hcv in hiv patients, cure and beyond

www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013

HCV in HIV patients,Cure and Beyond

K. Lacombe1, M. Lemoine2, G. Raguin3, A. Fontanet4, F. Zoulim5

1Université Pierre et Marie Curie, Paris VI – AP-HP, hôpital St Antoine – Inserm UMR-S7072Medical Research Council, The Gambia Unit, Banjul, The Gambia.3GIP ESTHER, Paris – France4Pasteur Institute, Paris - France5Université Lyon 2 - HCL, hôpital de la Croix Rousse - Inserm U1052, Lyon - France


HIV AND HCV:AN INTRICATE HISTORY

1


Evidence from databases from the bench and from the bedside

2

Deleterious and synergictic effect of HIV and HCV


HIV1 HCV2,3

Prevalence 34M0,8%

185M2,35%

Incidence 2,5M 4M

Mortality 1,7M 350 000

1UNAIDS Global Report 2012. 2Hanafiah, Hepatology 2012. 3Perz, J Hepatol 2006

4-5 M co-infected patients, depending on location and routes of transmission

4


Decreasing prevalence in Western countries

Ex: Cohorts of the Spanish AIDS Research Network1,2

1Perez Cachafeiro, Clin Infect Dis 2012. 2Serrano-Villar, CROI 2013

1996 1998 2000 2002 2004 2006 2008 2010 20120

10

20

30

40

50

60

70

80

% of HIV-HCV co-infected patients

1996 1998 2000 2002 2004 2006 2008 2010 20120

10

20

30

40

50

60

70

80

% of IDU among HIV patients% of HIV-HCV co-infected patients

5

Success of harm reduction (opiate substitution, needle exchange) Decrease in the HIV prevalence > HCV prevalence in IVDUs


Alarming increase of HCV and HIV prevalence in Eastern Europe

6

Bulgaria Greece Italy Cyprus Austria Romania0

10

20

30

40

50

60

70

80

20052010

Trends in HIV and HCV among injecting drug users in Eastern Europe , 2005 - 2010

Euro Surveill. 2011;16(48):pii=20031.

HCV prevalence


Africa and Asia, the hidden epidemics1,2

1Madhava V. Lancet 2002. 2Nelson P, Lancet 2011. 3Ba I, ICASA 20127

Dakar area – UDSEN study3

-est.size IVDUs: 1324- P(HIV): 5,2%- P (HCV): 23,3%


Evidence from databases from the bench and from the bedside

2

Deleterious and synergictics effect of HIV and HCV


Enhanced fibrosis progression Hepatic stellate cells infected by HIV through CCR5 receptors leading to the promotion of myofibroblastic differenciation and ultimately accelerating fibrosing process1

Activation of reactive oxygen species by HCV and HIV in HSC triggers a cascade of proteinesactivation increased expression of profibrogenic genes and decreased expression of antifibrogenic genes2

1Tuyama AC, Hepatology 2010. 2 Lin W, J Infect Dis 2013. 3Babu CK, PlosOne 2009.

Increased apoptosis of HCV-infected hepatocytes through HIV-mediated TRAIL (TNF Related Apoptosis Inducing Ligand) upregulation3

9


Influence of impaired CD4+ T-cells on NK cell anti-fibrotic activity 1

1Glässner, J Hepatol 2013

10

NK-cell anti fibrotic activity mediated by Il-2 upregulated by CD4-T cells

HIV-HCV infection impaired secretion of Il2 due to CD4-T cell dysfunction

results in impaired NK cell anti-fibrotic activity


Evidence from databases from the bench from the bedside

2

Deleterious and synergictics effect of HIV and HCV


Liver-related death: top 4 in the causes of death in HIV patients1

1Weber R. 19th IAC, Washington, USA, 2012. Abst THAB0310412


Liver-related death: 1st cause of death in HIV-HCV patients1

UnknownOther

SuicideOverdose

lungnon HIV infections

CardiovscularHIV

Cancer (non HIV non HCV)Liver (including HCC)

