Patients infected with hcv-5 present the same response rate than patients infected with HCV-1: results from the Belgian randomised trial for naive and relapsers (BERNAR)

D’heygere F, George C, Nevens F, Van Vlierberghe H, Van Der Meeren O.

 

Introduction

HCV genotype 5 (HCV-5) shows a world-wide distribution mainly restricted to South Africa. However, a cluster of at least 80 patients has been detected in Belgium. The response rate of patients infected with HCV-5 has been poorly documented to date, but it has been suggested that HCV-5 could respond better to therapy than HCV-1.

 

Method

We reviewed the HCV-5 patients from the database of the Belgian Randomised Trial for Naïve and Relapsers (BERNAR-1), which has enrolled 443 patients that were naïve to therapy or relapsed after a conventional interferon (IFN) based therapy. Patients received either peginterferon alfa-2a (40KD) (PEGASYS) 180µg qw for 48 weeks (n=11), either IFN 6 MIU tiw for 12 weeks then 3MIU tiw for 36 weeks (n=10), both in combination with ribavirin 1000-1200mg/day for 48 weeks. A subset of HCV-1 infected patients was then selected from the study database to match the HCV-5 population according to age category (< vs >40), gender (male vs female), baseline viral load category (< vs >=800,000IU/mL), cirrhosis status (yes vs no), pretreatment status (naïve versus relapse) and treatment group (PEGASYS vs IFN).

 

Results

21 patients with HCV-5 infection, and 21 patients with HCV-1 infection fully matching the characteristics of the HCV-5 patients, were identified in our database. In both groups, patients were mostly female (52%), naïve to therapy (81%), aged >40 (95%), had baseline viral load<800,000IU/mL (62%) and no cirrhosis (80%). A sustained virological response (SVR) was observed in 10/21 patients in the HCV-5 group (48%) and in 8/21 patients in the HCV-1 group (38%; p=0.530); in the PEGASYS group, the SVR rate was 55% in both HCV-5 and HCV-1 patients.

 

Conclusions

Patients infected with HCV-5 present the same response rate than patients infected with HCV-1. When treated with peginterferon alfa-2a (40KD) plus ribavirin for 48 weeks, 55% of patients achieved an SVR.


 

Combined pegylated interferon alfa-2a and ribavirin in treatment of chronic hepatitis C in Egypt (ANRS 1211 Trial)

Elmakhzangy H, Rekacewicz C, Shouman SI, Mohamed HN, Esmat G, Ismail A, Rafaat R, El Hosseiny M, El-Daly M, El-Kafrawy S, Abdel-Hamid M, Fontanet A, Pol S, Mohamed MK.

 

Background and aims

While Hepatitis C Virus (HCV) genotype 4 is widely prevalent in Egypt and the Middle East, it is emerging in many European countries among intravenous drug users. To date the efficacy of combined pegylated interferon -2a (PEG-INF) with ribavirin (RBV) therapy has mainly been reported for other genotypes. The aim of the study was to evaluate the efficacy and tolerance of this combined therapy in chronic hepatitis C naïve patients in Egypt.

 

Method

Chronically HCV infected patients were enrolled in an open label trial after signing an informed consent. Patients with advanced and decompensated cirrhosis were not included. The study regimen was PEG-INF (180mg/week) and RBV (11.5mg/kg/day) for 48 weeks. If patients were still positive for HCV viremia after 24 weeks of therapy, the treatment was interrupted. The efficacy was assess at the end of treatment (End of treatment response ETR) and 6 months after the end of treatment (sustainable virological response SVR) by an undetectable HCV viremia.

 

Results

Among the 100 patients enrolled, 85% were males, the mean (± S.D.) age was 42 years (±8.8), the mean Body Mass Index (BMI) was 29 Kg/m2 (±5.1) and the pretreatment liver histology showed for 49 patients a A1-F1 METAVIR index while 35 patients had a A3 or F3 index. Treatment was interrupted after the 24 first weeks of treatment for 22 patients because of a positive HCV viremia. Among the 95 patients with data available at week 48, the ETR was 69.5 % (95% CI [59.2% – 78.5%]). The ETR varied according to the METAVIR index from 54% to 78%, respectively, for A3 or F3 patients and A1-F1 (P<0.05). The SR evaluated on the 80 patients who have already reached the 72 week visit was 61% (95% CI [49.7% – 71.4%]).

 

Conclusion

SVR with combined therapy among these patients presumably infected with genotype 4 falls within the range observed with other genotypes. Treatment was well tolerated.


Age and sustained virological response in patients with persistently ‘normal’ alt and chronic hepatitis C treated with peginterferon alfa-2a (40KD) plus ribavirin

Gane E, Pockros PJ, Farci P, Diago M, Lardelli P, Blotner S, Martinelli A.

 

Introduction

Data suggest that there may be a negative relationship between increasing age and sustained virological response (SVR) in patients with chronic hepatitis C (CHC). This analysis aimed to explore the relationship between age, baseline characteristics and SVR in CHC patients with persistently ‘normal’ ALT treated with peginterferon alfa-2a (40KD) and ribavirin.

 

Methods

422 patients with ALT levels within the normal laboratory range (≤ 30IU/L) on ≥3 occasions over 18 months were randomised to receive 24 or 48 weeks treatment with peginterferon alfa-2a (40KD) 180mg/week plus ribavirin 800mg/day, or no treatment. All patients were monitored for 72 weeks (Zeuzem, Gastroenterology 2004). The study was initiated before prospective studies indicated that ribavirin 1000/1200mg/day is optimal for genotype 1. The primary endpoint was SVR, defined as undetectable HCV RNA by qualitative PCR after 24 weeks untreated follow-up. Results were retrospectively analysed according to age (≤40 or >40 years) and HCV genotype (1 vs 2/3).

 

Results (table)

Patients aged >40 years had lower SVR rates (overall and across each genotype) than patients aged ≤40. Baseline demographics also differed between the two groups, with the older subgroup having a higher proportion of males and African Americans, and a greater BMI and pre-treatment HCV RNA titre than the younger subgroup.

 

Conclusions

In patients with CHC and persistently ‘normal’ ALT levels, age appears to be an important factor in determining response to peginterferon alfa-2a (40KD) plus ribavirin. This may support the consideration of antiviral therapy once a positive diagnosis has been made. However, the role of other confounding factors (male gender, African American race and high baseline HCV titre) cannot be excluded. Further studies are warranted.

 

Genotype & treatment duration (N)

Baseline characteristics by age group (≤40 vs >40yr) –N (%)

SVR rate %

Male gender

AA race

BMI

HCV RNA

≤40

>40

≤40

>40

≤40

>40

≤40

>40

≤40

>40

G1 24wk (144)

24 (47)

39 (42)

3 (6)

10 (11)

24.5

26.4

0.8

1.1

12

14

G1 48wk (141)

15 (33)

39 (41)

1 (2)

12 (13)

25.2

27.3

0.6

1.1

54

34

G2,3 24wk (58)

7 (37)

16 (41)

1 (5)

3 (8)

25.2

27.1

1.4

1.8

79

69

G2,3 48wk (59)

7 (29)

18 (51)

2 (8)

3 (9)

23.6

26.0

0.9

1.9

88

71

AA = African American race; BMI = mean body mass index in kg/m2; Mean HCV RNA level in IU/mL x 106


Cost-effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in treatment of chronic hepatitis C (CHC) in HIV-HCV co-infection

Hornberger J, Carosi G, Puoti M, Bruno R, Green J, Katel KK, Giuliani G.

Introduction

The recent AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) demonstrated the efficacy of peginterferon alfa-2a plus ribavirin (RBV) and interferon alfa plus ribavirin (IFN/RBV) in patients co-infected with HIV-HCV.  The cost-effectiveness of treating CHC with peginterferon alfa-2a/RBV has not been assessed in this patient population.

