The Treatment of Hepatitis C HCV in African Americans

1
The Treatment ofHepatitis C (HCV) inAfrican
Americans

• Lennox J. Jeffers, MD
• Professor of MedicineUniversity of Miami School
  of MedicineMiami, Florida

This study was conducted by Roche Labs Inc.,
Nutley, NJ.
2
Prevalence of HCV by Gender and Race
Males
Females
10
Black
Black
Patients With Anti-HCV ()
Patients With Anti-HCV ()
White
White
6-11
12-19
20-29
30-39
40-49
50-59
70
60-69
6-11
12-19
20-29
30-39
40-49
50-59
70
60-69
Age
Age
Alter et al. N Engl J Med. 1999341556-562.
3
African Americans andHCV Infection
Background

• Risk factors for acquiring HCV are similar
  despite higher prevalence in African Americans
• After adjusting for risk factors(IVDU,
  socioeconomic class, etc)racial differences in
  prevalence disappear
• Rare in childhood but earlier onset ofanti-HCV
  positivity in African Americans

Alter et al. N Engl J Med. 1999341556-562.
4
Critical Issues for Black Patients with HCV

• Genotype 1 virus responsible for 90 of HCV in
  black patients
• Host factors (BMI, immunologic)
• High prevalence
• Access to care
• Under-representation in clinical trials

5
Efficacy of Pegylated Interferon and Ribavirinin
Black Patients
6
Recent Publications

• Peginterferon ?-2b and ribavirin for the
  treatment of HCV in blacks and non-Hispanic
  whites(NHWs)1
• Peginterferon ?-2a (40 kd) and ribavirin for
  black American patients with chronic HCV Genotype
  12

1 Muir AJ. et al. N Eng J Med. 2004
3502265-2271. 2 Jeffers LJ. et al. Hepatology.
2004391702-1708.
7
Peginterferon ?-2b and Ribavirin for the
Treatment of HCV in Blacks and NHWs

• Methods
• N200 (100 blacks, 100 NHWs)
• Peginterferon ?-2b and ribavirin x 48 weeks
• Similar proportions of Genotype 1 in each group

Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
8
Peginterferon ?-2b and Ribavirin for the
Treatment of HCV in Blacks and NHWs
(cont)

• Study Design
• Multicenter (16 sites)
• Peginterferon ?-2b 1.5 mcg/week for 48 weeks
  ribavirin 1000 mg qd x 12 weeks, then 800 mg qd
  for weeks 13-48
• Growth factors were not used
• Equal proportions of Genotype 1 in each group
• Safety assessed at weeks 1, 2, 4, then q 4 weeks
  during treatment and at weeks 52, 56, 60 and 72
• Compliance assessed at each visit
• Serum HCV RNA measured by RT-PCR
• Adverse events (AEs) evaluated with the use of
  WHO grades
• Depression evaluated using CESD scale

Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
9
Endpoints

• Primary
• SVR (absence of HCV RNA 24 weekspost-treatment)
• Secondary
• Histologic and virologic response atend of
  treatment

Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
10
Results

• Patient characteristics
• 116 black and 128 NHW patients were screened
• 98 of patients were Genotype 1
• Most common reasons for exclusion were
• Neutropenia (in 10 black patients)
• Non-genotype 1 (in 19 NHW patients)
• Baseline characteristics similar except
• Black patients were heavier and had higher
  incidence of diabetes mellitus and hypertension

Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
11
Results
(cont)

• Compliance
• 81 of black patients and 79 NHW patients
  completed therapy
• 17 black patients and 21 NHW patientsdid not
  complete therapy
• Most common reason for discontinuation was
  depression (4 of blacks vs 6 of NHW)

Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
12
Safety

• Rates of AEs
• Similar in the 2 groups
• Dose reductions occurred in 22 of blacks and24
  of NHWs
• Bone marrow suppression was observed inboth
  groups
• Dose reductions similar in both groups
• Depression reported in 18 of blacks and20 of
  NHWs
• 21 of blacks vs 22 of NHWs required initiation
  of antidepressant meds during treatment

Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
13
Virologic Response Rates
P value lt.001 for all categories. Muir AJ. et al.
N Eng J Med. 20043502265-2271.
14
Histologic Response Rates
Mean change in DiseaseActivity Scores P.37
Mean change in Fibrosis Scores P.79
Muir AJ. et al. N Eng J Med. 20043502265-2271.
15
Prognostic Factors Analyzed to Determine Effect
on Sustained Virologic Response (SVR)

