Prof. Chutima Pramoolsinsap

21 March 2013

Today’s talk

Epidemiology and natural history of HBV/HCV and HCV/HIV co-infection

Clinical scenarios and risk of HCC in HBV/HCV and HCV/HIV co-infection

Guidelines management of of HBV/HCV and HCV/HIV co-infected patients

Optimizing treatment and apropriate antiretroviral regimens for HCV/HIV co-infection

Using fibrosis level to determine treatment-naive, experienced patients, relapsed

previously and nonresponders to peginterferon/ribavirin dual therapy

Drug–drug Interactions between HCV agents and HIV agents

Guidelines for the use of Boceprevir and Telaprevir in HCV/HIV co-infection

New HCV agents and future directions in treating HCV/ HIV co-infection

HBV HCV

Natural history and epidemiology of HBV / HCV co-infection

Because of the shared modes of transmission risk factors of HBV/HCV

coinfection were similar to HBV or HCV monoinfection

High-risk populations: IDU, on hemodialysis, HIV-positive ,ß-thalassemia etc

2 -10% of patients with CH-C have HBsAg positive

5-10% of patients with CH-B have anti-HCV positive

HBV and HCV interact with each other and affect the immune response.

HCV infection can suppress HBV replication mediated by HCV core protein

HBV/HCV co-infected patients had higher rate of HCV RNA clearance as

compared to ones with HCV mono-infection (71% vs 14%)

Annual rate of HBsAg seroconversion 2.08% in HBV/HCV co-infection V.S

0.43% in HBV mono-infection.

Liver injury was more severe in dual infection than in HCV mono-infection

Clinical scenarios of HBV and HCV infection

Simultaneous

coinfection with HBV and HCV

HCV superinfection

HBV superinfection

Occult

HBV infection

in patients with HCV infection

HBV infected patient

HCV infected patient

Uninfected person

HBV + HCV exposure

HCV exposure HBV exposure

Persistent

detectable HBV

DNA in liver or

serum and

undetectable HBsAg in blood

HBV/HCV co-infection is associated with increased risk of HCC

HCC incidence per 100 person years in patients with

HBV/HCV co-infection 6.4

HBV mono-infection 2.0

HCV mono-infection 3.7

Cumulative rate of HCC at 10 years:

HBV/HCV co-infection 45%

HBV mono-infection 16%

HCV mono-infection 28%

Natural history of HBV / HCV co-infection

Risk of HCC among HBV/HCV co-infected subjects in HBV endemic area: a community-based cohort study

Infection status

No. of subjects

Person-years

No. of HCC

HR* (95% CI)

HBsAg(−) / anti-HCV(−) 5744 53,504 16 1.0 (reference)

HBsAg(+) / anti-HCV(−) 335 2,981 15 17.1 (8.4-34.8

HBsAg(−) / anti-HCV(+) 360 3,731 12 10.4 (4.9-22.1)

HBsAg(+) / anti-HCV(+) 14 133 3 115.0 (32.5-407.3)

SI # and 95% CI: 4.5 (1.3-15.5)

* HR: age- and sex-adjusted. # SI: synergy index=(RR11-1)/(RR01+RR10-2), RR11=relative risk of the joint effect of 2 risk factors; RR01 and RR10=relative risk of each risk factor in the absence of the other.

BMC Cancer 2012, 12:452

HCC incidence 79/100,000 person-years (50 incident cases among 6,694 cases within 63,170

person-years, F.U 9.4 years ); seroprevalence of HBsAg and anti-HCV was 5.2% and 5.6%.

Hazard ratios (HRs) of HCC according to HCV infection status and genotype

Anti-HCV

HCV

RNA

HCV

genotype

No. of subjects

No. of HCC

Person-

years

Incidence

(100,000 /person-yr)

HR*

HR**

Negative

6083

31

56,516.3

54.9

1.0 (reference)

1.0 (reference)

Positive Positive 1 52 8 476.5 1,678.9 28.3 29.7

2 84 1 850.7 117.6 2.1 2.2

1 and 2 6 2 51.1 3,913.9 65.0 68.7

Negative 109 2 1045.2 191.4 3.4 2.6

*HR; age- and sex-adjusted. **HR; age-, sex- and HBsAg positivity-adjusted. 236 subjects including 2 HCC cases had no information on anti-HCV, and were excluded from analysis.

BMC Cancer 2012, 12:452

Pooled unadjusted risk estimates for prospective studies and retrospective

studies comparing HCC risk in occult HBV-infected vs non-infected patients

Liver International. 2012;32(2):231-240.

Retrospective studies Prospective studies

non-infected patients occult HBV-infected non-infected patients occult HBV-infected

RRunadjusted=2.44, 95% CI=1.46, 4.01, P=0.001 ORunadjusted=6.08, 95% CI=3.45, 10.72, P<0.001

16/1583 studies; N=3256; 838 (25.7%) had HCC and 863 (26.5%) had occult HBV infection.

Comparing HCC risk in occult HBV /HCV-co-infected patients with

non-infected patients and HCV mono-infection

RR=2.83, 95% CI=1.56–4.10, P<0.001

non-infected patients occult HBV-infected HCV monoinfection occult HBV/HCV-infected

RR 2.86 (95% CI=1.59, 4.13, P<0.001

occult HBV/HCV coinfection vs non-infection occult HBV/HCV co infection vs HCV monoinfection

Liver International. 2012;32(2):231-240.

