Treating hepatitis B&C in South Africa

Report
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
Peginterferon alfa-2a
Entecavir
Lamivudine
1990
Interferon alfa-2b
1998
2002
Adefovir
2005
Tenofovir
2006
Telbivudine
2008
4 Phases of Chronic HBV Infection
Current Understanding of HBV Infection
HBeAg
Anti-HBeAg
ALT activity
HBV DNA
Phase
Liver
Immune
Tolerant
Immune
Clearance
Immune
control
Minimal
inflammation
and fibrosis
Chronic active
inflammation
Mild hepatitis
and minimal
fibrosis
Reactivation
Optimal treatment times
Yim HJ, et al. Hepatology. 2006;43:S173-S181.
Active
inflammation
REVEAL Study: Risk of HCC and Cirrhosis
according to baseline HBV viral load
HBV DNA, copies/mL
HCC (% per Yr)[1]
1.2
1.0
0.8
0.6
0.4
< 300
300-9999
10,000-99,999
100,000-999,999
≥ 1 million
3.0
2.5
Cirrhosis (% per Yr)[2]
1.4
HBV DNA, copies/mL
2.0
< 300
300-9999
10,000-99,999
100,000-999,999
≥ 1 million
1.5
1.0
0.2
0.5
0
0
85 % HBeAg neg
1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
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
Combined Analysis
(Noncirrhotic and Cirrhotic)
30
Cumulative HCC Cases (n)
•
Predicted
Observed
25
20
15
SIR = 0.50*
(95% CI: 0.2940.837)
1st significant
difference
10
5
0
0
48
96 144 192 240 288 336
Wk
*Statistically significant.
Kim WR, et al. EASL 2013. Abstract 43.
Treatment Criteria for Chronic Hepatitis B
HBeAg pos and HBeAg neg Disease
Recommended HBV DNA and ALT levels ± Liver Biopsy
HBeAg Positive
Liver Society
Guidelines*
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†
> 20,000
> 2 x ULN‡ or
(+) biopsy
≥ 20,000**
≥ 2 x ULN‡ or
(+) biopsy
AASLD
2009[3]
*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.
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.
SAfr Med J2013;103(5):335-349. DOI:10.7196/SAMJ.6452
GUIDELINE
1. Introduction
Hepatitis B is an important public
South African guideline for the management of chronic
in South Africa (SA). Prior to the i
hepatitisB: 2013
of the hepatitis B vaccine into the So
C W N Spearman, MB ChB, FCP (SA), MM ed, PhD; M W Sonderup, MB ChB, BPharm, FCP (SA); JF Botha, MB ChB, FCP (SA);
Expanded Programme of Immunisatio
S W van der Merwe, MB ChB, MSc, MMed, PhD; E Song, MB ChB, FCP (SA), FRCP (London); C Kassianides, MB ChB, FCP (SA);
K A Newton, MB ChB, FCP (SA); H N Hairwadzi, MB ChB, MMed, PhD
1995, prevalence rates of thisdisease wer
[2]
Division of Hepatology, Department of Medicine, University
of Cape Town,unlike
South Africa
However,
countries
such
as
Taiwan,
SA has had
South African Gastroenterology Society, Mowbray, Cape Town, South Africa
Sandton Clinic, Bryanston, Johannesburg, South Africa vaccination programme to ensure complete vaccination
Department of Immunology, University of Pretoria, South Africa
Department of Clinical and Experimental Medicine, University
of Leuven,the
Flanders,
Belgium
addition,
HIV/AIDS
pandemic has had a potentially
Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
influence on the natural history of patients co-infected w
Donald Gordon Medical Centre, Johannesburg, South Africa
Morningside Clinic, Sandton, Johannesburg, South Africa
hepatitis
B virus (HBV).[3]
Gastroenterology Foundation of South Africa, Mowbray,the
Cape Town,
South Africa
Department of Gastroenterology, Division of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa
The spectrum of disease and natural history of ch
Corresponding authors: C W N Spearman ([email protected]) and M W Sonderup ([email protected])
infection is diverse, ranging from a low viraemic immune
to progressive chronic hepatitis, with the potential for
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 thecomplications
exposure to, and prevalence
chronic HBsAgliver
positivityfailure
remain unacceptably
high.
of ofcirrhosis,
and hepatocellula
Those with chronic hepatitis B virus infection have an elevated risk of developing cirrhosis with end-stage liver disease and a markedly
[4] of cirrhosis.
elevated risk of hepatocellular carcinoma, independent
of the presence
(HCC).
