HV & HIV

HIV, Hepatitis B and C: global prevalence

1. WHO Factsheets HBV, HCV, HIV; 2. Alter MJ. J Hepatol 2006; 44(Suppl.1): S6-S9.

350.000.000

170.000.000

33.000.000

2-4.000.000

4-5.000.000

HBV IN HIV

Prevalence of HBsAg+ in HIV Infected Patients

· EuroSIDA Cohort (n= 9802) : Patients screened for HBsAg: 5883 (60%) HBsAg+: 530 (9%)

- South: 9.1%

- Central: 9.2%

- North: 9.7%

- East: 6%

Konopnicki D, et al. AIDS. 2005.

Influence of HIV on CHBIn the Pre HAART era, HIV in HBsAg positive patients (compared toHBV mono-infected):

· Increased the risk of chronic infection after contamination

· Reduced the seroconversion rates to anti-HBe and anti- HBs

· Increased HBV replication

· Frequent reactivation related to CD4 decline

· Accelerated fibrosis progression

· Increased risk of liver decompensation, HCC and liver death

Bodsworth, JID 1989 ; Hadler, JID 1991 ; Krogsgaard, Hepatology 1987 ; Bodsworth, JID 1989 ; Gilson, AIDS 1997. Piroth, J Hepatol 2002; Vogel Cancer Res 1991; Corallini Cncer Res 1993 ; Altavilla Am J Pathol 2000 ; Bodsworth, JID 1989 ; Mills,

Gastroenterol 1990 ; Goldin, J Clin Pathol 1990 ; Gilson, AIDS 1997 ; Thio, Lancet 2002 ; Di Martino, Gastroenterol 2002; Colin Hepatol 1999; Perillo, Ann Int Med 1986 ; McDonald, J Hepatol 1987

Treatment of HBV in HIV Co-infected Patients

Licensed for

HIV HBV

Interferon (IFN) Lamivudine (LAM) Emtricitabine (FTC) Entecavir (ETV) () Telbivudine (LDT) Adefovir dipivoxil (ADV) Tenofovir disoproxil fumarate (TDF)

TDF vs. TDF+LAM (48 weeks)

3/50

12/50

29/50

42/50

1/25

9/25

14/25

19/25

0

20

40

60

80

100

DNA<3log

AST<45U/L

HBeAgloss

HBsAgloss

Patie

nts

(%)

TDF TDF+LAM

Schmutz G, et al. AIDS. 2006.

LAM Naive(n=9)

LAM Experienced(n=47)

HBV DNA <15 UI/mL

9 41

Mean time to DNA < LOD (weeks)

49 67

Tuma R, et al. AASLD 2008, Abstract 967.

Tenofovir Disoproxil Fumarate

TDF + LAM (48 weeks)

Matthews G et al. Hepatology 2008

W48 outcomes LAMN=12

TDFN=12

TDF+LAMN=12 p

Median DNA Reduction 4.07 4.57 4.73 .7

DNA <3 log 46% 92% 91% .01

HBeAg loss 3 1 3

Anti-HBe Seroconversion 1 1 3

HBsAg loss 1 1 1

Tenofovir Disoproxil Fumarate

TDF- vs LAM- containing HAART in ARV-naïve HIV/HBeAg+ Co-infected Patients (TICO Study):

Randomized Thai trial (1:1:1) of LAM vs TDF vs LAM/TDF within an EFV-based HAART regimen

Treatment Algorithm Patients with Compensated Liver Disease and

No Indication for HIV Therapy (CD4 count >350/µL)

• No treatment• Monitor every

6–12 months

HBV DNA2000 IU/mL

HBV DNA

HBV DNA<2000 IU/mL

ALT ElevatedALT Normal

• Monitor ALT every 3-12 months

• Consider biopsy and treat if disease present

• PEG IFN• ADV+LdT• Early HAART initiation –TDF+LAM/FTC

ECC Statement. J Hepatol. 2005.Rockstroh et al. HIV Medicine 2008.

Treatment Algorithm Patients with Compensated Liver Disease and Indication for HIV Therapy (CD4 count <350/µL)

HBV DNA≥2000 IU/ml

HBV DNA<2000 IU/ml

HAART includingTDF+3T/FTC

Substitute one NRTI byTDF or add TDF*

Patients without HBV-associated LAM resistance

Patients with cirrhosis

ECC Statement. J Hepatol. 2005.Rockstroh et al. HIV Medicine 2008.

Patients with HBV-associated LAM resistance HAART regimen

of choice

HAART includingTDF+LAM/FTC

*If feasible and appropriate from the perspective

of maintaining HIV suppression.

Refer patient for liver transplantation

evaluation if decompensation

HBV DNA

Conclusions

· Viral hepatitis coinfections are major factors of mortality and morbidity in the HIV infected population

· It is crucial to determine those patients who are in need for treatment

· Viral and host factors can predict the chance of cure

· DAAs for HCV will soon be available but lack data on HIV coinfection

· Tenofovir is the actual agent of choice in HBV coinfection

HCV in HIV

Fibrosis progression

Poynard, T. et al. J Hepatol 2003;38:257-265

4,682 patients

180 HIV-HCV701 Alcohol812 HBV382 Hemochromatosis2,313 HCV 93 Steatosis BMI>25200 PBC

1.00

0 20 40 60 80

Haza

rd fu

nctio

n

Age in years

Progression to cirrhosis

Treatment of HCV IN HIV

SVR = regression, NR = progression ?

