Treating hepatitis B and C (in South Africa )

Dr Mark Sonderup

Division of Hepatology and Department of Medicine University of Cape Town & Groote Schuur Hospital

Treatment of Hepatitis B

Evolution of HBV Therapy

Interferon alfa-2b

Lamivudine

Adefovir

Peginterferon alfa-2a

Telbivudine

Tenofovir

1990 1998 2002 2005 2006 2008

Entecavir

Phase Immune Tolerant

Immune Clearance

Immune control

Reactivation

Liver Minimal

inflammation and fibrosis

Chronic active inflammation

Mild hepatitis and minimal

fibrosis

Active inflammation

Yim HJ, et al. Hepatology. 2006;43:S173-S181.

Optimal treatment times

Anti-HBeAg

HBV DNA

ALT activity

Current Understanding of HBV Infection

4 Phases of Chronic HBV Infection

HBeAg

REVEAL Study: Risk of HCC and Cirrhosis

according to baseline HBV viral load

HBV DNA, copies/mL

HC

C (

% p

er Y

r)[1

]

1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

< 300

300-9999

10,000-99,999

100,000-999,999

≥ 1 million

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0

Cir

rho

sis

(% p

er Y

r)[2

]

HBV DNA, copies/mL

< 300

300-9999

10,000-99,999

100,000-999,999

≥ 1 million

3.0

2.5

2.0

1.5

1.0

0.5

0

85 % HBeAg neg

HCC Incidence in TDF Studies Lower Than Predicted by REACH-B Risk Model

• Analysis of actual HCC incidence vs REACH-B predictions in 152 cirrhotic, 482 noncirrhotic pts treated with TDF for 8 yrs in studies 102 (HBeAg-) and 103 (HBeAg+)

• Noncirrhotics: 8 observed cases vs 18 predicted over 7 yrs

– Significant difference from Wk 240: 55% reduction in HCC

• Cirrhotics: observed cases matched prediction over first 4 yrs; no observed cases in last 3 yrs

• Combined analysis: 50% lower HCC incidence at Yr 7

Kim WR, et al. EASL 2013. Abstract 43.

Cu

mu

lati

ve H

CC

Cas

es (

n)

Wk

0 48 96 144 192 240 288 336 0

5

10

15

20

25

30

Predicted Observed

1st significant difference

SIR = 0.50* (95% CI: 0.294-

0.837)

*Statistically significant.

Combined Analysis (Noncirrhotic and Cirrhotic)

Liver Society

Guidelines*

HBeAg Positive HBeAg Negative

HBV DNA,

IU/mL

ALT HBV DNA,

IU/mL

ALT

EASL 2009[1] > 2000 > ULN† > 2000 > ULN†

APASL 2008[2] ≥ 20,000 > 2 x ULN† ≥ 2000 > 2 x ULN†

AASLD 2009[3] > 20,000 > 2 x ULN‡ or

(+) biopsy ≥ 20,000**

≥ 2 x ULN‡ or

(+) biopsy

1. EASL. J Hepatol. 2009;50:227-242. 2. Liaw YF, et al. Hepatol Int. 2008;3:263-283. 3. Lok ASF, McMahon BJ. Hepatology. 2009;50:661-662.

Treatment Criteria for Chronic Hepatitis B HBeAg pos and HBeAg neg Disease

Recommended HBV DNA and ALT levels ± Liver Biopsy

*Although ALT and HBV DNA are primary tests used to determine treatment candidacy, the levels of elevation that warrant consideration of treatment are not universally agreed upon. †Laboratory normal. ‡30 U/L for men and 19 U/L for women. **In patients older than 40 yrs of age, 2000 IU/mL should be considered as a cutoff for treatment.

336 May 2013, Vol. 103, No. 5 SAMJ

GUIDELINE

1. IntroductionHepatitis B is an important public health issue

in South Africa (SA). Prior to the introduction

of the hepatitis B vaccine into the South African

Expanded Programme of Immunisation (EPI) in

1995, prevalence rates of this disease were 0.3 - 15%.[1]

However, unlike countries such as Taiwan,[2] SA has had no catch-up

vaccination programme to ensure complete vaccination coverage. In

addition, the HIV/AIDS pandemic has had a potentially deleterious

influence on the natural history of patients co-infected with HIV and

the hepatitis B virus (HBV).[3]

The spectrum of disease and natural history of chronic HBV

infection is diverse, ranging from a low viraemic immune control state

to progressive chronic hepatitis, with the potential for the ensuing

complications of cirrhosis, liver failure and hepatocellular carcinoma

(HCC). [4] As understanding of the natural history of chronic hepatitis B

increased over the past decade, there have been significant therapeutic

advances. The decision to treat and the choice of therapy is dependent

on both the phase of chronic infection and patient factors.

This guideline draws on the recently published guidelines by

the American Association for the Study of Liver Disease (AASLD),

the European Association for the Study of the Liver (EASL),

the Asia-Pacific Association for the Study of the Liver (APASL),

National Institutes of Health (NIH) and the World Gastroenterology

Organisation (WGO).[5-9] It serves as an attempt to contextualise

practice guidelines on the management of chronic hepatitis B in SA.