Asunderstanding of thenatural history of chron
1
1,2
4,5
2,10
1
2
3
4
5
6
7
8
9
10
6,7
1
2,3
8,9
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
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)
Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.
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
Outcome (%)
-Not head-to-head trials; different patient populations and trial designs
head trials; different patient populations and trial designs
HBeAg Loss
HBeAg Seroconversion
100
100
80
80
60
60
40
17-32
33
21
20
0
LAM
ETV
18
TDF
40
20
PegIFN
0
22
LAM
12-18
21
21
ADV
ETV
TDF
30
PegIFN
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.
Lowest HBsAg levels at week 12 are associated
with highest rate of sustained immune control
HBeAg positive patients treated with PEG-IFN-2a +/- lamivudine for 48 weeks
HBeAg seroconversion
6 months post-treatment (%)
60
57%
50
40
32%
30
20
16%
10
0
51/90
72/223
14/86
Low
(<1500)
Medium
(1500–20,000)
High
(>20,000)
HBsAg at week 12 (IU/mL)
P<0.0001 for <1500 IU/mL vs higher levels
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
Virologic response in HBeAg- Patients
(Undetectable* HBV DNA at Wk 48-52)
Patients With Undetectable
HBV DNA (%)
Not head-to-head trials; different patient populations and trial designs
93
100
80
60-73
63
60
40
20
0
LAM
TDF
PegIFN
*By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.
Adapted from Lok AS, et al. Hepatology 2007;45:507-539, Lok AS, et al. Hepatology
2009;50:661-662
Undetectable HBV DNA Over Time in
HBeAg-Negative Patients
Not head-to-head trials; different patient populations and trial designs
Extended Treatment With Nucleos(t)ide Analogues vs
Limited Duration (1 Yr) Peginterferon Treatment
Undetectable HBV DNA (%)
100
93
80
91
87
Entecavir
Tenofovir
Peginterferon
63
60
40
20
15
16
0
*Single center study.
1 Yr
2 Yrs
3 Yrs
HBsAg Loss Over Time in HBeAg
Negative Patients
Not head-to-head trials; different patient populations and trial designs
100
On Extended Treatment With Nucleos(t)ide Analogues* vs
Limited Duration (1 yr) Peginterferon Treatment
Patients (%)
80
Entecavir
Tenofovir
Peginterferon
60
40
20
0
<1 0
4
1.0 Yr
<1 0
12
6
1.5-2.0 Yrs
NA 0
3.0-4.0 Yrs
*With sustained undetectable HBV DNA.
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, more than HBV DNA, can distinguish
between relapsers and responders to PEG-IFN in
HBeAg Negative patients
Sustained responders
(N=12)*
8
Relapsers (N=18)**
Non-responders (N=18)
4
HBsAg (log IU/mL)
HBV DNA (log copies/mL)
7
6
5
4
3
2
3
2
1
1
Treatment period
0
0
12
24
48
72
Time (weeks)
0
96
Treatment period
0
12
24
48
72
Time (weeks)
96
*HBV DNA undetectable by PCR 1 year post-treatment
**HBV DNA undetectable at EOT but detected in following 24 weeks
Moucari et al. Hepatology 2009
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
 Nearly 100% of patients who achieve SVR remain undetectable
during long-term follow-up[1-4]
Patients With SVR (%)
100
99[1]
99[2]
100[3]
100[4]
80
60
40
20
0
3.9 yrs
(mean)
3.4 yrs
3.3 yrs
(median)
(median)
Duration of Follow-up
5.4 yrs
(median)
1. Swain MG, et al. Gastroenterology. 2010;139:1593-1601. 2. Giannini EG, et al. Aliment Pharmacol Ther. 2010;31:502508. 3. Maylin S, et al. Gastroenterology. 2008;135:821-829. 4. George SL, et al. Hepatology. 2009;49:729-738.
