hcv treatment in the hiv co-infected...

Hugo E. Vargas, MD, FACG

HCV Treatment in the HIV co-infected2014

HCV Treatment in the HIV co-infected201420142014

Hugo E. Vargas, MD. FACP,FACG, AGAFHugo E. Vargas, MD. FACP,FACG, AGAF

Professor of MedicineProfessor of Medicine

Mayo College of MedicineMayo College of Medicine

Ch i Di i i f H t lCh i Di i i f H t l

Hugo E. Vargas, MD. FACP,FACG, AGAFHugo E. Vargas, MD. FACP,FACG, AGAF

Professor of MedicineProfessor of Medicine

Mayo College of MedicineMayo College of Medicine

Ch i Di i i f H t lCh i Di i i f H t lChair, Division of HepatologyChair, Division of HepatologyChair, Division of HepatologyChair, Division of Hepatology

Disclosure:Sources of Research Support

• MerckId i• Idenix

• AbbVie• BMS• Gilead• Janssen• I belong to the ABIM test writing panel for Hepatology.

No information about the test will be disclosed

©2012 MFMER | slide-2

No information about the test will be disclosed.

I WILL DISCUSS AGENTS CURRENTLY UNDER INVESTIGATION

ACG Eastern Regional Postgraduate Course - Washington, DC Copyright 2014 American College of Gastroenterology

1


Educational Goals

• Delineate the impact of HIV/HCV co-infected populationpopulation

• Discuss the new agents introduced in to market and how they will change the standard of care

• Discuss the outlook for the HCV for HIV co-infected patients in the next 2 years


• Review a proposed treatment strategy

Educational Goals

• Disclaimers:• Recommendations are still germinal• Need durability, applicability data outside

clinical trials• Will discuss agents that are not yet available



2


Case Presentation

27 yo man from England

• He is MSM HIV+ for 5 yrs normal CD4 count• He is MSM, HIV+ for 5 yrs, normal CD4 count• On HAART (on efavirenz+truvada)

• Living in New York for a work assignment

• Presents for fitness to work exam

• LIT’s abnormal, PCP obtains HCV Ab which is positive


positive

• Denies IV drug use

• Genotype 1a

What would you do?

Ch k IL28B it 3 th d l t• Check IL28B, wait 3 months and re-evaluate

• Obtain a liver biopsy and write pre-approval for SOF/IFN/RBV

• Obtain liver biopsy and refer to ID specialist

• Obtain liver biopsy and refer to clinical trial


Obtain liver biopsy and refer to clinical trial

• Obtain HBV serologies, liver biopsy and refer for tretament


3


The burden of HCV


Worldwide Burden of Disease due to HCV is Increasing

• WHO estimates 130 170 million people (3% of world's• WHO estimates 130-170 million people, (3% of world s population) HCV infected and at risk of cirrhosis/HCC

• There are 3 to 4 million new infections/yr

• HCV is responsible for 50–76% of all HCC and 50-60% of all liver transplants in the developed world


• HCV-associated cirrhosis leads to liver failure and death in about 20%-25% of cirrhotic patients

World Health Organization


4


Disease Burden of Patients Infected 20 Years or More is Peaking Now

Complications from chronic hepatitis C develop slowly over a period of 20–30 years

Patients infected

Infected > 20 y

Pre

vale

nce

(%)

4.0

3.0

2.0


P

1960 1970 1980 1990 2000 2010 2020 2030

1.0

0.0

Davis GL. Rev Gastroenterol Disord 2004

HIV

7

6

Deaths from HCV in the United States Continue to Rise; Deaths from HBV and HIV are Decreasing

Ra

te p

er

10

0,0

00

Pe

rso

ns 5

4

3

2

Hepatitis C

HCV was the contributing or underlying cause of death


Year

1999 2000 2001 2002 2003 2004 2005 2006 2007

1

0

Hepatitis B

y gfor 15,106 individuals in 2007

Ly KN et al. Ann Intern Med 2012


5


Persons for whom routine HCV testing is recommended

• Persons who ever injected illegal drugs, including those who injected once or a few times many years ago

• Persons who received a blood transfusion or organ transplant before J l 1992before July 1992

• Persons who received clotting factor concentrates before 1987• Persons who were ever on long-term dialysis• Children born to HCV-positive women• Health care, emergency medical, and public safety workers after

needlesticks, sharps, or mucosal exposures to HCV-positive blood


• Persons with evidence of chronic liver disease• HIV infected patients• Persons born between 1945-1965

CDC .gov

Background and Epidemiology

• HIV accelerates the natural course of HCV

• Successful antiretroviral therapy can slow fibrosis progression.py p g• Not to the rate in HIV-/HCV+ patients

• Liver disease associated with HCV infection has become a leading cause of morbidity and mortality among HCV/HIV-co-infected patients

• HIV/HCV epidemiology• Approximately 25% of HIV+ patients are co-infected with HCV