16/1583 studies; N=3256; 838 (25.7%) had HCC and 863 (26.5%) had occult HBV infection.

HBV HCV

Interferon and ribavirin in Asian patients with HCV/HBV coinfection: Meta-analysis

Virology Journal 2012;9:186

54

76

62

69

37

56

79

64

71

60

0

10

20

30

40

50

60

70

80

90

100

Yu Liu Chuang Hung Liu

HCV-HBV

HCV

Overall SVR (%)

N 50 46 161 160 42 84 36 72 24 30

Total 111 studies, 5 cohort studies, N = 705 patients

Interferon and ribavirin in Asian patients with HCV/HBV coinfection

Virology Journal 2012;9:186

40

72

47 58

44

77 81

52

0

20

40

60

80

100

Yu Liu Chuang Hung

Genotype 1

N 30 25 97 110 21 48 17 34 N 20 21 64 50

75 82

71

50

0

20

40

60

80

100

Yu Liu

Genotype non-1

SVR (%) SVR (%)

Interferon and ribavirin in Asian patients with HCV/HBV coinfection

Virology Journal 2012;9:186

38

9.3

22.2

29

13

8.7

23.6

16.6

0

5

10

15

20

25

30

35

40

45

50

Yu Liu Hung Liu

HCV-HBV

HCV

Overall relapse rate (%)

N 50 46 161 160 36 72 24 30

Interferon and ribavirin in Asian patients with HCV/HBV coinfection

Virology Journal 2012;9:186

Genotype 1

N 30 25 97 110 N 20 21 64 50

20

4

14 8

0

20

40

60

80

100

Yu Liu

Genotype non-1

16 12 12 9

0

20

40

60

80

100

Yu Liu

Relapse rate (%) Relapse rate (%)

Interferon and ribavirin in Asian patients with HCV/HBV

coinfection and HCV monoinfection: a meta-analysis ALT normalization rates achieved at the end of follow up

Virology Journal 2012;9:186

Chung 2005 23 42 51 84 18.1% 0.78 (0.37 - 1.66)

Hung 2006 20 36 52 72 18.2% 0.48 (0.21 - 1.11)

Liu 2009 103 161 122 160 51.9% 0.55 (0.34 – 0.90)

Liu 2009 9 24 18 30 11.8% 0.40 (0.13 – 1.21)

Total (95% CI) 263 346 100% 0.56 (0.40 – 0.90)

Study of HBV / HCV HCV Odd Ratio Odd Ratio

subgroup Events Total Events Total Weights M.H fixed 95%CI M.H fixed 95%CI

Total events 155 243

Heterogeneity. Chi2 = 1.26, df=3 (p=05%)

Test for overall effects: Z = 324 (p=0.001)

0.01 0.1 1 10 100

Favours HBV/HCV Favours HCV

HBV/HCV coinfection have lower serum ALT normalization than those with HCV monoinfection at the end of follow-up (P = 0.001).

Interferon and ribavirin in Asian patients with HCV/HBV

coinfection and HCV monoinfection: a meta-analysis HBVDNA resurgence HCV SVR groups and HCV non-SVR groups in HBV/HCV coninfection

Virology Journal 2012;9:186

Liu 2003 2 9 2 15 20.5% 1.86 (0.21 – 16.18)

5 trials involving 705 patients were analyzed

Chuang 2005 13 29 1 13 13.4% 9.75 (1.12 – 85.16)

hung 2005 4 25 2 11 40.9% 0.86 (0.13 – 5.56)

Yu 2009 9 27 2 23 25.3% 5.25 (1.00 – 27.51)

Total (95% CI) 90 62 100% 3.36 (1.35 – 8.38)

Heterogeneity. Chi = 3.55, df=3 (p=0.31), p = 15%)

Test for overall effects: Z = 260 (p=0.009)

subgroup Events Total Events Total Weights M.H fixed 95%CI M.H fixed 95%CI

Favours HBV/HCV Favours HCV

Study of HBV / HCV HCV Odd Ratio Odd Ratio

0.01 0.1 1 10 100

Total events 28 7

Viral interaction of HBV and HCV in HCV/HBV coinfected patients

The rate of HBV DNA resurgence in HBV/HCV coinfection patients with HCV SVR was significantly

higher than in those without HCV SVR (OR = 3.36, 95% CI: 1.35–8.38, P = 0.009)

SVR and Relapse rate in HBV/HCV co-infection compared with HCV mono-infection

HBV/HCV HCV OR(95% CI)

P

Studies (n)

Sample size

Event (%)

Sample size

Event (%)

SVR 5 313 213 (68) 392 276 (70.4) 0.87 (0.62-1.21)

0.38

HCV relapse 4 270 49 (18.1) 308

42 (13.6) 1.55 (0.98-2.47)

0.06

HCV genotype 1 relapse

2 127 27(21.3) 135 13 (9.6) 2.4 (1.17-4.91)

0.19

HCV non-

genotype 1 relapse

2

84 7(8.3) 71 7 (9.8) 0.9 (0.3-2.71)

0.85

Virology Journal 2012;9:186

PegIFN alfa 2a + ribavirin in patients with HCV/HBV or HCV alone – study design

HC

V-i

nfe

cte

d

pati

en

ts (

N=

160)

72 48 24

HCV genotype 2 or 3

PEGASYS (180 µg/week) +

RBV (1000–1200 mg/day)* (N=110)

PEGASYS (180 µg/week) +

RBV (800 mg/day) (N=50)

HCV genotype 1

0 Weeks *1000 mg/day if body weight <75 kg; 1200 mg/day if body weight ≥75 kg

Follow up

Follow up

Co

infe

cte

d H

CV

/HB

V

pa

tien

ts (

N=

161)

PEGASYS (180 µg/week) +

RBV (1000–1200 mg/day)* (N=97)

PEGASYS (180 µg/week) +

RBV (800 mg/day) (N=64)

HCV genotype 1/HBV

HCV genotype 2 or 3/HBV

Follow up

Follow up

Liu et al. Gastroenterology 2009

Liu et al. Gastroenterology 2009

HBsAg clearance occurred in 10% of cases

However, for patients who had undetectable HBV DNA at baseline, 36% HBV DNA rebound during the treatment period or follow-up.

