Epidemiology

80. Mortality Among Individuals Tested for Hepatitis C Antibody (anti-HCV) in British Columbia, Canada, 1992-2004.

A. Yu; J. J. Spinelli; J. A. Buxton; M. Krajden

Purpose:

Describe all cause and disease specific mortality in individuals who underwent serological testing for hepatitis C virus (HCV).

Methods:

The BC Centre for Disease Control performs > 95% of HCV testing in a region of 4M people. Serological test data were linked to BC Vital Statistics cause of death information. Subjects had to be registered with the BC Medical Services Plan and have at least one anti-HCV test on record to be included. Four categories of subjects were defined from anti-HCV testing patterns and results: those who were: 1) anti-HCV non-reactive at baseline and were only tested once (SNR), 2) had serial multiple non-reactive tests (MNR), 3) tested anti-HCV reactive at baseline (REAC), and 4) underwent a seroconversion (SERO). A seroconversion identifies incident infections and was defined as a non-reactive anti-HCV test followed by a reactive anti-HCV test. For each cause of death category, mortality among anti-HCV testers was compared to an age, sex and calendar-year standardized expected mortality rate derived from the general population. The reported standardized mortality ratio (SMR) is the relative risk of mortality compared to the general population (Table). Liver related deaths include: viral hepatitis, liver cancer, alcoholic and non-alcoholic liver disease. Drug related deaths include: drug-induced mental disorders resulting in death, and intentional, accidental and undetermined overdoses.

Results:

There were 375,734 anti-HCV testers (1,412,011 person-years (PY)) in SNR; 90,130 testers (297,621 PY) in MNR; 29,686 testers (168,440 PY) in REAC and 2,834 testers (10,749 PY) in the SERO categories. Mean age at entry for each group was 40.5 yrs among SNR, 39.5 yrs among MNR, and 42.2 yrs among REAC, and 33.0 yrs among SERO. Anti-HCV tested groups had consistently higher SMRs referent to the general population.

Conclusions:

The SMR was highest in those who underwent a seroconversion where drug related and HIV infection were important contributors to mortality at a young age prior to the development of viral sequelae. Liver disease, drug use and HIV infection were important contributors to increased mortality in the REAC group. The SMR was also increased in the both single and multiple negative testers.

Cause of death	SNR	MNR	REAC	SERO
All cause	1.71	3.28	4.97	10.60
Liver related	4.53	12.96	26.45	18.98
Viral hepatitis	1.46	4.00	66.75	38.81
Liver cancer	5.08	9.09	20.43	14.13
Liver disease (Alcoholic + Non-alcoholic)	4.97	17.29	14.17	12.86
Drug related	1.71	4.75	20.20	41.16
HIV	2.19	5.32	24.83	32.83

Epidemiology

81. Genotype 1 versus Genotypes 2 and 3, Female Gender and Younger Age Are Associated with Recovery from Hepatitis C Virus Infection in Alaska Native and American Indian Persons.

S. Livingston; D. L. Bruden; L. J. Townshend-Bulson; C. E. Homan; B. J. McMahon; J. Pawlotsky; S. Chevaliez; M. Bruce; H. R. Rosen; D. R. Gretch

Background:

Acute HCV infection in HIV-infected men-who-have-sex-with-men (MSM) is an emerging world-wide epidemic. We have reported rapid fibrosis progression in these patients but little else has been described of US outbreaks. We therefore report risk factors for acquisition, treatment response, and fibrosis progression in an outbreak in New York City.

Methods:

Acute HCV infection was defined as newly-identified HCV antibody with either new ALT elevation, >1 log fluctuation in HCV viral load (VL), or high clinical suspicion. All treated patients received pegylated interferon and ribavirin. An age-matched case-control study was performed to identify sexual and drug use risk factors for acute HCV infection, analyzed using McNemar’s test.

Results:

We enrolled 51 HIV-infected MSM with 53 episodes acute HCV infection. Median age was 40 years; median CD4 count 471 cells/μL. In only 5 (9%) episodes did spontaneously clearance occur.

In the case-control study of 21 matched pairs, the only factors associated with a significant risk of HCV infection were unprotected receptive anal intercourse with (p=0.04) or without (p=0.03) ejaculation; unprotected receptive oral sex with ejaculation (p=0.03); use of sex toys (p=0.03); “sex while high” (p=0.01); and marijuana use (p=0.04). Conversely, protected receptive anal intercourse, protected receptive oral sex, fisting, nor injection drug use, sharing injection equipment, or transfusions were associated (all, p>0.05).

Of 16 patients who completed therapy and sustained virological response (SVR) evaluation, 12 (75%) had SVR. Of the 4 patients who failed therapy, 3 initiated treatment >6 months after first ALT elevation.

Liver biopsy was performed in 30 patients (median 4.4 months after first ALT elevation); 21 had stage 2 fibrosis (Scheuer, scale 0 to 4) and 2 had stage 3 fibrosis (77% ≥ stage 2), while only 5 had stage 1, and 2 had stage 0 (24% < stage 2). Fibrosis increased with time-to-biopsy (linear regression, p=0.04): of the 7 biopsies performed more than 1 year (range 14-53 mo) after first ALT elevation, all had ≥ stage 2 fibrosis.

Conclusions:

Acute HCV infection of HIV-infected MSM in New York City is sexually transmitted and results in significant liver fibrosis. Treatment is highly successful when initiated in the acute phase but may be less successful if initiated soon after. Thus, it is crucial to detect HCV infection in the acute phase to allow successful treatment and prevent further progression of the already significant liver fibrosis. We therefore recommend ALT testing every 3 months and HCV antibody testing every 6-12 months for all HIV-infected MSM. Promotion of safe sex is also warranted.

Epidemiology

83. Predicting clearance of acute HCV in HIV-positive patients.

E. C. Thomson; J. Main; J. N. Weber; V. M. Fleming; P. Klenerman; P. Karayannis

Background:

An epidemic of acute hepatitis C virus (HCV) infection in HIV-positive men is emerging in Europe, the USA and Australia. We aimed to characterize the natural history of primary HCV in this setting and to assess clinical and virological factors which predict the outcome of infection.

Methods:

100 patients were recruited and followed at 1-3 monthly intervals for a median of 3 years. The primary endpoints were spontaneous clearance of HCV and sustained virologic response (SVR) after anti-viral treatment. We used logistic regression to assess the impact of clinical and virological variables on outcome, including liver function, CD4 count, rate of HCV-RNA decline and clonal sequence evolution within the HCV E2 envelope gene.

Results:

16% of patients cleared HCV spontaneously while 84% progressed towards chronicity. The latter group included a significant proportion of "fluctuating" progressors (37%), in whom a fall followed by a rise (>1log₁₀) in viremia was observed. Spontaneous clearance was associated with a >1.7log₁₀ viral load drop within 100 days of infection (OR=2.49; p=0.01), high CD4 count (650 versus 520x10⁶/l; OR=1.002; p=0.04) and high peak bilirubin (23 versus 18μmol/l; OR=1.02; p=0.03). Superinfection occurred in 40% and was associated with a "fluctuating" progressive course (p=0.002). The SVR rate was 70%. Both spontaneous clearance and SVR were associated with low viral diversity and dN/dS ratios.

Conclusions:

Spontaneous clearance of acute HCV in HIV positive subjects can be predicted by high CD4 count, high peak bilirubin and rapid decline in HCV viral load. Viral diversification impacts significantly on both spontaneous clearance and SVR.

Epidemiology

773. Hepatitis C Virus (HCV) Infection and Re-Infection in Illicit Drug Users.

A. Barrieshee; H. Tossonian; J. Grebely; J. D. Raffa; L. Gallagher; M. M. Storms; F. Duncan; S. DeVlaming; B. Conway

Introduction:

Over 300,000 Canadians are living with chronic HCV infection, over half being current or former IDUs. The possibility of re-infection is often cited as a reason for not initiating treatment in this group of patients, although recent observational data suggest that the rate of re-infection may be reduced following spontaneous or treatment-induced virologic clearance, although such data are often retrospective and incomplete. With this in mind, we have undertaken a systematic, prospective study to evaluate the incidence of HCV viremia in IDUs at risk of new infection.

Methods:

We indentified a cohort of IDUs receiving care at the Pender Community Health Centre on Vancouver’s Downtown East Side. Potential subjects were identified as either never having been infected with HCV (non-infected arm), having spontaneously cleared the virus (spontaneous arm), or having achieved a sustained virologic response on antiviral treatment (SVR arm). A questionnaire to identify demographics, health status, risk behavior and drug use was administered at baseline and every 6 months, along with blood tests to identify their HCV status.

Results:

A total of 518 subjects were screened (12/07 – 02/09), with 245 (47%) being viremic and 69 (13 %) meeting criteria for inclusion in the study: 18 in the non-infected, 29 in the spontaneous and 22 in the SVR arms respectively. There were no significant differences among the 3 groups with respect to age, ethnicity, source of income, unstable housing, and being on opiate maintenance program. Over 5-18 months follow-up, 20% of the non-infected group became viremic, as compared to 0% of the other two groups (p=0.04). Injecting drugs in past 30 days (p=0.004), sharing non injection equipment (p=0.015), heroin, amphetamines, and combined drugs use was significantly higher in the non-infected arm compared to SVR arm (p=0.02, 0.04 and 0.02 respectively). There were no significant differences in drug use and risk behavior between non-infected and spontaneous arms.

Conclusion:

We have now demonstrated in a prospective cohort with systematic follow-up that viremic HCV infection is more likely to occur in those who have never been previously infected, and that this susceptibility to infection cannot be completely explained by an increase in risk behavior, at least as compared to individuals who have cleared their viremia spontaneously. Whether a decreased rate of viremia following SVR relates to some host-related protective factors or is due to a change in IDU-related risk as a result of engagement in the health care system is currently under study in our centre.

HCV Treatment: Acute

774. Immediate versus delayed antiviral treatment in patients with acute hepatitis C: A model-based decision analysis.

S. Deuffic-Burban; H. Castel; J. Wiegand; M. P. Manns; H. Wedemeyer; P. Mathurin; Y. Yazdanpanah

Background:

Because of the lack of large and homogeneous clinical trials it is not clear when antiviral treatment should be initiated in patients with acute hepatitis C. The possibility of spontaneous viral clearance argues for the watch-and-wait strategy. However, early initiation of antiviral therapy could increase the sustained virological response (SVR) rate.

Aim:

To assess optimal timing of treatment in acute hepatitis C using a model-based decision analysis.

Methods:

A decision tree compares 3 different time points of HCV treatment with pegylated interferon in symptomatic (AHCs) and asymptomatic (AHCa) patients with acute hepatitis C without spontaneous HCV clearance:

1) Treatment initiation during the first two months following transmission;

2) During the month 3;

3) During the month 4 or 5.

We estimate the spontaneous HCV clearance probability in AHCs and AHCa patients (Table). We hypothesize that ALT elevation occurs two months after transmission. We apply different probabilities of SVR according to the delay between transmission and HCV treatment initiation (Table). The study outcome was the probability of still being HCV-RNA positive at 6 months, i.e. developing chronic hepatitis C (CHC).

Results:

The probability of developing CHC (Table) is the lowest when treatment is initiated during the first two months following transmission regardless of the presence of symptoms (AHCs: 7.2%; AHCa: 6.9%). The probability of developing CHC is not lower when treatment is initiated during month 3 vs. during month 4 or 5 of transmission (AHCs: 22.8% vs. 15.7%; AHCa: 21.8% vs. 16.8%).

Conclusion:

Our results, based on a decision model, show that in patients such as health care workers, in whom HCV-RNA is detected in the first 2 months following transmission, treatment should be immediately initiated. In those in whom acute HCV infection is detected more than 2 months following transmission, treatment at 4 or 5 months of transmission may be preferred because of a higher rate of spontaneous HCV clearance after 2 months and a low HCV treatment efficacy differential between month 3 and month 4-5.

	Model inputs			Model outputs
Days from transmission	Spontaneous HCV clearance (%)†		SVR after treatment (%)‡	CHC (%)§
	AHCs	AHCa		AHCs	AHCa
0-61	3.0	7.2	92.6	7.2	6.9
62-91	3.0	7.2	76.5	22.8	21.8
92-152	26.5	21.7	78.6	15.6	16.8

†From Santantonio et al, Clin Infect Dis 2006;43:1154-9

‡From Wiegand et al, Hepatology 2006;43:250-6.

§Probability of progression to chronic hepatitis C

.¥No data available; conservative assumption hypothesing that the probability of clearance before month 3 equal to month 3.

Epidemiology

775. Risk Factors for Primary Hepatocellular Carcinoma in Hospitalized Patients in the United States in 2006.

F. Aslinia; C. D. Howell

Background and Aims:

The incidence of hepatocellular carcinoma (HCC) in the US has more than doubled during the past 2 decades, with the highest incidence in African Americans and other races compared to White Americans. The aim of the current study was to compare the risk factors for HCC in US racial groups.

Methods:

We analyzed 5893 HCC cases (ICD-9: 155.00) among African Americans (AA), Asians or Pacific Islanders (AS-PI), Hispanics, Native Americans, Caucasians(CA), and other races in the Nationwide Inpatient Sample (NIS) Database from 2006, a stratified 20% sample of non-federal hospital discharges. The risk factors for HCC were hepatitis C infection (HCV), hepatitis B infection (HBV), alcoholic liver disease (ALD), diabetes mellitus (DM), and cryptogenic cirrhosis.

Results:

The mean age for hospitalized patients with HCC was 63+/-13 years and 73% were male. Compared to CA, AA and Hispanics were significantly younger (Table). Overall, HCV (24%), DM (16%), ALD (9%), HBV (6%) and cryptogenic cirrhosis (5%) were the more common single risk factors for HCC. The most common concurrent risk factors for HCC included ALD and HCV (9%), DM and HCV (7%), HBV and HCV (1.5%), ALD and HBV (0.6%) and ALD, HCV and HBV (0.6%). Compared to CA, HCV was more common in AA and Hispanics; HBV was more common in As-PI and AA; ALD was less common in AS-PI; and DM as the only risk factor and cryptogenic cirrhosis were less common in AA.

Conclusion:

● HCV was the single most common risk factor for HCC in hospitalized patients in the US in 2006, followed by DM, ALD and HBV.

● Major risk factors for HCC differ by race and ethnicity.

● HBV infection is the most common single etiology in Asians Pacific-islanders, but was more common in African-Americans, Hispanics and “other race/ethnicity’ relative to Caucasian-Americans.

● Alcoholic liver disease was more common among Hispanic cases, but was less common among African-Americans compared with Caucasia-Americans.

● Compared with Caucasian-American cases, diabetes mellitus was more common in Hispanic and “Other’ cases with HCC. However, as a single risk factor, diabetes was more common in African-Americans and Asian/Pacific Islanders.

● The ratio of HCC patients per 100,000 hospitalizations is greatest in Asian/Pacific Islanders.

● Diabetes mellitus was a more common risk factor for HCC in Native Americans compared to Caucasian-American cases, the limited sample of Native Americans probably explain the lack of significance.

● The racial and ethnic variability in risk factors should be when developing public health strategies for prevention of primary hepatocellular carcinoma in the United States.

HCC risk factors

Variables	CA	AA	Hispanics	As-PI	Native A.	Other	p
Patients (N)	2321	653	903	496	23	171	-
Race %	51	14	20	11	0.5	3.5	-
Age (mean+/-SD)	64+/-13	59+/-12	62+/-12	63+/-13	57+/-10	64+/-14	0.001
Male %	75	71	70	77	83	77	0.02
HCV without HBV or ALD %	20	35	27	21	9	23	0.001
HBV without HCV or ALD %	2	6	2	29	13	6	0.001
ALD without HCV or HBV %	10	6	12	2	17	5	0.001
Cryptogenic cirrhosis %	6	3	6	3	4	5	0.001
Diabetes with no identified HCC risk factors %	18	10	18	12	30	20	0.001

Epidemiology

776. Epidemiology of recently acquired hepatitis C virus (HCV) infection in HCV and HCV/HIV infected participants in the ATAHC study.

G. Matthews; J. Grebely; S. T. Pham; M. Hellard; P. Marks; W. Rawlinson; J. Kaldor; A. R. Lloyd; P. A. White; G. J. Dore

Aim:

The aim of this study was to compare the epidemiology of recent HCV infection (acute and early chronic HCV) between HCV and HCV/HIV infected participants and to investigate the existence of HCV transmission networks.

Methods

The Australian Trial in Acute Hepatitis C (ATAHC) is a prospective study of the natural history and treatment of recent HCV infection. Participants were eligible if they were within 6 months of their first anti-HCV antibody positive result and had documented anti-HCV seroconversion within 24 months, or acute clinical HCV within the past 12 months. Using real-time polymerase chain reaction (PCR), the region encoding envelope glycoprotein 1 (E1) and the hypervariable region 1 of E2 of the HCV genome was amplified, sequenced, and compared with unrelated E1/HVR-1 sequences.

Results

We compared the modes of HCV acquisition among HCV and HCV/HIV participants who received treatment for HCV. Using phylogenetic analysis we also investigated HCV transmission networks. Between June 2004 and February 2008, 167 were enrolled (79% injected in previous 6 months) and 109 were treated (HCV, n=74; HCV/HIV, n=35).

When compared to those with HCV alone, HCV/HIV participants were more often older (mean age: 42 vs. 31 years), male (100% vs. 62%) and had full-time or part time employment (49% vs. 24%), but had less often ever injected drugs (69% vs. 35%).

Sexual acquisition of HCV in ATAHC

● A further evaluation of mode of acquisition was carried out in all 167 subjects screened in the ATAHC study.

● Sexual acquisition was significantly more common in the HIV positive population than in the HIV negative population. In total 31 ATAHC subjects reported sexual acquisition of HCV including 22 HIV positive subjects.

● All HIV positive subjects reported MSN acquisition. Sixty-four percent with partner(s) of unknown status and 36% with a partner known to be HCV positive.

● Nine HIV negative subjects reported sexual acquisition—4 of these were cases of MSN acquisition with 3 of whom were with partners of unknown HCV status.

There were 5 cases of heterosexual acquisitions—4 of these were in females with a partner of known HCV status.

Clusters/Pairs

Phylogenetic testing found 4 clusters and 3 pairs that demonstrated 23/112 (21%) subjects in ATAHC had a virus identical to that of another subject. Of these 23 viruses 5 were in HIV negative subjects (representing 6% of the sequenced HIV negative population) and 18 were HIV positive (representing 51% of the sequenced HIV positive population).

Clusters/pairs were predominantly composed of HIV positive subjects and demonstrated mixing of subject with IDU and MSM as mode of exposure. In the only cluster demonstrating mixing between HIV negative and positive subjects (Cluster 2) both HIV negative subjects identified as MSM despite having most likely contracted HCV through IDU.

Conclusion

● HIV positive subjects in ATAHC are more likely to acquire HCV through sexual transmission than HIV negative subjects.

● Phylogenetic analysis reveals a number of HCV clusters supporting common transmission networks.

● Clusters are almost exclusively among MSN (mostly HIV positive), with both IDU and sexual risk exposure.

● Some evidence for bridging between HIV positive and negative MSM.

● No evidence of linkage between MSM and non-MSM populations.

Epidemiology

777. A simple strategy to screen for acute HCV infection among newly incarcerated injection drug users.

A. Y. Kim; C. E. Birch; E. H. Nagami; M. J. Bowen; G. M. Lauer; B. H. McGovern

Background:

● Newly incarcerated inmates with a history of recent onset injection drug use or sharing of paraphernalia are at high risk for acute HCV infection.

● A simple screening strategy evaluating risk behaviors alone may be an effective method for identifying acute HCV infection and would allow for timely therapeutic interventions

● The objective of this study was to evaluate whether risk factor-based screening of newly incarcerated inmates would enhance identification of acute/early HCV cases, including asymptomatic individuals.

Methods:

● A brief questionnaire was incorporated during intake medical evaluations at two Massachusetts state prisons in order to screen for recent onset of high-risk behaviors associated with acquisition of HCV infection.

● Those reporting prior HCV positivity most likely had chronic HCV and, thus, were not selected for further screening.

● Inmates who reported high risk behaviors prior to incarceration underwent an in-depth interview process with a clinical research nurse. Laboratory testing included: HCV antibody and aminotransferases.

● High-risk individuals with suspected acute HCV infection were enrolled in the study and underwent serologic testing for hepatitis A, B, and HIV and serial quantitative HCV RNA testing, as described in our prior report (CID 2009; 49: 1051-60).

Results:

Classification of risk-based screening questionnaire

	MCI-Concord (males)	MCI-Framingham (females)
Classification	n=2104 (64.6%)	n=1151 (35.4%)
High-risk	57 (2.7)	91 (7.9)
Low-risk	1651 (78.5)	535 (46.5)
Chronic*	296 (14.1)	522 (45.4)
Refusal	19 (0.90)	0 (0)

*Chronic HCV infection by patient self report

**84 questionnaires were incomplete (MCI-Concord n=81, MCI- Framingham, n=3)

Classification of Patients at High Risk for HCV Acquisition

	MCI-Concord Males	MCI-Framingham Females
High-risk patients n (%)	57 (38.5%)	91 (61.5%)
Age
Median years (range)	29 (20-51)	28.5 (18-48)
Race n (%)
Non-hispanic white	40 (70.2)	85 (93.4)
Non-hispanic black	2 (3.5)	2 (2.2)
Hispanic	12 (21.0)	1 (1.1)
Other/unknown*	3 (5.3)	3 (3.3)
HCV classification**
Acute/early HCV infection	13	21
Chronic	10	5
Prior Resolution	0	4
HCV seronegative	11	28
Misclassified	2	1
Identification rate of acute/early HCV infection (cases/month)	0.87	1.4

*Racial data on three patients could not be found

**53 patients did not undergo further assessment after the intake screening questionnaire: released n=30, refused n=8, lost to follow-up n=5, no show n=5, transferred n=4, no interpreter n=1.

