Parallel XXXIII: HCV: Therapeutic Trials

Tue, Nov 04 - 11:15 AM

 

 

Treatment – Predictors of Treatment Response

 

268. Sustained Virologic Response (SVR) and Predictors of Response in African American (AA) Patients in the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess OptimaL Pegylated Interferon Therapy) Phase 3b Study.  

J. McCone; K. Hu; J. G. McHutchison; M. L. Shiffman; J. W. King; S. K. Herrine; G. Galler; M. Sulkowski; F. Nunes; K. a. Brown; S. C. Gordon; K. D. Mullen; N. Ravendhran; W. M. Cassidy; R. H. Ghalib; W. Deng; S. Noviello; J. K. Albrecht; A. J. Muir.

Background:

Previous studies have reported that AA patients treated with peginterferon and ribavirin (R) have decreased SVR rates compared with non-AAs. A large number of AA patients were enrolled in the IDEAL trial providing a chance to evaluate this group’s SVR rates and response at earlier time points.

 

Methods:

In this trial, 3070 treatment-naive, HCV genotype 1 infected patients, including 570 AAs, were randomized (1:1:1) and treated for 48 weeks with PEG2b 1.5mcg/kg/week or PEG2b 1.0mcg/kg/week + R 800-1400mg/day, or PEG2a 180mcg/week + R 1000-1200mg/day. Treatment was terminated for patients who had a lack of virologic response at week 12 or 24. SVR, predictors of response, and safety in AAs were evaluated.

 

Results.

Of 570 AAs and 2500 non-AAs, 54%/60% were male with a mean age of 50/48 years, mean weight of 87/83 kg, 79%/82% had HCV-RNA >600,000 IU/mL with similar characteristics across the three arms. End-of-treatment (EOT) response, relapse and SVR for AAs and non-AAs are shown below. SVR for AAs is substantially lower compared with non-AAs for all treatment groups. The lower response rate in AAs is due to less response at EOT rather than increased relapse. AAs and non-AAs with rapid and early virologic responses (RVR and EVR, undetectable HCV RNA at Treatment Weeks 2, 4 and 12) are shown below. As with non-AAs EVR is predictive of SVR; however, fewer AAs have an early virologic response. Adverse events (AEs) were similar across the groups. Serious AEs/discontinuation due to AE for AAs: PEG2b1.5, 8%/14%; PEG2b1.0, 11%/10%; PEG2a, 12%/14%. Anemia (<10g/dL) and neutropenia (<750/mm3) were similar in AAs to non-AAs: PEG2b1.5, 28%/21%; PEG2b1.0, 31%/12%; PEG2a, 34%/31%. Erythropoietin use was 16% in AAs and non-AAs.

 

Conclusions:

Racial difference strongly influences SVR rates. Higher relapse rate was not the primary difference in the lower SVR rates in AAs compared with non-AAs, rather early response was a more important factor in predicting SVR in each of the three treatment arms.

 

Patterns of Virologic Response

 

PEG2b 1.5/R, %

PEG2b 1.0/R, %

PEG2a/R, %

 

AA

Non-AA

AA

Non-AA

AA

Non-AA

EOT

32

58

21

56

45

69

Relapse

26

23

16

20

37

31

SVR

23

44

17

43

26

44

No. of Patients Achieving SVR (SVR, %)

Undetectable Week 2

3/3
(100)

40/42
(95)

1/1
(100)

37/41
(90)

4/4
(100)

33/40
(83)

Undetectable Week 4

7/7
(100)

100/109
(92)

6/7
(86)

63/72
(88)

11/12
(92)

87/111
(78)

Undetectable Week 12

29/38(76)

299/369
(81)

20/26
(77)

283/340
(83)

38/57
(67)

306/409
(75)

Detectable ≥2 log drop at Week 12 and Undetectable Week 24

13/24(54)

57/133
(43)

9/19
(47)

66/135
(49)

13/34
(38)

53/159
(33)

 

HCV Drug Pipeline – Telaprevir

 

269. A Phase 2b Study of Telaprevir with Peginterferon-Alfa-2a and Ribavirin in Hepatitis C Genotype 1 Null and Partial Responders and Relapsers Following a Prior Course of Peginterferon-Alfa-2a/b and Ribavirin Therapy: PROVE3 Interim Results. 