 

Methods

 We developed a Markov Model of CHC disease progression in HIV-HCV co-infection to assess the cost-effectiveness of peginterferon alfa-2a/RBV compared with IFN/RBV.  Estimates of progression rates came from published studies.  Treatment effect on sustained virological response (SVR) was based on findings from APRICOT.  The analysis was a cohort of patients with mean age 40 years and HIV-HCV co-infection. Mortality from HIV was based on published results of HIV Swiss Cohort Study. Quality of life and costs for each health state were based on literature estimates and on the Italian health care setting. Costs in 2003 euros and benefits were discounted at 3%. The Italian National Health Service (NHS) perspective was used.

 

Results

In genotype 1 patients, quality-adjusted life years (QALYs) and costs increase with peginterferon alfa-2/RBV relative to IFN/RBV by 0.76 and € 7,324, respectively.  In genotype 2/3 patients, QALYs and costs increase by 1.44 years and € 6,222, respectively.  In genotype 1 and 2/3 patients, peginterferon alda-2a/RBV is cost-effective compared with IFN/RBV (Genotype 1, € 9,684 per QALY gained; Genotype 2/3 € 4,320 per QALY gained). 

 

Conclusions

Based on our model, peginterferon alfa-2a/RBV is predicted to increase overall survival, and has cost-effectiveness ratios against IFN/RBV that are within acceptable ranges adopted by the NHS. 


 

Peginterferon alfa-2a (40KD) plus ribavirin in cirrhotic patients with chronic hepatitis C: results of a multicentre open-label programme in Canada

Lee SS, Bain V, Peltekian K, Krajden M, Yoshida E, Deschesnes M, Heathcote EJ, Bailey R, Simonyi S, Sherman M.

Introduction

In the only prospective randomized study conducted exclusively in patients with bridging fibrosis/cirrhosis, the overall SVR rate after 48 weeks of treatment with peginterferon alfa-2a (40KD) (PEG-IFNa-2a) 180µg/week was 30% (Heathcote NEJM 2000;343:1673-80). Patients in clinical trials are highly selected and motivated, and whether the same response rates can be achieved in routine clinical practice remains unknown. We evaluated the efficacy and tolerability of PEG-IFNa-2a/ribavirin in treatment-naïve patients enrolled in a multicentre, open-label expanded access program in a routine clinical setting.

 

Methods

Anti-HCV antibody-positive adults with detectable HCV RNA (>600 IU/mL) were eligible. Patients with a histological diagnosis of fibrosis/cirrhosis (F3/F4) were eligible provided they had compensated liver disease (Child-Pugh A). At the investigator’s discretion patients were assigned to PEG-IFNa-2a 180µg/week plus ribavirin 800mg/day for 24 (A) or 48 weeks (B). The program was initiated before the optimal treatment duration and ribavirin dosage for genotype-1 and 2/3 were known. This analysis was conducted by intention-to-treat.

 

Results (Table)

174 of 508 (34%) patients had fibrosis/cirrhosis. These patients were older, had a higher BMI and were more likely to have genotype-1 infection than noncirrhotic patients. Most patients (380/508, 75%) were assigned to group B. The SVR rate in fibrotic/cirrhotic patients was 44% (34% in genotype-1, and 58% in genotypes 2/3). Noncirrhotic patients had higher SVRs: 41% in genotype-1; 77% in genotypes 2/3. The incidence of serious adverse events was similar in fibrotic/cirrhotic (5%) and noncirrhotic patients (5%).

 

Conclusion

The efficacy of PEG-IFNa-2a/ribavirin in this study was similar to that in cirrhotic patients treated with the same regimen in a randomized pivotal study in which different treatment durations and ribavirin dosages were compared (Hadziyannis. Ann Intern Med 2004;140:346). Our results demonstrate that this combination is effective and safe in patients with fibrosis/cirrhosis and results obtained in clinical trials can be achieved in routine clinical practice. Further improvement in SVR may be obtained with an optimal ribavirin dose in genotype-1 patients.

 

Patient group, Total N

Mean baseline characteristics

SVR by group and genotype, n (%)

Age (yr)

BMI

HCV genotype (%)

Aa

B

1

2/3

other

2/3

1

2/3

Cirrhotic, 174

48

28

118 (68)

53 (30)

3 (2)

23/35 (66)

40/118 (34)

8/18(44)

Noncirrhotic, 334

42

27

196 (59)

127 (38)

11 (3)

72/91 (79)

81/196 (41)

26/36(72)

A = PEG-IFNa-2a/ribavirin x 24wk; C = PEG-IFNa-2a/ribavirin x 48wk; SVR = undetectable HCV RNA (<50 IU/mL) 24-weeks after end of treatment. aNo genotype 1 patients were enrolled in group A.

 


 

Are changes in lymphocytes during peginterferon alfa-2a (40KD) and ribavirin treatment in patients with co-infection related to HCV response? Findings from APRICOT

Pérez-Guzmán E, Pastore G, Cadeo G, Antunes F, Staszewski S, Ortega E, Katlama C, Messinger D, Depamphilis J, Torriani F.

 

Introduction

In APRICOT, peginterferon alfa-2a (40KD) plus ribavirin produced a sustained virological response (SVR) rate of 40% in HIV-HCV co-infected patients, and did not adversely affect HIV disease status (Torriani, NEJM 2004). In this subsequent analysis of APRICOT data, we aimed to determine the effects of peginterferon alfa-2a (40KD) plus ribavirin treatment on CD4+ cells according to outcome (SVR vs. no SVR).

 

Methods

289 co-infected patients were treated with peginterferon alfa-2a (40KD) 180mg/week plus ribavirin 800mg/day. Patients had compensated liver disease, CD4+ count ≥100 cells/mL, and stable HIV disease. SVR was defined as undetectable HCV RNA (<50IU/mL) after 24 weeks of untreated follow-up. Blood samples were collected to monitor changes in lymphocytes. Only patients who received 48 weeks’ treatment were included in the analysis (n=217).

 

Results (FIGURE)

Total lymphocyte counts decreased from baseline during treatment (mean: -0.8 x109/L at week 48 in both subgroups) but returned to baseline levels during follow-up. CD4+ cell counts also decreased from baseline during treatment. The decrease was greater in patients achieving an SVR than in patients without an SVR, and was proportional to the baseline CD4+ count. As with lymphocytes, CD4+ cell counts returned to pre-treatment levels during follow-up. The mean percentage of CD4+ lymphocytes (%CD4+) increased slightly during treatment in both subgroups (maximum increase of 4% in each group after 24 weeks’ treatment). At week 72, there appeared to be a slight rebound in %CD4+ in patients who achieved an SVR, whereas %CD4+ returned to pre-treatment levels in those who did not achieve an SVR.

 

Conclusions

Changes in CD4+ cells associated with peginterferon alfa-2a (40KD) plus ribavirin treatment appear to be independent of HCV virological response. Although changes occur in CD4+ cells during treatment, levels return to baseline following treatment cessation.

 

 

z


 

Preliminary health outcomes results of treatment with peginterferon alfa-2a (40KD) plus ribavirin for chronic hepatitis C genotype 1 in daily routine clinical practice: the HERACLES project

Planas R, Solá R, Diago M, Olveira A, Romero-Gómez M, Barniol R, Benítez A, Casanovas T, Muñoz-Sánchez M, on behalf of the Heracles Study Group.

 

Introduction

Since publication of 12-week predictability data (Fried et al. NEJM 2002) much interest in Spain has focused on incorporating this criterion into Daily Clinical Practice (DCP).

 

Objective

To document DCP in treatment-naïve patients infected with HCV genotype 1 treated with peginterferon alfa-2a (40KD) plus ribavirin in centers with regulatory approval (Spanish R.D.561/1993) before both products were marketed in Spain.

 

Methods

This was an electronic observational, electronic data capture study. Eligible patients had detectable HCV RNA, elevated serum ALT levels and compensated liver disease.