Conclusions

● Systematic screening based on risk factors with targeted follow up successfully identifies persons with acute or early HCV in an incarcerated population.

● The nationwide implementation of this simple strategy among the ~675,000 admissions to state prisons yearly could potentially identify more than 7,000 annual cases of acute or early HCV infection in prison-based populations.

Epidemiology

778. New trends of HCV infection in China revealed by genetic analysis of first-time volunteer blood donors.

Y. Fu; W. Xia; Y. Wang; C. Li; S. Liu; O. Pybus; L. Lu; K. Nelson

Purpose:

To study HCV sero-prevalence and genotype distribution among first-time volunteer blood donors in China.

Methods:

Anti-HCV was detected by EIA; E1 and/or NS5B fragments were amplified by RT-PCR followed by sequencing and detailed phylogenetic analysis.

Results:

During 2004-2007, a total of 559,890 first-time volunteer blood donors were recruited at Guangzhou Blood Center among whom anti-HCV was detected in 1,877 (0.335%) donors. Compared to previous reports from China, the anti-HCV+ rate is the lower and reflects the success of changes to blood donor recruitment models in China. Stratification analyses revealed that anti-HCV+ is significantly higher (p<0.001) in males (0.366%) than females (0.281%) but significantly lower (p<0.001) in Guangdong donors (0.298%) than in non-Guangdong (0.396%) donors. The role of migrant laborers working in Guangdong is discussed. From 270 randomly selected donors who were HCV RNA+, we determined E1 and/or NS5B sequences in 236 donors.

These donors were divided into two groups: Group 1 contained 145 donors from Guangdong whilst Group 2 contained 91 donors from other areas. In group 1 subtype 6a was the most predominant, followed by 1b, 3a, 3b, 2a, and 1a (at frequencies 49.7%, 31.0%, 7.6%, 5.5%, 4.1%, and 2.1%, respectively). In group 2, 1b was the most predominant, followed by 2a, 6a, 3b, 3a, 6e, and 6n (at frequencies 57.1%, 13.2%, 11.0%, 9.9%, 4.4%, 2.2%, and 2.2%). Subtype 6a was significant more common (p<0.001) in group 1 than in group 2, while subtypes 1b (p<0.02) and 2a (p<0.001) were significantly higher in group 2. The male/female ratio in subtype 6a donors was higher (p<0.05) than that for subtype 1b donors, while the mean age of subtype 2a donors was about 8-10 years older (p<0.05) than that for other subtypes. The former finding suggests different risk factor for transmission of different subtypes, while the latter indicates a decline in subtype 2a incidence.

Conclusion:

As blood donor recruitment models changed in China (from paid donors to employer-organized donors and to volunteer donors among low-risk populations) there have been a consistent decrease in HCV sero-prevalence and a shift in HCV genotype distribution away from subtype 2a and towards subtype 6a.

Epidemiology

779. Observational outcomes in a cohort of women identified as hepatitis C (HCV) antibody positive during routine antenatal clinic (ANC) screening.

A. A. Alexanian; G. M. Oleszkiewicz; T. Al-Chalabi; S. Atabani; D. Muir; G. Tudor-Williams; . S. Brown.

Introduction:

Currently in the UK, routine ANC screening for HCV is neither recommended nor widely practiced. Our institution serves an inner city multi-ethnic population which sees approximately 4,000 pregnancies per year. We offer antenatal HCV testing utilising the same sample used for the HBV and HIV tests and see an uptake of 99.6%.

Methods:

A search of hospital records identified all pregnant women who tested positive for HCV antibody during ANC booking who were not previously aware of their status. Patients with a positive result are reviewed in the ANC by a dedicated hepatologist where patient education, repeat antibody testing, measurement of viral load and genotyping take place. After delivery, mother and child are referred to the Family Hepatitis Clinic where liver biopsy and treatment options can be discussed further. Outcomes were identified using computer based patient information systems, and review of patient notes and clinic correspondence.

Results:

Our eight year data identified 138 women who tested antibody positive of whom 115 were confirmed on repeat testing (incidence = 0.37%). 31 of those with a positive antibody had a negative HCV-RNA, indicating a spontaneous clearance rate of 29%. Of those HCV-RNA positive, 47 patients have been lost to follow-up, although 17 remain registered with their GP. 9 of the patients testing positive for HCV-RNA remain under active follow-up, but have currently deferred treatment. 4 are undergoing treatment. 15 patients (genotype 1 n=8, G2=2 G3=4, G4=1, age = 40.1±6.7 years) have completed treatment (peg-interferon + ribavirin), of which 12 have achieved SVR (80%), 1 has relapsed (G3), 2 failed to respond (G3 and 4).

Conclusions:

This study confirms that testing for HCV in an inner city ANC population is an effective method of case-finding and with good treatment outcomes. It allows the testing of potentially infected offspring and siblings, education of infected mothers and discussion of treatment possibilities in a cohort which appears to have an excellent response to treatment. Reasons for not entering treatment include further planned pregnancies, minimal liver disease on biopsy, social issues, concern at side effects and awaiting new treatment options. The significant drop-out from follow-up has alerted us to weaknesses in the system of referral, but may also reflect the demographics of our catchment area with many patients having registered with specialist homeless GPs, others moved from their GP or moved overseas.

Epidemiology

780. Examining the Influence of Medical Comorbidities on Hepatitis C Testing.

C. V. Almario; M. Velez; S. Trooskin; V. J. Navarro.

Objective:

Prior studies found that hepatitis C virus (HCV) risk assessment and testing in primary care clinics were suboptimal. The aims of our study were to determine the rate of HCV testing among patients with a HCV risk factor, and to test the hypothesis that patients with medical comorbidities were less likely to be tested for HCV versus those without comorbidities.

Methods:

Our study included patients in four urban primary care clinics with a documented HCV risk factor. Individual medical charts were reviewed by a team of trained chart reviewers. From the chart, we determined whether HCV antibody testing was performed. We also recorded any preexisting medical comorbidity mentioned in the chart. A binary logistic regression model was used to calculate adjusted odds ratios (AOR) with 95% confidence intervals (CI) for HCV testing among patients with 0 (reference), 1, or ≥ 2 medical comorbidities.

Results:

Of 944 individuals seen in primary care clinics, 184 had a HCV risk factor. Only 24% (44/184) were tested for HCV antibodies. The HCV risk factors that most commonly led to HCV testing were history of intravenous drug use (61%, 20/33) and significant other with HCV (80%, 4/5). Among patients with 0, 1, or ≥ 2 medical comorbidities, the HCV testing rate was 20% (16/81), 25% (15/59), and 30% (13/44), respectively. After adjusting for confounders with a logistic regression, no statistically significant association was found between HCV testing and number of medical comorbidities (Table).

Conclusion:

The HCV testing rate among patients with a HCV risk factor was low (24%). While there was a trend towards more frequent HCV testing with increasing number of medical comorbidities, this trend did not reach statistical significance. Thus, the presence of comorbidities did not negatively impact the HCV testing rate and cannot explain the low testing rate among patients with HCV risk factors.

Table. Rate of HCV testing according to number of medical comorbidities

No. of comorbidities per individual	Tested for HCV n (%)	Unadjusted OR (95% CI)	Adjusted OR (95% CI) ^a
≥ 2	13/44 (30)	1.7 (0.7 - 4.0)	1.3 (0.5 – 3.2)
1	15/59 (25)	1.4 (0.6 – 3.1)	1.1 (0.4 – 2.5)
0 (reference)	16/81 (20)	1	1

HCV, hepatitis C virus; OR, odds ratio; CI, confidence interval. ^a Adjusted for age, race/ethnicity, insurance status, and site of medical care (academic versus community setting).

Epidemiology

781. A prospective survey including 17,184 patients from a German metropolitan area reveals a high prevalence of chronic hepatitis C virus infection.

B. Schlosser; D. Domke; M. Möckel; M. Biermer; B. Fülöp; N. P. Haas; H. Bail; C. Müller; R. Tauber; T. Berg View Pres.

Introduction:

The prevalence of HCV antibodies (anti-HCV) in the general German population has been estimated to be around 0.5%. Screening for HCV is therefore only recommended in patients with either elevated ALT levels or significant risk factors for HCV transmission. However, in less than 50% of these patients the presence of anti-HCV could be attributed to any risk factors and ALT levels can be normal in up to 40%. These observations imply that in many patients and especially in those belonging to the non risk patients with normal ALT levels the diagnosis of chronic HCV hepatitis may be dismissed.

We therefore were interested to assess the anti-HCV prevalence in the metropolitan area of Berlin by analysing anti-HCV antibodies among patients being treated for a wide spectrum of different disorders in our traumatology and internal emergency wards.

Methods:

According to a new standard operating procedure, all 22,649 patients who were seen in our emergency ward between May 2008 and October 2009 and in whom a blood sample was taken as part of the routine medical work-up were tested for the presence of anti-HCV antibodies. Anti-HCV positive patients were further analysed for the presence of viremia by real-time PCR.

Results:

A total of 514 patients (2.4%) were found to be anti-HCV positive. 43% were female. The average age of these patients was 54 years and 68% were

● German Caucasians.

● Risk factors for HCV infection:

● No evidence for risk factors (number = 129, 17%)

● No complete evaluation (number =129, 23%

● Any Risk factor (number = 297, 60%)

● Surgery or blood products (number = 141, 27%)

● IVDA (number = 157, 31%)

So far, 469 patients had an HCV RNA (viral load) test of whom 69% were found to be HCV RNA positive. ALT levels were elevated in 60% of the viremic patients but also in 32 % of the anti-HCV positive but HCV RNA negative patients. Only 26% of the HCV RNA positive patients had a history of previous antiviral therapy. No difference in anti-HCV prevalence has been observed whether the patients from the traumatology (n=5507) or internal emergency ward (n=17143).

Conclusion:

● This large scale survey from a tertiary referral center revealed an unexpected high anti-HCV prevalence.

● Screening strategies based on risk factors and ALT level only will fail to detect a significant proportion of chronically infected patients.

● Given the improved treatment options against chronic HCV when initiated in early stages of the disease our data can be taken as a strong point for more general HCV screening at least in greater urban areas.

Epidemiology

782. Cost Effectiveness of STAT-C Agents in Treating Genotype 1 Chronic Hepatitis C.

P. G. Northup; A. M. Al-Osaimi; S. H. Caldwell; C. K. Argo.

Background:

The treatment of genotype 1 chronic hepatitis C (HCV) is evolving with the advent of a new class of drugs specifically targeted at the HCV molecule. Early clinical trial data show promise that the STAT-C agents will improve sustained virologic response (SVR) rates. This study was designed to explore the potential cost effectiveness of two of these agents: Boceprevir (BOC) and Telaprevir (TEL).

Methods:

A simple cost effectiveness model was developed to simulate a cohort of non-cirrhotic patients with genotype 1 HCV undergoing therapy with combination pegylated interferon (PEG-IFN) and ribavirin (RBV) along with Boceprevir or Telaprevir.

Three competing treatment strategies were simulated:

1) Standard of care 48 week, weight based PEG-IFN and RBV (SOC),

2) Twelve week course of TEL combined with PEG-IFN+RBV followed by 12 additional weeks of PEG-IFN+RBV and

3) Four week lead-in with PEG-IFN+RBV followed by 44 weeks of triple therapy BOC combined with PEG-IFN+RBV.

Rapid and early virologic response rates, treatment failure and breakthrough rates, growth factor requirements, and SVR rates were extracted from publically available phase 2 clinical trial results (PROVE 1 and SPRINT-1). PEG-IFN, RBV, and erythropoetic growth factor costs were extrapolated from commercially available pharmacy pricing guides. Progression to decompensated cirrhosis and the possibility of liver transplantation was simulated in treatment failures. Wide ranges of costs for the STAT-C agents were explored.

Results:

The treatment strategies using the STAT-C agents were more effective than the standard of care therapy. A 1,000 patient Monte Carlo simulation of the SOC treatment yielded 440 SVRs, 130 deaths from progression of liver disease, and 30 liver transplants. The TEL strategy yielded 640 SVRs, 100 deaths from disease progression, and 10 liver transplants. Finally, the BOC arm yielded 740 SVRs, 50 deaths from liver disease, and 10 liver transplants. The number needed to treat to prevent a death from liver disease or liver transplantation was 4 for the TEL arm and 2 for the BOC arm. Both TEL and BOC were highly cost-effective throughout a wide range of potential direct drug costs from $12,000 to $120,000. Assuming a base case cost of $50,000 for BOC or TEL for a complete course of therapy, the marginal cost effectiveness of TEL (over SOC) was $7,876 while the marginal cost effectiveness of BOC (over TEL) was $7,678.

Conclusions:

Despite the high up-front costs of TEL or BOC, both agents are likely to be highly cost effective in the treatment of genotype 1 HCV based on phase 2 clinical trial viral response data.

Epidemiology

784. Risk of Thromboembolic Events (TEs) Among Patients Infected With Hepatitis C.

U. Forssen; A. McAfee; C. Enger; D. Bennett; S. Shantakumar

Background:

In this study, the risk of thromboembolic events (TEs) in patients with and without hepatitis C was examined. Previous studies have shown that patients with cirrhosis have increased risk for portal vein thrombosis (PVT), but little published epidemiologic data exist on risk of PVT and other TEs among patients with hepatitis C, one of the most common causes of cirrhosis.

Methods:

Medical claims data from a large US health plan (12 million covered lives) were retrospectively analyzed to identify patients diagnosed with hepatitis C (ICD-9 codes 070.44, 070.54, 070.7, 070.70, 070.71) from January 1, 2000 through September 30, 2006. All patients were ≥18 years of age and continuously enrolled for ≥12 months before index diagnosis date. A cohort of patients without hepatitis C were randomly selected and matched 3:1 to each patient with hepatitis C based on age, gender, and calendar year. ICD-9 diagnosis codes were used to identify TEs during the study period, from index date through December 31, 2006, or withdrawal from plan. TEs of interest included both venous TEs (pulmonary embolism, deep vein thrombosis, and other TEs) and arterial TEs (ischemic stroke, transient ischemic attack, unstable angina, and myocardial infarction). The events were evaluated separately as well as together. Incidence rate ratios (IRR) and 95% confidence intervals (CI) comparing hepatitis C to a non-hepatitis C cohort were estimated using Poisson regression.

Results:

Of the 21,919 eligible patients with hepatitis C and no history of TE, 833 patients (3.8%) experienced at least 1 TE during the study period. During the same period, 2.5% of patients without hepatitis C (1703/67,109) experienced a TE. After adjusting for age, gender, hypertension, and steroid use, patients with hepatitis C were 1.62 times more likely to experience any TE compared with patients without hepatitis C (IRR 1.62; 95% CI: 1.48–1.77). Patients with hepatitis C had consistently higher risks of several arterial and venous TEs: PVT (IRR 15.18; 95% CI: 6.22–37.03); ischemic stroke (IRR 1.76; 95% CI: 1.23–2.52); transient ischemic attack (IRR 1.57; 95% CI: 1.30–1.89); and unstable angina (IRR 1.22; 95% CI: 1.05–1.42). However, patients with hepatitis C did not have an increased risk of myocardial infarction (IRR 0.94; 95% CI: 0.73–1.20) or pulmonary embolism (IRR 1.02; 95% CI: 0.73–1.20), and their risk for deep vein thrombosis was elevated but not statistically significant (IRR 1.22; 95% CI: 0.80–1.86).

Conclusions:

In this study, HCV patients had an increased risk for several TEs. The biological mechanism for this is unknown but may be related to liver disease caused by the HCV infection and the development of cirrhosis in this patient group.

Epidemiology

785. Cluster of Acute HCV Genotype 4 Infections among HIV-positive Men who have Sex with Men (MSM).

M. Vogel; T. J. van de Laar; J. Henke; B. Kupfer; T. Kümmerle; H. Rasokat; S. Mauss; G. Fätkenheuer; S. M. Bruisten; J. K. Rockstroh.

Background:

In the last years there has been an ongoing epidemic of acute HCV infections among HIV-positive men who have sex with men. A recent analysis of patients at Bonn University revealed a high proportion of HCV genotype 4 infections. There is concern that transmission occurs mainly via sexual networks and is related to a common source.

Methods:

HIV-positive MSM diagnosed with recent HCV genotype 4 infections in the middle rhine region of Germany were enrolled into a molecular phylogenetic study. Using real-time polymerase chain reaction (PCR), the NS5B region of the HCV genome (436 base pair) was amplified, sequenced, and compared with unrelated NS5B sequences and with cases from a previous international phylogenetic analysis.

Results:

14 HIV-positive men who have sex with men with acute HCV genotype 4 infections were identified at three large HIV-centers in Cologne, Bonn and Düsseldorf between 2003 – 2009. Patients were a median 42 years old at the time of diagnosis of acute HCV infection. 13 had reported unsafe sex with men as transmission risk factor, in one patient the transmission route remained unclear. Intravenous drug abuse was denied by all patients. All cases were part of a monophyletic genotype 4d cluster, clustering with previous strains identified during outbreaks of acute HCV among MSM in Berlin Amsterdam, Rotterdam, Paris and London.

Conclusion:

HCV may be sexually transmitted in HIV-positive MSM. The high phylogenetic relationship of HCV strains among cases and linkage to cases in different European cities suggest a transmission via sexual networks across Europe.

Epidemiology

787. High risk of hepatocellular carcinoma in immigrant patients with advanced fibrosis and chronic hepatitis C in a Canadian tertiary referral clinic.

W. Chen; G. Tomlinson; M. Krahn; E. Heathcote.

Background:

The proportion of immigrants among patients with chronic hepatitis C (CHC) is over 30% in our tertiary liver clinic in Toronto.

Aims:

To investigate differences regarding liver-related long-term outcomes according to immigrant status in patients with advanced hepatic fibrosis and CHC.

Methods:

A retrospective cohort study was designed to select patients with CHC and liver biopsy proven advanced fibrosis (stage 3 or 4) attending our clinic. The follow-up time was from the date of liver biopsy to Dec 31, 2008. Review of medical records was conducted to collect data to establish immigrant status according to place of birth, baseline characteristics, and the liver-related long-term outcomes (decompensation, hepatocellular carcinoma (HCC), liver transplant, and death) during follow-up. Descriptive statistical methods were used for the direct comparisons by immigrant status. Kaplan-Meier (KM) regression analyses compared the curves free of each liver-related long-term outcome by immigrant status. Cox proportional-hazards regression analyses explored possible risk factors contributing to any significant findings identified by KM analyses.

Results:

318 patients were included (40% were immigrants). Relative to Canadian-born patients, immigrant patients were significantly: older (55.0 years vs. 48.0 years; p<0.001); less likely to be male (56.3% vs. 71.6%; p=0.005); comprise fewer Caucasians (68.8% vs. 97.4%; p<0.001), more Asians (18.8% vs. 0.5%; p<0.001), as well as fewer heavy drinkers (23.4% vs. 47.4%; p<0.001), heavy smokers (11.7% vs. 26.3%; p=0.002), and subjects with a history of injection drug use (11.7% vs. 54.7%; p<0.001); and more diabetics (31.3% vs. 20.5%; p=0.03). KM analyses indicated that immigrants with CHC had a significantly lower curve free of HCC than Canadian-born patients (p=0.005). Univariate Cox proportional-hazards analyses indicated that “immigrants” (Hazard ratio (HR) 2.22, 95% CI 1.26 to 3.91; p=0.006), age (HR 1.07, 95% CI 1.04 to 1.09; p<0.0001), heavy drinking (HR 2.69, 95% CI 1.53 to 4.72; p=0.0006), heavy smoking (HR 2.03, 95% CI 1.12 to 3.68; p=0.02), and diabetes (HR 2.06, 95% CI 1.18 to 3.60; p=0.01) were significantly associated with the risk of HCC. Further multivariate Cox proportional-hazards analyses showed that the HR associated with ‘immigrants’ for HCC became non-significant (HR 1.37, 95% CI 0.74 to 2.52; p=0.318) after the adjustment of age and diabetes.

Conclusion:

As a result of being older at diagnosis and a higher prevalence of diabetes, immigrants with CHC and an advanced stage of hepatic fibrosis had a much higher risk of HCC than Canadian-born patients with CHC.

Epidemiology

788. HCV Viral Evolution in HCV/HIV Coinfected Subjects After Initiation of HAART.

P. J. Zamor; J. Blackard; C. M. Martin; K. E. Sherman.

Introduction:

Due to shared routes of transmission, approximately 20-30% of individuals with HIV-1 infection are also co-infected with chronic Hepatitis C (HCV). Liver related morbidity and mortality have emerged as prominent issues in the post-highly active antiretroviral therapy (HAART) era for the treatment of HIV-1. In addition, HCV accelerates hepatic fibrosis by unknown mechanisms in those with HIV-1 co-infection. While it has been previously demonstrated that increased HCV quasispecies diversity blunts the response to interferon based treatment, it is not clear how HCV evolves in the setting of HAART in HCV/HIV co-infected individuals. We speculated that immune pressure would increase following HAART initiation, resulting in rapid divergence of HCV quasispecies. We utilized samples derived samples from the AIDS Clinical Trials Group (ACTG 384).