SVR in HCV/HBV coinfected patients is similar to HCV monoinfection

PegIFN alfa 2a + ribavirin in patients with HCV/HBV or HCV alone

11% (18/143) HBsAg clearance in coinfected patients

Seroconversion to anti-HBs noted in 8/18 cases (44.4%) 6 months post-treatment

Multiple logistic regression analysis : no difference in SVR of HCV RNA with peg-IFN/RBV between dually infected patients and HCV monoinfected patients.

Liu et al. Gastroenterology 2009

Odds ratio

(95% confidence interval)

P

Age, yr 0.99 (0.93–1.05) 0.72

Gender, female vs male 1.10 (0.28–4.39) 0.89

Body weight, kg 0.99 (0.93–1.06) 0.87

Log10HCV RNA 0.67 (0.42–1.09) 0.11

Log10ALT 1.00 (0.99–1.01) 0.80

HCV genotype, 2/3 vs 1 0.62 (0.18–1.12) 0.44

HCV sustained response 1.81 (0.32–10.16) 0.50

HBsAg level IU/mL 0.09 (0.03–0.29) <0.001

PegIFN alfa 2a + ribavirin in HCV/HBV coinfected patients: HBsAg clearance and HBs Ag seroconversion

Liu et al. Gastroenterology 2009

Peg-IFN plus ribavirin treatment trials in HBV/HCV-coinfected patients

Reference

Patients

(n)

HCV SVR

(%)

HBV DNA

negative (%)

HBsAg loss

(%)

HBV #

reactivation (%)

Potthoff, 2008 19 74 33 0 31

Liu, 2009 161 72*, 83** 56 11 35

Senturk, 2008 17 6 na na na

Yu, 2009 50 40*, 75** 100 0 24

*HCV GT1,** HCV GT2/3, na=not applicable, # HBV DNA negative pretreatment

J Hepatol 2008;49:688-94. Gastroenterology 2009:136:496-504. Neth J Med2008;66:191-5. Liver Int 2009;29:1485-93.

HBV reactivation 24-35% in HBV/HCV co-infected patients treated with pegIFN and ribavirin.

Suppression of HCV replication can result in HBV rebound

IFN plus Lamivudine for HBV/HCV Coinfection

8 patients with dually-active HBV and HCV (HBeAg-positive, HBV

DNA-positive or HCV RNA-positive) were treated with 5 MU IFN and

100 mg/day lamivudine for 12 months, followed by lamivudine

alone for 6 months.

SVR for HCV was 50%.

HBeAg clearance in 3/8 patients, 2/8 seroconverted to anti-HBe.

3 patients had clearance of HBV DNA by PCR at EOT, however,

HBV DNA detectable again in 2 patients at end of follow up.

J. Hepatol. 2004; 41: 1064–5.

Months 12 18 24 44

HBV/HCV

Coinfection

N=24

HBV

monoinfection

N=24 1/24(4.2%)

8/17(47%)

0/7 (0%)

HBV DNA (-)

87.5% 95.8% 100%

83.3% 91.6% 100%

Mean HBV-DNA

1.1 × 105 IU/mL

Mean HBV-DNA

4.3 × 105 IU/mL

deterioration in

Child class

17 HBV/HCV RNA (+)

24 HBV

monoinfection

7 HBV/HCV RNA (-)

Oral NA RX

3/24 (12.5 %) HCV reactivation

Tolerability and efficacy of nucleos(t)ide analogues in HBV-DNA-

positive cirrhotic patients with HBV/HCV dual infection.

J Viral Hepat.2012;19(12):890-6

48 HBV-DNA-positive cirrhotic patients treated for at least 2 year

2011 EASL Clinical Practice Guidelines: Management of hepatitis C virus infection

HCV-HBV co-infection

1. Patients should be treated with pegylated IFN-α and ibavirin,

following the same rules as monoinfected patients (B2).

2. If HBV replicates at significant levels before, during or after HCV

clearance, concurrent HBV nucleoside/nucleotide analogue

therapy is indicated (C2).

J Hepatol. 2011;55(2):245-64

2012 APASL consensus: HCV and HBV coinfection management

HBV and HCV coinfected patients may be selected for antiviral treatment by

the same criteria as those used for patients with monoinfection.

Determine which virus is dominant in patients with dual infection before

commencing treatment.

Patients with anti-HCV, HBsAg, and HCV PCR positive, recommend PegIFN/RBV

treatment, 48 weeks for HCV genotype 1 and 24 weeks for HCV genotype 2 or 3

For patients positive both anti-HCV and HBsAg, but have significant levels of

HBV DNA and undetectable serum HCV RNA, peginterferon alfa or nucleos(t)ide

analogs or both can be used.