2. Pathogenesis and natural history See Table 1. Hepatitis is an enveloped partially double-stranded

DNA virus belonging to the Hepadnaviridae family. It is 100 times

more infectious than HIV and can be transmitted by perinatal,

percutaneous and sexual exposure.[10] Close person-to-person contact

is an important form of transmission, most notably among children

in highly endemic areas, such as in SA.[5,10]

Liver injury due to hepatitis B is mainly caused by cellular immune

mediated mechanisms with cytotoxic T lymphocyte lysis of infected

hepatocytes. The magnitude of the individual’s adaptive cellular

immune response to HBV-related antigens determines the outcome of

acute HBV infection, as well as the degree of liver injury. Chronically

infected patients are unable to sustain an immune response to HBV

and may experience intermittent episodes of hepatocyte destruction in

an attempt to clear virally infected hepatocytes, in what can be termed

‘flares’. Note that, during the acute infection, hepatitis B does not appear

to induce an intra-hepatic innate immune response. Instead, it acts as a

‘stealth’ virus early in the infection.[9]

Age is also an important host factor determining the risk of

chronicity. Following acute exposure to HBV, 90% of neonates born

to hepatitis B ‘e’ antigen (HBeAg)-positive mothers, 20 - 50% of

South African guideline for the management of chronic

hepatitis B: 2013

C W N Spearman,1 MB ChB, FCP (SA), MMed, PhD; M W Sonderup,1,2 MB ChB, BPharm, FCP (SA); J F Botha,2,3 MB ChB, FCP (SA);

S W van der Merwe,4,5 MB ChB, MSc, MMed, PhD; E Song,6,7 MB ChB, FCP (SA), FRCP (London); C Kassianides,8,9 MB ChB, FCP (SA);

K A Newton,2,10 MB ChB, FCP (SA); H N Hairwadzi,1 MB ChB, MMed, PhD

1 Division of Hepatology, Department of Medicine, University of Cape Town, South Africa2 South African Gastroenterology Society, Mowbray, Cape Town, South Africa3 Sandton Clinic, Bryanston, Johannesburg, South Africa4 Department of Immunology, University of Pretoria, South Africa 5 Department of Clinical and Experimental Medicine, University of Leuven, Flanders, Belgium6 Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa 7 Donald Gordon Medical Centre, Johannesburg, South Africa8 Morningside Clinic, Sandton, Johannesburg, South Africa9 Gastroenterology Foundation of South Africa, Mowbray, Cape Town, South Africa10 Department of Gastroenterology, Division of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa

Corresponding authors: C W N Spearman (wendy.spearman@uct.ac.za) and M W Sonderup (msonderup@samedical.co.za)

Hepatitis B remains a significant yet preventable health issue in South Africa. The introduction of the hepatitis B vaccine into the country

some 18 years ago has demonstrated benefit, but the exposure to, and prevalence of chronic HBsAg positivity remain unacceptably high.

Those with chronic hepatitis B virus infection have an elevated risk of developing cirrhosis with end-stage liver disease and a markedly

elevated risk of hepatocellular carcinoma, independent of the presence of cirrhosis.

The challenge in South Africa remains prevention through the universal vaccination coverage of all children and the identification of

those with chronic hepatitis B virus infection. Over the last decade our understanding of hepatitis B and its behaviour and natural history in

those with chronic infection has significantly improved. This understanding is key to identifying those who warrant further evaluation and

therapy. A number of global societies have updated their guidelines in recent years. This document draws on these guidelines and serves to

contextualise, for South Africa, practice guidelines for the management of chronic hepatitis B.

S Afr Med J 2013;103(5):335-349. D OI:10.7196/SAMJ.6452

336 May 2013, Vol. 103, No. 5 SAMJ

GUIDELINE

1. IntroductionHepatitis B is an important public health issue

in South Africa (SA). Prior to the introduction

of the hepatitis B vaccine into the South African

Expanded Programme of Immunisation (EPI) in

1995, prevalence rates of this disease were 0.3 - 15%.[1]

However, unlike countries such as Taiwan,[2] SA has had no catch-up

vaccination programme to ensure complete vaccination coverage. In

addition, the HIV/AIDS pandemic has had a potentially deleterious

influence on the natural history of patients co-infected with HIV and

the hepatitis B virus (HBV).[3]

The spectrum of disease and natural history of chronic HBV

infection is diverse, ranging from a low viraemic immune control state

to progressive chronic hepatitis, with the potential for the ensuing

complications of cirrhosis, liver failure and hepatocellular carcinoma

(HCC). [4] As understanding of the natural history of chronic hepatitis B

increased over the past decade, there have been significant therapeutic

advances. The decision to treat and the choice of therapy is dependent

on both the phase of chronic infection and patient factors.

This guideline draws on the recently published guidelines by

the American Association for the Study of Liver Disease (AASLD),

the European Association for the Study of the Liver (EASL),

the Asia-Pacific Association for the Study of the Liver (APASL),

National Institutes of Health (NIH) and the World Gastroenterology

Organisation (WGO).[5-9] It serves as an attempt to contextualise

practice guidelines on the management of chronic hepatitis B in SA.