Methods:

21 HCV/HIV co-infected subjects, naïve to both HAART and anti-HCV therapy, were included in this study. 10 had available serum samples at both time points: baseline (week 0) and 24 weeks post-initiation of HAART. The HAART regimen consisted of either the non-nucleoside efavirenz or protease inhibitor nelfinavir or both efavirenz and nelfinavir. A 346 base-pair nucleotide fragment of the Hypervariable Region 1 (HVR1) of the E2 region of HCV was amplified and directly sequenced. Week 0 and week 24 samples were compared by calculating both genetic distance (GD) and nonsynonymous (dN)/synonymous (dS) ratios using Mega 4 software.

Results:

8 of the 10 samples demonstrated no genetic divergence between time points. Therefore, these 8 samples had no changes in dN/dS between time points, indicating no viral evolution attributable to immune selection pressure. The remaining two subjects mutated as demonstrated by mean GD values of .022 and .045; of these two subjects one indicated negative selection with dN/dS ration of .1707 while the other indicated positive selection with a dN/dS ratio of 1.5625.

Conclusions:

In this study of HCV/HIV co-infected subjects, HCV evolution was prospectively assessed before and after initiation of HAART. 10% of subjects (n=1) exhibited genetic variability and immune selection, but 90% did not. Studies with larger cohorts of patients and later time points may elucidate HCV viral evolution in the setting of HAART therapy.

Epidemiology

789. Predictors of spontaneous viral clearance of hepatitis C virus among HIV-1 infected individuals. A single-center cohort study.

L. N. Clausen; N. Weis; K. Schønning; M. Fenger; H. Krarup; J. Bukh; T. Benfield

Background:

Co-infection with hepatitis C virus (HCV) is a major problem among HIV-infected individuals. However, little is known about determinants leading to either spontaneous viral clearance or chronic infection.

Methods:

● Data from our ongoing, hospital-based cohort study of HIV-infected individuals was analyzed using multivariate logistic regression analysis and expressed as odds ratio (OR) with 95% confidence interval (CI).

● Subjects with a positive anti-HCV antibody test were included. HCV clearance was defined as the presence of anti-HCV without HCV RNA in serum or plasma specimens from at least two measurements more than 6 months apart.

Results:

Of 2196 HIV-infected individuals followed at Hvidovre Hospital

● 383 were positive for HCV antibodies.

● 53 individuals were excluded because of HCV treatment and missing samples so there the final inclusion numbered 330.

Of the 330 included,

● the majority were male (66%), Caucasian (93%), European (92%), and had acquired HIV-infection through intravenous drug use (IVDU) (79%).

● 25 (8%) were hepatitis B surface antigen (HBsAg) positive.

Seventy-six individuals had cleared their HCV infection and 254 had chronic HCV infection giving a spontaneous rate of clearance of 23%. Among HBsAg posirtive individuals 56% had cleared infection.

In contrast, heterosexually exposed individuals had an unusual high rate of chronicity reaching 94%.

Individuals exposed to HIV through intravenous drug use, men having sex with men or HBsAg positivity were more likely to spontaneously clear HCV. Race, origin, AIDS, antiretroviral therapy or female sex were not association with HCV clearance.

Conclusion:

● HIV exposure group MSM and IDU have higher rate of spontaneous HCV clearance than heterosexual individuals.

● IDUs and MSM may have a higher clearance rate due to their repeated exposure to low dose HCV leading to immune memory.

● Our data suggest an interaction of hepatitis B virus (HBV) and HCV infection that influence the outcome of acute HCV infection in HIV infected individuals.

Epidemiology

790. Epidemiology and Phylogenetic Analysis of Hepatitis C Virus Genotype 4 in Denmark.

M. B. Eriksen; L. B. Jørgensen; H. Krarup; A. L. Laursen; P. B. Christensen; A. Møller; P. Schlichting; C. Kuiken; N. Weis.

Background:

Denmark has a low incidence of hepatitis C virus (HCV) and displays the same distribution of HCV genotypes as do other European countries, with genotypes 1a, 3a and 2b as the most prevalent and genotype 4 less present. The prevalence of HCV genotype 4 in Europe is increasing, particularly among injecting drug users (IDUs). HCV genotype 4d was described in a Danish patient for the first time in 1993, but the heterogenity and epidemiology of HCV genotype 4 in Denmark has never been previously described.

Aim:

To describe the epidemiology of HCV genotype 4 in Denmark as regards distribution of subtypes, routes of infection, ethnic origin and co-infection with hepatitis B virus (HBV) and/or Human Immunodeficiency Virus (HIV).

Patients and Methods:

Samples from 74 patients with chronic HCV infection collected in Denmark between 1999 – 2007. Genotyping was based on amplification and sequencing of part of the core/E1 region.

Results:

The three most prevalent genotype 4 subtypes found in 80 % of the patients were subtype 4d, 4a and 4r, infecting 25 patients (34 %), 22 patients (30 %) and 12 patients (16 %), respectively. Additionally, subtypes 4h, 4k, 4l, 4n and 4o were also present. Five patients (7 %) were infected with strains not possible to subtype and were designated 4UN. Patients of ethnic Danish and African (excluding Egyptian) origin accounted for 13 and 23 patients respectively, representing almost half of the patients (49 %). Five patients (7 %) were of Egypt origin. The remaining patients originated from Eastern Europe, Southern Europe, North America, The Middle East and Pakistan. The primary route of infection was injecting drug use (IDU), responsible for infection in 12 patients (16 %). Blood transfusion, sexual contact, vaccination, needle injury and tattooing/piercing were other causes of infections. Among the dominating subtype 4d, 11 patients (44 %) were of ethnic Danish origin – 9 of these patients (82 %) were infected by IDU. Nine patients (12 %) were co-infected with HIV of whom one patient (1 %) was co-infected with both HIV and HBV. Subtype 4d also dominated among HCV/HIV co-infected patients. Four of the 9 (44 %) co-infected patients, including the one HCV/HBV/HIV co-infected patient, were infected with subtype 4d.

Conclusion:

The present study shows a wide distribution of HCV genotype 4 subtypes among patients with chronic hepatitis C infection in Denmark. Remarkably, ethnic Danes infected by IDU constitute a major group of patients and IDU are the dominating cause of infection. This may have important implications for future treatment options in this group.

HCV Therapies Pegasys

115. Outcome of Sustained Virological Responders (SVR) and Non-responders in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial.

T. R. Morgan; M. G. Ghany; H. Kim; K. K. Snow; K. Lindsay; A. S. Lok

Retrospective studies have suggested that subjects with chronic hepatitis C (CHC) and advanced fibrosis who achieve an SVR have a lower risk of developing hepatic decompensation and hepatocellular carcinoma (HCC). However, most of these studies had a short duration of follow up and none was performed in a US population. The HALT-C trial was a prospective study to determine whether low dose peginterferon could prevent liver disease progression in non-responders with CHC.

Aim:

To compare the rate of clinical outcomes between patients who achieved an SVR during the lead-in phase of HALT-C and non-responders in the control arm of the randomized phase.

Methods:

We attempted to determine liver-related outcomes (decompensation, HCC or death) on all SVR patients (n=180). Consenting SVR patients had a physical exam, blood tests and an ultrasound (US) or were interviewed by phone. Non-responders (n=309) were evaluated every 3 months for 3.5 years and then every 6 months.

Results:

Data were obtained on 140 (78%) SVR patients (105 in-person, 32 by phone interview and 3 who had died). Median follow up for SVR patients was 85.8 months (range: 68.0 to 101.1), and for control patients 78.4 months (range: 11.7 to 102.8). At study entry, SVR patients were less likely to have cirrhosis or genotype 1 infection, and had higher platelet counts, ALT and albumin compared to non-responders. One SVR patient had relapse of viremia. SVR patients had a significant improvement in platelet counts, albumin and ALT from baseline to last follow-up while non-responders had a significant decrease in platelet counts and albumin and an increase in bilirubin. Four (2.9%) SVR patients developed 5 clinical outcomes (1 liver related death, 2 HCCs and 2 variceal hemorrhages) compared to 102 clinical outcomes (20 liver related deaths, 20 HCCs and 62 decompensation events) in 68 (22%) control patients. By life-table analysis, the cumulative rate of the first clinical outcome in the SVR versus the control patients at 2.5, 5 and 7.5 years was 0%,1.4% and 3.7% vs. 4.6%, 15.2% and 27.7%, respectively (p < 0.0001). The adjusted hazard ratio (HR) for time to development of the first clinical outcome was significantly higher in non-responder controls than SVR patients (HR = 7.09, 95% CI: 2.56-19.6).

Conclusion:

Patients with advanced CHC who achieve an SVR remain at risk for development of hepatic decompensation and HCC, although this risk is markedly lower compared to non-responders. These results highlight the long-term clinical benefit of achieving an SVR but also underscore the importance of continued monitoring of persons with advanced CHC who achieve an SVR.

HCV Therapies: General

116. HCV-Genotype-Specific Influences on Incident Diabetes: the Effect of Sustained Viral Response to Antiviral Therapy.

M. Manos; W. Zhao; V. Shvachko

Evidence suggests HCV infection increases the risk of diabetes through viral-genotype-specific mechanisms. To assess how HCV antiviral therapy affects diabetes, we studied post treatment (any IFN/ribavirin) incident diabetes in patients treated 1999-2006 in the Northern California Kaiser Permanente Medical Care Program. We used electronic health plan records of 2,040 mono-infected patients without diabetes history prior to therapy end.

Overall, 60% were men, mean age 50 years, and 47% had SVR. Most (68%) were non-Hispanic white, 7% black, 8% Asian and 15% Hispanic. Based on BMI and age, 52% were considered to have a high diabetes risk (HDR) profile. The overall incidence (per 100 person yr, [95% CI]) of diabetes was significantly lower for those with SVR: 0.97 (0.69-1.37) vs 2.48 (2.02-3.04). Diabetes incidence was most dramatically decreased with SVR in those with a HDR profile: 1.43 (0.94-2.15) vs 3.88 (3.09- 4.86). In others, the SVR effect was not significant: 0.57 (0.31-1.05) vs 1.02 (0.64-1.60).

Using Cox proportional hazard models, we determined the correlates of incident diabetes by HCV genotype (GT) for 1,164 GT-1, 408 GT-2, and 326 GT-3 patients. The figure shows adjusted hazard ratios for key factors, by genotype. Age and cirrhosis history were also accounted for. HDR profile was a significant risk factor in all cases, particularly GT-2. While strongly reducing diabetes risk in GT-1 and GT-3 patients, SVR did not significantly affect risk in GT-2 cases. Blacks (vs non-Hispanic Whites) and men were at higher risk among GT-1 cases. Hispanics appeared at higher risk among GT-2 patients.

Successfully treated patients had less than half the diabetes incidence of patients without SVR, suggesting that viral clearance ameliorates the risk conferred by HCV. We also found differences in SVR effect between HCV genotypes, suggesting a lesser role of GT-2 in diabetes risk.

Risk Factors for Diabetes

HCV Therapies: General

117. Sustained Virologic Response is Independently Associated with Improvement in Insulin Resistance in Genotype 1, but not Genotype 2/3, Chronic HCV Patients.

A. J. Thompson; K. Patel; H. L. Tillmann; J. McCarthy; S. Zeuzem; Y. Benhamou; D. R. Nelson; M. S. Sulkowski; M. Torbenson; E. Pulkstenis; G. M. Subramanian; J. G. McHutchison

Background:

Chronic infection with hepatitis C virus (HCV) has been associated with an increased prevalence of diabetes and insulin resistance (IR). More recently a genotype-specific association between genotype 1 HCV and IR has been proposed. However, whether this is a causal relationship remains unclear. To answer this question, we investigated the association of sustained virological response (SVR) with IR in patients enrolled in the ACHIEVE 1 and ACHIEVE 2/3 trials.

Methods:

2255 treatment-naïve patients with chronic HCV-1 or HCV-2/3 were enrolled in two separate phase 3, active-controlled studies of albinterferon alfa-2b plus ribavirin for 48 or 24 weeks, respectively. IR was measured at weeks 0, 12, 24 ± 48 and at post-treatment week 12 using the homeostasis model for assessment (HOMA-IR). Clinical evaluation included age, gender, race, body mass index (BMI), HCV viral load, ALT, GGT, total cholesterol, triglycerides, and baseline liver biopsy evaluated for steatosis, METAVIR inflammatory grade and fibrosis stage by a single pathologist. We considered IR categorically, setting a threshold of HOMA-IR > 3 (Moucari, Gastroenterology, 2008). In addition, we considered change in HOMA-IR post-therapy as a continuous variable. HOMA-IR data were log-transformed for analysis as a continuous variable. ACHIEVE 1 and ACHIEVE 2/3 cohorts were analyzed separately.

Results:

Matched pre and 12-week post HOMA-IR measurements were available from 1038 non-diabetic patients (HCV-1=497, HCV-2/3=541). The SVR rate was 60% and 84% in the HCV-1 and HCV-2/3 patients, respectively. Baseline mean HOMA-IR scores were higher in patients infected with HCV-1 than HCV-2/3 (3.4 and 2.9, respectively). SVR was associated with a reduction in prevalence of IR in HCV-1, but not HCV-2/3 patients (Table 1). SVR was also associated with a reduction in mean HOMA-IR in HCV-1, but not HCV-2/3 patients (Table 1). This was independent of change in BMI, ALT, GGT and lipid levels. HOMA-IR did not change in non-responders (NR). No association of SVR with IR was seen when HCV-2 and HCV-3 patients were considered separately.

Conclusion:

SVR was associated with a reduction in HOMA-IR in patients infected with HCV-1 but not HCV-2/3. This suggests that HCV-1 may play a causal role in the development of IR, which may be reversed by viral eradication.

	Pre-treatment	Post-treatment	p-value
% patients (HOMA-IR>3)
Genotype 1 SVR No SVR	86/300 (29%) 76/197 (39%)	56/300 (19%) 81/197 (41%)	(McNemar’s test) < 0.0001 0.58
Genotype 2/3 SVR No SVR	108/454 (28%) 38/87 (44%)	98/454 (26%) 36/87 (41%)	0.35 0.83
Mean log10(HOMA-IR)
Genotype 1 SVR No SVR	0.30 ± 0.31 0.40 ± 0.27	0.24 ± 0.29 0.43 ± 0.29	(paired t-test) 0.004 0.16
Genotype 2/3 SVR No SVR	0.28 ± 0.28 0.38 ± 0.30	0.26 ± 0.27 0.35 ± 0.31	0.11 0.18

HCV Therapy: Treatment Outcomes

119. Long-term Survival of Sustained Virologic Responders to Pegylated Interferon Therapy for Chronic Hepatitis C.

N. Chandok; W. Kim; R. Pedersen; T. M. Therneau; K. Canterbury; L. M. Stadheim; J. B. Gross; J. J. Poterucha

Background/aim:

The goal of therapy (Tx) for chronic hepatitis C virus (HCV) infection is sustained virologic response (SVR: HCV RNA negative 6 months after cessation of Tx). Long-term benefits of SVR have been presumed, but not well documented. We compared patient survival by virologic response.

Methods:

Based on a database that prospectively tracked anti-HCV Tx, all patients who received pegylated interferon (p-IFN) were identified. Tx response was categorized into: (1) SVR, (2) relapse (R: HCV RNA negative at end of Tx, but no SVR), (3) non-response (NR: all others), (4) early termination (ET: Tx discontinuation before planned assessment at 12 or 24 weeks). Survival information (death or liver transplantation) was extracted from medical records as well as the National Death Registry (Accurint system).

Results:

Between 03/01 and 10/08, 515 patients received standard p-IFN Tx, mostly in combination with ribavirin(RBV). Genotype 1 (G1) was most common (64%), followed G2 (15%), G3 (15%) and others (5%). SVR was reached in 46% (34% for G1, 78% for G2, 65% for G3 and 48% for other). In the figure, SVR was associated with significantly lower mortality (5-year Kaplan-Meier mortality=3%, hazard ratio=0.26, p<0.01) compared to R(12%), NR(12%), or ET(19%). When the analysis was stratified by cirrhosis, which was associated with higher mortality and lower SVR, no benefit in survival from SVR was found among patients with cirrhosis (5 year mortality: SVR=22.3% versus non-SVR=26.3, p=0.71). In contrast, in patients without cirrhosis, SVR led to decreased mortality (5 year mortality: SVR=1.2% versus non-SVR=6.5%, p=0.01). Thus, the number needed to treat in non-cirrhotic HCV patients to avoid one death within 5 years was 19.

Conclusion:

To our knowledge, this is the first evidence that p-IFN (in combination with RBV) leads to improved survival in patients who achieve SVR.

HCV Therapy: General

124. A Novel Innate Immune Mechanism of Action of Ribavirin in Antiviral Therapy.

E. Thomas; J. J. Feld; M. W. Fried; T. Liang

Background

The combination of interferon and ribavirin is the standard treatment for chronic hepatitis C. Data from our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection (Feld JJ et al., Hepatology. 2007 Nov;46(5):1548-63).

Aim

In order to further characterize the mechanisms of action of ribavirin in combination antiviral therapy, the primary focus of this study is to examine the effect of ribavirin treatment on ISG induction in mammalian cells grown in tissue culture using various molecular techniques. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo.

Method and Results

Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs which are also upregulated in ribavirin treated HepG2 cells. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Furthermore, additional augmentation of gene induction is observed with the transfection of poly (IC) into ribavirin and interferon treated cells when compared to cells treated with these agents separately. Direct upregulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signal transduction and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-Kappa B pathways in the action of ribavirin. However, guanosine could block ISG induction by ribavirin whereas loxoribine, a guanosine analog, had minimal effect. Additional experiments demonstrated the involvement of a short-lived transcriptional repressor whose activity is inhibited by ribavirin resulting in the upregulation of these antiviral genes.

Conclusion

In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavrin is valuable in identifying novel antiviral molecules that could ultimately eradicate hepatitis C in all infected individuals when used in combination with interferon.

Experimental Therapies: General

225. Safety, Tolerability, Pharmacokinetics and Antiviral Activity following Single- and Multiple-Dose Administration of BMS-650032, a Novel HCV NS3 Inhibitor, in Subjects with Chronic Genotype 1 HCV Infection.

C. Pasquinelli; T. Eley; C. Villegas; K. Sandy; E. Mathias; P. Wendelburg; S. Liao; F. McPhee; P. M. Scola; L. Sun; T. C. Marbury; E. Lawitz; R. Goldwater; M. Rodriguez-Torres; M. p. DeMicco; M. Ababa; D. Wright; M. Charlton; W. K. Kraft; J. Lopez-Talavera; D. M. Grasela

Background:

BMS-650032 is a potent and selective HCV NS3 protease inhibitor with in vitro pico-molar potency against NS3/4A protease complexes representing genotypes 1a and 1b. BMS-650032 was safe and well tolerated at single doses up to 1200 mg and up to 600 mg Q12h for 14 days in healthy subjects.

Methods:

Two randomized, placebo-controlled studies evaluated single and multiple ascending doses of BMS-650032 in adult subjects chronically infected with HCV genotype 1 without cirrhosis. Both studies evaluated the safety, tolerability, pharmacokinetics and antiviral effect of BMS-650032. In Study 002 (SAD), BMS-650032 was administered to treatment-naïve and experienced subjects at doses of 10, 50, 200 and 600 mg (6 subjects per dose; active:placebo = 5:1). Study 004 (MAD) included naïve subjects only and evaluated 3 days of BMS-650032 at doses of 200, 400, and 600 mg Q12h (5 subjects per dose; active:placebo = 4:1).

Results:

There were no deaths or discontinuations due to AEs and all AEs were mild to moderate. There was no clinically relevant effect on physical exams, ECGs, or labs in either study. Study 002: BMS-650032 exposures increased in a.dose-related manner. Tmax was ~2 to 4 h, mean terminal half-life was ~15 to 20 h, and mean oral clearance ranged from 302 to 491 L/h, which is potentially consistent with preferential hepatic uptake noted in animals. Exposures to BMS-650032 in HCV-infected subjects were similar to or higher than those observed in healthy subjects. Actively treated subjects experienced a mean decline in HCV RNA of ~0.5 log10 (range of decline, 0.1 to 1.1 log10), of ~2.0 log10 (range of decline, 1.6 to 2.4 log10) and of ~2.1 log10 (range of decline, 1.5 to 2.5 log10) at 16 hours after a single 50, 200 and 600 mg dose of BMS 650032, respectively. Maximal activity of the 600 mg dose occurred at hour 24, with a mean decline of HCV RNA of ~2.4 log10 (range of decline, 1.6 to 3.3 log10). Study 004: Maximal antiviral responses with 200 and 400 mg Q12H BMS-650032 were observed at Day 3; actively treated subjects experienced a mean decline in HCV RNA of 3.1 log10 (200 mg Q12h: Range of decline, 2.1 to 4.1 log10) and 3.30 log10 (400 mg Q12: Range of decline, 2.7 to 3.8 log10). Data are pending on subjects who were administered 600 mg Q12h BMS-650032.

Conclusions

Based on the favorable safety, tolerability, and antiviral activity demonstrated herein, further development of BMS-650032 in combination with peg-IFN/RBV, an NS5A inhibitor and/or with other direct acting antivirals is warranted.