 

Results (table)

A total of 494 patients have been enrolled. Age, weight, BMI, gender, liver damage on biopsy, baseline viral load, treatment adherence, serum ALT, AST, ALP, leucocytes, platelets and albumin and their possible relationship with early virological response at week 12 (EVR12) and week 24 (EVR24) have been analyzed. Of the factors analyzed, only treatment adherence had a significant relationship with EVR12 (p=0.0297) and only baseline HCV RNA levels were correlated with EVR24 (p=0.0463). Safety data was consistent with the known profile of this combination.

 

Conclusions

The evaluation of EVR12 is feasible under DCP in Spain. Adherence with the prescribed dose of peginterferon alfa-2a (40KD) has a significant influence on the chances of achieving an EVR12. Thus adherence should be encouraged and closely monitored, particularly early during the course of treatment.

 

N (%)

Week 12

Week 24

Scheduled visit

391

291

HCV RNA determined

313

209

EVR (≥2-log10 decrease in HCV RNA)

236 (75)

176 (84)

 


 

Peginterferon alfa-2a (40KD) plus ribavirin is as effective in patients relapsing after conventional interferon based therapy than in naïve patients: results from the BERNAR-1 trial

Nevens F, Van Vlierberghe H, D'heygere F, Delwaide J, Adler M, Henrion J, Henry JP, Hendlisz A, Michielsen P, Bastens B, Brenard R, Van Der Meeren O.

 

Background

Treatment with peginterferon alfa plus ribavirin (RBV) is standard of care in the initial treatment of chronic hepatitis C (CHC). The Belgian Randomised trial for Naïve and Relapsers (BERNAR-1) investigated the safety and efficacy of this regimen versus a conventional interferon-based combination therapy, and compared naïve patients versus patients who relapsed after initial treatment with conventional interferon with or without ribavirin.

 

Methods

Study medication consisted of peginterferon alfa-2a (40KD) (PEGASYS) 180µg qw for 48 weeks, or interferon alfa-2a 6MIU tiw for 12 weeks then 3MIU tiw for 36 weeks (IFN), both combined with RBV (1,000 or 1,200mg/day) for 48 weeks. Randomisation was stratified according to pretreatment status (treatment-naïve versus relapse) and presence of cirrhosis.

 

Results

443 patients were randomised and received at least one dose of study medication (ITT, missing=failure). The baseline parameters were well balanced across treatment arms. The patients were predominantly male (54%), Caucasian (91%), older than 40 (68%), with a BMI >25kg/m² (50%); 16% had cirrhosis; 22% were relapsers. At baseline, 63% of patients had genotype 1 infection and 34% had HCV-RNA >800,000IU/mL. A significantly higher proportion of patients in the PEGASYS group than in the IFN group had a sustained virological response (SVR): 52% vs. 27%, p<0.001. The proportion of patients with SVR in the naïve population was 54% (PEGASYS) versus 27% (IFN); in the relapse group, 43% (PEGASYS) vs. 26% (IFN). The difference between treatment groups was highly statistically significant in both naïve and relapse populations (p<0.001), while the difference in response rate between naïve and relapsers was not statistically significant (p=0.237).

 

Conclusions

The CHC population in Belgium shows various factors usually associated with lower response to therapy. Despite this, peginterferon alfa-2a (40KD) plus ribavirin demonstrates efficacy results of 54% SVR that are consistent with previous reports. In patients relapsing after conventional interferon-based therapy, once-weekly peginterferon alfa-2a (40KD) plus ribavirin provides similar response rate than in naïve patients.


 

The influence of cumulative peginterferon alfa-2a (40 KD) and ribavirin (RBV) exposure on sustained virological response (SVR) rates in patients with genotype 1 chronic hepatitis C

Reddy KR, Hadziyannis SJ, Diago M, Marcellin P, Lopez-Talavera JC, Wright T.

 

Introduction

Patients who receive full doses and durations of PEG-IFN /RBV combination therapy have higher SVR rates. In this analysis, we investigated the relationship between cumulative drug exposure to RBV, and SVR rates.

 

Methods

Pooled data from 569 patients randomized to 48 weeks of PEG-IFN alfa-2a (40KD) 180 μg/wk + RBV 1000/1200 mg/d in two phase III trials were analyzed. Cumulative exposure defined as total drug administered (based on recorded at clinic visits and validated against diaries) was evaluated.

 

Results

Of 427 patients (75%) who completed treatment with PEG-IFN, 182 (43%) had their RBV dose reduced to <97% compared with 114 (27%) who had their PEG-IFN dose reduced to <97%; 62 patients (15%) had reductions of both drugs to <97%. SVR rates for patients who completed treatment with decreasing cumulative RBV dose were: 66% (>97% dose), 59% (80-97%), 57% (60-80%) and 33% (<60%). Only 12 patients (3%) discontinued RBV prior to week 42 while remaining on treatment with PEG-IFN (table). Discontinuations for both drugs were due to insufficient therapeutic response (n=53), laboratory abnormalities/adverse events (n=65), or other reasons (n=24).

 

Conclusion

In conclusion, patients were more likely to maintain assigned doses of PEG-IFN alfa-2a (40KD) compared to assigned doses of RBV throughout treatment. Discontinuation of RBV before 42 weeks in PEG-IFN treatment completers was uncommon, but the results suggested that SVR was diminished from ~61% in those completing both therapies (even if at reduced doses) to ~42%. All of these factors are likely to compromise response. Avoiding RBV dose reductions and dose discontinuations will likely improve overall SVR, although the magnitude of this benefit remains to be determined.

 

SVR by duration of RBV exposure and % cumulative exposure to PEG-IFN alfa-2a (40KD)

 

Proportion of optimal cumulative PEG-IFN alfa-2a (40KD) dose over 48 weeks

Duration

>97%

≤97%

 

Discontinued PEG-IFN alfa-2a (40KD)

RBV discontinuation before 12 weeks of therapy

0% (0/3)

0% (0/1)

0% (0/26)*

RBV discontinuation between 12 weeks and 36 weeks

66.6% (2/3)

66.7% (2/3)

8.2% (8/98)

RBV discontinuation after >36 weeks and before 42 weeks

0% (0/0)

50% (1/2)

8.3% (1/12)

RBV continued for longer than  42 weeks

62.8% (193/307)

57.4% (62/108)

16.7% (1/6)

 


 

Peginterferon alfa-2a (40KD) (PEG-IFNa-2a) plus ribavirin in cirrhotic patients with chronic hepatitis C: Results of a multicentre open-label expanded access program in Canada

Sherman M, Yoshida E, Deschesnes M, Krajden M, Bain V, Peltekian K, Anderson F, Kaita K, Simonyi S, Lee SS.

 

Introduction

Management of relapsers and nonresponders to previous interferon-based therapy is an important, but unresolved issue. We evaluated the efficacy and tolerability of peginterferon alfa-2a (40KD) (PEG-IFNa-2a) plus ribavirin in this important subgroup in a multicentre, open-label expanded access program in a routine clinical setting.

 

Methods

Anti-HCV-antibody-positive adults with detectable HCV RNA (>600 IU/mL) who failed to respond or relapsed after previous conventional interferon mono- or combination therapy were eligible. Patients were assigned to PEG-IFNa-2a 180 µg/week plus ribavirin 800 mg/day for 24 (A) or 48 weeks (B) at the discretion of the investigator. The program was initiated before the optimal treatment duration and ribavirin dosage for genotype-1 and 2/3 were determined. SVR was defined as undetectable HCV RNA (<50 IU/mL) 24-weeks after treatment completion. This analysis was conducted by intention-to-treat.