2. Pathogenesis and natural history See Table 1. Hepatitis is an enveloped partially double-stranded

DNA virus belonging to the Hepadnaviridae family. It is 100 times

more infectious than HIV and can be transmitted by perinatal,

percutaneous and sexual exposure.[10] Close person-to-person contact

is an important form of transmission, most notably among children

in highly endemic areas, such as in SA.[5,10]

Liver injury due to hepatitis B is mainly caused by cellular immune

mediated mechanisms with cytotoxic T lymphocyte lysis of infected

hepatocytes. The magnitude of the individual’s adaptive cellular

immune response to HBV-related antigens determines the outcome of

acute HBV infection, as well as the degree of liver injury. Chronically

infected patients are unable to sustain an immune response to HBV

and may experience intermittent episodes of hepatocyte destruction in

an attempt to clear virally infected hepatocytes, in what can be termed

‘flares’. Note that, during the acute infection, hepatitis B does not appear

to induce an intra-hepatic innate immune response. Instead, it acts as a

‘stealth’ virus early in the infection.[9]

Age is also an important host factor determining the risk of

chronicity. Following acute exposure to HBV, 90% of neonates born

to hepatitis B ‘e’ antigen (HBeAg)-positive mothers, 20 - 50% of

South African guideline for the management of chronic

hepatitis B: 2013

C W N Spearman,1 MB ChB, FCP (SA), MMed, PhD; M W Sonderup,1,2 MB ChB, BPharm, FCP (SA); J F Botha,2,3 MB ChB, FCP (SA);

S W van der Merwe,4,5 MB ChB, MSc, MMed, PhD; E Song,6,7 MB ChB, FCP (SA), FRCP (London); C Kassianides,8,9 MB ChB, FCP (SA);

K A Newton,2,10 MB ChB, FCP (SA); H N Hairwadzi,1 MB ChB, MMed, PhD

1 Division of Hepatology, Department of Medicine, University of Cape Town, South Africa2 South African Gastroenterology Society, Mowbray, Cape Town, South Africa3 Sandton Clinic, Bryanston, Johannesburg, South Africa4 Department of Immunology, University of Pretoria, South Africa 5 Department of Clinical and Experimental Medicine, University of Leuven, Flanders, Belgium6 Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa 7 Donald Gordon Medical Centre, Johannesburg, South Africa8 Morningside Clinic, Sandton, Johannesburg, South Africa9 Gastroenterology Foundation of South Africa, Mowbray, Cape Town, South Africa10 Department of Gastroenterology, Division of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa

Corresponding authors: C W N Spearman (wendy.spearman@uct.ac.za) and M W Sonderup (msonderup@samedical.co.za)

Hepatitis B remains a significant yet preventable health issue in South Africa. The introduction of the hepatitis B vaccine into the country

some 18 years ago has demonstrated benefit, but the exposure to, and prevalence of chronic HBsAg positivity remain unacceptably high.

Those with chronic hepatitis B virus infection have an elevated risk of developing cirrhosis with end-stage liver disease and a markedly

elevated risk of hepatocellular carcinoma, independent of the presence of cirrhosis.

The challenge in South Africa remains prevention through the universal vaccination coverage of all children and the identification of

those with chronic hepatitis B virus infection. Over the last decade our understanding of hepatitis B and its behaviour and natural history in

those with chronic infection has significantly improved. This understanding is key to identifying those who warrant further evaluation and

therapy. A number of global societies have updated their guidelines in recent years. This document draws on these guidelines and serves to

contextualise, for South Africa, practice guidelines for the management of chronic hepatitis B.

S Afr Med J 2013;103(5):335-349. DOI:10.7196/SAMJ.6452

NIH Guidelines: Indications for HBV

Treatment

Patients for Whom Therapy Is Indicated

Patients who have

- Acute liver failure

- Decompensated cirrhosis

- Cirrhosis or advanced fibrosis and HBV DNA in serum

- Patients who will be receiving cancer chemotherapy or immunosuppressive

therapy

Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

NIH Guidelines: Indications for HBV

Treatment

Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

Patients for Whom Therapy May Be Indicated

• Active liver disease without advanced fibrosis or cirrhosis

- HBeAg pos or HBeAg neg chronic hepatitis B

Patients for Whom Immediate Therapy Is Not Routinely

Indicated

• Immune-tolerant phase (HBeAg pos, high serum HBV DNA levels, normal

ALT or little activity on liver biopsy)

• Inactive carrier or immune control phase (HBeAg neg, low or undetectable

levels of serum HBV DNA, and persistently normal ALT)

• Occult HBV infection (serum HBV DNA pos, IgG core pos, HBsAg neg)

Two Treatment strategies for CHB

Interferon-based therapy

• Dual Antiviral and immunomodulatory activity

• Finite course of treatment

• Aim for sustained off-treatment immune control ( HBsAg +, HBeAg - )

through dual mode of action

Nucleos(t)ide analogue therapy

• Antiviral activity

• Long-term (potentially indefinite) treatment

• Aim for on-treatment viral suppression ( HBV DNA -)

• Maintained through continuous antiviral therapy

• Suppression of replication to undetectable levels to avoid resistance

HBeAg Positive Disease

End-points of treatment

• Ideal end-point sAg loss sAb

• Durable eAg loss and seroconversion

• Durable suppression of HBV DNA to low or undetectable

HBeAg loss and seroconversion in

HBeAg+ Patients after 1 Yr of Treatment

Ou

tco

me

(%)

Lok AS, et al. Hepatology. 2007;45:507-539. Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

Marcellin P, et al. N Engl J Med. 2003;348:808-816. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med.

2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Janssen HL, et al. Lancet. 2005;365;123-129.