Experimental Therapies: Silibinin

226. Silibinin and Related Compounds are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase.

A. Ahmed-Belkacem; N. Ahnou; L. Barbotte; C. Wychowski; R. Brillet; R. Pohl; J. Pawlotsky

Only approximately 50% of patients with HCV genotype 1 infection eradicate infection upon pegIFN-ribavirin therapy. Current HCV drug discovery efforts focus on developing molecules that specifically inhibit HCV enzymes, such as the RNA-dependent RNA polymerase (RdRp) or the NS3/4A protease. Silymarin is a mixture of flavonolignans extracted from the milk thistle, which contains several molecules including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silichristin, and silidianin. Intravenous infusion of Legalon SIL®, a commercially available preparation of silibinin, induces dose-dependent reduction of HCV RNA levels. Our aim was to test the isomers contained in silymarin preparations for their ability to inhibit HCV enzymatic functions and replication in different models.

Methods:

The inhibitory activity of silymarin components was tested in HCV RdRp and NS3/4A protease enzyme assays. Their ability to inhibit replication of an HCV genotype 1b replicon and the JFH1 infectious HCV model in cell culture was also studied. The effect of amino acid substitutions known to confer HCV resistance to RdRp inhibitors was tested.

Results:

Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms and Legalon SIL®, a commercially available intravenous preparation of silibinin, inhibited HCV RNA-dependent RNA polymerase function, with inhibitory concentrations 50% (IC50s) of the order of 75-100 micromolar. Silibinin A and silibinin B also inhibited HCV genotype 1b replicon replication with effective concentrations 50% (EC50s) of the micromolar order, and HCV genotype 2a strain JFH1 replication in cell culture with EC50s approximately one log above those observed in the replicon system. None of the tested silymarin components showed any inhibitory activity in the NS3/4A protease assay, up to a concentration of 200 µM. No cytotoxic effect was observed at inhibitory concentrations in two different human cell lines (Huh7 and HEK 293). Amino acid substitutions known to confer resistance to RdRp inhibitors, including 2’-methyl nucleoside analogues (S282T) and non-nucleoside inhibitors (P495L, M423T, H95Q, and C316Y, located in thumb 1, thumb 2, palm 1 and palm 2 RdRp domains, respectively) did not confer resistance to silibinin in the RdRp enzyme assay.

Conclusions:

Silibinin A and silibinin B, as well as Legalon SIL®, inhibit HCV replication in cell culture. This effect is at least partly explained by the ability of these compounds to directly inhibit HCV RdRp activity. These results provide a basis for the optimization and subsequent development of members of the Flavonoid family as specific HCV antivirals.

Experimental Therapies: General

228. Phase I clinical trial with a novel HCV therapeutic vaccine TG4040: Interim results of biomarker and immunomonitoring analyzes.

G. Honnet; L. Veron; D. Olivier; B. Grellier; B. Marie-Bastien; E. Bonfils; B. Calmels; A. Fournillier; D. Agathon; B. Burtin; V. Leroy; J. h. Zarski; M. Maynard-Muet; C. Trepo; F. T. Habersetzer; J. Bonnefoy; G. Inchauspe; C. Bain

Correlates of self-limited acute HCV infection involve broad, robust and sustained cellular immune responses, in particular IFN-γ producing T cell effectors mainly targeting non structural (NS) HCV proteins. By contrast, when persistent infection is established, HCV-specific T cells are barely detectable, weak, with limited specificity and eventually inefficient at eliminating viral infection. In this context, TG4040, an MVA-based therapeutic vaccine encoding NS3, NS4 and NS5B, aims at triggering HCV-specific T cell immune responses capable of controlling viral replication.

TG4040.01, an open-label, multicenter, dose escalation phase I study aims at evaluating, besides safety, biological activity of TG4040 in treatment-naïve HCV subjects. Effect of TG4040 injections was evaluated in a comprehensive program of biomarker and immunomonitoring analyzes, including both classical assays such as ELISpot IFN-γ or proliferation but also innovative multiparametric approaches such as Luminex-based analyses and gene expression profiling. Responses to HCV antigens were evaluated by use of large pools of peptides overlapping NS3 and NS4B as well as one TG4040-unrelated HCV antigen, NS5A. In parallel, both humoral and cellular responses to MVA vector were evaluated. A total of 15 patients who received 3 different vaccine doses were evaluated. Six of 15 patients received 3 weekly injections of TG4040, the remaining 9 patients receiving a 4th injection at month 6.

In all assessable patients, MVA-specific T cell responses were detected as early as one week after first vaccination, increased up to 6 months and were boosted in patients who received the 4th vaccine injection. Cellular immune responses specific of NS3 and NS4B were detectable at baseline in only 1 of 15 patients but were induced or increased in 5 of 15 patients after TG4040 injections. Overall, kinetics of induction of these responses paralleled viral load fluctuations, with a peak between day 22 and month 2 that corresponded to the nadir of viral load. The strongest vaccine-specific T cell responses (detected by ELISpot IFN-γ) were observed in patients displaying the highest decrease in viral load following vaccination, specifically in the 2 patients who lowered the viral load by 0.8 to 1.5 log compared with pre-vaccination loads. These interim results demonstrate that TG4040 is immunogenic in treatment naïve chronic patients. Results of Luminex analyzes as well a gene expression profiles will be presented.

Experimental Therapies: General

LB3. SILEN-C1: Early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype 1 HCV infection.

M. S. Sulkowski; P. Ferenci; C. Emanoil; T. Asselah; F. Caruntu; J. Lalezari; M. Bourlière; S. Mauss; J. Grange; T. Berg; S. Zeuzem; A. Streinu-Cercel ; D. Wright; D. M. Jensen; C. Haefner; Y. Datsenko; J. O. Stern; G. Nehmiz; G. Steinmann

Background:

BI 201335 is a potent HCV NS3/4A protease inhibitor given once daily (QD). BI 201335 is being studied in chronic HCV genotype-1 (GT1) infection for 24 weeks in combination with pegylated interferon + ribavirin (PegIFN/RBV) in large phase II trials.

Methods:

In a double-blind, randomized, placebo-controlled, parallel group design, HCV GT1 treatment-naïve (TN) patients (pts) were randomized 1:2:2:1 to (1) placebo, (2) 240 mg BI 201335, (3) 240 mg BI 201335 with a 3 day lead-in phase (LI) of PegIFN/RBV, and (4) 120 mg BI 201335 with a 3 day LI. In each group, treatment is for 24 weeks (wks) with a background of PegIFN (180 mcg/wk) and RBV (1000/1200mg/d) for 24 or 48 wks. VL was measured by Roche TaqMan (LLOD 10 IU/ml, LLOQ 25 IU/ml). VL rebound is defined as an increase ≥ 1 log from nadir or confirmed increase ≥ 100 IU/ml if previously undetectable. Results after 12 weeks of therapy are reported in this protocol-defined interim analysis.

Results:

232 males and 195 females were entered. Mean age=45.6 + 10.5 years, BMI=26.0 + 4.7 kg/m2; mean LOG10 VL (IU/mL) at baseline=6.4.

BI 201335 with PegIFN/RBV demonstrated rapid, potent antiviral activity with virologic responses at weeks 4 and 12 (see table).

Mean ALT/AST improved with treatment in all groups. 16 pts reported drug-related SAEs. 18 (5.0%) pts discontinued BI 201335 due to (S)AE of which 1.7% were due to rash. Jaundice was seen in 15.9% of pts in the BI 201335 groups versus 1.4% receiving placebo. As reported previously, BI 201335 leads to a dose-dependent unconjugated hyperbilirubinemia with levels reaching a plateau in 2-4 weeks. Median (range) total bilirubin change was +1.0 (0.1-8.0), +1.5 (0.1-9.1), and +0.6 (0.2-3.9) mg/dl for BI 201335 groups 2, 3 and 4, respectively, at week 4. Other AEs were mostly mild to moderate and typical of PegIFN/RBV. Rash was observed more frequently with BI 201335. Severe rashes occurred in 2.5% and 1.4% of pts treated with BI 201335 and placebo, respectively. Changes in hematology parameters typical of PegIFN/RBV were observed in a similar pattern in all groups.

Conclusions:

SILEN-C1 confirmed robust antiviral activity with good tolerability and safety of BI 201335 given once daily in combination with PegIFN/RBV in treatment-naïve patients with chronic HCV GT-1 infection.

Treatment	Virological Response (wk 4)*		Virological Response (wk 12)*		Viral Rebound (%)*
	< 25 IU/ml (%)	< 10 IU/ml (%)	< 25 IU/ml (%)	< 10 IU/ml( %)
(1) Placebo (N=71)	15.5	4.2	57.8	42.3	2.8
(2) 240 mg QD (N=144)	93.8	77.1	91.0	89.6	4.9
(3) 240 mg QD / LI (N=145)	84.1	62.1	82.1	80.0	4.1
(4) 120 mg QD / LI (N=69)	89.9	69.6	87.0	84.1	2.9

*Some data not available for all patients at week 4 and 12; ITT:missing=failure

Experimental Therapies: General

LB4. Once Daily Narlaprevir (SCH 900518) in Combination with PEGINTRON™ (Peginterferon alfa-2b)/Ribavirin for Treatment-Naïve Subjects with Genotype-1 CHC: Interim Results from NEXT-1, a Phase 2a Study.

J. M. Vierling; F. Poordad; E. Lawitz; R. H. Ghalib; W. M. Lee; N. Ravendhran; J. S. Galati; B. R. Bacon; S. L. Flamm; L. A. Balart; B. Freilich; E. R. Schiff; I. M. Jacobson; P. Y. Kwo; S. C. Gordon; M. S. Sulkowski; N. Boparai; E. I. Chaudhri; C. Brass; E. A. Hughes; J. K. Albrecht

Background:

Narlaprevir (NVR) is a HCV NS3 protease inhibitor that can be dosed once daily when used in combination with low dose ritonavir (RTV). NEXT-1 is being conducted to identify the optimal treatment regimen of narlaprevir plus PegIntron, ribavirin and ritonavir.

Methods:

Response guided treatment of 12 weeks of narlaprevir (200 mg or 400 mg once a day) with ritonavir (100 mg once a day), PegIntron (1.5 mcg/kg/ weekly), and weight based ribavirin (600-1400 mg/day) with or without a 4 week lead-in of PegIntron plus ribavirin , or 12 weeks of narlaprevir (100 mg twice a day) with ritonavir (100 mg twice a day) and PegIntron/ribavirin, all followed by an additional 12 or 36 weeks of PegIntron/rivavirin based on response at treatment week 4 of narlaprevi/ritonavir, are being compared to PegIntron plus riavirin for 48 weeks. The primary endpoint is rapid virological response, undetectable HCV-RNA [Roche Cobas Taqman; LLD=9.3 IU/mL] after 4 weeks of treatment with narlaprevir/ritonavir.

Growth factors (erythropoietin and C-CSF) are permitted in the study.

Results:

Of 111 patients (6 arms) treated in the US (approximate percentages): 13% were Black, 58% male, 78% had high viral load (>600,000 IU/mL), and 61% had subtype 1a (TRUGENE™).

Sixty-five to 87% were HCV RNA negative (<19 UY/mL) by week 12 in the narlaprevir groups compared to 17% in the PegIntron/ribavirin control group.

The side effects that were found to be more common in the narlaprevir groups was anemia (18 to 44%) compared to 6% in the control group. Dizziness was also more common in the narlaprevir groups (18 to 26%) compared to 6% in the control group.

A total of 20 patients discontinued treatment due to side effects—12 to 16% in the nalaprevir arms compared to 39% in the PegIntron/ribavirin control group.

Summary

· Narlaprevir once a day with ritonavir has potent anti-HCV activity

o Trough narlaprevir concentrations achieved 11-25 times the EC₉₀

o 200 mg/ 400 mg narlaprevir once a day achieved undetectable HCV-RNA levels:

§ Week 4 – 58-87% of patients

§ Week 12 – 84-87% of patients

· No unique or treatment limiting adverse events were reported by the authors

o Use of low-dose ritonavir as a metabolic inhibitor was well tolerated

· AE profile consistent with PegIntron/ribavirin with the following observations

o Increased frequency of anemia; no discontinuations due to anemia

o Similar rates of nadir neutrophil levels below 0.75 x 10⁹/L

· Studies evaluating 200 mg and 400 mg nalaprevir once a day with ritonavir (with and without a lead-in) are currently planned

Experimental Therapies: General

LB6. Treatment-naïve, HCV genotype 1-infected subjects show significantly greater HCV RNA decreases when treated with 28 days of ABT-333 plus peginterferon and ribavirin compared to peginterferon and ribavirin alone.

M. Rodriguez-Torres; E. Lawitz; D. Cohen; L. M. Larsen; R. Menon; C. Collins; T. Marsh; S. Gibbs; B. Bernstein

Objective:

ABT-333 is a potent nonnucleoside HCV polymerase inhibitor with a favorable safety profile in healthy subjects. This study assesses the safety, antiviral activity, and pharmacokinetics (PK) of ABT-333 with peginterferon α-2a (pegIFN) and ribavirin (RBV) in HCV-infected subjects.

Methods:

30 HCV genotype 1-infected, treatment-naïve subjects were randomized to ABT-333 300 mg BID (N=8), 600 mg BID (N=8), 1200 mg QD (N=8), or placebo (n=6) for 28 days (2 days monotherapy plus 26 days with pegIFN 180 μg/wk + RBV 1000-1200 mg/d, weight-based). Safety was monitored by adverse events (AEs) and lab results. ABT-333 PK profile was assessed on Day 1; samples were also collected Days 2, 4, 5, 10, 17, 24 and 28.

Results:

Subjects were primarily male (70%) and white (90%); 43% were of Latino ethnicity. At baseline, the mean (SD) age was 46.5 (9.8) yrs and the mean weight was 78.6 (13.2) kg. Treatment with ABT-333+pegIFN/RBV resulted in statistically significantly greater decreases in HCV RNA versus placebo+pegIFN/RBV.

In all the groups who were treated with ABT-333 plus Peg/ribavirin—at Day 28 41.7% (10 out of 24 patients) had less than 25 IU/mL HCV RNA compared to 0% (0 out of 6 patients) in the placebo group (without ABT-333).

The side effects were reported to be mild in severity (85%) with 63% believed to be from Peg/riabivirn. There were no serious AEs or discontinuations due to AEs. Lab abnormalities were similar in subjects receiving ABT-333 and placebo.

Conclusion:

ABT-333 was well tolerated for 28 days when dosed with pegIFN/RBV and resulted in significant decreases in HCV RNA versus pegIFN/RBV alone.

Experimental Therapies: General

LB14. Hepatitis C virus (HCV) antibody seroconversion in a U.S. HIV-infected male clinical trials population

M. Holubar; L. E. Taylor; K. Wu; R. Bosch; K. H. Mayer; K. T. Tashima

Purpose:

Outbreaks of sexually transmitted HCV infection have been reported among HIV-seropositive (HIV+) men who have sex with men (MSM) in Europe, Australia, New York and California. Whether this is occurring across the U.S. is unknown.

Methods:

We evaluated the determinants of HCV antibody (Ab) seroconversion incidence among HIV positive male participants of the AIDS Clinical Trial Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort.

ALLRT is a long-term follow-up study of HIV positive persons randomized into selected U.S.-based clinical trials conducted by the ACTG. Seventeen ACTG studies performed HCV Ab testing from 1996-2002. HCV Ab testing at ALLRT entry began in 2002 with re-testing every 96 weeks added in 2006.

2,365 male subjects had an initial negative HCV Ab result. 1,830 of these had at least 1 subsequent HCV Ab test and were included in this analysis, contributing >7,000 person-years.

We determined HCV seroconversion incidence from 1996-2008. To control for increased surveillance and variable Ab follow-up times after 1996, date of seroconversion was re-assigned as halfway between the date of the last negative and first positive HCV Ab. We evaluated associations with self-reported (previously, 5.3% or currently, 0.5%) injection drug use (IDU), time-varying CD4+ cell count and HIV RNA using multivariate Poisson regression. No sexual or non-IDU risk factor data was available.

Results:

● Of 1,830 males, 57% were White, 22% Black, 18% Hispanic, 2% Asian-Pacific Islander, 1% American Indian

● 70% attended college.

● At the time of initial negative HCV Ab, mean age was 42 years (range 17-79, 52% >40),

● 94% were on highly active antiretroviral therapy (HAART) and,

● 6% reported current or prior IDU.

● Participants had varying lengths of follow-up, with 47% contributing >4 years of person-time.

● Thirty-six seroconverted, with overall incidence of 0.51 per 100 person-years (95% CI = 0.36-0.7).

● Mean age at seroconversion was 46 years (range 22-69, 72% >40). Seroconversion was associated with IDU (25% of seroconverters reported IDU history versus 5% of non-seroconverters, p<0.001), while 75% (n=27) seroconverted in the absence of reported IDU (incidence 2.67 per 100 person-years in IDUs, 0.40 in non-IDUs).

● Seroconversion was associated with HIV RNA >400 copies/ml (44% at time of Ab-positivity vs. 21% at time of last negative Ab, p<0.001) but not with CD4+ cell count.

Conclusions:

● Incident HCV infection is occurring in a U.S. HIV positive male population despite engagement in care with HAART, potentially through non-parenteral means.

● 75% seroconverted in the absence of IDU

● HCV Ab development was not related to immune status, but was associated with inadequate HIV suppression.

● Irrespective of perceived risk, all HIV positive persons should be screened annual with HCV Ab

Experimental Therapies: General

LB15. GI-5005 Therapeutic Vaccine Plus Peg-IFN/Ribavirin Improves End of Treatment Response at 48 Weeks Versus Peg-IFN/Ribavirin in Naive Genotype 1 Chronic HCV Patients.

J. G. McHutchison; I. M. Jacobson; T. D. Boyer; E. R. Schiff; G. T. Everson; W. M. Lee; P. Pockros; R. M. Chasen; J. M. Vierling; E. Lawitz; M. Kugelmas; N. Tsai; B. R. Armstrong; T. C. Rodell; D. Apelian

Background and aims:

GI-5005 is a whole heat-killed S. cerevisiae therapeutic vaccine expressing HCV NS3 and Core antigens. GI-5005 elicits antigen-specific T-cell responses (Hepatology 2007; 46: 816A) with the goal of improving the rate of immune-mediated elimination of HCV-infected hepatic cells.

Methods:

Naïve and non-responder (NR) chronic HCV genotype 1 patients were randomized 1:1, and stratified by prior treatment status in this open label trial; Arm 1- GI-5005 monotherapy run-in consisting of five weekly followed by 2 monthly subcutaneous (SC) doses of 40YU (1 YU = 107 yeast) GI-5005 over 12 weeks, followed by triple therapy consisting of monthly 40YU GI-5005 doses plus 48 weeks pegIFN α-2a/ribavirin (SOC), Arm 2- SOC alone. NRs will receive 72 weeks of triple therapy versus SOC.

Results:

Triple therapy was well tolerated with no significant new toxicities observed and an equivalent number of SOC discontinuations due to adverse events in each group; Triple therapy - 5/68 (7.3%) and SOC 5/65 (7.7%). Improvement in end of treatment response (HCV RNA < 25IU/mL by PCR assay at 48 weeks) was observed in naïve genotype 1 patients in the triple therapy group compared to SOC alone (all randomized); Triple therapy - 37/53 (70%) vs SOC- 27/49 (55%), one-tailed Fisher’s exact test p=0.09. Complete response (HCV RNA <25IU/mL) was assessed in NRs at week 48 (all randomized); Triple therapy - 6/19 (32%) vs SOC- 6/19 (32%). Race, baseline viral load, SOC compliance, and discontinuations did not reveal a significant influence on the observed treatment effect.

Conclusions:

Triple therapy with GI-5005 plus pegIFN/ribavirin is well tolerated and improved week 48 ETR rates compared to SOC in genotype 1 naïve patients. Final sustained virologic response 24 weeks post-treatment will be reported after completion of the trial. These data support further investigation of GI-5005 triple therapy as well as novel combination strategies for GI-5005 with other HCV inhibitory agents.

Current Therapy: Pegasys

61. Standard versus higher induction doses of peginterferon alfa-2a (40KD) and/or higher ribavirin (RBV) in HCV G1 patients with high viral load and body weight ≥85 kg: Final results of the PROGRESS study.

K. Reddy; M. L. Shiffman; M. Rodriguez-Torres; D. Abdurakhmanov; I. Bakulin; G. Faria Silva ; H. Cheinquer; M. Rabbia; J. Depamphilis; M. McKenna; S. Harrison

Background:

Patients infected with HCV G1 with a high viral load and high body weight achieve lower rates of SVR compared to G1 patients with lower viral load and body weight. The PROGRESS study investigated higher induction doses of peginterferon alfa-2a (PEGASYS^®) and/or higher RBV doses to explore the impact on rates of SVR and safety.

Methods:

Overall 1175 G1 patients with a baseline viral load ≥400,000 IU/mL and body weight ≥85 kg were randomized (in a ratio of 1:1:2:2) to 48 wks of 180 µg/wk peginterferon alfa-2a (40KD) plus RBV either at a dose of 1200 mg/day or 1400/1600 mg/day (groups A and B) or 12 wks of 360 µg/wk peginterferon alfa-2a (40KD) followed by a further 36 wks of 180 µg/wk plus RBV either at a dose of 1200 mg/day or 1400/1600 mg/day (groups C and D). For arms B and D, RBV was given at 1400 mg for patients 85 to <95kg and at 1600 mg for ≥95kg. The primary efficacy endpoint was SVR (% of patients with HCV RNA <15 IU/mL) 24 wks after untreated follow-up.

Results:

Baseline characteristics and treatment outcome are described in the table. The odds ratio (95% CI; p-value) of SVR among groups C+D versus A+B was 1.075 (0.831-1.391; p=0.584) and the odds for SVR among groups B+D versus A+C was 1.004 (0.788-1.279; p=0.974).