 

Results (table)

120 relapsers (35 to monotherapy, 80 to combination therapy; details unknown for 5) and 241 nonresponders (53 to monotherapy, 180 to combination therapy, details unknown for 8) were enrolled. Baseline characteristics were similar in both groups although more nonresponders had genotype-1 infection (84% vs. 65%). Most patients were assigned to group B (323/355, 91%). Among relapsers to monotherapy 10/24 genotype-1 patients and 7/10 genotype 2/3 patients had SVRs. Among relapsers to combination therapy 17/54 genotype-1 patients and 12/23 genotype 2/3 patients had SVRs. Among nonresponders to monotherapy 9/42 genotype-1 patients and 4/10 genotype 2/3 patients had SVRs. Among nonresponders to combination therapy 30/153 genotype-1 patients and 7/21 genotype 2/3 patients had SVRs. The incidence of serious adverse events was similar in nonresponders (5%) and relapsers (8%).

 

Conclusions

The overall SVR rate was 40% (48/120) in relapsers and 23% (55/241) in nonresponders after treatment with PEG-IFNa-2a plus RBV 800 mg/day. These ‘real world’ results in a large patient cohort demonstrate that it is possible to cure previous nonresponders and relapsers to interferon-based therapy. Use of optimal treatment regimens may yield even higher SVR rates in these difficult-to-treat patients.

 

Patient group, N

Mean baseline characteristics

SVR  by genotype, n (%)

Male (%)

Age (yr)

BMI

Advanced fibrosis (%)

HCV genotype (%)

All

1

2/3

1

2/3

 

 

 

Rel, 120

83 (69)

47.3

27.2±5.0

56 (47)

78 (65)

38 (32)

48 (40)

27 (35)

19 (50)

NR, 241

173 (72)

47.5

27.6±4.4

120 (50)

202 (84)

32 (13)

55 (23)

39 (19)

11 (34)

NR = patients who did not have a virological response at any time during a previous course of IFN or IFN/RBV; Rel = patients who relapsed after an on-treatment virological response during a previous course of IFN or IFN/RBV. Advanced fibrosis = bridging fibrosis or cirrhosis

 


 

Pegylated interfon for treatment of acute hepatitis C in Egypt (ANRS 1213 Trial)

Shouman SI, Mohamed MK, Esmat G, Attalla M, Mansour H, Rekacewicz C, Rafaat R, Sharaf N, El Hosseiny M, El-Daly M, El-Kafrawy S, Abdel-Hamid M, Pol S, Fontanet A.

 

Background and aims

Early treatment of acute hepatitic C with standard interferon has shown sustainable viral response in patients predominantly infected by genotypes 1, 2 and 3. However, response to treatment of patients infected with genotype 4 and efficacy of pegylated interferon in the treatment of acute hepatitis C, have not been studied yet. The aim of the study was to evaluate the efficacy and tolerance of three-month pegylated interferon (PEG-IFNα-2a) alone in Egyptian patients with acute hepatitis C.

 

Method

Symptomatic acute hepatitis C patients were enrolled sequentially in an open arm clinical trial. Patients were identified through an ongoing surveillance study in two Fever Hospitals in Greater Cairo. Only patients who maintained a positive HCV viremia 3 month after the onset of symptoms were treated. The study regimen was PEG-IFNα-2a (180mg/week) for 12 weeks. If patients were still positive for HCV viremia at 12 weeks of treatment they continued for another 12 weeks of therapy. The efficacy criteria was sustainable virological response with negative HCV viremia 6 months after the end of treatment.

 

Results

Between May 2003 and April 2004, 14 patients were enrolled: 9 were males; the median age was 30.5 years (range 21 to 53); and the modes of infection were IVDU (5), medical procedures (6), needle stick injury (1) and occupational exposure (2). All patients had a negative HCV RNA PCR after 12 weeks of treatment. Of the 12 patients who completed their 6-month follow-up after the end of treatment, 10 (83% - 95% CI [52%-98%]) were still HCV RNA PCR negative. Data from the 2 remaining patients are still awaited. No major side effects were observed during the course of treatment.

 

Conclusion

These preliminary results show a good response rate among Egyptian patients presumably infected with HCV genotype 4. Pegylated interferon monotherapy, administered only once per week for 12 weeks is highly effective in treating non resolved acute HCV.


 

Evidence that serum ribavirin steady-state concentrations do not correlate with early virological response during peginterferon alfa-2a + ribavirin combination therapy for chronic hepatitis C

Souvignet C, Stanke-Labesque F, Bronowicki J-P, Larrat S, Quesada J-L, Zarski J-P.

 

Background/aims

Ribavirin in combination with pegylated interferon is the standard treatment for chronic hepatitis C. Despite recommendations for ribavirin dosage based on body weight of the patient, serum ribavirin concentrations display high inter-individual variability that could explain severe side effects or lack of efficacy in some patients. The present study aimed to define the relation between serum ribavirin concentration and viral load drop on combination treatment.

Methods

Thirty-six patients chronically infected with the hepatitis C virus (genotypes 1 or 4) were treated with standard treatment (180 µg Peginterferon alfa-2a once weekly and 1000-1200 mg ribavirin twice daily). During the first three months of treatment, the serum ribavirin concentration was sequentially monitored using a HPLC specific assay, in parallel with measures of viral load (Roche Amplicor™ HCV test, v2.0) and haemoglobin level at the same time points (Days 0, 7 and 14, and Weeks 4 and 12).

Results

The steady-state concentration of ribavirin was reached at Week 4: 1.99 ± 0.73 mg/ml (Variation coefficient = 41 %). Mean drop of viral load was -2.26 ± 0.97 log UI/ml at Week 4 and -2.93 ± 0.77 log UI/ml at Week 12. Undetectable HCV-RNA was noted in 36 percent of the patients at Week 4 and 83 percent at Week 12. No significant correlation was found between serum ribavirin concentration (Week 4) and viral load drop (Week 12): r = 0.071 (p = 0.679). The ribavirin concentration that gave an early virological response in 50 percent of the patients (ED50) was 2.17 mg/ml. The ribavirin concentration that gave 2 g/dL drop of haemoglobin in 50 percent of the patients (TD50) was 2.44 mg/ml at the same timepoint (Week 12).

Conclusions

During the first three months of combination treatment for chronic hepatitis C (Peginterferon alfa-2a + ribavirine), the drop of viral load does not correlate with serum ribavirin concentration. These data suggest that interindividual variations of serum ribavirin levels do not significantly impact early virological response rate. Actually, the interest of therapeutic drug monitoring of ribavirin will depend on further analysis of sustained virologic response data after long-term follow-up of this patient cohort.


 

Clustering of poor prognostic factors in patients with chronic hepatitis C

Swain M, Foster GR, Fried MW, Hadziyannis SJ, Heathcote EJ, Jensen D, Lee SM, Pockros PJ, Sulkowski M, Trepo C.

 

Introduction

Body weight is a modifiable factor that influences the outcome of interferon-based therapy for chronic hepatitis C. Sustained virological response (SVR) rates tend to decrease as body weight increases. The mechanism whereby body weight affects the response to treatment is not completely understood, but is likely to be multifactorial. We assessed the complex relationship between body weight and a range of baseline host- and hepatitis C virus (HCV)-related factors that influence the outcome of interferon-based therapy.

 

Methods

Baseline data from two multinational, randomized, controlled phase III studies assessing the efficacy and safety of peg-IFNα-2a (40KD)/ribavirin for the treatment of hepatitis C were combined (NEJM. 2002;347:975; Ann Intern Med 2004;140:346). Patients were classified into 3 groups: <65 kg, 65–<85 kg, and ³85 kg. Baseline patient- and HCV-related characteristics were analyzed according to body weight.

Results(table)

Data from a total of 2404 patients were included in the analysis. Body weight was positively correlated with body mass index (BMI), the proportion of male patients, the proportion of black patients, those reported to have acquired HCV through intravenous drug use (IVDU), and with a histological diagnosis of cirrhosis. A greater proportion of patients infected with HCV genotype 1 were in the highest weight group (³85 kg) than in the other lower weight groups, although this was not statistically significant. There was no apparent correlation between body weight and ALT levels.

Conclusions

Body weight has a complex relationship with a range of patient- and disease-related characteristics. In general, patients in the highest weight group were much more likely to be male, black, to have cirrhosis and to have been infected through IVDU. This clustering of poor prognostic characteristics may explain the lower SVR rates observed in heavier patients. 