• Black race
• Male sex
• Age (40 yr)
• gtHigh school education
• Weight 75 kg
• Ribavirin doses 10.6 mg/kg

• HCV RNA level 500,000 IU/ml
• Duration of infection 20 yr
• Cirrhosis
• Steatosis
• Diabetes

Black race was the only predictor of response
(Plt.001).
Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
16
Conclusions

• Clear difference in SVR between blacks and NHWs
• Black race was the only predictor of response
• Similar types and severities of AEs
• Similar numbers of episodes of anemia and
  neutropenia
• Similar rates of dose reduction and D/C rates
• Lack of early virologic response (EVR) is a
  predictor of non-response
• Reasons for differences in response remain unclear

Muir AJ. et al. N Eng J Med. 2004 3502265-2271.
17
Peginterferon ?-2a (40kd) and Ribavirin for Black
American Patients with Chronic HCV Genotype 1
Patient Selection

• Male and female patients 18 years or older
• HCV
• Non-Hispanic black or white
• Treatment-naïve with interferon or ribavirin
• HCV Genotype 1

Jeffers LJ. et al. Hepatology. 2004 391702-1708.
18
Study Design

• Open-label, non-comparative, multicenter
• Conducted at 11 clinical sites
• Peginterferon ?-2a 180 mcg SQ weekly 1000 mg/d
  ribavirin (1200 mg/d for patients weighing 75
  kg)
• 48 weeks with treatment with 24 weeks of F/U
• Stepwise dose reductions allowed to manage AEs or
  laboratory abnormalities

Jeffers LJ. et al. Hepatology. 2004 391702-1708.
19
Endpoints

• Primary
• SVR (undetectable lt50 IU/mL of serum HCV RNA as
  measured by the AMPLICOR HCVTest at 72 weeks)
• Secondary
• Virologic response over time (each visit)
• Utility of EVR

Jeffers LJ. et al. Hepatology. 2004 391702-1708.
20
Demographics

• 108 patients enrolled
• 80 blacks (2 patients never received study drug)
• 28 whites
• Patient Characteristics
• Groups were similar except mean weight of black
  groupwas 6 kg greater
• Proportion of males higher in black group (72 vs
  61)
• HAI activity and fibrosis scores comparable
• 1 patient in each group had cirrhosis
• 80 of blacks vs 79 of whites completed treatment

Jeffers LJ. et al. Hepatology. 2004 391702-1708.
21
Safety

• No unexpected or unusual patterns of AEs
• Neutropenia was most common reasonfor dose
  modification of peginterferon ?-2
• Blacks 37
• Whites 18

Jeffers LJ. et al. Hepatology. 2004 391702-1708.
22
Virologic Response Rates
95 CI 30-71
95 CI 21-57
95 CI 21-44
95 CI 16-35
26
39
32
50
SVR for patients completing 48 weeks of treatment
SVR
Plt.001 for all categories. Muir AJ. et al. N Eng
J Med. 20043502265-2271.
23
Virologic Response Over Time
Virologic Response ()
Study Week
Virologic Response Serum HCV RNA lt50 IU/mL
Jeffers LJ. et al. Hepatology. 2004391702-1708.
24
Prognostic Factors Analyzed to Determine Effect
on SVR

• Age (gt40 vs ?40)
• Sex (female vs male)
• Weight (gt85 kg vs ?85 kg)
• Baseline ALT (gt3 x ULN vs ?3 x ULN)
• Baseline HCV RNA (gt800,000 IU/mL vs ?800,000
  IU/mL)
• Baseline total HAI score

Jeffers LJ. et al. Hepatology. 2004391702-1708.
25
Independent Factors Associated with SVR

• Baseline HCV RNA lt800,000 IU/mL
• Age lt 40
• ALT lt 3x ULN

Plt.05
Jeffers LJ. et al. Hepatology. 2004391702-1708.
26
Conclusions

• Lower SVR in blacks than whites, consistent
  withprevious findings
• Age, viral load, and ALT were significant
  predictors of SVR
• Lack of EVR at week 12 predicts failure to
  achieve SVR
• Positive predictive value of EVR at week 12 is
  lower in black group
• Undetectable HCV RNA at week 12 is a
  superiorpredictor of SVR
• Constitutional neutropenia in blacks does not
  appear to increase risk for serious infections

Jeffers LJ. et al. Hepatology. 2004391702-1708.