0 5 10 15 20 25 30 35 40

43 %12 %

8 %5 %4 %4 %4 %2 %6 %7 %

Decompensated cirrhosisHCCPost-transplantation

Cirrhotic Patients: > 50% deaths related to HCVNon cirrhotic patients : 60% deaths non related to HCV nor HIV

1HSogni P. Conference on French HIV-HCV Consensus Guidelines, 2012

13


Overall, ESLD and death remain higher in HIV-HCV patientsIn cART era1

1Lo Re V, WEAB0102, IAC 2012, Washington DC - USA

14

Cum. I X 1,5


HCV INFECTION: A CURABLE DISEASE

15


% o

f pati

ents

with

sust

aine

d vi

rolo

gica

l res

pons

e (S

VR)

IFN

24 W

70

50

30

20

10

60

40

IFN

48 W

IFN+RBV

24 W

IFN+RBV

48 W

PEG-IFN+RBV

48 W

0

80

90

IFN = Interferon-αPEG-INF = Peg-Interferon-αRBV = RibavirinW = weeksPEG = PEG-IFN-α

2002

2011

1999

2014

PEG-IFN+RBV

+new PI Telaprevir

Or Boceprevir

INF-free regimens12 weeks

? 95-100% SVR

16 16


Evidence for cure arguments from virologyarguments from immunologyarguments from geneticsarguments from therapeutics

17


Absence of virus integration in human genome

Host cell Host cell Host cell

Nucleus Nucleus Nucleus

cccDNA

Host DNA

proviral DNA

HCV RNA

Long term reduction of viral replication

Life long suppressionof viral replication

Definitive viral suppression= possible SVR

HBV HIV HCV

1Thomas XV. PlosOne 2012.18


No persistance of mutations in the viral genome

Extended follow-up of G1 HCV mono-infected patients included in telaprevir phase II trials1

Absence of detectable mutations in 89% of patients who had failed after a median 25 months of f/u from treatment discontinuation

HCV is not HIV: no archived mutations

1Zeuzem S, AASLD 2010. Abst 227.

19


Evidence for cure arguments from virologyarguments from immunologyarguments from geneticsarguments from therapeutic field

17


cART may restore an anti-HCV T-cell response1

T cell ELISpot responses to hepatitis C virus (HCV) core peptides before and on successful combination antiretroviral therapy

1Rohrbach J. Gut 2010

21

Argument for early introduction of cART ?


Il28B polymorphism, a genetic determinant of treatment response1

1Thompson AJ, Gastroenterol 2012. 2Lawitz E, EASL 2013

SVRPeg-IFN – RBV1

SVRNS3-4A + PR2

SVRNew DAA (SOF)3

CC 69% 90% - TVR82% - BOC

98%

CT - TT 33% – 27% 71% - 73% TVR71% - 69% BOC

88%

22


Evidence for cure arguments from virologyarguments from immunologyarguments from geneticsarguments from therapeutic field

17


A viral genome with multiple therapeutic targets

Bartenschlager, Nature Rev 2013

24


New drugs in HIV patients: efficient in naive / relapsers…

SVR12 with telaprevir1

SVR12 with boceprevir2

1st generationNS3/4 inhibitors

2nd generationNS3/4 inhibitors

SVR12 with simeprevir (TMC435)3

EVR with faldaprevir (BI201335)3

1Sulkowski M. Ann Intern Med 2013. 2Sulkowski, AASLD2012. 3Dieterich D. CROI 2013. 4Dieterich D. CROI 2013 25


New drugs in HIV patients: … and also in partial / null responders

EVR in pretreated patients(TELAPREVIH)1

1Cotte L. CROI 2013. 2Poizot-Martin I. CROI 2013.