In HCV/HBV coinfected patients who achieve SVR with PegIFN/RBV treatment,

long-term follow-up and monitoring for relapse of HBV infection are recommended.

Hepatol Int 2012;6:409-435

Prevalence of HIV/HCV coinfection worldwide

33-40 million

130-145 million

4-5 million

HIV HCV

HIV/HCV

Alter MJ. J of Hepatology. 2006

UNAIDS, WHO. 2006 . Hepatobiliary Pancreat Dis Int. 2011; 10: 122-127

Time (years)

Giordano T, et al. Arch Intern Med 2004

Increase HCC in HCV / HIV Co-infection

N= 11,678 HIV-only and 4761 coinfected patients

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

1.8%

2.0%

0 2 4 6 8 10

Cu

mu

lati

ve

In

cid

en

ce

HCV and HIV

HIV-only

Increase in HCC in HCV/HIV Co-infection

1.32 /1000 person-years

Cox multivariate proportional hazards regression model, coinfected patients had

adjusted HR for HCC 5.35 compared with HIV-only (95% CI2.34-12.20; P<.001)

0.20 /1000 person-years

Effect of HIV on the natural history of

hepatitis C virus

HIV / HCV-coinfected persons compared with HCV-monoinfected patients

Less clear HCV after acute infection: 5% vs 14-45%

Higher HCV RNA levels

Higher risk for advanced hepatic fibrosis and cirrhosis

3- to 21-fold increase risk of end-stage liver disease

Risk of HCC

Increases risk of HCC vs HIV-monoinfection (HR 5.35, 95% CI: 2.34–12.20)

comparable to HCV-monoinfection (adjusted HR 0.84, 95% CI: 0.55–1.27)

Higher risk of death: RR 2.26, 95% CI: 1.51–3.38

Predictors of death among HIV / HCV-coinfected patients

Child-Pugh score (HR 1.20, 95% CI: 1.08–1.37)

CD4 < 100 cells/mm3 (HR 2.48, 95% CI: 1.52–4.06)

Hepatic encephalopathy (HR 2.45, 95% CI: 1.41–4.27)

Clin Liver Dis. 2008 Aug;12(3):587-609.

D:A:D: All-Cause and Cause-Specific Mortality Rates Continue to

Decline in the Current Era of Antiretroviral Treatment

D:A:D study, 11 cohorts of HIV-infected persons from Europe, USA, and Australia; 49,734 patients

Cause of death changed over time

Proportion of deaths attributed to AIDS-related causes fell from 34% in 1999-2000 to 22% in 2009-2011

Proportion of deaths attributed to NADM increased from 8% in 1999-2000 to 20% in 2009-2011

Cause of Death, % 1999-2000

(n = 255)

2009-2011

(n = 548)

AIDS 34 22

Liver related 16 9

CVD related 10 10

NADM* related 8 20

Other/unknown 32 39

Weber R, Smith C, D:A:D Study Group. XIX International AIDS Conference; July 22-27, 2012 Washington, DC. Abstract THAB0304

*Non-AIDS–defining malignancies

Higher Risk of Decompensation with HIV/HCV co-infection

Compared to HCV mono-infection Despite ART

4280 HCV/HIV coinfected patients on ART; and 6079 HCV monoinfected patients.

Age averaged 48.3 years in HCV/HIV group and 47.1 in HCV monoinfection group.

HCV-RNA > 400,000 IU/mL 65.2% in HCV/HIV coinfecttion and 55.0% in HCV monoinfection

45% had a pre-ART CD4 < 200.

Median FU. 6.8 years in HCV/HIV coinfection, and 9.9 years in HCV monoinfection group.

XIX International AIDS Conference, July 22-27, 2012, Washington, DC

Outcome HIV/HCV Co-infection (%)

HCV Monoinfection (%)

P-value aHR , 95% CI

Hepatic decompensation

6.3% 5.0% 0.004 1.83, (1.54 -2.18)

Ascites 83% 77% 0.1

Variceal bleeding 26% 55% < 0.001

Liver cancer 1.2% 0.9% 0.25 1.69,(1.13 -2.52)

Severe liver event 7.7% 6.0% 0.001 1.77, (1.52 -2.06)

Mortality 32.9% 15.4% < 0.001

Liver-related death 7.8% 20.1% < 0.001

Pathogenesis in HIV/HCV co-infection

Curr HIV/AIDS Rep. 2011;8: 12-22

HIV/HCV

HIV-Related Microbial Translocation and Progression of Hepatitis C

GASTROENTEROLOGY 2008;135:226–233

DHHS and IAS-USA 2012: Preferred/Recommended First-line ART Regimens

DHHS Guidelines March 2012. Thompson MA, et al. JAMA. 2012;308:387-402.

DHHS IAS-USA

DHHS Guidelines March 2012. Thompson MA, et al. JAMA. 2012;308:387-402.

DHHS IAS-USA

DHHS and IAS-USA 2012: Alternative ART Regimens

Optimizing Treatment of

HCV/HIV-Coinfected Patients

SVR, PEGIFN + RBV vs. IFN + RBV, All Genotypes

Treatment of HIV/HCV-infected patients:

a meta-analysis.

HIV Med. 2007 Jul;8(5):312-21.

6 RCTs, n=1756 patients

OR 2.94 (1.70, 5.08)

SVR, PEGIFN + RBV vs. IFN + RBV, Genotypes 1,4

HIV Med. 2007 Jul;8(5):312-21.