Outcomes in advanced fibrosis
with/without a SVR
50
50
5-yr occurrence
40
SVR:
No SVR:
30
4.4% (CI: 0% to 12.9%)
12.9% (CI: 7.7% to 18.0%)
P = .024
20
10
0
5-yr occurrence
40
SVR:
No SVR:
30
0%
13.3% (CI: 8.4% to 18.2%)
P = .001 (log likelihood)
20
10
0
0
1
2
3
4 5
Year
6
7
8
At risk 337 261 192 160 124
0
5 11 16 20
95
24
79
25
49
28
31
30
At risk 142 76
Events 0
0
14
1
8
1
6
1
5
1
No SVR Events
SVR
Liver Failure
Liver Failure (%)
Liver-Related Death (%)
Liver-Related Death
48
0
35
0
25
0
0
1
2
3
4 5
Year
6
7
8
At risk 337 256 183 155 121
Events 0
8 21 24 27
92
29
74
31
44
35
27
35
At risk 142 76
Events 0
0
14
1
8
1
6
1
5
1
48
0
35
0
25
0
Veldt BJ, et al. Ann Intern Med. 2007;147:677-684
Evolution of hepatitis C therapy
Discovery of HCV genome
Treatment with IFN alfa for 24 or 48 weeks – 3x
weekly dosing – Poor outcomes
Addition of RBV to IFN alfa improved outcomes
Peg-IFN mono – once-weekly dosing
Peg-IFN α plus RBV becomes gold standard
1989
2011
Results of HCV Rx : overall SVR rates
70
63
60
50
41
39
IFN
+ RBV
19981,2
PEG-IFN
2000-20023,4,5
40
30
20
10
13
6
0
IFN
24 wk
19981
IFN
48 wk
19981
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
80
PegIFN + Ribavirin
70
76
60
50
40
46
30
20
10
0
Genotype 1
Genotype 2/3
Fried et al. N Engl J Med. 2002.
Predicting an SVR
Viral kinetics :
Response guided
therapy
Early virological response (EVR):
HCV RNA ↓ ≥ 2 logs or Undetectable
at Week 12
8
HCV RNA (log10 IU/mL)
7
PegIFN/RBV
6
5
2 log decline
66% SVR
4
3
2
EVR
Limit of detection
1
SVR
0
0 4 8 12 18
Weeks
24
30 36
42 48 54 60 66 72 78
EVR is an essential predictor of achieving SVR:
12-week stopping rule
EVR*
Yes
SVR
86%
Overall
(n=390)
65%
(n=253)
All patients
(n=453)
No
14%
(n=63)
Early virological response = >2 log10 drop in
HCV RNA or undetectable at week 12
NPV=97%
3%
(n=2)
Ferenci P, et al.
Rapid Virological response (RVR):
HCV RNA Undetectable at week 4
8
HCV RNA (log10 IU/mL)
7
PegIFN/RBV
6
5
2 log decline
90% SVR
4
3
2
RVR
Limit of detection
1
SVR
0
0 4 8 12 18
Weeks
24
30 36
42 48 54 60 66 72 78
SVR in Patients Who Achieved an RVR
Similar Across Genotypes
100
88%
100%
86%
86%
90
282
257
9
Geno 1
Geno 2
Geno 3
Geno 4
SVR (%)
80
60
40
20
0
n=
Patients With RVR
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
HCV negative at week 4 and 12
eRVR = Extended RVR
IL28B
60 Mb
A Polymorphism on Chromosome 19 Predicts SVR
19q13.13
3 kb
IL28B gene IFN Lambda-3 gene
Single Nucleotide Polymorphism
rs12979860
Chromosome 19
Ge D, et al. Nature. 2009;461:399-401.
IL28B rs12979860 polymorphism genotype
frequency by population
100
16
Percent
80
48
60
40
35
38
46
50
20
36
19
12
0
C/C
C/T
T/T
European
Americans
African
Americans
Hispanics
Ge D, et al. Nature. 2009;461:399-401.
Response Rates by IL28B Polymorphism:
GT 1 Treated With PegIFN/RBV
100
SVR (%)
80
60
40
20
0
n=
TT
CT
CC
Ge D, et al. Nature. 2009;461:399-401.