HBeAg Loss HBeAg Seroconversion 100

80

60

40

20

0

17-32 21

18 22 12-18 21 21

100

80

60

40

20

0

33 30

-Not head-to-head trials; different patient populations and trial designs

head trials; different patient populations and trial designs

LAM ETV TDF Peg-IFN

LAM ADV ETV TDF Peg-IFN

Lowest HBsAg levels at week 12 are associated

with highest rate of sustained immune control

P<0.0001 for <1500 IU/mL vs higher levels

HBsAg at week 12 (IU/mL)

HB

eA

g s

ero

co

nve

rsio

n

6 m

on

ths

po

st-

tre

atm

en

t (%

)

60

50

40

30

20

10

0 Low

(<1500)

Medium

(1500–20,000)

High

(>20,000)

57%

32%

16%

51/90 72/223 14/86

HBeAg positive patients treated with PEG-IFN-2a +/- lamivudine for 48 weeks

Piratvisuth et al. APASL 2010

HBeAg Negative Disease

End-points of Treatment

• Ideal end-point sAg loss sAb

• Durable suppression of HBV DNA to low or undetectable levels

• NUC therapy long-term as relapse common after stopping treatment

LAM TDF Peg-

IFN *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.

60-73 63

Adapted from Lok AS, et al. Hepatology 2007;45:507-539, Lok AS, et al. Hepatology 2009;50:661-662

93

Virologic response in HBeAg- Patients

(Undetectable* HBV DNA at Wk 48-52) P

ati

en

ts W

ith

Un

dete

cta

ble

HB

V D

NA

(%

)

Not head-to-head trials; different patient populations and trial designs

100

80

60

40

20

0

Undetectable HBV DNA Over Time in

HBeAg-Negative Patients

Extended Treatment With Nucleos(t)ide Analogues vs

Limited Duration (1 Yr) Peginterferon Treatment

Not head-to-head trials; different patient populations and trial designs

Entecavir

Tenofovir

Peginterferon

Un

det

ecta

ble

HB

V D

NA

(%

)

93 87 91

1 Yr 2 Yrs 3 Yrs

100

80

60

40

20

0

63

15 16

*Single center study.

Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455.

Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. APASL 2009. Abstract PE086. Shouval D,

et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481.

HBsAg Loss Over Time in HBeAg

Negative Patients

On Extended Treatment With Nucleos(t)ide Analogues* vs

Limited Duration (1 yr) Peginterferon Treatment

Not head-to-head trials; different patient populations and trial designs

Pati

en

ts (

%)

< 1 0 4

0

100

80

60

40

20

0 < 1

12

NA

Entecavir

Tenofovir

Peginterferon

0 6

1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs

*With sustained undetectable HBV DNA.

Treatment period

HBsAg, more than HBV DNA, can distinguish

between relapsers and responders to PEG-IFN in

HBeAg Negative patients

Moucari et al. Hepatology 2009

Sustained responders (N=12)*

Relapsers (N=18)** Non-responders (N=18)

Treatment period

12 24 48 72 96

1

2

3

4

0

HB

sA

g (

log

IU

/m

L)

Time (weeks)

0 0

Time (weeks)

12 24 48 72 96

1

2

3

4

5

6

7

8

HB

V D

NA

(lo

g co

pie

s/m

L)

0

*HBV DNA undetectable by PCR 1 year post-treatment

**HBV DNA undetectable at EOT but detected in following 24 weeks

To assess and Rx a patient with chronic HBV in 2013 you need the following as a minimum:

1. ALT/AST 2. TBr/albumin/INR 3. HBeAg, eAb 4. HBV viral load 5. US liver 6. Exclude HIV/HCV 7. Access to TDF [LAM] 8. IFN for selected patients

Treatment of Hepatitis C

Definitions : Virological Response

Rapid virological response (RVR) • Undetectable HCV RNA 4 weeks after initiating treatment

Complete early virological response (cEVR) • Undetectable HCV at 12 weeks of treatment

Sustained virological response (SVR) • Undetectable HCV RNA levels at 24 weeks post-treatment

Zeuzem et al. N Engl J Med. 2000.

SVR = Viral Cure

1. Swain MG, et al. Gastroenterology. 2010;139:1593-1601. 2. Giannini EG, et al. Aliment Pharmacol Ther. 2010;31:502-

508. 3. Maylin S, et al. Gastroenterology. 2008;135:821-829. 4. George SL, et al. Hepatology. 2009;49:729-738.

0

20

40

60

80

100

Duration of Follow-up

Pati

ents

Wit

h S

VR

(%

)

3.9 yrs (mean)

3.4 yrs (median)

3.3 yrs (median)

5.4 yrs (median)

99[1] 99[2] 100[3] 100[4]

Nearly 100% of patients who achieve SVR remain undetectable during long-term follow-up[1-4]

At risk 337 261 192 160 124 95 79 49 31 Events 0 5 11 16 20 24 25 28 30 At risk 142 76 48 35 25 14 8 6 5 Events 0 0 0 0 0 1 1 1 1

At risk 337 256 183 155 121 92 74 44 27 Events 0 8 21 24 27 29 31 35 35

At risk 142 76 48 35 25 14 8 6 5 Events 0 0 0 0 0 1 1 1 1

Outcomes in advanced fibrosis with/without a SVR

Liver Failure Liver-Related Death

Live

r-R

ela

ted

De

ath

(%

)