6 RCTs, n=1756 patients

OR 4.38 (2.85, 6.75)

Treatment of HIV/HCV-infected patients:

a meta-analysis.

SVR, PEGIFN+RBV vs. IFN+RBV, Genotypes 2,3

HIV Med. 2007 Jul;8(5):312-21.

6 RCTs, n=1756 patients

OR 2.33 (0.80, 6.77)

Treatment of HIV/HCV-infected patients:

a meta-analysis.

Efficacy of PegIFN plus Ribavirin in HIV/HCV-coinfection

ACTG5071 APRICOT RIBAVIC Laguno PRESCO

Patients (n) 66 289 194 52 389

PEG-INF α 2a 2a 2b 2b 2a

Liver cirrhosis 11% 15% 39% (F3-F4) 19% 28% (F3-F4)

Genotype 1,4 77% 67% 61% 63% 61%

Mean CD4+ 495 520 477 570 546

HAART 85% 83% 83% 94% 74%

Discontinuation

rate due to AE*

12% 25% 17% 17% 9%

Discontinuation

rate due to

other reasons

- 31% 39% 23% 7%

SVR (ITT)** 27% 40% 27% 44% 50%

*adverse events, **intent-to-treat analysis

N Engl J Med 2004; 351:438–50. AIDS Res Hum Retrovir 2007, 23: 972-82. Hepatology 2009;49;1335-74.HIV Clin Trials 2012; 13:142–52

HCV Treatment in HIV/HCV- coinfected Patients

Combination pegylated interferon plus ribavirin for 48 weeks represents

the standard of care for treating chronic HCV in HIV-infected individuals.

SVR rates are lower than HCV-monoinfected patients in

HCV genotype 1 = 42%–52%

HCV genotypes 2 and 3 = 78%–84%

Possible reasons for the poorer SVR rates among HIV/HCV-coinfected

patients include

High HCV RNA levels

Qualitative defects in cellular and innate immune response Lower doses of ribavirin or dose escalation administered in

the treatment trials

HIV/HCV coinfected patients with advanced HIV disease (CD4 count<100/lL)

should receive HAART, with HCV treatment delayed until immune function is

improved, until CD4 count > 200/lL is achieved (I).

ART in naive HIV/HCV coinfected patients with CD4 count 100–350/lL should

commence HAART prior to HCV treatment (I).

HIV/HCV coinfected patients with CD4 > 350/lL should be considered for HCV

treatment and do not require HAART (I).

PegIFN / RBV combination therapy for 48 weeks for HCV treatment;

weight-based ribavirin dosing for HCV genotype 1 patients (I).

Undetectable HCV RNA at week 4 of treatment is the best predictor of SVR in

HCV/HIV coinfected patients. Extending PegIFN / RBV treatment beyond 48

weeks may not improve the overall treatment outcomes.

2012 APASL consensus: HIV and HCV coinfection management

Hepatol Int 2012;6:409-435

Deferral of HCV treatment should be considered in HIV/HCV coinfected

patients with HCV genotype 1 and high viral load (>800,000 IU/mL) if early

liver disease (F0/1) is detected on liver biopsy (I).

Insufficient evidence to support administration of HCV treatment to patients

with persistently normal ALT levels, but treatment could be considered in

those with moderate or severe fibrosis (II-2).

SVR to PegIFN/RBV therapy reduces liver-related complications and mortality

in HCV/HIV coinfected patients.

Didanosine, zidovudine, and stavudin should be avoided if the HCV

treatment regimen includes ribavirin.

IL28B gene variations may independently predict SVR in HCV/ HIV coinfected patients with genotype 1 as in HCV monoinfection

Hepatol Int 2012;6:409-435

2012 APASL consensus: HIV / HCV coinfection management

HIV-HCV coinfection

Indications for HCV treatment are identical to those in patients with HCV monoinfection (B2).

The same pegylated IFN-a regimen should be used in HIV/HCV co-infected patients as in patients without HIV infection, but ribavirin should always be weight-based dosed (B2).

Longer treatment duration (72 weeks for genotype 1 and 48 weeks for genotypes 2 and 3) may be needed (B2).

2011 EASL Clinical Practice Guidelines: Management of HIV / HCV coinfection

J Hepatol. 2011;55(2):245-64

European AIDS Clinical Society guidelines for use of Peginterferon/ribavirin therapy in HCV/HIV coinfected patients

European AIDS Clinical Society HIV treatment guidelines, version 6.0.

HCV RNA negative

HCV RNA positive

Genotype 2/3

Genotype 1/4

> 2 log drop

in HCV RNA

< 2 log drop

in HCV RNA

HCV RNA negative

HCV RNA positive

Genotype 2/3

Genotype 1/4

48 wks of therapy

72 wks of therapy

Stop

Stop

*In patients with baseline low HCV RNA and minimal liver fibrosis

24 wks of Therapy*

WK 4 WK 12 WK 24 WK 48 WK 72

Multivariate Analysis of Baseline Predictors of

SVR to PegIFN/RBV

ITT analysis of patients from IDEAL study (genotype1HCV) who consented to genetic

testing, regardless of adherence level(n=1604), and 67 patients from another trial

Race based on self-report, similar to clinical practice setting

Thompson AJ, et al. Gastroenterology. 2010;139:120-129.