EVR in pretreated patients (BOCEPREVIH)2

26

63% response rate at W16 (EVR)

88% response rate at W16 (EVR)


New drugs in HIV patients: … albeit mildly tolerated

Adapted from ClinicalCareOptions

RASH

34% w/ TVR, none w/ BOC

ANEMIA

41% w/BOC, 18% w/ TVR

Mild (≤ 25% BSA)

Moderate (25% to 50%

BSA)

Severe (> 50% BSA) Use of RBV decrease before EPO

27


Present and future trials in HIV patients1

1Clinicaltrials.gov: last accessed 22/06/2013

GENO DRUG DURATION

NCT01667731 G1, G2, G3 SOF + RBV 12 – 24 Ws

NCT01565889 G1 SOF + PEG + RBV 12

NCT01471574 G1 Dacla + PEG + RBV 24

NCT01878799 G1 SOF + GS8558 12

NCT01725542 G1, G4 Dacla + asuna + PEG + RBV

24

28


Encouraging results with new compounds

New viral targets: other viral proteins targeted in the HCV replication cycle: oNS4B (that can be inhibited by silibilin)o p7

Host-cell factorso CYPA inhibitors (alisporivir)omiR-122 (miravirsen)oMonoclonal antibodies (undirect antiviral properties):

SIMTUZUMAB (GS-6624), BAVITUXIMAB

29


FUTURE CHALLENGES

30

Cure, but what stands beyond ?


Avoiding new infectionsOpimizing treatment strategiesOvercoming barriers to care

31


Acute hepatitis C in MSM: how to curb the epidemics?

1Rockstroh, JIAS 2012. 2MartinT, IAS 2013. 3Thomson, AIDS 2009. 4Linas, Clin Infect Dis 2012. 5Boesecke C, CROI 2012. 6Fierer, CROI 2013. 4Boesecke, AASLD 2012

1

Eurosida for Eurocoord

32

PREVENTION (STI+++)Information ++

To reduce rate of re-infection2

SCREENING +++ Define best

screening algorithm3,4

TREATMENTDefine best

treatment strategy5,6


Hepatitis C and IV drug use: increasing effectiveness of harm reduction programs

Who should be treated ?1: « breaking the taboos is required in the fight against hepatitis C among PWID »2

1Martin, Hepatology 2012. 2Brugmann, Hepatology 2012

33

Cost-effectiveness study :- In IVDUs population with 20 – 40% HCV prevalence : more cost-effective to treat IVDUs- in IVDUs population with at least 60% HCV prevalence : more cost-effective to treat ex / no IVDUs because of high rate of re-infections in IVDUs

Emphasis on harm reduction programmes in populations with high HCV prevalence and treatment to be considered at a patient land not mass level


Hepatitis C and nosocomial transmission, a persistant risk factor in RLS

1Kandell AM. BMC Infect Dis, 2012

34

In Egypt, HCV transmission associated with medical procedures1

Risk factors OR 95% CI

Hospital exposure- IV - administred fluids 13,7 5,6 – 33,5

- hospital admission 7,8 4,3 – 14,3

- invasive procedure 4,7 2,8 – 7,9

Outpatient care-abcess drainage 33,4 4,2 – 267,9

- injections with re-used syringes 23,1 4,7 - 153


Treatment as prevention concept in HCV

1Durier N. Plos One 2012

1

35


The vaccine issue

Several ongoing trials with vaccine candidates for the prevention of HCV infection1

1Fauvelle C, Microbiol Pathogenesis 2013

Immunization = most cost-effective way of prevention of transmitted diseases

HCV vaccine research > 20 years but no vaccine available yet lack of animal models ability of HCV to escape host immunity genetic variability of host defenses

36



31


Course of treatment: with or without IFN?• Drawbacks of IFN-based regimen: tolerability and suboptimal

response in patients w/prior failure with IFN

• Challenges: combining drugs with different targets of action = highest potency / barrier to resistance and best safety profile1

• Remaining questions: efficacy in cirrhotics, prior null responders, difficult to treat genotypes (G3) ?2

• HIV patients: - PHOTON study (SOF + RBV in G1) - Abbott M12-240 (antipolymerase + PI + anti- NS5A + RTV), end of 2013

1Liang TJ, NEJM 2013. 2Dusheiko J, Lancet 2013.