Patient- and HCV-related factors at baseline according to body weight

Characteristic*

Body weight in kg (N)

 

<65 (512)

65 to <85 (1145)

³85 (747)

p

Male – n (%)

144 (28.1)

855 (74.7)

638 (85.4)

< 0.0001

Black race – n (%)

8 (1.6)

27 (2.4)

56 (7.5)

<0.0001

Age – yearsa

41.1 ± 11.0

42.9 ± 10.0

42.6 ± 8.1

0.005

BMI – kg/m2a

21.8 ± 2.3

25.4 ± 2.7

31.2 ± 4.8

< 0.0001

Infected by IVDU – n (%)

136 (26.6)

395 (34.5)

318 (42.6)

< 0.0001

Serum ALT ± SD – IU/La

83.5 ± 59.5

90.0 ± 61.4

88.2 ± 61.9

0.4721

Cirrhosis – n (%)

68 (13.3)

217 (19.0)

179 (24.0)

< 0.0001

Country USA

107 (20.9)

351 (30.7)

443 (59.3)

< 0.0001

Serum HCV RNA (106 copies/mL)a

5.8 ± 8.5

6.3 ± 7.1

5.9 ± 6.3

0.0009

HCV genotype 1 – n (%)

305 (59.6)

685 (59.8)

478 (64.0)

0.0853

HCV genotype 2 or 3 – n (%)

184 (35.9)

417 (36.4)

244 (32.7)

0.0853

aMean ± SD; *Cochran-Armintage Trend test for binary data and Jonckheere-Terpstra Trend test for ordinal/continuous data

 


 

Prediction of sustained virological response at week 4 of peginterferon alfa-2a (40KD) plus ribavirin treatment in chronic hepatitis C patients with persistently ‘normal’ ALT levels

Tran A, Gitlin N, Rodriguez-Torres M, O'Brien C, Zeuzem S, Lardelli P, Blotner S, Tong M.

 

Introduction

In general, the absence of an early virological response (EVR) at week 12 of combination therapy with peginterferon alfa-2a (40KD) plus ribavirin has high negative predictive value (NPV) for the probability of achieving an SVR. We aimed to determine whether this criterion could be applied at week 4 of treatment.

 

Methods

422 patients with persistently normal ALT levels (£30 IU/L, on ≥3 occasions over 18-months) were randomized to 24 or 48wks of treatment with peginterferon alfa-2a (40KD) 180µg/wk/RBV 800mg/d. The study was conceived before pivotal studies revealed that RBV 1000/1200mg/day is optimal for genotype 1. SVR was defined as undetectable HCV RNA (<50 IU/mL) after 24wks of follow-up. Rapid virological response (RVR) was defined as undetectable HCV RNA or a ≥2-log10 decline in HCV RNA at week 4.

 

Results (table)

The negative predictive value of an RVR in genotype 1 patients treated for 48 weeks (79%) is lower than that of an EVR at week 12 in the same group (96%, J Hepatol 2004;40(Suppl):48). However, when only patients with genotype 1 and a high viral load are considered, the NPV is 100% at week 4. The NPV of an RVR was 50% in the overall genotype 2/3 patient population. 

 

Conclusions

The results show that general treatment decisions should not be based on an RVR at week 4 in patients treated with peginterferon alfa-2a (40KD) plus ribavirin. The high NPV of an RVR at week 4 in genotype 1, HVL patients is intriguing. Extending treatment duration to 72 weeks in patients without an RVR (predominantly genotype 1, ≈40% HVL) significantly improved SVR rates in a recent trial (TeraViC-4, J Hepatol 2004;40(suppl 1):150). Thus, further study is required to determine the optimal duration of treatment for genotype 1 patients without an RVR at week 4.

 

Patients (N)

With a rapid virological response at wk 4 (%):

With an SVR  at wk 72 (%):

PPV

NPV

All genotype 1 pts treated x 48 wk (141)

61/141 (43)

57/141 (40)

66%

79%

Genotype 1 HVL treated x 48 wk (51)

25/51 (49)

14/51 (27)

56%

100%

All genotype 2,3 pts treated x 24 or 48 wks (117)

109/117 (93)

88/117 (75)

77%

50%

Genotype 2,3 HVL treated x 24 or 48 wks (56)

51/56 (91)

39/56 (70)

71%

40%

HVL = high viral load = HCV RNA >800,000 IU/mL ; PPV = positive predictive value (probability of an SVR after an RVR); NPV = negative predictive value (probability of no SVR without an RVR)

 


Peginterferon alfa-2a (40KD) plus ribavirin in treatment-naive patients with chronic hepatitis C and genotype 2 or 3 infection: individual estimated probability of sustained virological response (SVR)

Weiland O, Fried MW, Hadziyannis SJ, Messinger D, Freivogel K, Chaneac M, Foster GR.

 

Introduction

We constructed an "SVR Calculator'' for the purpose of estimating the probability that an individual patient will achieve an SVR after treatment with peginterferon alfa-2a (40KD) (peg-IFNα-2a) plus ribavirin. The probability can be calculated at baseline, or after 12 weeks’ treatment, and can include assumptions about adherence.

 

Methods

A logistic regression model was developed with data from genotype 2/3 patients treated with peg-IFNα-2a 180mcg/wk and ribavirin 800 or 1000/1200mg/day for 24 or 48wks in two pivotal trials (Fried NEJM 2002; Hadziyannis Ann Intern Med 2004). The influence of pre-treatment (gender, age, race, BMI, bodyweight, viral load, ALT quotient, histology (non-cirrhotic vs cirrhotic) and treatment-related factors (duration, ribavirin dose, adherence) on SVR rates was examined. Data outside the 5th-95th percentiles were excluded to minimize the influence of extreme values. A ‘model’ patient was created with the median values of variables that significantly influenced SVR rates. The probability of an SVR in a hypothetical patient is estimated by varying input parameters.

 

Results

Data from 532 genotype 2/3 patients were used to populate the model. Baseline viral load and adherence significantly modified the probability of an SVR for genotype 2 patients. Significant factors that affected the probability of achieving an SVR for genotype 3 patients are tabulated. The probability of an SVR in the model genotype 3 patient (BMI=25; HCV-RNA=3.3x106copies/mL, noncirrhotic) was 80% (95% CI: 74%-85%). Treatment duration (24/48wk) and ribavirin dose (800 or 1000/1200mg/d) were not significant factors for either genotype 2 or 3.

 

Conclusion

By varying the input parameters the individual probability of achieving an SVR with peg-IFNα-2a plus ribavirin in a patient infected with genotype 2 or 3 can be calculated. This tool can be used to guide treatment decisions and to help motivate patients to stay on therapy.

Probability of an SVR (%, 95% CI)  in a  genotype 3 patient after treatment with peginterferon alfa-2a (40KD) plus ribavirin*

Population

Viral load (copies/mL)

BMI (kg/m2)

Cirrhosis

(no. of pts used in the model)

1 x 106

24 x 106

18

30

Yes

No

All pts (n = 318)

84 (73–91)

78 (69–85)

88 (8094)

72 (61–81)

72 (60–82)

80 (7485)

Adherent pts (n=247)y

93 (8497)

88 (81–93)

95 (90–98)

83 (73–90)

83 (72–91)

90 (85–93)

Pts with an EVR (n = 304)

88 (77–95)

81 (72–88)

91 (83–96)

76 (65–85)

75 (63–85)

84 (77–89)

Adherent pts with an EVR (n =245)y

94 (85–97)

88 (81–93)

96 (90–98)

84 (74–91)

83 (72–91)

90 (86–94)

*Estimated by modifying the baseline characteristics of the model patient as indicated. Treatment duration 24 or 48 weeks with ribavirin 800-1200 mg/day. EVR: undetectable HCV RNA or 2-log10 decrease in HCV RNA at wk 12; SVR: Undetectable HCV RNA <50 IU/mL at end of follow-up. yAdherence = treatment with both drugs for >80% of the planned duration

 


 

Are there differences in baseline characteristics or treatment outcomes with peginterferon alfa-2a (40KD) (PEG-IFNα-2a) and ribavirin in patients infected with HCV genotype 1a versus 1b?