Conclusions:

In these difficult to cure patients high and comparable rates of SVR were achieved across all treatment arms. Higher rates of SVR were observed among patients ≥95 kg and those with a NAS (non alcoholic fatty liver disease activity score) score ≥3 with induction dosing of peginterferon alfa-2a (40KD) and/or higher RBV doses. Higher doses of peginterferon alfa-2a (40KD) and/or RBV were well tolerated with a similar proportion of patients reporting SAEs and discontinuing peginterferon alfa-2a or RBV for safety reasons.

Parameter	Arm A Peg-IFN α-2a 180 µg +RBV 1200 mg/d (n=191)	Arm B Peg-IFN α-2a 180 µg +RBV 1400/1600 mg/d (n=189)	Arm C Peg-IFN α-2a 360/180 µg +RBV 1200 mg/d (n=382)	Arm D Peg-IFN α-2a 360/180 µg +RBV 1400/1600 mg/d (n=383)
Baseline (median) Male sex, n (%) Mean age (years) Caucasian, n (%) Black, n (%) Weight (kg) HCV RNA (IU/mL) Cirrhosis, n (%)	154 (81%) 46.1 166 (87%) 24 (13%) 96.3 3,075,000 23 (12%)	148 (78%) 45.1 154 (81%) 29 (15%) 95.0 3,430,000 19 (10%)	292 (76%) 45.7 333 (87%) 38 (10%) 95.0 3,470,000 31 (8%)	310 (81%) 46.0 329 (86%) 43 (11%) 95.4 3,540,000 46 (12%)
Drug d/c due to AEs RBV, n (%) PegIFN alfa-2a, n (%) Pts with SAEs, n (%) Deaths, n (%)	22 (12%) 20 (10%) 22 (12%) 1 (<1%)	17 (9%) 17 (9%) 20 (11%) 2 (1%)	40 (10%) 38 (10%) 36 (9%) 1 (<1%)	47 (12%) 43 (11%) 39 (10%) 2 (<1%)
RVR, % cEVR, % Overall SVR, n (%) Pts <95 kg SVR, n/N (%) Pts ≥95 kg SVR, n/N (%) NAS 0–2 SVR,n/N (%) NAS ≥3 SVR,n/N (%)	12% 53% 72 (38%) 40/82 (49%) 32/109 (29%) 62/129 (48%) 10/61 (16%)	12% 55% 81 (43%) 40/90 (44%) 40/97 (41%) 65/132 (49%) 16/56 (29%)	17% 58% 166 (44%) 87/188 (46%) 78/191 (41%) 133/284 (47%) 33/96 (34%)	16% 61% 156 (41%) 80/182 (44%) 76/200 (38%) 107/265 (40%) 48/117 (41%)

Experimental Therapies: Boceprevir

62. High Sustained Virologic Response (SVR) in Genotype 1 (G1) Null Responders to Peg-Interfeon alfa-2b (P) plus Ribavirin (R) When Treated with Boceprevir (Boc) Combination Therapy.

P. Y. Kwo; E. Lawitz; J. McCone; E. R. Schiff; J. M. Vierling; D. Pound; M. Davis; J. S. Galati; S. C. Gordon; N. Ravendhran; L. Rossaro; F. H. Anderson; I. M. Jacobson; R. Rubin; K. Koury ; N. Boparai; E. I. Chaudhri; C. A. Brass; J. K. Albrecht

Introduction:

HCV SPRINT-1 had two arms with a 4-week lead-in:

● (a) PegIntron (1.5 μg/kg/ once a week) plus ribavirin (800-1400 mg/day) prior to the addition of boceprevir (800 mg three times a day) than triple peg/riba/boc for an additional 24 weeks (103 patients) or,

● (b) PegIntron (1.5 μg/kg/once a week) plus ribavirin (800-1400 mg/day) for 4 weeks prior to the addition of bocepresvir (800 mg three times a day) than triple peg/riba/boc for an addition 44 weeks (103 patients).

All patients were naïve gentoype1 patients . This design allowed the determination of viral response based on precisely defined PegIntron/ribavirin. Data from IDEAL demonstrating that a 1 log₁₀ decrease in viral load at week4 corresponded to a ~2 log₁₀ decrease at W12, permitted definition of a ‘null’ response to P/R therapy (<1 log₁₀@W4). Viral response was assessed by Roche Taq-Man (LLD=15 IU/ml) at multiple times including 24-week post-treatment (SVR).

Results:

● Patients were all genotype 1 (1a or1b) with 15% Black, 6- 7% cirrhotics and 87-90% high viral load (> 600,000 IU/ml); male 50-56%.

● Undetectable HCV RNA was achieved in 44% of the 28 week arm and 86% in the 48 week arm.

● Sustained virological response rates were as follows:

o Group a = 56%

o Group b = 75%

Summary

● Boceprevir significantly improves SVR

o Boceprevir with standard of care for 48 weeks nearly doubles SVR

● Patients with <1 log drop in viral load (null response) after 4 weeks of PegIntron/ribavirin lead-in went on to achieve SVR:

o 25% (7/28) of those who received 28 week of treatment

o 55% (12/22) of those who received 48 weeks of treatment

● 77% (113/147) of patients who had a greater than or equal to a 1.0 log drop in viral load (non-null response) after 4 weeks of PegIntron/ribavirin went on to achieve an SVR

● Black race was the only baseline predictor for null response at week 4

Conclusion:

● Ongoing boceprevir studies will further define the relationship of Week 4 PegIntron/ribavirin (lead-in) response to achievement of SVR

● Despite the small numbers of patients, these results suggest that null responders may achieve an SVR

● Risk of developing protease inhibitor resistance should be weighed against the benefits of treatment

Note: Side effect profile was not presented.

Experimental Therapies: General

63. Early Viral Response (EVR) Rates in Treatment-naïve Patients with Chronic Hepatitis C (CHC) Genotype 1 Infection Treated with MK-7009, a Novel NS3/4a Protease Inhibitor, in Combination with Pegylated Interferon Alfa-2a and Ribavirin for 28 Days.

M. P. Manns; E. J. Gane; M. Rodriguez-Torres; A. D. Stoehr; C. Yeh; P. Marcellin; R. T. Wiedmann; P. Hwang; R. J. Barnard; E. Quirk; N. A. Kartsonis; A. W. Lee

Background:

MK-7009 is a noncovalent competitive inhibitor of HCV NS3/4a protease which significantly improved rapid viral response (RVR) rates in CHC subjects when administered in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for 28 days (i.e., "triple therapy"). We now report updated efficacy and safety for patients treated with continued peg-IFN/RBV for 12 weeks total.

Methods:

This is a randomized, placebo-controlled, double-blind study of MK-7009 in treatment-naïve CHC patients. MK-7009 was administered for 28 days with peg-IFN/RBV in 1 of 5 regimens: placebo, 300 mg BID, 600 mg BID, 600 mg QD, or 800 mg QD; all patients continue peg-IFN/RBV for an additional 44 weeks. HCV RNA was determined by Roche Cobas Taqman PCR with a lower limit of detection (LLOD) ~ 10 IU/mL. RVR and EVR are defined as the percentage of treated patients below LLOD at 4 and 12 weeks, respectively.

Results:

94 subjects (mean age 46.1 years, 59% male, mean baseline HCV RNA 6.70 log10 IU/mL) were randomized and treated. The proportion of subjects who achieved RVR in the MK-7009-containing arms ranged from 69% to 82%, vs. 6% of the control (p < 0.0001 for each MK-7009 dose group, per-protocol analysis). Preliminary data for 81 patients through Week 12 indicate continued viral suppression on peg-IFN/RBV only treatment, as 77 to 89% of subjects originally treated with triple therapy achieved EVR vs. 60% of control (per-protocol analysis). Resistant HCV variants at NS3/4a positions 155 and 168 were detected in viral breakthrough patients randomized to receive MK-7009. MK-7009 in combination with peg-IFN/RBV was well tolerated, with no serious adverse events (SAEs) during the MK-7009 treatment and follow-up period (42 days). There were 3 SAEs reported during the peg-IFN/RBV continuation period, none of which were related to MK-7009. Non-serious AEs were collected, but not prompted for, after day 42 of the study.

Conclusions:

In this first study of MK-7009 in combination with peg-IFN/RBV, MK-7009 is a well-tolerated and potent inhibitor of HCV. This interim analysis indicates high rates of viral suppression to undetectable levels through 12 weeks in subjects treated with MK-7009 in combination with standard therapy for the initial 28 days. The results support further development of MK-7009 for HCV treatment.

MK7009 Dose group	Week 4 <10 IU/mL n/N	Week 4 % <10 IU/mL (RVR)	Week 12 <10 IU/mL n/N	Week 12 % <10 IU/mL (EVR)
300 mg BID	12/16	75	12/15	80
600 mg BID	15/19	79	16/18	89
600 mg QD	11/16	69	14/16	88
800 mg QD	14/17	82	13/17	77
Placebo	1/18	6	9/15	60

Experimental Therapies: Albuferon

64. Efficacy and Safety of albinterferon alfa-2b in Combination with ribavirin in Treatment Naïve Patients with chronic hepatitis C genotype 1.

M. S. Sulkowski; S. Zeuzem; E. Lawitz; M. Grigorescu; A. D. Tice ; V. K. Rustgi; M. Rodriguez-Torres; Y. Lurie; J. Cianciara; B. R. Bacon; V. G. Bain; W. Kryczka; E. Pulkstenis; G. M. Subramanian; J. G. McHutchison

Background:

A phase 3, randomized, active-controlled, multi-center study evaluated the efficacy and safety of albinterferon alfa-2b (albIFN), a genetic fusion polypeptide of albumin and interferon alfa-2b in chronic HCV-1 patients.

Methods:

In total, 1331 patients were randomized 1:1:1 to one of the 3 treatment groups: albIFN 900 µg q2wk; albIFN 1200 µg q2wk (dose reduced to 900 µg); PEG-IFNα2a 180 µg q1wk for 48 wks, in combination with weight-based ribavirin 1000-1200 mg/day. Randomization was stratified by baseline HCV RNA levels (≥ or < 800,000 IU/mL), BMI (≥ or < 25 kg/m2) and race (Black/African-American or other). The primary endpoint was sustained virologic response SVR, (defined as serum HCV RNA < 15 IU/mL at wk 72).

Results:

The study achieved the primary objective of demonstrating non-inferiority of albIFN 900 µg (p=0.0008) and albIFN 1200 µg (p=0.0029) versus PEG-IFNα2a for SVR. In the intention-to-treat population, SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) in the PEG-IFNα2a, albIFN 900 and albIFN 1200 groups, respectively. Multivariate analysis identified the following predictors of SVR: HCV RNA <400,000 IU/mL, age <45, normal GGT, high ALT, F0-2 fibrosis, and race (non-black), consistent with previous studies. Early antiviral response had a high positive predictive value (PPV) for SVR in all treatment groups. The PPV of initial virologic response at Week 2 (IVR; >2 log viral decline or HCV RNA < LOQ) was 73-84%; the PPV of rapid virologic response at Week 4 (RVR; HCV RNA

Conclusions:

Albinterferon alfa-2b 900µg administered q2wk demonstrated comparable efficacy to PEG-IFNα2a in patients with chronic HCV-1. The overall incidence of serious or severe adverse events was similar between these two treatments.

Experimental Therapies: General

65. Sustained Virologic Response (SVR) Results for Weight-Based-Taribavirin Versus Weight-Based-Ribavirin, in Naïve Chronic-Hepatitis C, Genotype 1 Patients.

F. Poordad; E. Lawitz; T. Hassanein; M. L. Shiffman; B. R. Bacon; A. Muir; J. Heise; D. Halliman; E. Chun; J. M. Hammond

Background and Aims:

Taribavirin (TBV) is an oral pro-drug of ribavirin (RBV) associated with less anemia than RBV. This trial aimed to determine the optimal weight-based dose (WBD) of TBV given with peginterferon alfa-2b (PEG-IFN alfa-2b) and to confirm anemia benefits.

Methods:

A US phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in treatment-naïve, genotype 1 patients stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800-1400 mg/day) with PEG-IFN alfa-2b for 48 weeks.

Results:

278 patients were randomized: mean age 49 yr; 61% male; 30% African-American or Latino; 81% viral load ≥400,000 IU/mL; 30% bridging fibrosis; and mean body weight 82 kg. Virologic response rates for treatment weeks (TWs) 4, 12, and 48, and rates of sustained virologic response (SVR), relapse, and anemia are shown in the table. The most common adverse events (AEs) in all groups were fatigue, diarrhea, insomnia, and chills. Diarrhea, reported about twice as frequently in TBV patients during treatment, was generally mild, self-limited, and not dose-limiting.

Conclusions:

All doses of TBV demonstrated efficacy and tolerability comparable with RBV. Response rates were comparable to those from studies with similar patient demographics, including higher proportions of African-Americans and Latinos, and patients with advanced fibrosis. Anemia rates for TBV 20 – 25 mg/kg consistently were statistically significantly lower compared to RBV. The 25 mg/kg dose of TBV provides the optimal balance of safety and efficacy. Weight-based dosing with TBV is an effective alternative to RBV for chronic hepatitis C treatment with a significant reduction in anemia.

Efficacy and Safety Results (intent-to-treat analysis)*

	TBV 20 mg/kg n=67 (%)	TBV 25 mg/kg n=70 (%)	TBV 30 mg/kg n=68 (%)	RBV 800-1400mg n=70 (%)
TW4^1	11 (16.4)	10 (14.3)	11 (16.2)	8 (11.4)
TW12^1	28 (41.8)	29 (41.4)	17 (25.0)	22 (31.4)
TW48^1	30 (44.8)	27 (38.6)	23 (33.8)	26 (37.1)
SVR1	19 (28.4)	19 (27.1)	19 (27.9)	19 (27.1)
Relapse rate %	34.5	20.8	13.6	20.8
Anemia^2	9 (13.4)†	11 (15.7)†	19 (27.9)	23 (32.9)

¹ HCV RNA undetectable <39 IU/mL 2 Anemia: hemoglobin <10 g/dL on treatment * Please note 278 patients were randomized, however only 275 were actually given drug † P<0.05 vs. RBV

Experimental Therapies: Telaprevir

66. PROVE3 Final Results and 1-Year Durability of SVR with Telaprevir-Based Regimen in Hepatitis C Genotype 1-Infected Patients with Prior Non-response, Viral Breakthrough or Relapse to Peginterferon-Alfa-2a/b and Ribavirin Therapy.

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

Background:

PROVE3 is a randomized Phase 2 study assessing safety and efficacy of telaprevir (T) plus Peginterferon-alfa-2a (P) ± Ribavirin (R) in HCV genotype 1 pts who failed prior PR treatment.

Methods:

Randomization was 1:1:1:1 to: T/PR for 12-wks, then PR for 12-wks (T12/PR24); T/PR for 24-wks, then PR for 24-wks (T24/PR48); T/P for 24-wks (T24/P24); or placebo/PR (P 180 μg/wk, R 1000–1200 mg/day) for 24-wks, then PR for 24-wks (PR48). Treatment was discontinued if a protocol-defined stopping rule was met. HCV RNA was assessed 48-wks after treatment only in pts in T arms who completed treatment and achieved SVR.

Results:

Of 453 pts included in ITT analysis, 418 (92%) had baseline HCV RNA ≥800,000 IU/mL, (267) 59% had genotype 1a, 196 (43%) had cirrhosis or bridging fibrosis and 40 (9%) were black; 235 (52%) completed assigned treatment. Discontinuation due to protocol-defined stopping rules were 15% in T12/PR24, 23% in T24/PR48, 37% in T12/P24, and 59% in PR48. 10%, 25%, 9% and 4% of pts discontinued due to AEs in T12/PR24, T24/PR48, T24/P24, and PR48, respectively. Viral breakthrough rates were 11%, 10%, 21%, and 3% in T12/PR24, T24/PR48, T24/P24, and PR48, respectively. Relapse rates were 28%, 4%, 53% and 52% in T12/PR24, T24/PR48, T24/P24, and PR48, respectively, 24-wks after treatment. In the T regimens, no late relapses occurred 48-wks after treatment. AEs occurring with a greater incidence in T12/PR24 or T24/PR48 than PR48 included fatigue, nausea, headache, rash, pruritus, diarrhea, anemia, insomnia, pyrexia, alopecia, and chills. Grade 3 rash was observed in 5%, 4%, 3% and 0% of pts in T12/PR24, T24/PR48, T24/P24, and PR48, respectively. Grade 3 anemia was observed in 0%, 6%, 1% and 1% of pts in T12/PR24, T24/PR48, T24/P24 and PR48, respectively.

Conclusions:

● SVR rates in all treatment groups receiving telaprevir, Pegasys, ribavirin regimens were significantly higher than with control arm of Pegasys/ribavirin (standard of care) Other than 1 patient lost to follow-up, all pts who completed telaprevir regimen and achieved SVR maintained virologic response 48-wks after the end of treatment.

● The general safety profile of these regimens was similar to that observed in treatment-naïve pts. Pts who failed prior PR therapy can successfully be treated with a T-based regimen and maintain SVR 1 year after the end of treatment.

Pts achieving SVR (undetectable HCV RNA 24-wks after end of treatment) (*statistical comparison to PR48)	T12/PR24 n/N (%)	T24/PR48 n/N (%)	T24/P24 n/N (%)	PR48 n/N (%)
All Patients	59/115 (51) (P<0.001*)	60/113 (53) (P<0.001*)	27/111 (24) (P=0.024*)	16/114 (14)
Prior Non-responders (never undetectable)	26/66 (39) (P<0.001*)	24/64 (38) (P<0.001*)	7/62 (11) (P=0.297)	6/68 (9)
Prior Relapsers	29/42 (69) (P<0.001*)	31/41 (76) (P<0.001*)	16/38 (42) (P=0.029*)	8/41 (20)
Prior Breakthroughs	4/7 (57)	5/8 (63)	4/11 (36)	2/5 (40)
Pts with SVR maintaining undetectable HCV RNA 48-wks after end of treatment	T12/PR24 n/N (%)	T24/PR48 n/N (%)	T24/P24 n/N (%)	PR48 n/N (%)
Patients (excluding premature DC or PR48)	56‡/57 (98)	50/50 (100)	25/25 (100)	NA

‡ 1 Patient lost to follow-up

Current Treatment: General

758. Use of Telemedicine and the “Warm Line” for the Treatment of Hepatitis C Infection (HCV) in the Correctional Setting to Reduce Barriers to Specialty Care

P. Nachin; M. Kerbleski; A. Gaglioti; M. Mahoney; R. Protell; L. Kohler; J. C. Imperial

Background:

The seroprevalence of HCV is estimated to be approximately twenty times higher in the incarcerated population than the general population. Up to 35% of inmates have chronic HCV (Hunt and Saab, 2009). The prevalence of cirrhosis in incarcerated populations is unknown.

Purpose:

To identify, triage, and treat patients with chronic hepatitis C (HCV) within the California Department of Corrections and Rehabilitation (CDCR) and to estimate the prevalence of cirrhosis and end stage liver disease in this population.

Methods:

In May, 2008, the California Prison Health Care Services (CPHCS) collaborated with the University of California San Francisco Correctional Medicine Consultative Network (CMCN) to improve access to HCV treatment in California state prisons. A multidisciplinary, primary care-based model using an evidence-based approach to treatment and management of chronic liver disease was created. To increase capacity to treat HCV among primary care and nursing providers within CDCR, CMCN held a HCV training conference in October, 2008.

Hepatologists treated patients via telemedicine in response to primary care provider-initiated referrals. The CMCN “warm line” was established to further assist CPHCS clinicians managing HCV. Consultations were requested by phone, fax, or e-mail to CMCN hepatology nurses. Warm line access was available weekdays during business hours and inquiries were answered within 24 hours. Hepatologists provided written consultation notes and faxed copies to each provider.

A chart review of all telemedicine and warm line consultations was completed. Patients with liver biopsy results of Metavir stage 3-4 or platelet counts of <140,000 were assumed to have cirrhosis.

Results:

● Data collected from 514 new patients (492 male/22 female) HCV telemedicine consults between April 2008 and July 2009.

● Advanced fibrosis, defined as platelet count <140,000 ul/L and/or liver biopsy results of F3 or F4 was found in 186 (36%) patients

● 18 patients (9.6%) developed complications related to end stage liver disease (ESLD)

● 5 patients (2.6%) developed hepatocellular carcinoma (HCC)

● 7 patients (1.7%) died from liver-related events

Conclusion:

● Academic partnerships can facilitate access to HCV care for the incarnated population

● HCV nurse specialists and hepatologists are able to efficiently improve quality and access to care using telemedicine and ‘warm line’ consults

● The high prevalence of advanced fibrosis in the incarcerated should inspire strategies for identification and treatment of patients with more advanced liver disease

● Patients easily cured with short duration of therapy should be identified and treated

Barriers to Care:

● Prevalence data for HCV/HBV/HIV unknown

● Inadequate education

● No system-wide computerized medical records

● Pharmacy data on prescriptions written only means for following numbers of treated patients

● No data on side effects, dose reductions, interruptions, SVR

o 1100 patients started on treatment

o 20M spent on medications within the first year of program

Future Directions

● Universal screening at reception centers is cirtical to obtain adequate prevalence data in the incarcerated population

● Transition programs for referral to community clinics for parolees may shift cost burden and facilitate continuity of care

Experimental Therapies: Telaprevir

793. Dynamic response of innate immunity induced by telaprevir and PEG-IFN/RBV treatment and its association with virological response and HCV variants.