38


Drug-drug interactions with ARVsTVR BOC New DAAs

NRTI

All (except those contra-indicated with PR: AZT, DDI, D4T)

?

NNRTI

efavirenz +1pill x 3 /day Increased neuro effects of EFV

?

rilpivirine ?

PI

atazanavir ?

lopinavir ?

darunavir ?

fosamprenavir ?

AI

raltegravir ?

39


Cost-effectiveness: who should be treated and how and when?

• Cost-effectiveness study performed in France1

• F0-F1 delaying treatment until F2 (1000-1200€ / QALY gained / patients

• F2 delaying treatment until F3 or arrival of DAAs

• Sensitivity: in F2 patients, might reconsider if late arrival of DAAs, lower SVR with DAAs when treated at F3, alcohol abuse

1Deuffic-Durban S, EASL 2013

40


Is liver monitoring indicated in SVR patients ?

1Berenguer J, Clin Infect Dis 2012

Overalldeaths

Liver related deaths

Non liver- related deaths

Non liver- non AIDS-

related deaths

Clear benefit of SVR41


Is liver monitoring indicated in SVR patients ?

But risk of HCC still present: regular liver assessment +++

1Aleman. Clin Infect Dis 201342


ESLD: facilitate access to liver transplantation

Patients survival post trplst stratified by HIV status1

1Terrault N, Am J Transplant. 2012

Differences in patients survival only due to presence of HIV in patients with HIV, risk factors for death = older age of donor, HCV+ graft, low BMI, kidney trsplt if none of those factors: equal survival

43



31


Multiple barriers at multiple steps of the continuum of care

Adapted from G. Matthews

45


Overcoming patients and providers barriers

• Treatment efficacy is identical wether patients are coming from a middle or low income country2

• Intrication of individual and social factors (stigma, discrimination, housing problems, geographical access, criminalisation, compartmentalized nature of health care systems1

1Ford N, Bull World Health Organ 2012. 2Harris M, Harm reduction 2013.

46


Overcoming providers barriers

Easier assessment of the infection and the liver disease2

-Dry-blood spots (HCV viral load quantification/genotyping)- Portable Fibroscan (Echosens)- Portable sonography

Rapid Testing1

- Point-of-care tests- Salivary rapid testing

1Yaari A, J Viral Methods 2006. 2Tuaillon E, Hepatology 2010 47

Mostly unavailable in RLS= advocacy a priority


Overcoming the costs barrier

http://www.medicinespatentpool.org

48

History of HIV


Costs in RLS: lessons from HIV/AIDS experience

• In 2000: ART: $10,000-15,000/patient/year • Today < $100/year In 2000, only 0.1% received ARV in Africa Today, almost 68% of women and 47% of men in needs in low/midlle

income countries

49


Treatment for All is answering to the civil society‘s demand

International conference on HIV/AIDS, Washington 2012

50


ACKNOWLEDGMENTSPierre-Marie Girard, Jürgen Rockstroh, Sanjay Baghani, Patrick Ingiliz, Alexandra Calmy, Christoph Boesecke, Nicolas Durier, Isabelle Andrieux-Meyer, Serge Eholié, Anders Boyd, Maria Winnock, Dominique Salmon, Philippe Sogni, Yasdan Yasdanpanah, Sylvie Deuffic-Burban, Ralph Chami, Bogdana Coudsy, Gail Matthews, Amir Guidoum, Niklas Luhmann, Audrey Coilly.

hcv in hiv patients, cure and beyond

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