Zarski J-P, Smith C, Hadziyannis SJ, Rakela J, Hassanein T, Lee SD.

 

Introduction

We compared baseline characteristics and outcomes in HCV genotype 1a/1b patients enrolled in pivotal trials of PEG-IFNα-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®) (Fried NEJM 2002; Hadziyannis Ann Intern Med 2004).

 

Methods

Baseline characteristics of all genotype 1 patients treated with combination therapy were included. SVR rates in patients treated with PEG-IFNα-2a (40KD) 180 mg/week plus RBV 1000/1200 mg/d were compared. SVR was defined as undetectable serum HCV RNA (<50 IU/mL) at end 24 weeks’ follow-up. Data were analyzed by univariate and multivariate logistic regression analysis.

 

Results (ITT)

1323 genotype 1 patients were enrolled in the trials. Genotype 1b patients tended to be older (mean age 45 vs. 41 yrs), were more likely to be Asian (11% vs. 2%), and to have cirrhosis/bridging fibrosis (23% vs. 17%), and were less likely to have acquired HCV through intravenous drug use (IVDU; 21% vs. 44%) and to be from the US (29% vs. 51%) than genotype 1a patients. Factors significantly and independently associated with higher odds of genotype 1a vs. 1b infection ae shown in the figure.

The ITT population included 567 genotype 1a/1b patients. A total of 119/265 (45%; 95%CI: 39-51%) genotype 1a patients and 160/302 (53%; 95%CI: 47-59%) genotype 1b patients achieved an SVR. The SVR rate was significantly higher in genotype 1b than 1a patients in the univariate analysis (P=0.0039) and when adjusted for prognostic factors in the multivariate analysis (P=0.0016).

 

Conclusion

There are subtle but significant differences in the characteristics of patients infected with genotype 1a and 1b. In this retrospective analysis SVR rates were significantly higher in genotype 1b-infected patients treated for 48 weeks with PEG-IFNα-2a (40KD) plus RBV.


 

Effect of genotype and other baseline factors on response to peginterferon alfa-2a (40KD) (PEGASYS®) in HBeAg-positive chronic hepatitis B: results from a large, randomised study

Cooksley G, Manns M, Lau GKK, Liaw Y-F, Marcellin P, Chow WC, Thongsawat S, Gane E, Fried MW, Zahm F.

 

Background

Recent data show that peginterferon alfa-2a (40KD) (PEGASYS®) provides significantly higher rates of sustained HBeAg seroconversion than lamivudine in HBeAg-positive chronic hepatitis B (CHB) [Lau et al, AASLD 2004]. Baseline factors, such as HBV genotype, ALT or HBV-DNA have been shown to influence treatment response in CHB.

 

Objectives

To study the impact of baseline factors on sustained HBeAg seroconversion in a large, multinational study in HBeAg-positive CHB

 

Methods

HBeAg-positive patients (n=814) received (1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine. Patients were treated for 48 weeks and assessed after 24-weeks of follow-up (week 72).

 

Results

Overall, HBeAg seroconversion rates at week 72 were significantly higher with peginterferon alfa-2a (32%; P<0.001) and combination therapy (27%; P=0.023) than with lamivudine (19%). In multivariate analyses, high ALT, low HBV-DNA, and low HBeAg levels at baseline were significant predictors of HBeAg seroconversion (P≤0.001). Rates of HBeAg seroconversion stratified by genotype and other relevant baseline factors are presented in the Table.

 

Conclusions

HBV genotype C patients receiving peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy responded equally well to treatment as genotype B patients. This contrasts with data on conventional IFNa, which identified genotype C as being more ‘difficult-to-treat’. High ALT, low HBV-DNA and low HBeAg levels at baseline were predictive of response in patients with HBeAg-positive CHB. However, patients with normal/low ALT, who are currently not recommended for treatment due to poor response, may benefit from peginterferon alfa-2a monotherapy.

 

Table 1: HBeAg seroconversion rates at week 72 by baseline variables

 

PEGASYS

+ placebo

(n=271)

PEGASYS

+ lamivudine

(n=271)

Lamivudine

 

(n=272)

Genotype

  A

  B

  C

  D

 

12/23 (52%)

23/76 (30%)

50/162 (31%)

2/9 (22%)

 

4/18 (22%)

24/82 (29%)

43/156 (28%)

2/11 (18%)

 

3/15 (20%)

17/73 (23%)

26/162 (18%)

3/17 (18%)

ALT (x ULN)

 <=2*

 >2–5

 >5

  

27/92 (29%)#

36/121 (30%)

24/58 (41%)

 

19/93 (20%)§

30/111 (27%)

25/67 (37%)

 

19/96 (20%) 20/129 (16%)

13/47 (28%)

HBV-DNA

(log10 cp/ml)

 <=9.07

 >9.07–10.26

 >10.26

 

 

37/70 (53%)

39/138 (28%)

11/63 (17%)

 

 

20/56 (36%)

40/147 (27%)

14/68 (21%)

 

 

24/78 (31%)

21/123 (17%)

7/71 (10%)

HBeAg (IU/ml)

 <=186.3 (median)

 >186.3 (median)

 

57/138 (41%)

29/129 (22%)

 

44/127 (35%)

30/143 (21%)

 

38/138 (28%)

12/131 (9%)

*ALT values were abnormal (ie, >1 x ULN) at screening but normal at baseline in:  # 20 patients;  § 14  patients and 26 patients

 


on-treatment predictors of sustained biochemical and virological response in patients with HBeag-negative chronic hepatitis B (CHB) treated with peginterferon alfa-2a (40KD) (pegasys®)

Farci P, Marcellin P, Lu Z-M, Diago M, Lai M-Y, Gurel S, Kittis G, Yurdaydin C, Zahm F, Bonino F.

 

Background

Patients with HBeAg-negative CHB had significantly higher rates of response, sustained for 24 weeks after the end of treatment, with peginterferon alfa-2a (40KD) (PEGASYS®) or peginterferon alfa-2a plus lamivudine than with lamivudine monotherapy [Marcellin et al., NEJM 2004]. In patients with chronic hepatitis C, week 12 HCV-RNA levels are used to identify patients unlikely to achieve a therapeutic response, thereby avoiding unnecessary treatment and reducing costs. Similar on-treatment predictors of response in patients with CHB have yet to be defined.  

 

Objectives

To evaluate on-treatment predictors of response among patients receiving peginterferon alfa-2a (PEGASYS®) monotherapy in a large multinational study in patients with HBeAg-negative CHB.

 

Methods

HBeAg-negative patients in one study arm (n=177) received peginterferon alfa-2a 180μg once-weekly for 48 weeks and were assessed 24 weeks after the end of treatment (week 72). HBV DNA on treatment was analysed for the potential in predicting sustained [1] ALT normalisation and [2] HBV DNA <20,000 copies/ml, both measured at week 72. 

 

Results

At week 72, rates of ALT normalisation and HBV-DNA <20,000 copies/ml were significantly higher in patients with HBV-DNA <400 copies/ml at week 12 (70% and 61%, respectively) than in patients with HBV-DNA ≥400 copies/ml (53% and 31%; P=0.023 and P<0.001). Therefore, patients reaching HBV-DNA <400 copies/ml at week 12, had the best chance of a sustained response. Patients who did not have a 1.0 log reduction in HBV-DNA from baseline or who had HBV-DNA levels >7.0 log at week 12 had an approximately 80% probability of not achieving a sustained response. However, <10% of patients receiving peginterferon alfa-2a monotherapy met these criteria, and 20% of them achieved a sustained response at week 72 despite the modest initial HBV-DNA response.