Y. Asahina; I. Hirayama; N. Tamaki; Y. Yasui; T. Tanaka; M. Sato; K. Ueda; T. Kuzuya; K. Tsuchiya; H. Nakanishi; J. Itakura; M. Kurosaki; N. Izumi

Background:

The RIG-I/IPS-1 system plays an essential role in the innate antiviral response. HCV evades the innate immune response using the NS3/4A protease that ablates RIG-I signaling by cleaving IPS-1. The innate immune response during inhibition of NS3/4A by telaprevir (TVR) is unclear.

Aim:

To elucidate the effect of antiviral therapy on innate immunity and the relation between the innate immune response and clinical efficacy of antiviral treatments, including HCV mutation.

Methods:

Biopsy-proven chronic hepatitis C genotype 1b patients treated with TVR alone or with PEG-IFN/RBV combination therapy were studied (n=128). To elucidate the effect of TVR itself, the innate immune response and HCV variants were studied in patients treated with 24 weeks of TVR monotherapy, which was previously approved for phase II study. Expression levels of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), ubiquitin E3-ligase (RNF125), and modulators (ISG15 and USP18) in the liver and the peripheral blood mononuclear cells were quantified. Written informed consent was obtained from all patients.

Results:

HCV-RNA decreased rapidly in all patients treated with TVR alone (mean 3.8 log IU/mL reduction at day 3). The T54A variant predominated during the initial phase of steep viral decline in most patients who demonstrated subsequent viral rebound, and was replaced by the A156T variant and low levels of V36A/A156S variants during the rebound phase. However, an opposite pattern of variant replacement was observed in some patients. Expressions of viral sensors and modulators were significantly suppressed during the initial phase of steep viral decline (mean 42% reduction) and suppression continued thereafter except in a patient who showed a sustained suppression of HCV-RNA without any variant throughout the 24-week dosage period. In this patient, RIG-I expression was restored 2.2-fold from the basal level after 8 days, and IPS-1 expression also increased at this point. In patients with PEG-IFN/RBV combination therapy, a larger fold change of RIG-I peak inductions by PEG-IFN was observed in sustained viral responders compared with nonvirological responders (NVR). The hepatic expression of viral sensors was significantly upregulated in NVR. In contrast, IPS-1 and RNF125 were significantly suppressed in NVR. In the entire HCV genome, core R70Q and L91M mutations were significantly associated with NVR independent of a higher RIG-I/IPS-1 ratio.

Conclusion:

The dynamic response of innate immunity induced by TVR or PEG-IFN/RBV is associated with virological response to the therapies, which independently related with a specific pattern of HCV variants.

Current HCV Therapy: Side Effects

794. Global review of the rate of interstitial pneumonitis among hepatitis virus C-infected patients treated with pegylated interferon ± ribavirin.

A. Tietz; J. Liu; M. Peng; M. T. Schaerer; J. Solsky

Background:

Interstitial lung disease is an imprecise clinical term that refers to a diverse range of over 200 inflammatory and fibrotic disease entities that affect the lung parenchyma. Despite efforts to establish consistency in the reporting of interstitial lung disease, challenges remain in terms of classification and categorization, diagnosis and terminology utilized in various parts of the world. Very little epidemiologic data are available on interstitial lung disease; however, a US study suggested that the annual incidence is higher in males (31.5/100,000) than females (26.1/100,000) and that the prevalence increases with age. Interstitial lung disease is a known rare adverse event reported with the use of alpha interferon’s, with the highest rates reported in Japan. The higher reporting rate of interstitial pneumonitis (IP) in Japan has created interest and warrants further investigation into its underlying cause.

Methods:

Using systemically collected data from 12 randomized clinical trials (ex-Japan), and spontaneous reports in the Roche global safety database (ADVENT), the frequency of IP was estimated in patients treated with peginterferon alfa-2a ± ribavirin. IP was defined as interstitial lung disease, alveolitis, pulmonary fibrosis, pneumonitis and pulmonary toxicity.

Results:

One case (0.02%) of IP was reported among the 6180 patients included in the integrated clinical trials database. Based on the estimated worldwide cumulative number of 926,000 patients exposed to peginterferon alfa-2a (42,600 in Japan and 883,000 in the USA/rest of world [ROW]), the 228 reported cases of IP in the ADVENT safety database represent a reporting rate of 0.02%, with a proportional reporting ratio (PRR) of 1.7 (p<0.0001). Of these cases, 140 were reported in Japan (PRR 2.9; p<0.0001), 34 in the USA (PRR 0.7; p=0.06) and 54 ROW (PRR 1.2; p=0.11), representing reporting rates of 0.3% in Japan and 0.01% in the USA and ROW. Furthermore, the yearly reporting rate has remained unchanged over the past 3 years in Japan, USA and ROW. Japanese patients with reported IP were older (mean age: 66 versus 50–55 years in USA/ROW), and were more likely to have been treated with peginterferon alfa-2a monotherapy (81% versus 21–39% in USA/ROW). A review of individual cases suggests a lack of precision in diagnosis or terminology.

Conclusions:

● The overall reporting rates of IP with peginterferon alfa-2a ± ribavirin from randomized clinical trials and the ADVENT database remain low and unchanged from time of approval.

● The higher rate of IP reported in Japan compared with USA/ROW may result from differences in patient demography, diagnostic criteria and terminology.

● There is no evidence to suggest that the risk of death attributable to IP is higher in perinterferon alfa-2a (40KD) patients from any region, or in Japanese patients with a prior history of IP.

● IP remains a rare AE and the global reporting rate remains constant and consistent with peginterferon alfa-2a labelling, which is reflected in all current local labels worldwide.

Current HCV Therapy: General

795. Clinical efficacy and cost effectiveness analysis of peginterferon and ribavirin therapy in patients after curative treatment for hepatocellular carcinoma associated with hepatitis C.

K. Tsuchiya; Y. Asahina; N. Tamaki; M. Sato; T. Tanaka; I. Hirayama; Y. Yasui; T. Hosokawa; T. Kuzuya; H. Nakanishi; J. Itakura; M. Kurosaki; N. Izumi

Background:

Despite curative treatment of hepatocellular carcinoma(HCC), HCC frequently develops at newly foci, leading poor prognosis

Aim:

To evaluate the efficacy and cost effectiveness of peginterferon and ribavirin (PEG-IFN/RBV) therapy in patients after curative treatment for HCC

Method:

In 2636 biopsy proven chronic hepatitis C patients, the primary preventive efficacy against HCC by IFN therapy, including PEG-IFN/RBV, was determined. Furthermore, a cohort of 547 patients curatively treated with radiofrequency ablation (RFA) as an initial therapy was analyzed. These patients were divided into a sustained viral response (SVR) group and non-responder or untreated by IFN group. Then recurrence rate of HCC and survival rate were analyzed. Finally, 69 patients were enrolled in a prospective randomized study at 13 centers in order to evaluate the efficacy and cost effectiveness of PEG-IFN/RBV after locally curative treatment for HCC

Results:

(1)The cumulative incidence of HCC was significantly lower in patients with viral eradication than in those without eradication (at 15 years, 4.4% vs. 21.1%, p<.001). The use of PEG-IFN/RBV was independently associated with viral eradication. (2)The cumulative survival rate among HCC patients with curative RFA was significantly higher in SVR group than in non-SVR group (at 5years, 93.3% vs. 62.5%, p=0018). The rate of second recurrence of new foci was significantly lower than in SVR patients than in non-SVR group (at 5 years, 43.2% vs. 71.1%, p=0.018), although the rate of first recurrence was similar. (3) In a prospective study, efficacy of PEG-IFN/RBV after curative treatment for HCC was favorable with SVR rate of 34.9% (ITT). SVR rate was 30% in genotype 1 with high viral load and 70% in genotype 2. HCV genotype and viral load before PEG-IFN/RBV therapy were significantly associated with SVR. There was no second recurrence in SVR group at 2 year and the total cost during 2 years from the start on this study including the treatment for recurrence of HCC was significantly lower in SVR group than in non-SVR group (p=0.048). The major reason for dropout was HCC recurrence (10.1%) and no serious adverse effects were observed.

Conclusion:

Viral eradication by PEG-IFN/RBV therapy prevents the second recurrence and enhances the survival. Moreover it curtails the cost of patients after curative treatment for HCC associated with hepatitis C.

HCV Therapy: General

802. Long term follow-up of chronic hepatitis C patients after interferon based anti-viral therapy.

H. Hofer; T. Scherzer; S. Beinhardt; K. Rutter; A. Stättermayer; P. E. Steindl-Munda; P. Ferenci

Background and Aim:

Antiviral therapy of patients with chronic hepatitis C is aimed to reduce long-term complications like liver cirrhosis, portal hypertension and hepatocellular carcinoma. Persistence of HCV at low levels after therapy induced resolution of chronic hepatitis C has been reported. Aim of the present study was to evaluate clinical outcome of antiviral therapy in a large cohort of chronic hepatitis C patients with emphasize on prevention of long-term complications and durability of HCV eradication in SVR-patients.

Patients and Methods:

● Five hundred and sixty three patients (male=378, female=185; HCV genotype 1: 55.4%, HCV genotype 2: 2.3% HCV genotype 3: 20.1%, HCV genotype 4: 10.8%; 26.3% with pre-treatment cirrhosis) who received antiviral therapy between 1988 and 2006 were regularly followed.

● Out of this 563 patients 251 patients (male=164, female=87; HCV genothpe 1: 50.0%, HCV genotype 2: 4.0%, HCV genotype 3: 27.6%, HCV genotype 4: 12.4%, and 26.2% with pre-treatment cirrhosis) with a SVR and a follow up time of >12 months after the end of therapy were evaluated.

● Twelve patients received monotherapy with standard interferon-alpha, 64 received standard interferon-alpha in combination with ribavirin, one patient received pegylated interferon alone and 174 received pegylated interferon in combination with ribavirin.

● Serum HCV-RNA was tested by the COBAS AMPLICOR HCV test, v2.0 or COBAS TaqMan HCV test, respectively.

Results:

● The median follow-up duration was 56.0 [12-214] months [range].

● All 251 sustained virological responders (100%) with long-term follow-up remained HCV RNA negative during follow up.

● No late relapses were observed so far.

● 222/250 (88.8%) patients had transaminases within the normal range.

● In three patients (1.2%) with SVR a hepatocellular carcinoma was diagnosed during follow up.

● One additional patient developed decompensated cirrhosis (Child C) 4 years after therapy.

Conclusion:

● No recurrence of HCV infection was observed in any patient with SVR after antiviral therapy and the vast majority of patients with a successful HCV eradication remain free of liver disease after long term follow up.

● Thus, long-term prognosis of SVR patients (up to 18 years) is promising, although the risk of HCC development and of progressive liver disease is not prevented completely.

HCV Populations: Injection Drug Users

805. Treatment of chronic hepatitis C virus infection in IVDU: long term (4 year) follow up.

J. D. Farley

Background:

Treatment of HCV in IDU has been demonstrated to be effective. Previous reports suggest reinfection and relapse in IDU is low. There is little data on the long term follow up of those successfully treated. We encourage regular follow up and monitoring of HCV status of those treated for HCV in our clinic. We previously reported 18 reinfection cases occurring in our patient population (AASLD 2008). As of May 30, 2009 we have 33 confirmed HCV reinfection cases. We now report on the outcome of a 4-year follow up evaluation after successful treatment of HCV in IDU.

Methods:

Retrospective chart review of HCV patients who were successfully treated (had sustained virologic response) with Pegylated interferon alfa or beta and Ribavirin combination therapy.

Results Summary:

● To date, data is available on 174 individuals who likely acquired HCV from IVDU, complete HCV treatment were followed up for a range of six months to four years.

o Of the 174 individuals, 50 (29%) admitted to continuing IVDU after SVR;

o 16 (9%) were on methadone maintenance treatment

● During the follow-up period, 34 individuals became reinfected (after SVR),. 24 with a different genotype; 10 had the same genotype (as in their original infection).

● Reinfection occurred a mean of 46.6 weeks after the schedule SVR (SD of 50.0 weeks). The time to occurrence of reinfection varied from during treatment to four years after achieving SVR.

● The likely causes of reinfection included IVDU (76%), percutaneous contact (9%), and tattooing (15%).

● Of 34 reinfected individuals, 10 (29%) were re-treated.

o 4 completed the second treatment with satisfactory EOT response

§ One achieved SVR

§ The results of the SVR are pending for three

§ Three did not finish treatment because of adverse reactions

§ The outcome results are pending for three

§ One individual had spontaneous clearance after reinfection.

Conclusion:

● Treating HCV in IDU is feasible and effective.

● Reinfection is a significant occurrence among IVDU (in our experience unlike reports of others’ experiences) and may occur during or after treatment.

o Last year, we reported 15 cases of reinfection. As we continue to monitor, an additional 19 cases have been identified making a total of 34 noted to date. This we feel is less than the true occurrence.

● We believe our higher numbers of reinfection cases identified may be explained because of the larger numbers we treated and the longer period of observation (at least 4 years) than others’ reports. Also, we routinely recommend and follow up all our IDUs treated for HCV after SVR determination: we test for possible reinfection at six or twelve monthly intervals (or more frequently in those with known continued high risk IVDU.

● There is continued high risk activity after HCV treatment in many. Whether factors such as methadone maintenance treatment use or other substitution therapies correlate with lower likelihood of reinfection is unclear at this time.

● We recommend more frequent monitoring and couseling if IDUs as well as re-genotyping of those when HCV RNA is detected. The likelihood of reinfection must be considered and continually emphasized and addition issues and practices addressed otherwise, reinfection occurrence could decrease overall effectiveness of any HCV treatment programs for intravenous drug users.

HCV Therapy: General

812. Retreatment With Peginterferon (PEG-IFN) alfa-2b Plus Ribavirin (RBV) of Chronic Hepatitis C Genotype 1 Patients Who Were Nonresponders to Peginterferon alfa-2a: Final Results of ESPECIAL.

S. Zeuzem; M. Diago; T. Pohle; A. Andriulli; U. Spengler; A. Gatta; A. Maieron; C. Herold; X. Yu; R. Faruqi; E. I. Chaudhri; L. Pedicone

Purpose:

Patients with chronic hepatitis C virus (HCV) genotype 1 (G1) infection who were nonresponders to therapy are difficult to retreat with current therapies. In a recent study with PEG-IFN alfa-2a plus RBV,16% and 7% of patients receiving 72 and 48 weeks’ treatment, respectively, attained sustained virologic response (SVR).¹

The objective was to determine if HCV G1 patients who were nonresponders to PEG-IFN alfa-2a/RBV responded to retreatment with PEG-IFN alfa-2b/RBV.

Method:

This was an open-label, international, multicenter, single-arm study of PEG-IFN alfa-2b 1.5 μg/kg/wk plus RBV 800-1400 mg/d, in adult patients with HCV G1 who were nonresponders (previous failure to achieve a 2 log drop in viral load at week 12, or detectable viral load at end of treatment) to previous treatment with PEG-IFN alfa-2a 180 μg/wk plus RBV 1000-1200 mg/d. Patients received 48 weeks of treatment; those patients not achieving complete or partial early VR (cEVR, undetectable HCV-RNA; pEVR, ≥2 log drop by PCR at week 12), were discontinued from the study. The primary endpoint was proportion of patients who achieved SVR (HCV-RNA <30 IU/mL via PCR-based TaqMan assay) at 24 weeks post end of treatment. Secondary endpoints included cEVR or pEVR at week 12, response rate after 48 weeks’ treatment, and undetectable HCV-RNA at 4 weeks’ treatment (rapid VR).

Results:

117 patients were enrolled, and 12 completed the study; the overall discontinuation rate was 89.7% (105/117). The primary reason for discontinuation was treatment failure (67.5%, 79/117); the majority of these patients were withdrawn from the study after week 12 due to nonresponse (non-EVR) per protocol. Most enrolled patients had baseline HCV RNA >800,000 IU/mL (88.9%, 104/117), and insulin resistance with HOMA-IR ≥2 (65.8%, 77/117). No patients attained RVR, and 23 (19.7%) attained EVR. One subject (0.9%) attained SVR. End of treatment response after 48 weeks was observed in 6 (5.1%) patients; however, all 6 patients failed to achieve SVR due to relapse. Adverse event profile was consistent with that previously reported with PEG-IFN alfa-2b/RBV therapy.

Conclusion:

In this open-label study, patients were true previous nonresponders; none achieved RVR, <20% attained EVR, and only 1 patient achieved SVR. Failure to achieve ≥2 log drop in HCV RNA after 12 weeks’ treatment remains a reliable predictor of nonresponse. The results of this study confirm that patients with HCV G1 who were true previous nonresponders to an adequate dose and duration of PEG-IFN alfa-2a/RBV are not optimal candidates for retreatment with current standard of care.

¹. Jensen DM, et al. Ann Intern Med. 2009;150(8):528-40.

HCV Populations: Injection Drug Users

813. Combination antiviral therapy for chronic hepatitis C in illicit drug users: meta-analysis of prospective studies.

B. Zanini; L. Covolo; F. Donato; A. Lanzini

Aim:

According to most recent international guidelines, ongoing illicit drug use is no longer regarded as a contraindication to antiviral therapy for Chronic Hepatitis C (CHC); nevertheless in clinical practice only few IDUs access specific treatment for hepatitis C virus because of prejudice of poor adherence and of lack of treatment efficacy. The aim of our meta-analysis was to assess efficacy and safety of combination therapy of recombinant or pegylated interferon alpha plus ribavirin in the treatment of CHC in IDUs.

Methods:

We performed a sensitive search of three electronic bibliographic databases (Medline, Embase and the Cochrane Library) and a hand-searching revision of abstract-books from five international liver meetings for papers and abstracts that met pre-defined search criteria. Search term used were “hepatitis C” or “HCV” or “peginterferon” or “interferon” or “antiviral therapy” AND “methadone” or “IDUs”. Data for meta-analysis were collected according to QUORUM (Quality of Reporting Meta-analyses) statement guidelines. For inclusion into the meta-analysis, the studies had to meet the following criteria: (1) sample size over 15 patients, (2) clear definition of antiviral schedule for type, dose and duration of treatment, (3) uniform combination antiviral therapy for the whole study population.

Results:

Out of 95 papers and abstracts, 13 prospective studies were included (3 case-control, 2 randomised and 8 observational in study design) and information on a cohort of 582 IDUs was analysed. The estimated overall Sustained Virologic Response (SVR) was 53% (41-65%, CI) and was similar to the SVR rate reported in registration trials of treatment of CHC that excluded IDUs from the study population: 50% (39-61%, CI). Among IDUs drop out and psychiatric severe adverse events leading to treatment discontinuation rates were 24% (18-29%, CI) and 4% (1-7%, CI) respectively. Such prevalences were similar to those reported in registration trials excluding IDUs in selection criteria: 26% (12-41%, CI) and 2% (0-6%, CI) respectively. Active ongoing drug use negatively affects rate of SVR (40%), while programs of management involving a multidisciplinary team and careful assessment of the psychiatric status of patients before and during treatment improve response rate (55% and 76%, respectively).

Conclusion:

Antiviral treatment for chronic hepatitis C in IDUs is effective and safe in clinical practice. Patients abstinence and multidisciplinary approach enhance treatment efficacy.

HCV Therapy: General

815. Retreatment of Chronic Hepatitis C- Genotype 1-infected Relapsers to Peginterferon/ribavirin with Consensus interferon/ribavirin or with Extended Duration Therapy Peginterferon/ribavirin.

B. Pearlman; C. Ehleben

Objective:

Relapse is an unfortunate outcome of interferon-based therapy for chronic hepatitis C virus (HCV) infection, and an optimal retreatment strategy remains uncertain. Up to 31% of genotype 1-infected patients will suffer relapse after 48 weeks of peginterferon alfa-2a and ribavirin (Ann Intern Med 140:346,2004). Relapsers to peginterferon/ribavirin with genotype one infection achieve an SVR rate of merely 23% with 48 weeks of peginterferon alfa-2b/ribavirin therapy (Gastroenterol 136:1618,2009). The use of consensus interferon/ribavirin (Hepatology 46:819A,2007) or the extension of treatment duration with peginterferon/ribavirin in the retreatment of relapsers may improve response rates.

Methods:

Genotype 1-infected patients who had relapsed to 48 weeks of peginterferon alfa-2a (180 mcg weekly) and ribavirin (800 to1,400 mg daily), despite 80/80/80 adherence, were randomized in a 2:2:1 ratio to: consensus interferon (15 mcg daily) for 48 weeks, peginterferon alfa-2b (1.5 mcg/kg weekly) for 72 weeks, peginterferon alfa-2b (1.5 mcg/kg weekly) for 48 weeks; all groups received weight-based ribavirin (800-1,400 mg daily) for the therapy duration. Serum RNA was measured by PCR, Taqman, Roche; detection limit 10 IU/ml. Growth factors were prohibited.

Results:

Complete data for 76 patients are currently available (n=30,32,14). Patients analyzed had statistically similar baseline characteristics including: 42% African-American, 72% high viral load (≥400,000 IU/ml), 27% F3/F4 fibrosis, 13% impaired fasting glucose and an average BMI of 29.5. Dose reductions and treatment discontinuations for adverse events or lab abnormalities were similar between the 48 treatment groups, but were higher in the 72 week arm; treatment discontinuations were 7% in both 48 week groups, but 16% in the 72 week group. SVR rates were 29% in the 48 week Peg group, significantly different from the rates of 47% and 50% in the consensus and extended peg groups, respectively( p=NS between the latter two groups). Relapse rates were 35% in the 48 week peg group, but 20% in the consensus group and 22% in the extended peg group. Interestingly, all obese patients (BMI ≥30) that completed therapy in both peg arms achieved SVR (n=12 in Peg-72 group; n=7 in Peg-48 group).