Predictor Adjusted Odds Ratio (95% CI) P Value

IL28B rs12979860 CC 5.2 (4.1-6.7) < .0001

HCV RNA level ≤ 600,000 IU/mL 3.1 (2.3-4.1) < .0001

White vs black 2.8 (2.0-4.0) < .0001

Hispanic vs black 2.1 (1.3-3.6) .0041

METAVIR F0-F2 2.7 (1.8-4.0) < .0001

Fasting blood sugar < 5.6 mmol/L* 1.7 (1.3-2.2) < .0001

*100.8 mg/dL.

IL28B Genotype Predicts Likelihood of

Achieving SVR

Recommendation: IL28B genotype testing may be considered prior to therapy if

more information about probability of response or treatment duration desired

1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

SPRINT-2: BOC + PR48[1]

SV

R (

%)

44/

55

82/

115

26/

44

CC CT TT

80

100

80

60

40

20

0

71

59

n/

N =

ADVANCE: T12PR48*[2]

SV

R (

%)

45/

50

48/

68

16/

22

CC CT TT

90 100

80

60

40

20

0

71 73

n/

N =

IL28B Genotype Predicts Likelihood of SVR With Triple Therapy

*IL28B testing in ADVANCE was in whites only.

IL28B Genotype Predicts Likelihood of

Eligibility for Shortened Therapy

Recommendation: IL28B genotype testing may be considered prior to therapy if

more information about probability of response or treatment duration desired

1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

SPRINT-2: BOC + PR[1]

Eli

gib

ilit

y f

or

RG

T (

%)

118/

132

158/

304

CC CT/TT

89 100

80

60

40

20

0

52

ADVANCE: T12PR*[2]

Eli

gib

ilit

y f

or

RG

T (

%)

39/

50

39/

68

10/

22

78

100

80

60

40

20

0

57

45

n/

N =

IL28B Genotype Predicts Likelihood of Short-Duration Therapy

*IL28B testing in ADVANCE was in whites only.

CC CT TT

n/

N =

New HCV agents and future directions

in treating patients with

HCV/HIV coinfection

Phases of therapeutic development for HCV treatment and the associated complexity of clinical management.

pegIFN+RBV

2010 2011 2012 2013 2014 2015

Treatment complexity

pegIFN+RBV+ DAA

New Standard of Care for Genotype 1 HCV

Treatment-Naive Patients

BOC + PegIFN + RBV

48 0 28 12 4

PegIFN + RBV

PegIFN + RBV

8 36

BOC + PegIFN + RBV

24

Early response*; stop at Wk 28; f/u 24 wks

F/u 24 wks

Boceprevir[1,2]

TVR + PegIFN + RBV

48 0 24 12 4

eRVR†; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u

24 wks

Telaprevir[2,3]

1. Boceprevir [package insert]. May 2011.

2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

3. 3. Telaprevir [package insert]. May 2011.

Recommendation: Optimal treatment for all genotype 1 treatment-naive patients is BOC or TVR + pegIFN/RBV

BOC and TVR should not be used without pegIFN/RBV

*Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy). †Undetectable HCV RNA at Wks 4 and 12 of triple therapy.

No eRVR; PegIFN + RBV

Telaprevir + PegIFN/RBV in GT1 HCV Tx-Naive

HCV/HIV Coinfected Patients

Multicenter, randomized, double-blind, placebo-controlled phase II trial

Placebo +

PegIFN/RBV

Placebo +

PegIFN/RBV

PegIFN/RBV

(n = 16)

Part B: Stable ART

HCV/HIV-coinfected patients on

stable ART,*

CD4+ cell count ≥ 300 cells/mm3,

HIV-1 RNA ≤ 50 copies/mL

(N = 47)

Follow-up

Part A: No Current ART

HCV/HIV-coinfected patients,

CD4+ cell count ≥ 500 cells/mm3,

HIV-1 RNA ≤ 100,000 copies/mL

(N = 13)

Follow-up

PegIFN/RBV

(n = 6)

PegIFN/RBV

(n = 7)

TVR† 750 mg

q8h +

PegIFN/RBV

PegIFN/RBV

(n = 31)

Wk 12 Wk 48 WK 72

(SVR24)

Wk 60

(SVR12)

TVR† 750 mg

q8h +

PegIFN/RBV

Sulkowski MS, et al. AASLD 2012. Abstract 54.

*Either EFV/TDF/FTC or ATV/RTV + TDF + (FTC or 3TC). †TVR dose increased to 1125 mg q8h with EFV.

SVR24 with TVR + PegIFN/RBV in

Genotype1 HCV/HIV Coinfected Patients

Higher SVR24 rate with TVR-based therapy

No significant drug–drug

interactions with TVR and ART

TVR plasma levels similar in

patients with or without ART

EFV and ATV/RTV plasma

levels similar in patients with

or without TVR

No HIV breakthroughs in patients

using ART during HCV treatment

Safety and tolerability similar to

treatment in patients with HCV

monoinfection

Telaprevir + PR Placebo + PR

74 71 69

80

45

33

50 50

0

20

40

60

80

100

28/

38

10/

22 5/

7

2/

6

11/

16

4/

8

12/

15

4/

8

SV

R2

4 (

%)

n/N =

Sulkowski MS, et al. AASLD 2012. Abstract 54.