• Approximately 80% of HIV+ patients who inject drugs are co-infected with HCV

• All patients with HIV infection should be tested for HCV

• HIV/HCV co-infected pts. were considered a “higher need” population


6


Sexual Transmission of HCV Among HIV+ MSM

• Reports of epidemic of sexually transmitted HCV among HIV+ MSM

U it d St t 6 f ld hi h i id t i HIV HIV• United States: 6-fold higher incidence rate in HIV+ vs HIV-MSM

• Swiss HIV Cohort Study: HCV incidence increased 18-fold from 1998 to 2011

• Australia: 9% of HIV+ MSM co-infected with HCV vs 1.9% HIV-MSM

• Netherlands: HIV/HCV co-infection prevalence increased from 14.6% to 20.9% from 2000-2007


14.6% to 20.9% from 2000 2007• Phylogenic analysis indicates HCV transmission clusters in

some areas

• Sexual practices may influence the incidence of HCV

Risk Factors for Sexual HCV Transmission Among HIV+ MSM

• Multiple factors associated with HCV transmissiontransmission

• Unprotected receptive anal intercourse• Online casual sexual partners• Sex at sex venues• Older age• Syphilis


Syphilis• Recreational drug use• Drinking > 13 alcoholic drinks per week

11. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 12. Larsen C, et al. PLoS ONE. 2011;6:e29322.


7


Screening, Surveillance, Treatment Initiation for HCV in HIV+ Patients

HIV t t t id li d• HIV treatment guidelines recommend:• HCV screening at HIV diagnosis, then

annually and as indicated• More frequent surveillance if ongoing risk

MSM, IDU)• HCV RNA if HCV Ab+ or suspected acute


HCV RNA if HCV Ab+ or suspected acute infection

New Molecular Targets Direct Antiviral Agents



8


The current/upcoming arsenal

• Protease inhibitors• Telaprevir

• NS5A Complex Inhibitors• Daclatasvirp

• Boceprevir• Simeprevir• Faldaprevir• Asunaprevir• ABT-450• MK 5172

• Ledipasvir• Ombitasvir• GS-5816• ACH-3102• PPI-668• GSK2336805


• MK-5172• Sovaprevir• ACH-2684

• GSK2336805• Samatasvir• MK-8742

The current/upcoming arsenal

• NS5B Nuc. Pol Inhibitor• Sofosbuvir

• NS5B Non-nuc. Pol Inhibitor

• Dasabuvir

• VX-135• IDX20963• ACH-3422

• Deleobuvir• BMS 791325• PPI-383• GS 9669• TMC 647055



9


DAA regimens:Telaprevir

• Two studies have been presenting data from which we can begin to make planswhich we can begin to make plans

• Multi-centric TPV trial (NCT00983853)• Reporting on 60 pts (with and without ART)

who were HCV treatment naïveSulkowski Ann Int Med 2013

• French TelapreVIH trial ARNS HC26


French TelapreVIH trial ARNS HC26 (NCTNCT01332955)

• 69 patients who had prior non response (23% cirrhosis)

DAA regimens:Boceprevir

• Two studies have been presenting data from which we can begin to make planswhich we can begin to make plans

• Multi-centric BOC trial (NCT00959699)• Reporting on 60 pts (with and without ART)

who were HCV treatment naïveSulkowski Lancet Inf Dis 2013

• French BocepreVIH trial ARNS HC27


French BocepreVIH trial ARNS HC27 (NCT01335529)

• 64 patients who had prior non response (17% cirrhosis)


10


Promising Results (Sulkowski Ann Int Med and Lancet Inf Dis 2013)

7480

SVR12

60.7

74

26.5

45

30

40

50

60

70

80

Exp

SOC


0

10

20

BOC TPV

HIV/HCV PatientPrior non-responders

• While the SVR data from TelapreVIH and e t e S data o e ap e a dBocepreVIH has not been presented

• On treatment with TPV (HIV regimens allowed efavirenz) week 16 results are >85%, with close to 90% response for relapsersBOC is quite effective in relapsers


• BOC is quite effective in relapsers(90%) with low null responders on-treatment response (38%)

Data presented at CROI 2013


11


Challenges With Telaprevir- or Boceprevir-Based HCV Therapy in Coinfected Patients

• Regimen complexity• High pill burdeng p• Long duration, complex RGT rules• Multiple drug-drug interactions• Overlapping toxicities• With/without food dosing requirements

• Tolerability


• Additional AEs beyond PEG/ribavirin• Rash• Asthenia

Specific Risks of Deferring Therapy in HIV/HCV-Coinfected Patients

• Accelerated rate of HCV-related hepatic fibrosis progression in co-infected patients withprogression in co infected patients with increasing immune deficiency

• Progression to cirrhosis risk 3-fold higher in co-infected vs HCV-mono-infected patients

• Relative risk of decompensated liver disease 6-fold higher in co-infected vs HCV-monoinfected patients


monoinfected patients

• Co-infected patients have reduced access to liver transplantation and reduced survival


12


HCV Coinfection vs Monoinfection: Cumulative Incidence of Decompensation

• 10-year hepatic decompensation risk 83% higher in coinfected patients• Adjusted HR 1.83 (95% CI: 1.54-2.18)Adjusted HR 1.83 (95% CI: 1.54 2.18)

HIV/HCV coinfectedHCV monoinfected

0 0740.1

0.2


P < .001

0.074

0.048

.