J. G. McHutchison; M. L. Shiffman; N. Terrault; M. P. Manns; A. M. Di Bisceglie; I. M. Jacobson; N. H. Afdhal; E. Heathcote; S. Zeuzem; H. W. Reesink; S. George; N. Adda; A. J. Muir.

Background:

PROVE3 is a randomized placebo-controlled Phase 2b study of telaprevir (TVR, T) combined with peginterferon-alfa-2a (Peg-IFN, P) and ribavirin (RBV, R) in null and partial responders and relapsers following PR therapy. We report on a planned interim ITT analysis performed when all enrolled pts had completed 36 wks.

 

Methods:

Pts were randomized to receive: TVR 750 mg q8h + Peg-IFN 180 μg/wk + RBV 1000–1200 mg/day for 12 wks followed by PR for 12 wks (T12/PR24); or all 3 drugs for 24 wks followed by PR for 24 wks (T24/PR48); or TVR and Peg-IFN for 24 wks (T24/P24). A control group was randomized to receive 48 wks of PR with TVR-matched placebo for the first 24 wks (PR48).

 

Results:

453 pts received ≥1 dose of study drug. 213 pts discontinued prior to wk 24: 157 due to stopping rule (not achieving RVR or EVR; or viral breakthrough) with 69 in PR48, 19 in T12/PR24, 25 in T24/PR48, 44 in T24/P24; 56 due to other reasons (AEs, withdrew consent). At wk 36, 5 (4%) pts in PR48, 13 (11%) in T12/PR24, 30 (26%) in T24/PR48 and 10 (9%) in T24/P24 discontinued due to AEs; skin and GI disorders were more frequent in TVR-based arms. Interim data on pts with undetectable HCV RNA (<10 IU/mL) by prior virologic response to PR regimen are shown (table).

 

Conclusions:

T/PR therapy resulted in substantially higher viral response rates (RVR, EVR and SVR12) in prior null and partial responders and relapsers, compared to historical viral response rates with PR. SVR12 rates in prior relapsers were similar to those in treatment-naïve pts given T/PR in PROVE1 and PROVE2. Compared to T/PR, response rates were lower in the T/P regimen. T/PR safety profile was similar to that seen in treatment-naïve pts. These data are encouraging; further data are required from this study and subsequent larger confirmatory studies.

 

Prior response
Visit, n (%)

PR48
N=114*

T12/PR24
N=115

T24/PR48
N=113

T24/P24
N=111

Non-response (Null or Partial)

 

 

 

 

Wk 4

0/68

33/66 (50)

22/64 (34)

20/62 (32)

Wk 12

2/68 (2.9)

47/66 (71)

35/64 (55)

23/62 (37)

EoT

N/A

43/66 (65)

N/A

21/62 (34)

SVR12

N/A

27/66 (41)

N/A

7/62 (11)

Relapse

 

 

 

 

Wk 4

0/42

32/40 (80)

29/41 (71)

28/39 (72)

Wk 12

7/42 (17)

35/40 (88)

32/41 (78)

32/41 (78)

EoT

N/A

33/40 (83)

N/A

27/39 (69)

SVR12

N/A

29/40 (72)

N/A

14/39 (36)

Breakthrough

 

 

 

 

Wk 4

0/3

4/9 (44)

6/8 (75)

3/10 (30)

Wk 12

0/3

4/9 (44)

6/8 (75)

5/50 (50)

EoT

N/A

4/9 (44)

N/A

3/10 (30)

SVR12

N/A

4/9 (44)

N/A

2/10 (20)

*Data missing for 1 pt; SVR12=undetectable HCV RNA 12 weeks post-treatment

 

Treatment – Side Effect Management

 

270. Es-Citalopram for the prevention of PEG-IFN-α and Ribavirin associated depression in HCV-infected patients without psychiatric risk factors (CIPPAD-study). 