Year

50 5-yr occurrence

SVR: 4.4% (CI: 0% to 12.9%) No SVR: 12.9% (CI: 7.7% to 18.0%) P = .024

Year

5-yr occurrence

SVR: 0% No SVR: 13.3% (CI: 8.4% to 18.2%) P = .001 (log likelihood)

0 8 1 2 3 4 5 6 7

Live

r Fa

ilure

(%

)

50

40

30

20

10

0

0 1 2 3 4 5 6 7 8

No SVR

SVR

40

30

20

10

0

Veldt BJ, et al. Ann Intern Med. 2007;147:677-684

Discovery of HCV genome

Addition of RBV to IFN alfa improved outcomes

Peg-IFN α plus RBV becomes gold standard

Treatment with IFN alfa for 24 or 48 weeks – 3x weekly dosing – Poor outcomes

Peg-IFN mono – once-weekly dosing

2011 1989

Evolution of hepatitis C therapy

Results of HCV Rx : overall SVR rates

6

13

41 39

63

0

10

20

30

40

50

60

70

IFN 24 wk 19981

IFN 48 wk 19981

IFN + RBV

19981,2

PEG-IFN 2000-20023,4,5

PEG-IFN + RBV

2001-20045,6,7

1. McHutchison et al. N Engl J Med. 1998. 2. Poynard et al. Lancet. 1998. 3. Zeuzem et al. N Engl J Med. 2000. 4. Lindsay et al. Hepatology. 2001. 5. Fried et al. N Engl J Med. 2002.

6. Manns et al. Lancet. 2001. 7. Hadziyannis et al. Ann Intern Med. 2004.

Peginterferon α-2a + Ribavirin : SVR According to Genotype

46

76

0

10

20

30

40

50

60

70

80

PegIFN + Ribavirin

Genotype 1 Genotype 2/3

Fried et al. N Engl J Med. 2002.

Predicting an SVR

Viral kinetics : Response guided

therapy

HC

V R

NA

(lo

g 10 IU

/mL)

0

1

2

3

4

5

6

7

8

2 log decline

Limit of detection

Early virological response (EVR): HCV RNA ↓ ≥ 2 logs or Undetectable

at Week 12

EVR

66% SVR

SVR

Weeks

PegIFN/RBV

0 4 12 18 24 30 36 42 48 54 60 66 72 8 78

86% (n=390)

65% (n=253)

SVR

Overall

14% (n=63)

3% (n=2)

EVR is an essential predictor of achieving SVR: 12-week stopping rule

All patients (n=453)

NPV=97%

EVR*

Yes

No

Early virological response = >2 log10 drop in HCV RNA or undetectable at week 12 Ferenci P, et al.

2 log decline

Limit of detection

Weeks

HC

V R

NA

(lo

g 10 IU

/mL)

RVR

90% SVR

0

1

2

3

4

5

6

7

8

Rapid Virological response (RVR): HCV RNA Undetectable at week 4

SVR

PegIFN/RBV

0 4 12 18 24 30 36 42 48 54 60 66 72 8 78

SVR in Patients Who Achieved an RVR Similar Across Genotypes

RVR = HCV RNA negative (<50 IU/mL) at week 4; genotypes 1 and 4, patients were treated for 48 weeks; genotypes 2 and 3 patients were treated for 24 weeks

90 282 257 9 0

20

40

60

80

100

Geno 1 Geno 2 Geno 3 Geno 4

SVR

(%

)

100%

86% 86% 88%

Patients With RVR

n=

HCV negative at week 4 and 12

eRVR = Extended RVR

IL28B

60 M

b

Chromosome 19

A Polymorphism on Chromosome 19 Predicts SVR

Single Nucleotide Polymorphism rs12979860

IL28B gene IFN Lambda-3 gene

3 k

b

19q13.13

Ge D, et al. Nature. 2009;461:399-401.

Americans Americans

12

36

19

50

48

46

38

16

35

0

20

40

60

80

100

European

African Hispanics

Perc

ent

C/C

C/T

T/T

IL28B rs12979860 polymorphism genotype frequency by population

Ge D, et al. Nature. 2009;461:399-401.

0

20

40

60

80

100

TT CT CC

SVR

(%

)

Ge D, et al. Nature. 2009;461:399-401.

n =

Response Rates by IL28B Polymorphism: GT 1 Treated With PegIFN/RBV

IL28B Genetic Variation and Viral Clearance with PEG/RBV

35

20 24

40

22

43

80

43

70

0

10

20

30

40

50

60

70

80

90

European Americans African Americans Hispanics

SVR

(%

± S

EM)

TT

CT

CC

The polymorphism on chromosome 19, rs12979860 (T/T, T/C, or C/C), was strongly associated with SVR in all patient groups.

Ge D, et al. Nature. 2009;461:399-401

IL28B Polymorphisms and Response to PegIFN/RBV by HCV Genotype

Stättermayer AF, et al. Clin Gastroenterol Hepatol. 2011;9:344-350.

100

80

60

40

20

SVR

(%

)

0

41

Genotype 1 Genotype 2/3 Genotype 4

45 50

78

25 32

CC

CT

TT

85 79

88

• CC IL-28B genotype is the strongest pre-Rx predictor of SVR

(OR 5.2; 95% CI, 4.1-6.7)

Thompson et al., Gastroenterology 2010;139:120-9

Predictive value of IL28B

IL28B polymorphisms are not predictive in hepatitis C genotype 5

infected South African patients

Mark W. Sonderup1, Wamda Abuelhassan2, C Wendy Spearman1 1. Department of Medicine and Division of Hepatology, Groote Schuur Hospital and University of Cape Town

2. Department of Gastroenterology, Chris Hani-Baragwanath Academic Hospital, University of the Witwatersrand , Soweto,

Johannesburg.