-1

0

1

2

3

4

0 5 10 15 20

Time (yr)

Fibr

osis

stag

e (M

etav

ir fib

rosis

uni

ts)

Untreated (n=29)

SVR (n=34)

NR/R (n=63)

Ingiliz, Benhamou et al., J Hepatol, submitted, under review

DAAs

Phase 3 PHOTON-1 Study DesignAll-Oral Therapy of SOF + RBV in HCV/HIV Co-infection

Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212

0 12 24 36

SOF 400mg + RBV 1000-1200mg SVR12

SOF 400mg + RBV 1000-1200 mg SVR12

Study Week

GT 2,3 TNn=68

GT 1 TNn=114

SOF 400mg + RBV 1000-1200 mg SVR12GT 2,3 TE

n=41

¨ Broad inclusion criteria– Cirrhosis permitted with no platelet cutoff– Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)

¨ Wide range of ART regimens allowed – Undetectable HIV RNA for >8 weeks on stable ART regimen

¨ Baseline CD4 count– ART treated: CD4 T-cell count >200 cells/mm3 and HIV RNA < 50 c/mL– ART untreated: CD4 T-cell count >500 cells/mm3

No response guided therapy

76

0102030405060708090

100

SVR12

HCV

RNA

< 25

IU/m

L (%

)

88

0102030405060708090

100

SVR12

67

0102030405060708090

100

SVR12

GT1 TN1 SOF + RBV x24 weeks

GT2 TN1 SOF + RBV x12 weeks

GT3 TN1 SOF + RBV x12 weeks

GT3 TE2 SOF + RBV x24 weeks

92

0

20

40

60

80

100

SVR12

1. Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212; 2. SOVALDI™ [PI]. Gilead Sciences, Inc. Foster City, CA December 2013

87/114 23/26 28/42 12/13

PHOTON-1 SVR12All-Oral Therapy of SOF + RBV in GT1, 2, 3 HCV Treatment-Naive

and GT 3 Treatment-Experienced/HIV Co-infection

¨ An all-oral regimen of SOF + RBV for 12–24 weeks resulted in high SVR12 rates in TN GT 1, 2 and 3 and TE GT 3 CHC with HIV coinfection – with SVR12 rates similar to mono-infection

¨ No HCV resistance was observed– No S282T mutations were observed in virologic failures via deep sequencing

¨ Two patients had HCV breakthrough; both had documented non-adherence to SOF ¨ Two other patients had transient HIV breakthrough; both had documented non-adherence to ART

Sulkowski MS, et al. AASLD 2014;

ION-4: Study Design

• Phase 3 open-label single-arm trial• US, Canada and New Zealand• Inclusion criteria:

- Treatment-naïve or experienced- 20% had compensated cirrhosis- HIV RNA <50 copies/mL, CD4 cell count> 100 cells/mm3

• ART regimens were TDF/FTC + one of the following:- Efavirenz- Raltegravir- Rilpivirine

Naggie et. al. CROI 2015. Abstract 152LB.

Ledipasvir-SofosbuvirN=335GT1 98%

0 12 24Week

SVR12

ION-4: ResultsOverall and by Cirrhosis & Treatment experience

Overall No cirrhosis Cirrhosis Naïve Experienced0

20

40

60

80

10096 96 94 95 97

Patie

nts

(%) w

ith S

VR 1

2

Naggie et. al. CROI 2015. Abstract 152LB.

Hepatitisweb studySource: Wyles DL, et al. N Engl J Med. 2015;373:714-25.

Treatment-ExperiencedN = 52

Treatment-NaïveN = 101 SVR12

Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV CoinfectionALLY-2 Trial: Design

Daclatasvir + Sofosbuvir

Daclatasvir + Sofosbuvir

Drug DosingDaclatasvir: 60 mg once daily; with efavirenz and nevirapine the dose was increased to 90 mg once daily and with ritonavir-boosted protease inhibitors the dose was decreased to 30 mg once dailySofosbuvir: 400 mg once daily

Week 0 2412

Treatment-NaïveN = 50 SVR12Daclatasvir + Sofosbuvir

SVR12

8 20

Hepatitisweb study

Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV CoinfectionALLY-2 Trial: Results for Genotype 1

SVR12, Genotype 1

Source: Wyles DL, et al. N Engl J Med. 2015;373:714-25.

0

20

40

60

80

10096

76

98

Patie

nts

with

SVR

12 (%

)

80/83 31/41 43/44

AIDS 2015Vancouver, BC

Session:TUAB02STUDY DESIGN

• An open-label, single-arm, multicenter study across Europe, The US and Australia

• Primary endpoint: SVR12 (HCV RNA <15 IU/mL*)• Treatment-naive patients with HCV GT1, 4 or 6 infection with or without

cirrhosis• Co-infected with HIV-1:

– Naive to ART with CD4+ >500 cells/mm3 and HIV RNA <50,000 copies/mL – On stable on ART† for ≥8 weeks and CD4+ >200 cells/mm3 and undetectable

HIV RNA

GRAZOPREVIR 100 mg / ELBASVIR 50 mg

D1 TW4 TW8 TW12 FUW4 FUW8 FUW12

n=218

*COBAS TaqMan v2.0 [LLoQ <15 IU/mL]† Stable antiretroviral therapy (ART) included tenofovir or abacavir, and either emtricitabine or lamivudine plus raltegravir, dolutegravir, or rilpivirine

Follow-up

AIDS 2015Vancouver, BC

Session:TUAB02SVR12

Discontinued unrelated to VF 1 0 1 0Relapse 5 4 0 1Reinfection 2 1 1 0

*2 patients with GT6 infection were also included; both patients achieved SVR12.GT = genotype

210/217*

96.3% 96.5% 95.5% 96.4%

0%

25%

50%

75%

100%

Full AnalysisSet

GT1a GT1b GT4

Patie

nts,

%

139/144

42/44

210/218*

27/28

Indications DAAs VHC

Mono Infection VHC = Co Infection VIH/VHC

VHV/VIH = Interactions médicamenteuses