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
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