Conclusions:

Approximately half of genotype 1-infected relapsers to peginterferon alfa-2a/ribavirin benefited from retreatment with consensus interferon/ribavirin or with extended duration therapy peginterferon alfa-2b/ribavirin. However, the extended therapy arm patients experienced higher rates of treatment discontinuations relative to those of the standard duration arms. The study is ongoing.

HCV Treatment: General

819. Low-to-moderate alcohol consumption has no impact on antiviral response to combination therapy in HCV patients with genotype 2 or 3.

R. J. Carvalho-Filho; H. Verbaan; K. Bjøro; H. Ring-Larsen; O. Dalgard

Introduction:

Chronic HCV infection is highly prevalent among alcoholic patients, with higher rates being observed in subjects with liver cirrhosis and hepatocellular carcinoma. The effect of low-to-moderate alcohol consumption during combination treatment on virological response is unknown.

Aims:

To assess the impact of alcohol use (prior to and during therapy) on adherence and on the rates of rapid virological response (RVR), sustained virological response (SVR), and relapse.

Methods:

Alcohol consumption was systematically assessed in 550 treatment-naïve patients infected with HCV genotype 2 or 3. Patients were recruited from two Scandinavian trials (n=122 and n=428) designed to evaluate SVR following 14 weeks vs. 24 weeks treatment.

All patients received pegylated interferon alfa-2b (1.5µg/kg/week) and weight-based ribavirin. In both trials, active heavy drinking (>40g/day) within the 6 months prior to treatment was an exclusion criteria, but light drinking was allowed. Patients were divided into two groups: “abstainers” versus “non-abstainers” and alcohol use was categorized in “pre-therapy use” (prior drinking) and “on-therapy use” (active drinking). Adequate adherence was defined as an intake >80% of drugs, for > 80% of planned duration. To evaluate SVR and relapse rates, a pooled, intention-to-treat analysis of the population who achieved RVR was used.

Results:

Mean age was 39.4±9.2 years, with 63% of males. G3 infection was identified in 80% of cases and 67% of subjects exhibited viral load >400,000IU/mL. Pre-therapy drinking was reported in 52% (10-40g/day in 17%) and on-treatment drinking was identified in 48% (≤10g/day in 89%, 10-30g/day in 8%, and 30-40g/day in 3%).

Adherence was not influenced by prior drinking (77% in non-abstainers versus 71% in abstainers; P=0.103) or by active drinking (79% in non-abstainers versus 81% in abstainers; P=0.557).

Active drinkers showed RVR rates similar to those of abstainers (71% versus 72%, respectively; P=0.784) and active drinking had no significant impact on SVR (79% in non-abstainers versus 85% in abstainers; P=0.122).

Among those who achieved RVR, SVR was independently associated with 24 weeks of therapy (OR=2.96; P=0.006) and with adequate adherence (OR=7.71; P<0.001). Likewise, in RVR patients, comparable SVR rates were observed in active drinkers and non-drinkers (87% versus 90%, respectively; P=0.430). Active drinkers and non-active drinkers showed similar relapse rates (8% in both groups; P=0.982).

Conclusions:

● Low-to-moderate alcohol consumption (<40g/day) during treatment appears NOT to exert a significant negative impact on HCV combination therapy outcomes in G2 and G3 patients, especially in those who achieve RVR.

HCV Treatment: General

820. Determinants of virologic relapse following hepatitis C antiviral therapy: Analysis of the Canadian POWeR Program.

C. Cooper; V. S. Feinman; C. Ghent; J. D. Farley; H. B. Witt-Sullivan; J. Robert; K. M. Peltekian; M. Poliquin; W. Ghesquiere; R. Woolstencroft; P. Marotta

Purpose:

POWeR program clinicians report on predictors of relapse in treatment-naïve chronic hepatitis C patients treated with PEG-IFN alfa-2b and weight-based ribavirin (RBV) in “real-life” Canadian clinical settings.

Methods:

POWeR was a Canadian open-label observational study conducted between 2002 and 2007. Patients received PEG-IFN alfa-2b (1.5μg/kg/wk) + weight-based RBV (800–1200mg/d) for standard treatment durations, as described previously. End of treatment (EOT) response was defined as undetectable HCV RNA at completion of therapy; sustained virologic response (SVR) was defined as undetectable HCV RNA 24 weeks post-treatment. Relapse was defined as undetectable HCV RNA at EOT and detectable or missing HCV RNA at follow-up. Relapse rates [((EOT-SVR)/EOT) X100] were analyzed by genotype, baseline viral load, weight and fibrosis score.

Results:

1950 HCV-infected subjects received at least one dose of study medication and were assessed by ITT analysis. EOT responses by genotype were: G1 51%, G2 86% and G3 77%; corresponding SVR rates were 39%, 73% and 65%. The relapse rate was significantly higher in G1 (25%) than in G2/G3 (16%) (p<0.0001). In G1, high baseline viral load (>600,000 IU/mL) did not appear to significantly influence relapse rate [23% LVL (60/261) vs 27% HVL (70/263), p=ns). G1 patients <75 kg had similar relapse rates to those ≥75 kg [23% (53/234) vs 26% (95/361), p=ns). Amongst patients with liver biopsy specimens, significantly higher relapse rates were observed in G1 with advanced fibrosis/cirrhosis (F3-F4; 34/97) versus minimal or mild fibrosis (≤F2; 45/254) (35% vs 18%; p<0.001); this effect was not observed in G2 or G3 subjects.

Conclusions:

Advanced fibrosis/cirrhosis significantly increased relapse rates in G1-infected patients, but not G2 or G3. The relapse rate in G1 subjects with F3-F4 disease nearly doubled compared to patients with ≤F2 disease. Baseline viral load and weight were not independently associated with increased relapse in “real-life” G1-infected patients treated with PEG-IFN alfa-2b plus weight-based RBV.

HCV Therapy: Side Effects

828. Thrombocytopenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C is not associated with severe bleedings.

R. Roomer; B. E. Hansen; H. L. Janssen; R. J. de Knegt

Background and aims:

A proportion of patients treated with peginterferon alfa (PEG-IFN) and ribavirin for chronic hepatitis C have dose reductions of PEG-IFN based on thrombocytopenia (platelet count <50000/μL). The aim of this study was to investigate the correlation between thrombocytopenia and the occurrence of (severe) bleedings during antiviral treatment for HCV infection.

Methods:

In this single center cohort study 321 patients treated with PEG-IFN and ribavirin between 2000 and 2009 were evaluated on thrombocytopenia, bleedings and dose reductions during HCV treatment. At every visit, patients were asked if bleeding occurred. Bleedings were defined as severe (hospital admission, permanent disability or death) and minor (no specific treatment or dose reduction). Statistical analysis was done with Chi square and Fisher’s exact test. Multivariate logistic regression was used to investigate the risk of bleeding per visit with correction of multiple visits per patient.

Results:

Average platelet count at baseline was 207000/μL for non-cirrhotic patients and 133000/μL for cirrhotic patients. 14 patients (4.4%) had baseline platelet counts <80000/μL. Median platelet drop was 37.7% from 191000 to 119000/μL (range 8000-284000/μL). Thrombocytopenia was observed in 31 patients (9.7%) at 167 visits. Platelet count <20000/μL was observed in 3 patients at 4 visits. Cirrhotic patients were more likely to develop thrombocytopenia than non-cirrhotic patients (34.3% vs. 3.1%, P<0.001). Forty-eight bleedings were observed in 27 patients (8.4%): 25 nose bleedings, 13 gingival, 2 gastrointestinal and 8 others. Only 1 bleeding (due to gastrointestinal angiodysplasia) was defined as severe. However, this patient was not thrombocytopenic at time of bleeding. In 13 patients (15.8%) PEG-IFN dose was reduced due to thrombocytopenia. In 2 patients PEG-IFN and ribavirin were discontinued due to thrombocytopenia and in 1 due to severe bleeding. One patient was treated with a platelet transfusion (platelet count 8000/μL). During visits, patients reported more minor bleedings when platelet count was <50000/μL compared to visits when platelet count was >50000/μL (12.0% vs. 1.0%, P<0.001). Females reported more bleedings than males (13.0% vs. 6.1%, p=0.032). In the multivariate analysis thrombocytopenia and cirrhosis were significant predictors of bleeding (p=0.003 and p=0.02).

Conclusion:

Thrombocytopenia during antiviral treatment is associated with bleedings, which were all minor. No severe bleedings occurred in any patient with platelet counts <50000/μL. Based on our data, revision of guidelines for dose reductions of PEG-IFN for thrombocytopenia should be considered.

HCV Populations

829. Pegylated interferon alfa-2a monotherapy for hemodialysis patients with acute hepatitis C.

C. Liu; C. Liang; C. Liu; S. Hsu; S. Chen; H. Tsai; P. Hung; J. Lin; M. Lai; P. Chen; J. Chen; D. Chen; J. Kao

Background:

The efficacy of pegylated interferon has not been adequately evaluated in hemodialysis patients with acute hepatitis C in view of the high incidence and prevalence of hepatitis C virus (HCV) infection.

Methods:

Thirty-five hemodialysis (HD) patients with acute hepatitis C from 2005 to 2009 who did not spontaneous resolve by 16 weeks were treated with weekly pegylated interferon alfa-2a 135 μg for 24 weeks. In addition, we reviewed clinical charts and tested HCV RNA in 36 patients who were diagnosed acute hepatitis C after HD but without treatment to serve as the control. The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks after the end of therapy, by intention-to-treat (ITT) analysis.

Results:

The baseline patient characteristics were well matched between the two groups. Of the 35 patients who received treatment, 24 (68.6%), 10 (28.6%), and 1(2.8%) had HCV genotype 1, 2, and 6 infection, respectively. The SVR rate was significantly higher in the treatment than that in the control group (88.5% versus 16.7%, p < 0.001). Two patients (5.5%) prematurely terminated treatment at weeks 8 and 10 due to constitutional symptoms, and both of them did not achieve SVR. All but one patient had rapid virologic response (RVR) and all patients who received more than 12 weeks of treatment had early and end of treatment virologic response.

Conclusions:

Pegylated interferon alfa-2a monotherapy is safe and can achieve high SVR rates in HD patients with acute hepatitis C. Treating these patients without spontaneous HCV clearance by week 16 can prevent these patients evolving to chronic infection

HCV Therapy: General

831. Sustained Virological Responders to Pegylated Interferon and Ribavirin Therapy may Show Transient HCV-RNA Positivity when Adequately Followed Up. Clinical Associations and Significance of this Phenomenon During 7-Year Follow-up of 506 Treated Patients.

E. G. Giannini; M. Basso; V. Savarino; A. Picciotto

Background:

There are few data in the literature regarding the long-term course of patients chronically infected with hepatitis C virus (HCV) after successful pegylated interferon (PEG-IFN) and ribavirin therapy. In particular, little is known about the rate of HCV-RNA positivization during long-term follow-up after sustained virological response (SVR) to antiviral treatment, and its clinical association and significance.

Aims:

To assess the rate of HCV-RNA positivization and its association with patients characteristics during long-term follow-up after PEG-IFN and ribavirin treatment in a large cohort of chronic HCV patients treated at a single Institution.

Methods:

In the 2001-2008 period, 506 patients were treated with PEG-IFN and ribavirin and 262 obtained a SVR (i.e., negative HCV-RNA 24 weeks after end of treatment, 52%). Among SVRs, 231 patients had a follow-up>48 weeks after the end of treatment (88%) and represented the study cohort. During follow-up, SVR patients underwent biochemical and virological (lower limit of detection 50IU/mL) evaluation every 6 months. We compared the characteristics of patients who showed persistently negative HCV-RNA to those of patients who showed positivity.

Results:

Median follow-up in the study cohort (n=231) was 164 weeks (range: 24-356 weeks). Among these patients, HCV-RNA was persistently negative in 211 (91%) and became positive in at least one control in 20 (9%). HCV-RNA was transiently and definitely positive in 18 (8%) and 2 (1%) of the SVR patients, respectively. Among baseline demographic (age, gender), clinical (aminotransferase levels, body mass index, prevalence of diabetes, presence of cirrhosis,), viral (HCV genotype, viraemia), and treatment-related (previous antiviral therapy, type of PEG-IFN, ribavirin dosage) characteristics the only difference between patients with persistently negative HCV-RNA and those with transient HCV-RNA positivity was the presence of a significantly higher body mass index in the latter group (26kg/m2 versus 23 kg/m2, p=0.0009). During follow-up, a significantly greater proportion of patients who had transient HCV-RNA positivity developed malignancy as compared to patients with persistently negative HCV-RNA (17% versus 1%, p=0.0007).

Conclusion:

If adequately followed-up, at least 8% of SVRs to PEG-IFN and ribavirin therapy may show transient HCV-RNA positivity. This phenomenon is more frequent among patients with high body mass index, and patients with transient HCV-RNA positivity have a greater incidence of malignancy during follow-up. The relationship between high body mass index and possible immunodepression in patients with chronic HCV deserves further evaluation.

HCV Populations: HIV/HCV Coinfection

843. Extension of Combination Therapy in HCV/HIV Co-infected Genotype 1 Patients: Effect on SVR.

T. Hassanein; R. S. Pozza; K. Biando; L. M. Richards; L. Petcharaporn; F. Barakat; M. El Kabany

Successful HCV Interferon (IFN) based therapy results in sustained virologic eradication of the HCV. Early clearance by week 12 indicates greater rates of SVR and lower rates of relapse. In HCV/HIV co-infected patients the rate of clearing HCV by week 12 occurs in less than 40%. More patients clear the virus between weeks 12 and 24 of therapy, particularly in genotype 1 patients and this response is termed slow response. Stopping treatment after 48 weeks in that group leads to a high relapse rate.

Aim:

The aim of our study was to explore the improvement in SVR and decrease in relapse rate with the extension of Interferon based therapy beyond 48 weeks in a group of patients who were slow responders.

Methods:

91 consecutive HCV/HIV co-infected genotype 1 patients were evaluated for combination therapy. The subjects of this analysis are 9 patients whose treatment course was extended beyond 48 weeks, 9 patients who received the standard 48 weeks and were slow responders and 15 patients who received the standard 48 weeks and were negative at week 12. The mean age was 46.7±7.4 years. 84.8% were males and 66.7% were Caucasian, 12.1% Hispanic, 9.1% African American and 12.1% other. 56.5% had a negative HIV RNA at baseline. 84.2% had mild-moderate fibrosis.

Results:

The mean treatment duration in the extended group was 61.5±6.8 versus 47.6±3.5 (p<0.001) in the non-extended slow responders. There was a significant difference in SVR rate between patients with extended therapy and non-extended slow responders (66.6% vs. 11.1%; p=0.016). However, their relapse rates were not significantly different between these 2 groups. The SVR and relapse rates were similar when comparing extended therapy and non-extended therapy patients who had a cEVR (66.7% vs. 66.6% and 22.2% vs. 26.7%).

Conclusions:

In HCV/HIV co-infected genotype 1 patients extended therapy, 1) was well tolerated and 2) significantly improved SVR rates in slow responders; 3) was equivalent to SVR rates in cEVR patients; 4) the mean weeks of extended therapy was around 62. In summary, extended treatment beyond week 48 improves SVR rates in slow responders. Extended treatment is not needed in patients who achieve cEVR. Further analysis are being conducted to determine the duration of extending treatment in slow responders to achieve the highest possible SVR rates.

Experimental Therapies: General

847. Silibinin for treatment of nonresponders to peginterferon/ribavirin – search for the optimal dosing schedule.

T. Scherzer; S. Beinhardt; K. Rutter; A. Stättermayer; A. Maieron; R. E. Stauber; M. Gschwantler; H. Kerschner; P. E. Steindl-Munda; H. Hofer; P. Ferenci

Background

Silibinin (SIL) has a potent antiviral activity against the hepatitis C virus (HCV) and has been used successfully in previous nonresponders to peginterferon/ribavirin therapy. The use of this drug is limited by the need for daily iv. infusions. The aim of this study was to study different dosing schedules including retreatment of patients with reincrease of viral load after a successful course of SIL.

Patients And Methods:

Sixty-one HCV nonresponders (age: 51±12 years; male: n=42, female: n=19, BMI: 26.1±4.0) were included in this multicenter study investigating the antiviral effect of several doses iv silibin in HCV nonresponders. This analysis compares 40 pts (HCV genotype (GT) 1: n=32, HCV GT3: n=2, HCV GT4: n=6) receiving either 15mg/kg (n=5) or 20mg/kg silibinin (Madaus-Rottapharm, Monza, Italy) for 2 weeks (wks; n=23) and a further group receiving 20mg/kg SIL for each 5 days/week for 3 wks (sparing of weekends; n=5) or continuously for 21 days (n=7). All patients received standard of care (SOC: 180 µg peginterferon alpha-2a plus 800-1200mg ribavirin) for 48 wks starting after the first week (wk) of iv SIL application.

Results:

In the 20mg/kg/2wks group 5/23 (22%) pts were HCV RNA negative at the end of of iv SIL therapy (wk2), 6 had a RVR, 3 of them are still HCV RNA negative on SOC treatment, one is HCV RNA negative at 3 month follow up (FU). At week 12, additional 7 pts were weak positive (=HCV-RNA detectable, but below the level of quantification; <15IU/mL). Compared to that, none of the pts who received 20mg/kg/5days/wk/3wks was HCV RNA negative at the end of iv SIL treatment (day 21), three were weak positive. RVR was achieved by 1 patient, 2 pts have a pEVR. Eight of the 10 weak positive pts became HCV RNA negative on SOC. Data of pts treated with 20mg/kg/3wks plus weekends will be shown at the meeting. Three pEVRs were retreated with 20mg/kg/2wks (n=2) or with 20mg/kg/3wks (n=8). 4/10 of the retreated pts became HCV RNA negative (all REL). Two pts receiving a third cycle got HCV RNA negative. Most patients are still on treatment; 5 were HCV-RNA neg at end of SOC treatment, all of them are still on follow up. SVR data will be available at the time of the meeting.

Conclusion:

Silibinin iv is a potent antiviral drug in patients with chronic hepatitis C. It has to be administered daily. HCV RNA negativity under iv silibinin therapy seems to be important for further virological response on SOC treatment. Whether a prolonged treatment with SIL increases the RVR rate and/or improves long term results is currently explored.

HCV Populations

848. Analysis of Reasons for Treatment Ineligibility in the IDEAL study: African Americans (AA) vs non-African Americans (non-AA).

M. Melia; A. Muir; J. McCone; M. L. Shiffman; J. W. King; S. K. Herrine; G. Galler; J. R. Bloomer; F. Nunes; K. Brown; K. D. Mullen; N. Ravendhran; W. M. Cassidy; R. H. Ghalib; N. Boparai; R. Jiang ; S. Noviello; C. A. Brass; J. K. Albrecht; J. G. McHutchison; M. S. Sulkowski

Background:

In IDEAL, of 4469 screened patients (pts) 23% did not meet protocol eligibility criteria. The objective of this retrospective analysis was to identify rates and reasons for ineligibility among African Americans (AA) and non-AA.

Methods:

3070 treatment-naive, hepatitis C virus (HCV) genotype 1–infected adults in the US including 19% AA were treated with peginterferon (PEG-IFN) alfa-2b 1.5 or 1µg/kg/wk plus ribavirin (RBV) 800-1400mg/d or PEG-IFN alfa-2a 180µg/wk plus RBV 1000-1200mg/d. Pts were required to meet criteria consistent with standard treatment guidelines: compensated liver disease; neutrophil count (ANC)≥1500/mm³; platelet count (PC)≥80,000/mm³; hemoglobin (Hb) ≥12 g/dL (women) and ≥13 g/dL (men); normal serum creatinine; no HIV or HBV; and/or no severe psychiatric disorders. Ineligibility according to self-reported race was evaluated for AA and non-AA.

Results:

Overall 40% AA and 28% non-AA patients failed screening, the major reasons being underlying medical conditions. AAs were more likely to fail for abnormal hematology or chemistry (Table). Of these, ANC <1500/mm³, elevated glucose or creatinine or low Hb were the most frequent reasons for AAs being ineligible for participation. AA patients with low ANC were made up of 7% <1500-1200/mm³ and 7% <1200/mm³.

Conclusions:

● In this study, underlying medical conditions were the largest barrier to entry for both AAs and non-AAs. Of these ANC<1500/mm3 was the most frequent reason for AAs and the only parameter that could be considered for protocol modification as the others require medical intervention.

● Subsequent protocols have modified the required ANC for AAs to ≥1200/mm3, which should increase eligibility for this criterion by 50%.

● Treatment regimens that do not include IFN are needed to expand treatment eligibility for many screen failures.

Exclusion Criteria^a	% Patients Failing Screening			Ineligible Patients (%) by Reason
	AA n=962	Non-AA n=3507	P value	AA n=284	Non-AA n=754	P value
ALL	40%	28%	<.0001	NA	NA
Abnormal Hematology^b	7%	2%	<.0001	23%	11%	<.0001
Abnormal Chemistry^b	6%	2%	<.0001	21%	10%	<.0001
Unstable Diabetes Mellitus	1%	0.4%	<.001	5%	2%	.01
Existing Medical Reason	8%	6%	.02	26%	26%	.98
Preexisting Psych Condition/CES-D Score >25	4%	4%	.31	14%	17%	.40
Drug/Alcohol Abuse	2%	3%	.12	7%	13%	.003
Exclusionary Virology	1%	5%	<.0001	5%	21%	<.0001
Nonprotocol reason	11%	7%	.0001	NA	NA

^aPts may have >1 reason for ineligibility. ^bIneligible AA vs Non-AA: ANC <1500/mm³ (14% vs 3%), ANC <1200/mm³ (7% vs 1%), Hb <12 or <13 g/dL (7% vs 4%), PC <80,000/mm³ (1% vs 4%); elevated glucose (8% vs 3%), elevated creatinine (5% vs 1%).