 

Conclusions

Reduction of HBV-DNA below 400 copies/ml at week 12 was associated with sustained response to peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy 24 weeks after the end of treatment. However, this association was not sufficiently strong to discriminate with precision, based on HBV-DNA levels at week 12, which patients were likely/ unlikely to have a response to peginterferon alfa-2a monotherapy at week 72.

 


greater viral suppression with lamivudine +/- peginterferon alfa-2a (Pegasys®) does not translate into improved rates of sustained HBeAg seroconversion: results from a large, multinational study

Fried MW, Lau GKK, Piratvisuth T, Luo K-X, Chow WC, Paik SW, Chang WY, Flisiak R, Pluck N, Berg T.

 

Background

It remains unclear whether HBV-DNA must be suppressed by a certain amount or below a specific level in order to achieve HBeAg seroconversion. Furthermore, the optimal duration of HBV-DNA suppression, before and after HBeAg seroconversion, that will sustain seroconversion remains unknown.

 

Objectives

To evaluate the association between on-treatment viral suppression and [1] HBeAg seroconversion and [2] YMDD mutation development in patients with HBeAg-positive chronic HBV enrolled in a large, randomised, multinational study of peginterferon alfa-2a (40KD) (PEGASYS®) alone, peginterferon alfa-2a plus lamivudine, and lamivudine alone.

 

Methods

HBeAg-positive patients (n=814) received (1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine alone. Patients were treated for 48 weeks and assessed after 24 weeks of follow-up (week 72). HBV-DNA was measured with COBAS-AMPLICOR HBV MONITOR®; YMDD mutants with the INNO-LiPA HBV DR assay.

 

Results

The relationship between end-of-treatment HBV-DNA response, occurrence of YMDD mutants and sustained HBeAg seroconversion are presented in the Table.

 

Conclusions

Mean HBV-DNA suppression was greater with peginterferon alfa-2a plus lamivudine and lamivudine monotherapy compared to peginterferon monotherapy (see Table). However, HBeAg seroconversion rates 24 weeks after the end of treatment were highest with peginterferon alfa-2a monotherapy, suggesting that that more potent HBV-DNA suppression does not necessarily translate into improved HBeAg seroconversion rates. Increased HBV-DNA suppression with combination therapy resulted in a lower incidence of YMDD mutation than seen with lamivudine alone.

 

HBV-DNA suppression at end of treatment, incidence of YMDD mutants and HBeAg seroconversion at week 72  [95% CI]

 

PEGASYS

+ placebo

(n=271)

PEGASYS

+ lamivudine

(n=271)

Lamivudine

 

(n=272)

Week 48 (end of treatment)

Mean HBV-DNA reduction

(log10 cp/ml) vs baseline

-4.5

[-4.1 to -4.9]

-7.2

[-6.9 to -7.5]

-5.8

[-5.4 to -6.1]

HBV-DNA <400 cp/ml

25% [20 to 31]

69% [63 to 74]

40% [34 to 46]

Presence of YMDD mutant

NA

11% [8 to 16]

35% [29 to 41]

Week 72 (24 weeks after the end of treatment)

HBeAg seroconversion

32% (p<0.001*)

27% (p=0.023*)

19%

 

HBeAg seroconversion in pts with HBV-DNA <400 cp/ml at week 48

49/68 (72%)

[60 to 82]

63/186 (34%)

[27 to 41]

36/108 (33%)

[25 to 43]

* vs. lamivudine

 


 

Sustained HbsAg seroconversion in patients with chronic hepatitis B treated with peginterferon alfa-2a (40KD) (pegasys®)

Hadziyannis S, Lau GKK, Marcellin P, Piratvisuth T, Cooksley G, Bonino F, Chuttaputti A, Diago M, Jin R, Pluck N.

 

Background

HBsAg seroconversion (loss of HBsAg and appearance of anti-HBs) is considered to be the ultimate goal of anti-HBV treatment. It is, however, a rare event occurring in a negligible number of patients treated with nucleos(t)ide analogues, mostly in patients with HBV genotype A and after >1 year of continuous therapy.

 

Objectives

To describe HBsAg responses in 1351 patients with HBeAg-positive or -negative CHB who were enrolled in two randomised, partially double-blind, multinational studies comparing peginterferon alfa-2a (40KD) (PEGASYS®), peginterferon alfa-2a plus lamivudine, and lamivudine alone.

 

Methods

HBeAg-positive (n=814) and -negative (n=537) patients received (1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine. Patients were treated for 48 weeks and assessed 24 weeks after the end of treatment (week 72). Patients were considered to have sustained HBsAg seroconversion only if they were HBsAg-negative/anti-HBs-positive at week 72.

 

Results

Over 75% of patients in the studies were of Asian origin; predominant HBV genotypes in the study populations were B (27%) and C (50%). Overall HBsAg seroconversion rates at week 72, and rates stratified by ethnicity and genotype are shown in the Table. HBsAg seroconversion only occurred in patients achieving HBeAg seroconversion - among responders with HBeAg seroconversion, the rate of HBsAg seroconversion was 10% with peginterferon alfa-2a-containing therapy and 0% with lamivudine.

 

Conclusions

In our study, patients treated with a peginterferon alfa-2a-containing regimen for a defined duration achieved sustained HBsAg seroconversion, while patients treated with lamivudine did not.  The magnitude of HBV-DNA suppression on treatment does not seem to be the major factor leading  to HBsAg response, but rather the additional immunomodulatory effect associated with peginterferon alfa-2a (40KD) (PEGASYS®) treatment.

 

HBsAg seroconversion at week 72 (24 weeks after the end of treatment)

 

HBeAg-positive CHB

HBeAg-negative CHB

PEGASYS + placebo

(n=271)

PEGASYS+ lamivudine

(n=271)

Lamivudine

 

(n=272)

PEGASYS

+ placebo

(n=177)

PEGASYS+ lamivudine

(n=179)

Lamivudine

 

(n=181)

Mean drop in HBV-DNA

(log10 cp/ml) at week 48

-4.5

-7.2

-5.8

-4.1

-5.0

-4.2

HBsAg seroconversion

8 (3%)

p=0.004*

8 (3%)

p=0.004*

0

 

5 (3%)

p=0.03*

3 (2%)

 

0

 

Asian/Oriental

Caucasian

 

 HBV genotype             A

            B

            C

            D

3/238 (1%)

5/24 (21%)

 

 

5/23 (22%)

0/76 (0%)

3/162 (2%)

0/9 (0%)

5/238 (2%)

3/23 (13%)

 

 

2/18 (11%)

1/82 (1%)

4/156 (3%)

0/11 (0%)

 

 

3/108 (3%)

2/66 (3%)

 

 

2/11 (18%)

1/43 (2%)

2/63 (3%)

0/55 (0%)

2/112 (2%)

1/65 (2%)

 

 

1/10 (10%)

2/41 (5%)

0/69 (0%)

0/54 (0%)

 

 

* vs. lamivudine

 


peginterferon alfa-2a (40KD) (PEGASYS®) versus peginterferon alfa-2a plus lamivudine versus lamivudine in HBeag-positive chronic HBV: effect of previous treatment and drug exposure on sustained response

Lau GKK, Piratvisuth T, Luo K-X, Marcellin P, Thongsawat S, Gane E, Fried MW, Cooksley G, Button P, Liaw Y-F.

 

Background

In chronic hepatitis C, previous treatment and extent of drug exposure seem to have an impact on response rates. In patients with chronic hepatitis B (CHB) the effects of previous anti-HBV treatment and exposure to study drug on responses to pegylated interferon are less well investigated. 

 

Objectives

 To investigate the effect of previous treatment and drug exposure on efficacy and safety in a randomised, partially double-blind, multinational study.

 

Methods

HBeAg-positive patients (n=814) received (1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine. Patients were treated for 48 weeks and assessed 24 weeks after the end of treatment (week 72). Treatment with any anti-HBV drug 6 months before study entry was not permitted. Analysis of drug exposure was performed only in the peginterferon alfa-2a monotherapy arm.