Phase II Study of BOC + PegIFN in

HCV/HIV-Coinfected Individuals

pegIFN/RBV*

Lead-in (N=64)

pegIFN/RBV*

Lead-in (N=34)

Placebo**/

pegIFN/RBV* (N=34)

Boc** +

pegIFN/RBV*

Lead-in (N=64)

*pegIFN 1.5 ug/kg/wk; ribavirin 600-1400 mg/day

** Boceprevir 800 mg x 3 daily

*** patients in placebo arem with HCV RNA> lower limit of quantification at wk 24 eligible to receive open-lable boceprevir plus pegIFN/RBV

Randomized 2:1; stratified by

cirrhosis/fibrosis and HCV RNA (< vs > 800,000 IU/mL)

HCV/genotype 1

HCV-coinfected

Patients naïve to

HCV treatment,

Receiving ART (N=98)

Wk4 Wk48 Wk72

Follow-up

Mallolas J, et al. EASL 2012. Abstract 50.

BOC + PegIFN in HCV/HIV co-infected Patients:

SVR12 Interim Analysis

Mallolas J, et al. EASL 2012. Abstract 50.

60.7

26.5

0

10

20

30

40

50

60

70

80

90

100

Boc/PR PR

*3 patients had not yet reached SVR12 time period

SVR12 (%)

Boc/pegIFN/RBV

pegIFN/RBV

Futility Rules for BOC or TVR + PegIFN/RBV in

Treatment-Naive Patients

1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

3. Telaprevir [package insert]. May 2011.

Recommendation: All therapy should be discontinued in patients with the following:

Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA

detection of approximately 10-15 IU/mL.

BOC[1,2]

Time Point Criteria Action

Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue all therapy

TVR[1,3]

Time Point Criteria Action

Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue pegIFN/RBV

Drug-drug interaction with TVR

Darunavir AUC decreased by 40%

Fosamprenavir AUC decreased by 47%

Lopinavir AUC was unchanged

Atazanavir AUC decreased by 17%

Conversely, HIV PIs significant reduce TVR concentrations

( AUC decreased by 20%–54%), with the smallest impact with atazanavir.

Efavirenz led to 20% reduction in AUC of TVR, use higher dose of

TVR 1125 mg every 8 hours in combination with efavirenz

Drug-drug interaction TVR and ART

BOC coadministered with efavirenz, concentration of efaviren increased,

concentration of BOC reduced.

BOC reduced concentration of ritonavir-boosted atazanavir, lopinavir, and

darunavir by 49%, 43%, and 59%, respectively.

Lopinavir/ritonavir and ritonavir-boosted darunavir decreased AUC of BOC

by 45% and 32%, respectively.

8 February 2012, FDA warning drug interactions between BOC and ritonavir-

boosted atazanavir, lopinavir, and darunavir reduce effectiveness when used

together.

Patients receiving other ART regimens may use BOC if switch to raltegravir

plus NRTIs for HIV treatment

Drug-drug interaction BOC and ART

DHHS Guidelines for the use of Boceprevir and Telaprevir in HCV/HIV-Coinfected Patients

Patient groups Recommendation

Patients not on ART: Use either BOC or TVR

Patients receiving raltegravir + 2-NRTI Use either BOC or TVR

Patients receiving atazanavir/ritonavir +2-NRTI: Use TVR at standard dose. Do not use BOC

Patients receiving efaviren + 2-NRTI Use TVR at increased dose

1125 mg every 7–9 hours. Do not use BOC

DHHS; US Department of Health and Human Services

NRTI; nucleoside reverse transcriptase inhibitors

Boceprevir (BOC), Telaprevir (TVR)

http://aidsinfo.nih.gov/guidelines

HHS Panel on Antiretroviral Guidelines

OARAC Guidelines for HIV/HCV coinfection

ddI should not be given with RBV because of potential for drug-drug

interactions, ddI-associated mitochondrial toxicity: hepatomegaly/steatosis,

pancreatitis, and lactic acidosis (AII).

Combined use of ZDV and RBV increased rates of anemia, making RBV dose

reduction necessary. Therefore, this combination should be avoided.

Risk of anemia may further increase when BOC or TVR is combined with

PegIFN/RBV, ZDV should not be given with this combination (AIII).

Abacavir (ABC) associated with decreased response to PegIFN/RBV in some,

but not all, due to impairment of RBV phosphorylation by abacavir. current

evidence is insufficient to recommend avoiding this combination

http://aidsinfo.nih.gov/guidelines

Working Group of the Office of AIDS Research Advisory Council (OARAC)

Newly Dx HCV genotype 1

Transient elastography (if available) and/or serum marker and/or liver biopsy

F 0/1 #

Treatment can deferred.

Consider pegIFN/RBV/PI

or pegIFN/RBV alone if

• low HCV RNA

• IL 28B CC genotype

• Absence of insulin resistance • High CD4+ cell count

Management of newly diagnosed genotype 1 HCV/HIV-coinfected patients

F 2/3 #

Treatment with

pegIFN/RBV and

Protease inhibitor

Treatment with

pegIFN/RBV/PI

If compensated disease;

Treatment should be

undergone in specialzed centers

# Metavir fibrosis score: F0 = no fibrosis, no septae; F2 = portal fibrosis, few septae; F3 = bridging fibrosis; F4 = cirrhosis

F 4 #

Liver Int. 2012

Limited efficacy with TVR and BOC in some patient groups

1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

5. Bronowicki J, et al. EASL 2012. Abstract 11. 6. Zeuzem S, et al. EASL 2011. Abstract 5.

0

20

40

60

80

100

SV

R (

%)

Relapser Naive

White/

Nonblack

Null

Responder

Naive

Black

Partial

Responder

Cirrhotic

Null

Responder

68-75[3,4]

53-62[3,4]

*Pooled TVR arms of REALIZE trial.