SVR (% ± SEM)
IL28B Genetic Variation and Viral
Clearance with PEG/RBV
90
80
70
60
50
40
30
20
10
0
80
70
35
43
40
TT
CT
20
European Americans
43
22
African Americans
24
CC
Hispanics
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
100
Genotype 1
Genotype 2/3
Genotype 4
88
85
CC
79 78
80
CT
SVR (%)
TT
60
45
40
50
41
32
25
20
0
Stättermayer AF, et al. Clin Gastroenterol Hepatol. 2011;9:344-350.
Predictive value of IL28B
• 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
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]
IL28B genotype – ethnic distribution
CC
22
31
CT
TT
47
Blacks
Caucasians
12%
47%
41%
8%
33%
CC
CT
TT
58%
CC
CT
TT
Treatment outcomes
100
80
60
%
40
20
100%
78%
62%
0
RVR
cEVR
SVR
* 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
Influence of ethnicity on achieving a SVR
100
90
p = NS
80
70
60
50
40
58%
59%
30
20
10
0
Caucasian
Black
SUMMARY : SVR predictive factors
Major factors[1-3]
Viral genotype (non–genotype 1)
IL28B allele (C/C vs. T/T)
Pretreatment HCV RNA
(≤ 600,000 IU/mL)
RVR
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
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.
The Evolution of HCV Therapy
1990-2000
The
Empiric
Phase
2000-2011
The
Refinement
Phase
•Viral kinetics
•Optimal dosing
•Special populations
•Non-responders
•Genomics
Weisberg IS, Sigal SH, Jacobson IM. Current Hepatitis Reports. 2007;6:75-82.
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
100
Relapsers
>
Naive
>
Partial Responders
69-83
SVR (%)
80
60
40
>
Null
Responders
63-75
40-59
29-40
20
0
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.
SVR Rates With BOC or TVR in
GT1 Treatment-Experienced Patients
100
PegIFN/RBV
69-83
BOC or TVR + pegIFN/RBV
SVR (%)
80
40-59
60
29-40
40
24-29
20
7-15
5
0
Relapsers[1,2]
Partial
Responders[1,2]
Null
Responders[2,3]
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.
PEG/RBV + Telaprevir or Boceprevir
SVR: PEG-IFN naïve, GT1a vs. 1b
Telaprevir – T12PR
100
90
80
70
60
50
40
30
20
10
0
79
71
GT1a
Boceprevir – BPR RGT
100
90
80
70
60
50
40
30
20
10
0
GT1b
P=PEG-IFN, R=Ribavirin, RGT=Response Guided Therapy
T=Telaprevir, B=Boceprevir
73
63
GT1a
GT1b
Jacobson I, NEJM 2011; 364: 2405
Zeuzem S, EASL 2011
PEG/RBV + Telaprevir
GT1, IFN-experienced
100
90
T12PR
PR
SVR (%)
80
70
60
50
40
30
20
10
0
F 0-2 F 3
F4
Relapser
F 0-2 F 3
F4
Partial responder
F 0-2 F 3
F4
Null responder
Zeuzem S, NEJM 2011; 364: 2417
PEG/RBV + Telaprevir or Boceprevir
SVR: GT1, IFN-naïve, IL28B Genotypes
T12PR vs. PR
100
90
80
70
60
50
40
30
20
10
0
90
73
71
64
25
CC
CT
BPR RGT vs. PR
PR
23
90
80
70
60
50
40
30
20
10
0
TT
P=PEG-IFN, R=Ribavirin, RGT=Response Guided Therapy
T=Telaprevir, B=Boceprevir
82
78
65
55
28
CC
CT
27
TT
Jacobson I, Poordad F
Investigational HCV Regimens
in Phase III Clinical Trials
•Regimens With 1 DAA
+ PegIFN alfa/RBV
 Faldaprevir* (BI 201335, PI)
•Regimens With 2 DAAs
+ PegIFN alfa/RBV
 Daclatasvir + asunaprevir*
•IFN-Free Regimens
 Sofosbuvir + RBV
 Sofosbuvir + GS-5885
(FDC) ± RBV
 Daclatasvir* (BMS-790052,
NS5A)
•New Interferons
 Daclatasvir + asunaprevir
 Simeprevir* (TMC435, PI)
 PegIFN lambda-1a + RBV
 Vaniprevir (MK-7009, PI)
 ABT-450/RTV + ABT-267
± ABT-333 ± RBV
 PegIFN lambda-1a +
daclatasvir + RBV
 Sofosbuvir* (GS-7977, NI)
•Alternative Dosing
 TVR BID* (approved PI)
*Studied with pegIFN-α2a. Studied with both pegIFN-α2a and pegIFN-α2b.