M. Schaefer; R. Sarkar; U. Spengler; T. Schlaepfer; J. Ockenga; A. Friebe; S. Effenberger; L. M. Heinze; P. Buggisch; J. Reimer; R. Link; A. Klein; B. Hintsche; V. Weich; F. Boemmel; S. Zeuzem; T. Berg.

Objective:

The “EsCItalopram for the Prevention of PEGASYSΘ Associated Depression study” (CIPPAD-study) is a prospective multicentre, randomized, parallel-group, double-blind, placebo-controlled clinical trial with the primary objective to evaluate the impact of a 2-week antidepressant pretreatment and continuous accompanying therapy with Escitalopram on the incidence and severity of interferon-alpha associated depression.

 

Study design:

Patients without any history of psychiatric or substance abuse disorder either received escitalopram 10 mg/day 2 weeks prior to commencement of HCV therapy and or received placebo. After the antidepressant pretreatment phase all patients were treated with pegylated interferon-alpha-2a (PEG-IFN-α-2a) plus ribavirin. Antidepressants treatment or placebo treatment was continued over the whole treatment period of 24 – 48 weeks (depending on response and genotype). The frequency and severity of depressive episodes were defined according to DSM-IV criteria for a “major depression” and by using the Montgomery Asperg Depression Scale (MADRS).

 

Results:

So far, preliminary data from 189 patients (87 in the placebo group and 102 in the verum group) are presented. No significant differences were found between groups regarding age and gender. Most depressive episodes developed until week 12 (63%), while 33% of the major depressive episodes were diagnosed between week 12 and 24 of antiviral treatment with PEG-IFN-α-2a and ribavirin. Highly significantly more patients in the placebo group (48.9%) were diagnosed from clinicians as having a major depressive episode if compared to the verum group (14.3%, χ2=28.13, df=1, p<0.001). Moreover, evaluation of the severity of depressive syndromes by MADRS-scores showed that significantly more patients in the placebo group reached moderate to severe depressive symptoms (defined as MADRS scores of 15 and above) during antiviral treatment (34.7%) if compared to the verum group (17.1%, χ2=8.13, df=1, p=0.004). Overall, patients in the placebo group had a 2.6 fold increased risk to reach MADRS depression scores = or over 15 (CI 95%: 1.33-4.98, OR=2.57). Significantly more patients in the placebo group needed an antidepressive rescue medication with mirtazapine (χ2=8.3, df=1, p=0.004). So far no significant differences between both groups were found regarding genotype distribution and sustained virological response.

 

Discussion:

Our preliminary results clearly indicate that an antidepressive pre-treatment with escitalopram was able to significantly reduce the frequency and severity of depressive episodes during antiviral therapy with PEG-IFN-a-2a in patients without psychiatric risk factors.

 

Treatment – General

 

271. Reduction of Insulin Resistance with Effective Clearance of Hepatitis C Infection: Results from the HALT-C Trial. 

A. Delgado-Borrego; S. H. Jordan; B. Negre; D. Healey; W. Lin; D. A. Ludwig; A. F. Lok; J. E. Everhart; R. T. Chung.

Background and Aims:

Hepatitis C infection is associated with increased prevalence of diabetes and insulin resistance(IR); whether this is a causal relationship has not been established. We performed a longitudinal study within the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis(HALT-C) Trial to evaluate changes in IR and response to antiviral therapy.

 

Methods:

Eligible patients had failed prior therapy with interferon(IFN) with or without ribavirin and had histologic evidence of advanced hepatic fibrosis. This analysis was restricted to patients who were known to be fasting at blood draw, did not have uncontrolled diabetes, and were infected with genotype non-3 HCV(n=96). Patients underwent 24 weeks of therapy with PEG IFN and ribavirin and were categorized into 3 groups based on week 20 status:null responders(NR) whose HCV RNA declined<1 log from baseline; partial responders(PR) whose HCV RNA declined>=1 log but were positive by qualitative Amplicor PCR; and responders(R) who had undetectable HCV RNA by qualitative Amplicor PCR (<100 IU/mL). Transcription-mediated amplification(TMA) (lower limit of HCV RNA detection of 5IU/mL) was used to further evaluate responders. Only one responder was TMA+ and subsequently reclassified as a PR. The primary outcome measure was the change in homeostasis model assessment(HOMA2-IR). Possible confounders, including adipokines and histology, were considered.