75-83[1,2]

40-59[1,2]

29-40[1,5]

14[6]*

42-62[3,4]

Naive

Cirrhotic

Treatment Naive

Previous Relapser

Previous Non-responder

F 0/1 Individual decision Individual decision/ Triple therapy

Defer

F 2/3 Triple therapy Triple therapy Defer*

F 4 Triple therapy Triple therapy Triple therapy

Management of geotype 1 HCV/HIV-coinfected patients according to fibrosis stage and previous treatment outcome

* Monitor fibrosis stage annually, preferably with 2 established methods.

Treat with triple therapy, if rapid progression

Liver Int. 2012

Phases of therapeutic development for HCV treatment and the associated complexity of clinical management.

pegIFN+RBV

2010 2011 2012 2013 2014 2015

Treatment complexity

pegIFN+RBV+ DAA

DAA combination

HCV Treatment with DAA Combination

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor binding

and endocytosis

Fusion and

uncoating

Transport

and release

(+) RNA

Translation and

polyprotein

processing

RNA replication

Virion

assembly

Membranous

web

ER lumen

LD

LD

ER lumen

LD

NS3/4

protease

inhibitors

NS5B polymerase

inhibitors

Nucleoside/nucleotide

Nonnucleoside

*Block replication complex formation, assembly

NS5A* inhibitors

HCV protease inhibitors resistance

Short-term resistance potential following PI exposure is greater for HCV than HIV

Low-fidelity HCV RNA–dependent RNA polymerase, combined with high

numbers of virions generated per day

Challenging structural characteristics of the HCV protease active site.

Estimated error rate of HCV RNA polymerase is 10−4 substitutions/ base / year

and 10-fold higher than that of HIV reverse transcriptase;

Combined with a virion production rate 100-fold higher than that of HIV,

suggests that resistant HCV variants are more likely to preexist and rapidly

outgrow wild-type virus under drug selective pressure

Summary data from phase III trials of BOC and TVR found resistance variants

53% and 74% of all subjects without SVR, respectively

JID 2013;207 (Suppl 1):S33-39

In treatment-naive subjects, rates of viral breakthrough/failure are similar for

TVR and BOC range from 5% to 15%

Sequencing of breakthrough viral isolates reveals universal presence of high–

fold-change drug-resistant variants, ie R155K-V36M double mutant in genotype

1a and A156T/V mutant in genotype 1b

Removal of RBV from treatment regimen results in increased viral breakthrough

24% with TVR plus PegIFN

Low-dose RBV (400–1000 mg) with BOC, resulted in virologic breakthrough 27%

vs 4%–12% with weight-based RBV dosing (600–1400 mg)

Poor response to lead-in therapy (<1 log10 decrease HCV RNA), resulted in 47%

resistance rate in treatment-naive subjects, vs. only 4% resistance rate in those

with a >1 log10 increase in HCV RNA load

HCV protease inhibitors resistance

JID 2013;207 (Suppl 1):S33-39

Antiviral Resistance and the Future Landscape of HCV Infection Therapy

Addition of HCV protease inhibitors (PIs) to PegIFN /RBV therapy has significantly improved

efficacy of HCV treatment.

However, for patients who do not respond to therapy, selection of HCV variants with

resistance to PIs is likely.

Resistant variants, i.e. R155K, A156T/V, result in extensive cross-resistance to other HCV PIs.

Despite rapid and frequent appearance of PI-resistant HCV variants, long-term clinical

implications are unknown.

Development of other HCV antivirals, i.e. NS5A inhibitors, next-generation NS3 protease

inhibitors, and NS5B nucleoside and nonnucleoside inhibitors, has provided a broad selection of potent antivirals such that IFN-free therapy is a reality

JID 2013;207 (Suppl 1):S33-39

Direct-Acting Antiviral Agents Currently in Phase 3 Trials (IFN free regimen)

Drug Type of agent

Genotype

Response in phase II

trials

Anticipated

completion of phase III trials

BI 20712715 NS5B inhibitor

(combination with

faldaprevir)

1 52%–69% SVR 12 in

treatment naive

August 2015

Asunaprevir (BMS 650032)

Protease inhibitor

(combination with

daclatasvir)

1 63%–87% SVR 4 in null

responders

July 2014

Sofosbuvir (GS 7977)

Nucleotide polymerase inhibitor

2,3 100% SVR in naive

July 2013

ABT-450/r, ABT

267, ABT-33321

Protease inhibitor,

NS5A inhibitor, non-

nucleoside polymerase

inhibitor

1 SVR 85%–99% in

naive/null responders

October 2014

Gatroenterology 2013;144:482–485

Summary: Present and Future Treatment in

HIV/HCV- Coinfected Patients

HCV is worse in HIV/HCV

Standard treatment with PegIFN/RBV for 48 wks has low rates of SVR.

High rates SVR of HCV-G1 treated with TVR or BOC combination with PegIFN/RBV.

ART regimen may need to be modified to reduce potential for drug-drug interactions

and/or drug toxicities

HAART favorably affects course of HCV in HIV-infected patients, decreases rate

of death attributable to liver disease, and should not be withheld because of fears

regarding toxicity. Treat based on individual benefits vs. risks

o Be aware of HAART interactions

o Patient must be committed to birth control

o Be alert to toxicities

Novel HCV treatment regimens by 2014, some experts recommend deferral HCV

treatment in HIV/HCV-coinfected patients with minimal hepatic fibrosis

Vaccinate all co-infected patients against HAV and HBV if seronegative

Thank you