 

Results

The effects of previous treatment with either interferon and/or lamivudine on HBeAg seroconversion rates are shown in the table. Regardless of whether patients were pre-treated or not, HBeAg seroconversion rates at week 72 were higher with peginterferon alfa-2a and combination therapy than with lamivudine.

 

The rate of adherence to peginterferon alfa-2a was high, with 78% of patients receiving >90% of the total drug dosage (>7776μg). HBeAg seroconversion rates were 28% in those receiving <90% of the total drug dosage and 33% in those receiving >90% of the total drug dosage.

 

Conclusions

Peginterferon alfa-2a (40KD) (PEGASYS®) provided higher rates of HBeAg seroconversion than lamivudine, irrespective of whether the patients had or had not received previous anti-HBV therapy. Previous treatment with interferon or lamivudine did not substantially affect HBeAg seroconversion rates with peginterferon alfa-2a in this study. Adherence to peginterferon alfa-2a in this study was excellent.

 

HBeAg seroconversion rates at week 72 by previous treatment

 

PEGASYS

+ placebo

(n=271)

PEGASYS

+ lamivudine

(n=271)

Lamivudine

 

(n=272)

All patients (ITT)

 

32%

p<0.001*

27%

p=0.023*

19%

 

Pts without previous     anti-HBV therapy

66/214 (31%)

p=0.018*

59/221 (27%)

p= 0.115*

42/208 (20%)

 

Pts with previous exposure to conventional IFN

13/30 (43%)

P=0.047*

11/32 (34%)

P=0.038*

4/32 (13%)

 

Pts with previous exposure to lamivudine

10/31 (32%)

P=0.065*

6/24 (25%)

P=0.253*

7/42 (17%)

 

* vs lamivudine

includes lamivudine and conventional or pegylated interferon

 


Sustained response to peginterferon alfa-2a (40KD) (PEGASYS®) in HBeAg-negative chronic hepatitis B.  1-year follow-up data from a large, randomised multinational study

Marcellin P, Lau GKK, Bonino F, Farci P, Hadziyannis S, Piratvisuth T, Germanidis G, Yurdaydin C, Lai M-Y, Pluck N.

 

Background

Patients with HBeAg-negative chronic hepatitis B (CHB) had significantly higher rates of sustained response with peginterferon alfa-2a (+/- lamivudine) than with lamivudine monotherapy [Marcellin et al, NEJM 2004].

 

Objectives

To assess the durability of response one year after the end of treatment.

 

Methods

HBeAg-negative patients received either peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine. Patients were treated for 48 weeks and assessed 24 weeks after the end of treatment (initial study). All study centres were offered participation in a roll-over 5-year long-term observational study (LT-study). Preliminary results generated 48 weeks after the end of treatment (week 96) are presented. 

 

Results

Thirteen of 54 (24%) study centres opted not to take part in the LT-study. Overall, 304 of 537 patients (57%) analysed in the initial study participated in the LT-study; more patients in the peginterferon alfa-2a-containing arms (63% and 62%) than in the lamivudine arm (45%) participated. The proportion of initial study non-responders not participating in the LT-study was higher in the lamivudine arm (65%) than in the peginterferon alfa-2a monotherapy arm (53%).

 

In the initial study, normal ALT, HBV-DNA <20,000 and <400 copies/ml, all assessed 24 weeks after the end of treatment, were significantly higher with peginterferon alfa-2a (+/- lamivudine) than with lamivudine (P<0.01). Rates of response in the initial and LT-studies are presented in the table. 

 

Conclusions

In patients with HBeAg-negative CHB receiving peginterferon alfa-2a, rates of biochemical and virologic response seen one year after the end of treatment were similar to those reported 24 weeks after the end of treatment in the initial study. A 48-week course of peginterferon alfa-2a (40KD) (PEGASYS®) is able to induce high rates of sustained biochemical and virological responses one year after treatment discontinuation.

 

 

Responses 24 weeks after the end of treatment

(initial study, all patients)

 

PEGASYS

PEGASYS+LAM

LAM

ALT normal #

105/177 (59%)

107/179 (60%)

80/181 (44%)

HBV DNA<20,000 copies/ml #

76/177 (43%)

79/179 (44%)

53/181 (29%)

HBV<400 copies/ml

34/177 (19%)

35/179 (20%)

12/181 (7%)

Responses 48 weeks after the end of treatment

(LT-study, all patients with available data ) 

ALT normal #

58/99 (59%)

51/98 (52%)

28/65 (43%)

HBV DNA<20,000 copies/ml #

41/97 (42%)

40/97 (41%)

20/65 (31%)

HBV<400 copies/ml *

17/102 (17%)

15/104 (14%)

6/75 (8%)

# co-primary endpoints in the initial study

*if week 96 value was missing, week 84 value was used

 


Effect of ALT flares on efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS®), peginterferon alfa-2a plus lamivudine and lamivudine in HBeAg-positive chronic hepatitis B (CHB)

Piratvisuth T, Luo K-X, Marcellin P, Chang WY, Berg T, Flisiak R, Chao Y-C, Paik SW, Thongsawat S, McCloud P

 

Background

In HBeAg-positive CHB, marked ALT flares during IFN-based treatment have been associated with HBeAg seroconversion and viral suppression. In contrast, marked flares after discontinuation of nucleos(t)ide analogues may lead to potentially life-threatening disease exacerbations.

 

Objectives

To investigate the effect of ALT elevations on efficacy and safety in a randomised, partially double-blind, multinational study.

 

Methods

 HBeAg-positive patients (n=814) received (1:1:1) either peginterferon alfa-2a (180μg once-weekly) + placebo, peginterferon alfa-2a + lamivudine (100mg once-daily) or lamivudine. Patients were treated for 48 weeks and assessed after 24 weeks follow-up (week 72). For this analysis, marked ALT elevations (maximums) were defined as either >10xULN or >5x baseline ALT levels (bALT), and moderate flares as >5-≤10xULN.

 

Results

On-treatment ALT >10xULN was seen in 18%, 13% and 11% of patients receiving peginterferon alfa-2a, combination therapy and lamivudine, respectively; and ALT >5x bALT in 5%, 6% and 4%, respectively. The association between on-treatment ALT maximums and HBeAg seroconversion at week 72 is shown in the Table. During follow-up, ALT >10xULN was seen in 12%, 13% and 15% of patients with peginterferon alfa-2a, combination therapy and lamivudine, respectively; and ALT >5x bALT in 7%, 11% and 11%, respectively.

Eight patients had a flare in ALT during follow-up that was considered a serious adverse event (4 following peginterferon alfa-2a ± lamivudine; 4 following lamivudine monotherapy). In 2 patients (of 272) receiving lamivudine monotherapy this led to hepatic decompensation – resulting in one liver transplant and one death. 

 

Conclusions

Marked on-treatment ALT elevations were generally more frequent with peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy and were more common in patients with HBeAg seroconversion 24 weeks after the end of treatment. In contrast, marked follow-up flares were generally more frequent with lamivudine and in two patients led to irreversible liver failure.

 

 

On-treatment ALT maximums and HBeAg seroconversion at week 72

 

PEGASYS

+ placebo

(n=271)

PEGASYS

+ lamivudine

(n=271)

Lamivudine

 

(n=272)

HBeAg seroconversion rates in:

 

All patients (ITT)

87/271 (32%)

74/271 (27%)

52/272 (19%)

 

Patients with ALT

>5x bALT

6/14 (43%)

6/16 (38%)

3/12 (25%)

 

Patients with ALT

>10x ULN

20/48 (42%)

12/35 (34%)

3/31 (10%)

Pts with ALT

>5-<10 x ULN

28/74 (38%)

27/86 (31%)

16/64 (25%)

Patients with ALT

<=5 x ULN

39/149 (26%)

35/150 (23%)

33/177 (19%)