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