63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA, USA November 9 - 13 2012

Demographic data of treated patients

Characteristic N = 32

Male, n (%) 18 (56%)

Age (y) mean ± SD Men Woman

53.2±11.5 53.4±10.3

Ethnic group — no. (%) Black Caucasian Mixed Ancestry

17 (53%) 12 (38%) 3 (9%)

Weight — kg median (range)

80 [53 – 130]

22

47

31

IL28B genotype – ethnic distribution

CC

CT

TT

12%

41%

47%

Blacks

CC

CT

TT

33%

58%

8%

Caucasians

CC

CT

TT

0

20

40

60

80

100

RVR cEVR SVR

62%

100%

78%

%

Treatment outcomes

* lower level of detection of HCV is <15IU/ml # RVR = rapid virological response, cEVR = complete early virological response, SVR = sustained virological response and defined as undetectable HCV RNA at the end of a 24-week follow-up period

RVR and IL28B polymorphism genotype

IL28B genotype

OR (95% CI) p- value

CC vs. non CC

1.6 (0.3 – 10.3) 0.58

CT vs. non CT 1.4 (0.3 – 5.9) 0.64

TT vs. non TT 0.4 (0.1 – 2.2) 0.33

SVR and IL28B polymorphism genotype

IL28B genotype

OR (95% CI) p- value

CC vs. non CC

0.6 (0.1 – 4.2) 0.62

CT vs. non CT 2.7 (0.4 – 16.7) 0.28

TT vs. non TT 0.5 (0.1 – 2.9) 0.45

0

10

20

30

40

50

60

70

80

90

100

Caucasian Black

58% 59%

p = NS

Influence of ethnicity on achieving a SVR

SUMMARY : SVR predictive factors

1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. 3. Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355. 4. Nguyen MH, et al. Am J Gastroenterol. 2008;103:1131-1135.

Other factors[1,2,4]

Dose of Peg-IFN Lower body weight (≤ 75 kg)

Dose of RBV Absence of insulin resistance

Female sex Elevated ALT levels (3 x ULN)

Younger age (younger than 40 yrs) Absence of bridging fibrosis or cirrhosis

Ethnicity - non-Black

Major factors[1-3]

Viral genotype (non–genotype 1) Pretreatment HCV RNA

(≤ 600,000 IU/mL)

IL28B allele (C/C vs. T/T) RVR

The Empiric Phase

Weisberg IS, Sigal SH, Jacobson IM. Current Hepatitis Reports. 2007;6:75-82.

•Viral kinetics •Optimal dosing •Special populations •Non-responders •Genomics

The Refinement

Phase

1990-2000 2000-2011

The Evolution of HCV Therapy

DAA – Direct Acting Antivirals: Protease Inhibitors

HCV structure

HCV (NS3) Protease Inhibitors

• Two protease inhibitors approved in 2011 for HCV genotype 1

• Telaprevir (Incivo/Incivek) and Boceprevir (Victrelis)

• As triple therapy in combination with pegylated interferon (PEG) and ribavirin (RBV)

SVR Rates With BOC or TVR + PR According to Treatment History

0

20

40

60

80

100

SVR

(%

)

Naive

63-75

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364: 2405-2416. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364:

2417-2428. Bronowicki JP, et al. EASL 2012.

Relapsers

69-83

Partial Responders

40-59

Null Responders

29-40

> > >

SVR Rates With BOC or TVR in GT1 Treatment-Experienced Patients

0

20

40

60

80

100

SVR

(%

)

Relapsers[1,2] Partial Responders[1,2]

69-83 PegIFN/RBV

1. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 2. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 3. Bronowicki JP, et al. EASL 2012. Abstract 11.

Null Responders[2,3]

BOC or TVR + pegIFN/RBV

24-29

40-59

7-15

29-40

5

PEG/RBV + Telaprevir or Boceprevir SVR: PEG-IFN naïve, GT1a vs. 1b

0

10

20

30

40

50

60

70

80

90

100

GT1a GT1b

0

10

20

30

40

50

60

70

80

90

100

GT1a GT1b

P=PEG-IFN, R=Ribavirin, RGT=Response Guided Therapy

T=Telaprevir, B=Boceprevir

Telaprevir – T12PR Boceprevir – BPR RGT

71

79

63

73

Jacobson I, NEJM 2011; 364: 2405

Zeuzem S, EASL 2011

PEG/RBV + Telaprevir GT1, IFN-experienced

0

10

20

30

40

50

60

70

80

90

100

F 0-2 F 3 F 4 F 0-2 F 3 F 4 F 0-2 F 3 F 4

T12PR

PR

Relapser Partial responder Null responder

SV

R (

%)

