA
RT
Nucleus
Provirus
RNA
J Antimicrob Chemother 2008;62:1-4.
[HBsAg] measurement
� Advantages:• Cheap
• Easy to perform (ELISA)
• Early decay on treatment associated with clearance
� Disadvantages:• Poor correlation with HBV-DNA
in partnership
with