 

Results:

Median baseline HOMA2-IR in the 3 groups were 4.3 for NR(n=38), 3.4 for PR(n=37), and 2.7 for R(n=21), p=0.14 across groups. A negative trend was observed between degree of baseline hepatic steatosis and response to therapy. There was no statistically significant difference across groups in the distribution of baseline histological cirrhosis or in serum TNF-α, adiponectin, or glucose levels. Our final model evaluated the difference in HOMA2-IR between week 0 and week 20 among the categories of virological response while controlling for baseline HCV RNA level, HOMA2-IR, and histological cirrhosis. The mean HOMA2-IR differences across the three virological response categories were +0.1 (NR), -0.72 (PR), -2.68 (R) (p =0.017).

 

Conclusion:

Reduction and clearance of hepatitis C virus are associated with improvement in HOMA2-IR. These results provide further evidence for a causal role of HCV in the development of insulin resistance.

 

Variable (Wk 0)
(Freq. or median)

NR (n=38)

PR (n=37)

R (n=21)

P Value

% Steatosis (score>1)

47.4

29.7

19.0

0.07

% Cirrhosis (fibrosis score>4)

39.5

56.8

38.1

0.2

TNF-α (pg/mL)

2.7

2.6

2.6

0.9

Adiponectin (ng/mL)

45.3

42.6

34.7

0.4

Glucose (mg/dl)

96

99

101

0.4

 

HCV Drug Pipeline – Taribavirin

 

272. Treatment Week 24 Results of Weight-based Taribavirin Versus Weight-Based Ribavirin, Both with Peginterferon alfa-2b, in Naïve Chronic Hepatitis C, Genotype 1 Patients. 

E. Lawitz; A. J. Muir; F. Poordad; E. Chun; J. Hammond.

Background and Aim:

Taribavirin (TBV) is an oral pro-drug of ribavirin (RBV). Previous studies have shown that using a fixed dose of TBV vs. RBV, both with peginterferon, yields better safety in terms of the incidence of anemia. This phase IIb study is being conducted to determine if weight-based dosing (WBD) with higher dosages of TBV can achieve comparable efficacy to that of RBV while maintaining the previously noted anemia advantage.

 

Methods:

A Phase IIb randomized, open-label, active-controlled, parallel group, study was conducted at US sites. Treatment naïve, genotype 1 patients, stratified by body weight and baseline viral load were randomized 1:1:1:1 to TBV 20, 25 or 30mg/kg/day or RBV (800, 1000, 1200, or 1400mg/day), both administered with peginterferon alfa-2b.

 

Results:

275 patients were randomized with the following patient demographics: mean age 48.8 yr, 61.1% male, 82.1 kg mean weight, 80.7% viral load ≥400,000 IU/mL, 17.8% African-American and 12% Hispanic. Treatment week (TW) 24 efficacy and safety results for the intention-to-treat (ITT) population are shown in Table 1. Response rates at TW4 and TW12 are also shown in Table 1.

 

The most common adverse events (AE) reported through TW24 were fatigue, headache, nausea and diarrhea, which were generally comparable in frequency except for diarrhea. This AE was reported approximately twice as frequently in the TBV patients, but was generally mild and not dose-limiting.

 

Conclusions:

The data from this Phase IIb study demonstrated comparable efficacy for weight-based dosing at 20, 25, and 30 mg/kg of TBV vs. RBV through TW24. TBV at 20 and 25 mg/kg was associated with significantly lower rates of anemia than RBV with similar tolerability. The results from this ongoing study suggest that, if maintained, weight-based dosing with TBV may provide a safe and effective alternative to current RBV in the treatment of chronic hepatitis C.