Zeuzem S, NEJM 2011; 364: 2417

PEG/RBV + Telaprevir or Boceprevir SVR: GT1, IFN-naïve, IL28B Genotypes

0

10

20

30

40

50

60

70

80

90

100

CC CT TT

0

10

20

30

40

50

60

70

80

90

CC CT TT

P=PEG-IFN, R=Ribavirin, RGT=Response Guided Therapy

T=Telaprevir, B=Boceprevir

T12PR vs. PR BPR RGT vs. PR

90

71 73

82

65 55

Jacobson I, Poordad F

64

25 23

78

28 27

PR

•Regimens With 1 DAA + PegIFN alfa/RBV

•Regimens With 2 DAAs + PegIFN alfa/RBV •IFN-Free Regimens

Faldaprevir* (BI 201335, PI)

Daclatasvir* (BMS-790052, NS5A)

Sofosbuvir* (GS-7977, NI)

Simeprevir* (TMC435, PI)

Vaniprevir (MK-7009, PI)

Daclatasvir + asunaprevir*

Sofosbuvir + RBV

Sofosbuvir + GS-5885 (FDC) ± RBV

Daclatasvir + asunaprevir

ABT-450/RTV + ABT-267 ± ABT-333 ± RBV

Investigational HCV Regimens in Phase III Clinical Trials

•New Interferons

PegIFN lambda-1a + RBV

PegIFN lambda-1a + daclatasvir + RBV

ClinicalTrials.gov.

•Alternative Dosing

TVR BID* (approved PI)

*Studied with pegIFN-α2a. Studied with both pegIFN-α2a and pegIFN-α2b.

Toward a Future of Personalized Medicine for HCV Therapy

Direct-Acting Antivirals

NNI + PI ± RBV

Nuc + RBV PegIFN +

RBV+ DAA Nuc + NS5A

Inh ± RBV Others?

Tertiary Centre Availability/# of patients per annum

Gauteng - CMAH Yes - ±6/year

Gauteng - CHB Yes - 5/year

KZN - IALCH Yes - no limit*

WC - Tygerberg Yes – 5/year

WC - GSH Yes – 6/year

HEPATITIS C Rx – AVAILABILITY OF PEG-IFN- RIBAVIRIN AT TERTIARY CENTRES IN SA

* Quaternary EDL – Peg-IFN/RBV not listed

Tertiary Centre Availability

Gauteng - CMAH No

Gauteng - CHB Yes – Peg-IFN

KZN - IALCH Yes – Peg and Std IFN

WC - Tygerberg No

WC - GSH Only STD IFN

HEPATITIS B Rx – AVAILABILITY OF Std and/or PEG-IFN AT TERTIARY CENTRES IN SA

Tertiary Centre Availability

Gauteng - CMAH Yes

Gauteng - CHB Yes

KZN - IALCH Yes

WC - Tygerberg Yes

WC - GSH Yes

HEPATITIS B Rx – AVAILABILITY OF Tenofovir/Lamivudine

Private sector – HEPATITIS C

• hepatitis C not a “PMB” • variation amongst funders • Discovery Health: ■ only consider funding if on classic/executive series ■ 20% co-payment • Medscheme administered funds: ■ mostly fund – variability on co-pay – usually no co-pay • LIMS – usually don’t consider funding Rx Usually will fund Rx – problems arise with: 1. Funding blood tests whilst on Rx 2. Ability to access GM-CSF (NeupogenR) and EPO if needed

sometimes problematic

Private sector – HEPATITIS B

• hepatitis B not a “PMB”

• Discovery Health: ■ NO funding for IFN or antivirals • Medscheme administered funds: ■ Will consider funding IFN with motivation ■ Antivirals – often not With motivation and appeal – may consider chronic benefits for long term antiviral Rx

Published: 2011/10/03

OPINION: When the private health sector falls short PROPONENTS on both sides of the NHI debate have emphasised improving service at public health facilities, Mark Sonderup, Wendy Spearman and Nathan Geffen write

PROPONENTS on both sides of the National Health Insurance (NHI) debate have emphasised improving service at public health facilities. They are right. Many clinics and hospitals are understaffed and poorly managed, with shortages of essential medicines and equipment. Patients have to wait in long queues. They are lucky if they see a pharmacist for assistance on the correct use of medicines. The reasons for this are many and complex. The fragmented apartheid health system, the poor leadership until 2008 on the HIV/AIDS crisis, under-resourcing and poor management skills have affected the public health system. The skewed distribution of resources between private and public healthcare is a crucial factor.

Medical schemes are the predominant way most private patients finance their healthcare. According to the Council for Medical Schemes, in 2009 there were about 8-million medical scheme beneficiaries — about 17% of the population. However, schemes don’t cover all expenses and many private-sector users have to pay for medical services.

By contrast, 70% of people predominantly use the public health system. According to the Health Systems Trust, per capita health expenditure in the private sector was nearly five-and-a-half times per capita public sector expenditure in 2009. Despite this, schemes do not cover the treatment of many diseases, with many patients falling into the void between the public and private sectors.

Perhaps spurred by the NHI discussions, private health providers are beginning to acknowledge that they need to do more and absorb a greater share of SA’s disease burden.

About two weeks before the release of the NHI green paper, the World Health Organisation marked World Hepatitis day. It passed fairly unnoticed in SA, a country where hepatitis B virus infection is endemic. Chronic hepatitis B infection accounts for about half of all cases of liver cancer in SA. Hepatitis C has a far lower prevalence but can cause chronic liver disease with high morbidity and mortality. Both infections are complicated in people with HIV. It is then ironic that treatments for chronic viral hepatitis are available in the public sector, but access in the private sector is more difficult where chronic viral hepatitis is not a prescribed minimum benefit (PMB).