00 1 2 3 4 5 6 7 8 9 10

Time to Decompensation

C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection

• Phase III randomized controlled trial

• 24- or 48-week regimens: SPV +• 24- or 48-week regimens: SPV + pegIFN/RBV for 12 weeks, then pegIFN/RBV alone

• HCV treatment-naive or -experienced HIV+ patients (N = 106)

• 88% on ART (VL < 50 cells/mL)• Excluded: boosted PIs,

NNRTIs other than RPV• Safety profile similar to

100

80

60

40

SV

R12

(%

)

7470

79

57

87


• Safety profile similar to monoinfected pts

• Pruritus and photosensitivity in 20% and 2%, respectively

• SVR comparable to GT1 HCV-monoinfected pts (80%)

7/10

16/28

20

0

78/106

Overall

42/53

Naive

13/ 15

Relapsers

n/N =

Partial Null


13


HIV patients should be in GENERAL mix


Advantages of Future HCV Therapies

• Once-daily dosing

Sh t d ti• Shorter duration

• Simpler regimens—no response-guided therapy

• Fewer adverse events

• Interferon-free

Hi h ffi


• High efficacy


14


PHOTON-1: Sofosbuvir + RBV in GT1/2/3 HIV/HCV Co-infection• Phase III open-label study

• 12- (GT2/3 treatment-naive) or 24-week regimens (GT1 t t t i GT2/3 t t t i d) f b i +treatment-naive, GT2/3 treatment experienced): sofosbuvir + RBV

• HCV treatment-naive or -experienced HIV+ patients (N = 223)

• Approximately 76% on ART (VL < 50 cells/mL), various standard regimens

• Safety profile similar to mono-infected patients; consistent with RBV


with RBV

• Most frequent AEs: fatigue, insomnia, headache, nausea, diarrhea

• 2 patients had transient HIV rebound due to non-adherence

Sulkowski et al AASLD 2013 and CROI 2014

PHOTON-1: Sofosbuvir + RBV in GT1/2/3 HIV/HCV Co-infection

76

8892

88

80

90

100

76

67

20

30

40

50

60

70

80


0

10

20

SVR12

G1 (naïve) G2 (naïve) G2 (TE) G3 (naïve) G3 (TE)

Sulkowski et al AASLD 2013 and CROI 2014


15


Selected Ongoing or Upcoming Clinical Trials in HIV/HCV Coinfection

S f b i + RBV GT1/4 i d GT2/3 i / i d ti t 12• Sofosbuvir + RBV: GT1/4 naive and GT2/3 naive/experienced patients, 12-24 weeks

• ABT450/r/ABT-267 + ABT-333 + RBV: TURQUOISE-1 study, GT1 naive/experienced patients, 12-24 weeks

• Daclatasvir + pegIFN lambda + RBV: DIMENSION study, GT1-4 naive patients, 24-48 weeks

• Daclatasvir + asunaprevir + pegINF/RBV: QUADRIH study, GT1/4 nulls, 28 weeks


weeks

• MK-5172 + MK-8742 + RBV: 047 study, GT2,4,5,6 naive patients

Treatment Recommendations

• HIV/HCV patients should have their disease stagedstaged

• Stage >2 patients:• G1 SOF+PEG/RBV 12 weeks or SOF+RBV

for 24 weeks• G2 SOF +RBV for 12 wks• G3 SOF +RBV for 24 wks (Add PEG and


G3 SOF +RBV for 24 wks (Add PEG and decrease to 12 wks if appropriate)

• Stage <2 patients:• Direct to clinical trial or await IFN free regimens


16


Case Presentation

27 yo man from England

• He is MSM HIV+ for 5 yrs normal CD4 count• He is MSM, HIV+ for 5 yrs, normal CD4 count• On HAART (on efavirenz+truvada)

• Living in New York for a work assignment

• Presents for fitness to work exam

• LIT’s abnormal, PCP obtains HCV Ab which is positive


positive

• Denies IV drug use

• Genotype 1a

What would you do?

Ch k IL28B it 3 th d l t• Check IL28B, wait 3 months and re-evaluate

• Obtain a liver biopsy and write pre-approval for SOF/IFN/RBV

• Obtain liver biopsy and refer to ID specialist

• Obtain liver biopsy and refer to clinical trial


Obtain liver biopsy and refer to clinical trial

• Obtain HBV serologies, liver biopsy and refer for tretament


17


Summary

• Liver disease leading cause of morbidity and mortality in HIV/HCV co-infection

• Antiretroviral therapy may slow progression

• HCV screening at HIV diagnosis and at least annually

• HCV treatment considerations• Treat now or wait for future options?• First-generation DAAs complex, long duration, AEs,

DDI


DDIs • New agents may improve outcomes with shorter

therapy, fewer AEs• Consider HCV disease stage and risk of progression

http://www.hcvguidelines.org/



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