 

Table 1: Efficacy/Safety (ITT)

Phase IIb

 

TBV
20 mg/kg
n=67

TBV
25 mg/kg
n=70

TBV
30 mg/kg
n=68

RBV
800-1400 mg
n=70

TW4
Undectectable1

11
(16.4%)

10
(14.3%)

11
(16.2%)

8
(11.4%)

TW12
Undectectable1

28
(41.8%)

29
(41.4%)

17
(25.0%)

22
(31.4%)

TW24
Undectectable1

35
(52.2%)

29
(41.4%)

27
(39.7%)

28
(40.0%)

Anemia rate TW 242

9
(13.4%)*

8
(11.4%)**

13
(19.1%)

21
(30.0%)

1HCV RNA <39 IU/mL
2Anemia rate defined as percentage of patients with Hgb level <10g/dL.
*p=0.023
*p=0.011

 

HCV – Treatment – General

 

273. Reduced Hepatic Inflammation is Related to HCV RNA Suppression and Correlates With Less Fibrosis Progression and Fewer Cirrhosis Complications in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. 

C. Morishima; M. L. Shiffman; K. Lindsay; G. Szabo; J. L. Dienstag; E. C. Wright.

Background:

During the HALT-C trial, long term peginterferon-alfa-2a (pegIFN) therapy did not affect overall liver fibrosis progression or clinical outcomes among prior IFN nonresponders with advanced hepatic fibrosis (≥Ishak stage 3), but ALT and hepatic necroinflammatory histologic activity index (HAI) were significantly reduced in treated vs untreated patients (Hepatology 2007; 46 (4S):290A). In this subanalysis, the relationship between reduction of hepatic inflammation and decline in HCV RNA levels, and impact on fibrosis progression and clinical outcomes were evaluated.

 

Methods:

657 patients who failed to achieve SVR with pegIFN 180 µg/week and ribavirin during the HALT-C lead-in phase and who had a follow-up biopsy 1.5 years (1.5Y) after randomization were evaluated. 328 were randomized to pegIFN (90 µg/week) and 329 to no additional treatment for 3.5Y (controls). No patient had a history of CTP>6, ascites, hepatic encephalopathy, variceal hemorrhage or hepatocellular carcinoma at study entry. Roche COBAS™ Monitor and Amplicor v.2.0 tests were used to measure serum HCV RNA. Change in liver histology between baseline and 1.5 or 3.5Y after randomization was defined as a 2 point difference in Ishak fibrosis or HAI score.

 

Results:

Patients were grouped according to their degree of HCV RNA suppression during lead-in (<2 log10, 2-4 logs10, > 4log10). Hepatic HAI improved from screening to 1.5Y in both the randomized treatment (26%, 37%, and 65%, according to HCV RNA suppression, p<0.001) and control (17%, 15%, and 41%, p<0.001) groups. Net improvement in HAI (%Improved-%Worse) also increased with greater HCV RNA suppression (3%, 19%, and 60% vs -14%, -17%, and 22%, treatment vs control). The percentage of patients with improved HAI was higher in treated vs control groups (38% vs 23%, p<0.001), even after adjusting for lead-in virologic responses. Patients with Ishak 3-4 fibrosis at entry and improved inflammation at 1.5Y had less fibrosis progression (p<0.001). Decreased hepatic inflammation at 1.5Y was associated with decreased mean ALT/ULN levels (-0.72 vs -0.24, p<0.001) and fewer subsequent clinical outcomes (9% vs 13%, p=0.001). The reduced rate of fibrosis progression or outcomes as related to HAI improvement was similar in both treatment and control groups.

 

Conclusions:

Reduced hepatic inflammation from screening to 1.5Y correlated with more profound viral suppression during lead-in, lower ALT and reduced fibrosis progression at 1.5Y, and fewer clinical outcomes after 1.5Y. In subjects treated with pegIFN who experience substantial HCV RNA suppression, reduced hepatic inflammation and fibrosis, and clinical benefit could follow.