ClinicalTrials.gov.
Toward a Future of Personalized
Medicine for HCV Therapy
Direct-Acting Antivirals
Nuc + RBV
NNI + PI
± RBV
Nuc + NS5A
Inh ± RBV
PegIFN +
RBV+ DAA
Others?
HEPATITIS C Rx – AVAILABILITY OF PEG-IFNRIBAVIRIN AT TERTIARY CENTRES IN SA
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
* Quaternary EDL – Peg-IFN/RBV not listed
HEPATITIS B Rx – AVAILABILITY OF Std and/or
PEG-IFN AT TERTIARY CENTRES IN SA
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
Tenofovir/Lamivudine
Tertiary Centre
Gauteng - CMAH
Availability
Yes
Gauteng - CHB
Yes
KZN - IALCH
Yes
WC - Tygerberg
Yes
WC - GSH
Yes
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, underresourcing 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 The consequence is that low cost medical schemes that cover the
not do enough, that it dumps patients on the public sector and is only basic needs of low-income people can no longer be efficiently
interested in “money first”. Sonderup, Spearman and Geffen recently designed and the unfortunate low income earners are denied cover. It
argued in the Business Day article, When the private sector falls
is then that they are driven into “the void between the public and
short, 3 Oct. 2011, that medical schemes are evil because they “do private sector”.
not cover the treatment of many diseases causing many patients to
fall into the void between the public and private sectors”. That “it is
Medical schemes are not charities; they are obliged by economic
then ironic that treatments for chronic viral hepatitis are available in realities and the interests of the members of their schemes to take
the public sector, but access in the private sector is more difficult
great care in managing available resources. If scheme managers
where chronic viral hepatitis is not a prescribed minimum benefit
were to recklessly pay claims that are not included in the agreements
(PMB)”. However, just because a condition is not a PMB, does
with scheme members they would be guilty of dereliction of duty and
not mean medical aids do not cover it. In fact, any legitimate
would threaten the solvency and continued existence of the schemes
treatment will be covered subject to the rules of the scheme. The only they are managing. They have to stick to the rules and ensure that
difference is that, if the condition is not a PMB, the scheme is not
they do not bankrupt the schemes.
obliged to pay the doctors in full regardless of what they charge for
their services.
Eminent economists have declared that because people’s health,
or lack of it, lies largely and increasingly within their own - and
Sonderup, Spearman and Geffen then suggest that “The Council for earlier their parents' - control, many, if not most health risks are
Medical Schemes must take steps to ensure that treatment for chronicactually uninsurable. Risk pooling and intense actuarial and
viral hepatitis becomes a PMB”. The fact that two of the critics in this managerial effort is employed in an attempt to overcome the innate
case happen to be hepatologists and are arguing that chronic viral
problems that are consequently bound to face private medical
hepatitis should be covered as a PMB is equally ironic. They are
scheme managers. Theirs is an almost impossible task and
surely arguing in their own self-interest and wish to have viral
regulatory interventions make their task even more difficult, very often
hepatitis declared a PMB to enhance their own incomes. It is
to the detriment of the majority of medical scheme members.
government that determines which conditions are included in the list
of PMBs, not medical schemes, and certainly no one individual
AUTHOR Jasson Urbach is a director of the Health Policy Unit (a
scheme. And herein lies an important point. When benefits are
division of the Free Market Foundation). This article may be
determined politically rather than by medical schemes responding to republished without prior consent but with acknowledgement to the
what individuals want, the benefit packages expand and their costs author. The views expressed in the article are the author’s and are
increase.
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

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