Treatment of hepatitis C is with pegylated interferon, a medication injected weekly, together with ribavirin, a tablet taken daily. Treatment is expensive, requires specialist care and lasts for 24 or 48 weeks. Nevertheless, a public-sector patient with hepatitis C can access treatment. This is not the case for patients on medical schemes because hepatitis C is not a PMB.

Several schemes do cover the cost of treatment as an ex gratia benefit and patients thus benefit. However, the country's biggest health insurer, Discovery Health, does not. Discovery offers treatment only for hepatitis C on its top two most expensive options and then a substantial co-payment is levied. Even for the well-off, this creates an invidious choice: risk financial ruin or risk morbidity and even death.

Treatment for hepatitis B is also not covered by medical schemes. The exception to this is HIV-positive patients with hepatitis B, as they can readily access antiretroviral therapy, in which two of the drugs used are active against the hepatitis B virus as well.

We therefore have a clear situation in which public-sector patients with hepatitis are better off than private medical scheme ones. This paints a distinctly more complicated picture of the differences in public and private healthcare in SA to the one we usually read about. In this case, the public sector is absorbing a great burden and providing good service, while medical schemes leave patients without care. Not only is private medical care much more expensive but, in this case, it offers less.

Medical schemes such as Discovery must do their share and cover the full cost of chronic viral hepatitis treatment. The Council for Medical Schemes must take steps to ensure that treatment for chronic viral hepatitis becomes a PMB.

These are all opportunities for the private sector to show whether it is interested in doing more to relieve the burden on the public health system or whether it is just making rhetorical noise in response to the perceived threat of NHI.

• Sonderup and Spearman are hepatologists at UCT and Groote Schuur Hospital. Geffen is with the Treatment Action Campaign.

Does the private health sector fall short? Author: Jasson Urbach Date: 10 October 2011

Critics of private health care in SA argue that the private sector does

not do enough, that it dumps patients on the public sector and is only

interested in “money first”. Sonderup, Spearman and Geffen recently

argued in the Business Day article, When the private sector falls

short, 3 Oct. 2011, that medical schemes are evil because they “do

not cover the treatment of many diseases causing many patients to

fall into the void between the public and private sectors”. That “it is

then ironic that treatments for chronic viral hepatitis are available in

the public sector, but access in the private sector is more difficult

where chronic viral hepatitis is not a prescribed minimum benefit

(PMB)”. However, just because a condition is not a PMB, does

not mean medical aids do not cover it. In fact, any legitimate

treatment will be covered subject to the rules of the scheme. The only

difference is that, if the condition is not a PMB, the scheme is not

obliged to pay the doctors in full regardless of what they charge for

their services. Sonderup, Spearman and Geffen then suggest that “The Council for

Medical Schemes must take steps to ensure that treatment for chronic

viral hepatitis becomes a PMB”. The fact that two of the critics in this

case happen to be hepatologists and are arguing that chronic viral

hepatitis should be covered as a PMB is equally ironic. They are

surely arguing in their own self-interest and wish to have viral

hepatitis declared a PMB to enhance their own incomes. It is

government that determines which conditions are included in the list

of PMBs, not medical schemes, and certainly no one individual

scheme. And herein lies an important point. When benefits are

determined politically rather than by medical schemes responding to

what individuals want, the benefit packages expand and their costs

increase.

The consequence is that low cost medical schemes that cover the basic needs of low-income people can no longer be efficiently designed and the unfortunate low income earners are denied cover. It is then that they are driven into “the void between the public and private sector”. Medical schemes are not charities; they are obliged by economic

realities and the interests of the members of their schemes to take

great care in managing available resources. If scheme managers

were to recklessly pay claims that are not included in the agreements

with scheme members they would be guilty of dereliction of duty and

would threaten the solvency and continued existence of the schemes

they are managing. They have to stick to the rules and ensure that

they do not bankrupt the schemes. Eminent economists have declared that because people’s health,

or lack of it, lies largely and increasingly within their own - and

earlier their parents' - control, many, if not most health risks are

actually uninsurable. Risk pooling and intense actuarial and

managerial effort is employed in an attempt to overcome the innate

problems that are consequently bound to face private medical

scheme managers. Theirs is an almost impossible task and

regulatory interventions make their task even more difficult, very often

to the detriment of the majority of medical scheme members. AUTHOR Jasson Urbach is a director of the Health Policy Unit (a

division of the Free Market Foundation). This article may be

republished without prior consent but with acknowledgement to the

author. The views expressed in the article are the author’s and are

not necessarily shared by the members of the Foundation.

HCV parameter Public Sector Private Sector

Diagnostic tools e.g. genotype/VL/biopsy

✔ ✔

Non-invasive fibrosis assessment e.g.

Fibroscan

X X

IL28-B ”✔"

”✔”

Peg-RBV ✔

±✔

DAAs X X

Follow up blood tests on Rx

✔

✔$$

HBV parameter Public Sector Private Sector

Diagnostic tools e.g. VL/biopsy

✔ ✔

Non-invasive fibrosis assessment e.g.

Fibroscan

X X

IFN/Peg-IFN limited

X

TDF/LAM ✔

X

Follow up blood tests on Rx

✔

-

Every doctor/HCW is an activist

"Knowing is not enough, we must apply. Willing is not enough, we must do," Goethe