HCV Populations

849. Efficacy of a “on-treatment viral response tailored regimen” with peginterferon (PegIFN) alfa 2b plus ribavirin in naïve genotype 1 chronic hepatitis C (CHC) Mexican patients.

J. F. Sanchez-Avila; E. Cerda; J. Garcia-Leiva; A. Chavez-Ayala; A. Loaeza del Castillo; M. Sanchez-Osorio; A. Meixueiro-Daza; A. J. Montano-Loza; N. Uribe-Uribe; F. Vargas-Vorackova; M. Uribe-Esquivel

Introduction:

Mexican CHC patients have been underrepresented in large PegIFN alfa plus ribavirin multicenter clinical trials. Recent reports show lower sustained virological response (SVR) in Latino genotype 1 CHC patients, with rates varying between 24 and 34%. Many of these patients show a gradual but slow reduction in HCV-RNA, suggesting that a prolonged 72-week therapy might be needed.

Aim:

To evaluate the efficacy of a “on-treatment viral response tailored regimen” with PegIFN alfa 2b plus ribavirin weight-based therapy in naïve genotype 1 CHC Mexican patients.

Patients and Methods.

Eighty-four genotype 1 not previously treated CHC Mexican patients (female 58%; age 48.8 ± 12.3 yrs) were included in this open-label trial. Informed consent in writing was obtained from each patient. All received 1.5 µg/kg/week of PegIFN alfa 2b plus ≥ 13.6 mg/day of ribavirin. The schedule of treatment was tailored according to “on- treatment viral response”, i.e. 48-week therapy if HCV-RNA was negative at week 12 (complete early viral response, EVR), or 72-week therapy if HCV-RNA was positive (but decreased ≥ 2 log-drop or parcial EVR) at week 12 and turned negative at week 24 (slow response). Antiviral therapy was discontinued in those who did not achieve an HCV-RNA ≥ 2 log-drop at week 12, and in those who were positive at week 24 or any other time thereafter. In all cases a pre-treatment liver biopsy was performed. The primary end-point was SVR response evaluated 24 weeks after the end of treatment.

Results:

Baseline HCV-RNA levels were 5.8 ± 0.8 log10 IU/ml. According to the METAVIR score, 38 (45%) cases showed advanced fibrosis (≥ 2), and 9 (10.7%) cirrhosis. Forty-three achieved complete EVR and 12 (14.2%) were slow responders. Treatment was discontinued in 19 (22.6%) at week 12 because of lack of viral response, in 9 (10.7%) at week 24 for persistent positivity of HCV-RNA, and in 3 (3.5%) for adverse events. Seventeen (20.2%) patients presented viral breakthrough or relapsed. SVR with the “on-treatment viral response tailored regimen” regimen was achieved in 36 (43%) patients, five of them slow responders. Response did not differ according to sex, age, baseline BMI, weight or ALT levels. However, a tendency for a higher baseline viral load (> 600,000 IU/ml) and higher degree of fibrosis was observed in non-responders (p<0.085 and p<0.09, respectively).

Conclusions:

A regimen tailored according to the “on treatment viral response” with PegIFN alfa 2b plus ribavirin weight-based derives in a 43% SVR in genotype 1 CHC Mexican patients, suggesting that this might be a way to increase the efficacy of CHC therapy in this difficult to treat population.

HCV Therapy: PegIntron

850. Outcomes of a large, inclusive population-based hepatitis C treatment program are similar to randomized controlled trials: Interim results of the Canadian REDIPEN Program.

C. Cooper; J. Robert; V. S. Feinman; M. Elkashab; F. H. Anderson; L. J. Scully; K. E. Doucette; H. B. Witt-Sullivan; R. J. Bailey; R. P. Myers; J. D. Farley; B. Romanoswki; R. Woolstencroft; N. Abadir; C. Ghent

Purpose:

To assess the outcomes of HCV Genotype 1 (G1)-infected individuals treated with peginterferon (PEG-IFN) alfa-2b and ribavirin (RBV) in “real life” Canadian academic and community clinical settings.

Methods:

The Canadian P04423 REDIPEN Program is a prospective observational study conducted in Canada at 59 academic and community centers since 2005. Patients are treated with PEG-IFN alfa-2b (1.5µg/kg/wk) plus weight-based RBV (800–1200mg/d) according to the standard of care. For intent-to-treat (ITT) analysis, patients missing follow-up information were classified as treatment failures.

Results:

1290 patients were enrolled and treated. At the time of analysis, 899 patients had evaluable data and 391 patients are currently on treatment or in follow up. Of 899 evaluated patients, the mean age was 46.7 (range 18.4-76.8) years, 66% were male and 64% were ≥75 kg. 86.4% were Caucasian, 7.8% Asian, 3.2% Aboriginal, and 1.5% black. Mean baseline viral load was 2.55 X 106 IU/mL. 449 patients had a liver biopsy: 63% had F0-F2 fibrosis and 37% had F3-F4. 472 patients (52.5%) were infected with HCV G1; 136 (15.1%) and 277 (30.8%) had G2 and G3 infection, respectively. Amongst G1 patients with treatment week 12 response data (including prior discontinuations), 65% (284/434) achieved an early virologic response (EVR). Of those with an EVR, 82% achieved undetectable HCV RNA (complete EVR; cEVR), 14% had a partial EVR (pEVR; minimum 2 log reduction in HCV RNA from baseline) and 4% had undefined response. G1 patients with cEVR and follow up information had higher SVR rates than those with partial EVR (69% vs 19%, P<.0001). By ITT analysis, the G1 SVR rate was 39% (183/472). The SVR rate in G1 patients who completed at least 12 weeks of therapy and had a known outcome was 48% (183/383). In G1 patients who achieved undetectable HCV RNA at end of treatment and had follow-up information, 16% (33/205) experienced a relapse.

Conclusions:

● A heterogeneous, but representative, population of Canadian G1 patients treated with PEG-IFN alfa-2b and weight-based RBV achieved similar results to subjects treated in controlled clinical trials performed in rigorous environments and with strict inclusion/exclusion criteria.

● These results support the general overall of outcomes achieved with PEG-IFN alfa-2b plus RBV in clinical trials to “real life” clinical practice.

● Interim SVR results are consistent with those reported with PEG-IFN alfa-2b plus ribavirin in the POWER Program and the IDEAL study.

o EVR is predictive of SVR

§ Patients with complete EVR have much higher probability of attaining SVR than patients with partial EVR

o Follow-up data were missing for many patients

§ In the ITT analysis, these patients were considered nonresponders for SVR.

Experimental Therapies: Albuferon

870. Comparative Safety, Tolerability, Viral and Pharmacodynamic Efficacy of Pegylated-interferons and albinterferon alfa-2b in HIV/HCV Genotype-1 Infected Patients.

E. Herrmann; M. Subramanian; M. A. Polis; S. Kottilil

Background:

Pegylated-interferon (Peg-IFN) and ribavirin (RBV) remain mainstay for treatment of HCV. Albinterferon alfa-2b (albIFN), a recombinant polypeptide composed of IFN-alfa2b genetically fused to human albumin has been developed as a novel anti-HCV agent. We compared the PK/PD parameters in HIV/HCV genotype 1 patients treated with Peg-IFN (Peginterferon alfa-2b or Peginterferon alfa-2a) or albIFN with RBV.

Methods:

Three clinical trials treated HIV/HCV co-infected genotype 1 patients with Peg-IFN α-2b (1.5ug/wk) (N=27), Peg-IFN α-2a (180ug/wk) (N=10) and albIFN (900ug/q2wk) (N=10); all with weight based RBV. HCV and HIV viral load were measured at baseline and frequently thereafter. Early virologic response (EVR) is defined as a two-log drop in HCV VL from baseline by week 12. Viral kinetics (VK) were analyzed using a full PK-PD model approach of each therapeutic approach to assess mean and maximum efficiency εmax and εmean of both compounds in addition to other VK parameters.

Results:

Patient demographics were similar across the 3 studies. All 3 combinations were equally tolerated among the three studies up until the time of follow up. EVR was 64% (18/27) for Peg-IFN α-2b , 60% (6/10) for Peg-IFN α-2a arm and 70% (7/10) for albIFN (P=NS). The SVR rates for Peg-IFN α-2b and Peg-IFN α-2a were 18% (5/27) and 40% (4/10) respectively (P=NS); SVR for albIFN is pending. When we compared PK/PD parameters, there were no differences in the infected cell loss rate for the three treatments (p>0.05). Interestingly, εmax and εmean values that determine the efficiency of each therapeutic regimen were also similar in those receiving Peg-IFN α-2b, Peg-IFN α-2a and albIFN arm (P>0.05, cf. Figure).

Conclusions:

Preliminary data suggest that albIFN/RBV therapy is effective in HIV-infected patients resulting in comparable rates of EVR observed with peg-IFN/RBV. VK/ PK/PD analysis suggests that albIFN therapy q2week may be as effective as the current standard weekly regimens available for treating HCV in HIV/HCV co-infected patients. Further follow up of patients treated with albIFN/RBV will determine whether VK data are predictive of SVR.

HCV Therapy: General

873. Non-compliance with current guidelines for treatment of chronic hepatitis C (CHC) is frequent in daily practice and may lead to an increase in SVR: Results of a large prospective cohort study.

C. Niederau; S. Mauss; D. Hueppe; E. Zehnter; U. Alshuth

In 2002/2003 controlled trials of both pegylated (PEG) interferons showed that the lack of an early virological response (EVR = ≥ 2 log decline of HCV-RNA at week 12) was associated with SVR rates of only 0-3 %; SVR was similarly bad when HCV-RNA was still positive at week 24. Thus, current guidelines created “stopping rules”; i.e. treatment should be stopped when there is no EVR and when HCV-RNA remains positive at week 24. We analysed the use of these guidelines under real life conditions.

Methods:

The ongoing study prospectively determines the quality of treatment for CHC in routine practice. From March 2003 to September 2008 a complete treatment course with PEG-IFN α-2a and ribavirin was documented in 4,127 naïve genotype 1 patients with a SVR of 41.4% (mean age 44 yrs, 59% men, 38% HVC-RNA >400,000 IU/ml).

Results:

The failure to determine the EVR (measurement of quantitative decrease of HCV-RNA at week 12) steadily decreased from 20% in 2003 to 12% in 2006/07. Treatment was stopped during the first 12 weeks in 301 patients. In 531 patients viral load was not determined at week 12. EVR was documented in 2.792 patients; there was no EVR in 503 patients. Unexpectedly, treatment was not stopped in the majority of patients without EVR; also many patients who were still HCV-RNA positive at week 24 continued treatment, usually for 48 weeks; thus, stopping rules at 12 and 24 weeks were systematically neglected. Even more unexpectedly SVR was quite high in patients who continued therapy despite the lack of EVR or of a negative HCV-RNA at week 24. Details are shown in the table.

Conclusions:

Guideline recommendations to analyze EVR at week 12 and HCV-RNA at week 24 were followed increasingly closely in daily practice during recent years; however, the corresponding “stopping rules” in non-responders were only followed by a minority of physicians. By not following the stopping rules, the subsequent SVR rates were 5- to 10-times higher than those seen in controlled trials. Further studies need to elucidate the reasons for this striking discrepancy which was shown for all types of non-responders. In any case, neglecting of the stopping rules may be in the best interest of the patient.

	therapy stop	SVR
no EVR at week 12 (n=503)	27.2% *	14.5%
nonresponse at weeks 12 and 24 (n=211)	50.2% **	10.4%
EVR but nonresponse at week 24 (n=599)	21.4% **	41.6%

* therapy stopped between weeks 12-24, ** therapy stopped between weeks 24-30

HCV Therapy: General

880. Treatment compliance in patients taking RibaPak® or ribavirin 200mg: Final analyses from the ADHERE registry.

V. K. Rustgi; I. Alam; B. Cecil; A. D. Tice ; T. Stainbrook; K. D. Ingram; E. B. Thompson; K. Kistler

Background:

Poor compliance to Hepatitis C virus (HCV) treatment is an important cause of treatment failure. Traditional ribavirin 200 mg (RBV) treatment is associated with a significant daily pill burden (up to 7 a day). RibaPak® (RBP) is available as 400mg and 600mg ribavirin tablets and offers simplified dosing at 2 pills a day. This study examined whether improved compliance was associated with RBP vs. RBV.

Methods:

Accurate Dosing in Hepatitis C: Examining the RibaPak® Experience (ADHERE) was a U.S., 24 week, multi-center, prospective, observational registry capturing data on compliance with RBP vs. RBV in adults with HCV; all subjects also received pegylated interferon. Compliance was measured by the proportion of subjects remaining on treatment over 24 weeks and, for those who remained on treatment, by pill counts at treatment weeks 0-4, 8-12 and 20-24.

Results:

503 patients (RBP = 346, RBV = 157) from 38 sites were included. Demographic characteristics, baseline mean viral load, and median drug dose prescribed (1000 mg) were similar between the groups. Subjects’ mean age was 48.5 years; 54% were men and the majority (71%) were Caucasian. A greater proportion of RBV subjects prematurely discontinued treatment compared to RBP subjects. While there was a significantly (P<0.04) greater proportion of RBP subjects remaining on treatment at both weeks 12 and 24, the greatest discrepancy in discontinuation rate was between 5 and 12 weeks where there was a 49% difference in the proportion of RBV (15.9%) vs. RBP (8.1%) subjects that discontinued. Furthermore, subjects who discontinued between 5 and 12 weeks missed a significantly (p=0.002) greater mean number of doses (8.9) during the 0 to 4 week treatment period vs. subjects who completed 12 weeks (2.5), suggesting that early non-compliance is associated with later discontinuation. For patients who remained on treatment, the median mg taken per day was significantly (p=0.01) greater for RBP (1200) vs. RBV (1000) at 12 weeks.

Conclusions:

● These data demonstrate higher compliance for RibavPak treated patients vs. ribavirin treated patients, in terms of staying on treatment, and including doses and mg of drug taken at 12 and 24 weeks.

● Importantly, there were no defining characteristics which would have pre-determined patients at high risk for treatment discontinuation.

● These data suggest first line treatment with RibaPak offers the best prospect for less discontinuation and improved treatment compliance when compared to conventional ribavirin. The cumulative impact of treatment discontinuation has the potential to impact SVR, quality of life, and overall healthcare costs.

HCV Populations: Injection Drug Users

887. Determinants of Engagement in Care of Inner City HCV-Infected Injection Drug Users (IDUs).

B. Conway; H. Tossonian; J. Grebely; J. D. Raffa; M. Krahn; M. M. Storms; E. Knight; J. Singer; B. Fischer

Objectives:

The majority of prevalent and incident cases of HCV infection in Canada occur in current and former IDUs.

There is an urgent need to better characterize this population in terms of:

● demographics,

● knowledge base about their disease and,

● willingness to enter into treatment, to better plan for the deployment of health care resources to accommodate their needs.

We conducted a prospective survey of attendees of four inner city British Columbia clinics to address these issues.

Methods:

HCV-infected patients (age ≥ 19 yrs) attending inner city clinics in Vancouver, Nanaimo and Victoria who have a history of injection drug use, illicit drug use in the past year (other than exclusively marijuana) and are HCV RNA positive.

A prospective survey was conducted by a trained interviewer (research assistant or research nurse) entitled HCV Drug Use Survey. This survey was developed by CARMHA/SFU. The survey elicited information about patient demographics, health and welfare (HCV status, source of income) and use of illicit drugs.

Results:

A total of 296 patients (64% male, 21% First Nations, median age 46) were included. Key baseline characteristics included: Unstable housing (65%), opiate substitution (55%), injection drugs (ever) (99%), injection drug( in last 30 days) (55%).

Of those not having sought treatment (n = 195), the main reasons were:

● Lack of information about treatment (27.2%),

● Absence of symptoms (16.9%),

● Perceived side effects of treatment (8.2%),

● Not interested (7.2%)

● Unstable drug use (6.7%),

● Non given (6.7%)

● Other medical co-morbities (4.1%)

● Haven not gotten around to it (4.1%)

Reasons given that were below 7% included other life priorities, physician advised therapy not needed, unsure, unstable living conditions, cost, newly diagnosed, cleared infection, under evaluation, unstable alcohol use, unknown HCV status.

Fifteen people were not included since they were not actively infected with hepatitis C so a total of 281 evaluated—86 who sought treatment and 195 who never sought treatment.

The reasons for not accepting treatment out of a total of 108 evaluated: treatment evaluation was ongoing (17.6%), concerns for side effects (15.7%), not interested (12%), absence of symptoms (10.2%), missed appointments (7.4%), unstable drug use (6.5%), unknown (6.5%) not ready yet (5.6%), other medical contraindications (5.6%) physician advised therapy not needed (4.6%), unstable living conditions (4.6%), issues with physician (1.9%), advanced disease (0.9%), and prison (0.9%).

Discussion:

● In addition to the issues of unstable addiction-related behaviour, the three key barriers to engaging more of the target population in systematic medical evaluation possible leading to HCV treatment are:

o Lack of interest in treatment

o Concern about treatment side effects

o A mistaken belief that the absence of symptoms precludes consideration for treatment

● The establishment of peer-driven discussion group led by HCV clinical and research staff will play an important role in making treatment more accessible and more desirable, especially when delivered in concert with addiction treatment services, and with specific protocols to address treatment toxicities in a proactive manner. Female sex appears to be a predictor of not receiving treatment and this will be further evaluated in our ongoing programs.

HCV Populations: Injection Drug Users

888. Treatment of recent hepatitis C virus infection in a predominantly injection drug user cohort: the ATAHC Study.

G. J. Dore; M. Hellard; G. Matthews; J. Grebely; P. S. Haber; K. Petoumenos; B. Yeung; P. Marks; I. van Beek; G. W. McCaughan; P. A. White; R. A. Ffrench; W. Rawlinson; A. R. Lloyd; J. Kaldor

Treatment of acute hepatitis C virus (HCV) infection produces high sustained virological response (SVR) rates, but few studies have examined outcomes among injecting drug users (IDUs).

We evaluated the efficacy of treatment of recent HCV infection (acute and early chronic HCV), within a predominantly IDU-acquired HCV population. The Australian Trial in Acute Hepatitis C (ATAHC) was a prospective study of the natural history and treatment of recent HCV infection. Participants were eligible if they were within 6 months of their first anti-HCV antibody positive result and had a documented anti-HCV seroconversion within 24 months, or acute clinical HCV within the past 12 months. HCV participants received PEG-IFN alfa-2a (180 µg/week, n=74) and HCV/HIV co-infected participants received PEG-IFN alfa-2a (180 µg/week) with ribavirin (n=35) for 24 weeks.

Between June 2004 and February 2008, 167 participants with recent HCV infection were enrolled (79% had injected in the previous 6 months). Among 74 HCV participants receiving PEG-IFN alfa-2a, the SVR was 55% overall and 72% among adherent participants (n=50). In multivariate analyses, baseline factors associated with reduced SVR included decreased social functioning and current opiate pharmacotherapy.

Among 35 HCV/HIV participants receiving PEG-IFN alfa-2a/ribavirin, the SVR was 74% overall and 75% among adherent participants (n=32). Among all adherent participants (n=82), there were 11 non-responders, 1 viral breakthrough and 8 viral relapses.

Treatment of recent HCV among adherent IDUs including those with HIV co-infection is effective. Strategies to enhance adherence among IDUs with recent HCV infection should improve treatment outcomes.

HCV Populations

889. Asian and White Patients With Chronic Hepatitis C (CHC) Achieve Similar Response Rates With Peginterferon (PEG-IFN) Alfa-2b Plus Ribavirin (RBV) in Genotypes (G) 2 and 3: Subanalysis of the REDD 2/3 Study.

M. P. Manns; M. Merican; Y. Ilan; Y. Lurie; S. M. Abu-Mouch; A. Sood; D. N. Reddy; A. Horban; S. Sharmila; H. Wedemeyer; X. Yu; R. Faruqi; E. I. Chaudhri; L. Pedicone

Purpose:

Ethnicity as a factor in prevalence, disease progression, and treatment outcome of CHC is well described in African Americans and whites but less well described in Asians. Global differences in variables such as obesity, nutrition, infections and alcohol consumption may also affect treatment response. Data on the efficacy of PEG-IFN plus RBV are sparse in the Asian population. Our aim was to evaluate efficacy and safety of PEG-IFN alfa-2b plus RBV in Asian vs white subjects with CHC G2 or G3 infection.

Method:

REDD 2/3 was an open-label, multicenter, parallel group study. Subjects were randomized 1:1:1 to receive 24 weeks (group A) or 16 weeks (group C) of PEG-IFN alfa-2b 1.5 µg/kg/wk plus 800-1200 mg/day RBV (WBD RBV), or 24 weeks PEG-IFN alfa-2b 1.0 µg/kg/wk plus WBD RBV (group B). REDD 2/3 comprised 2 cohorts: an investigator-initiated (real-life) German study (HepNet Cohort) and an industry-sponsored study (International Cohort) conducted in India, Indonesia, Israel, Malaysia, Poland, Singapore, and Thailand. This report is a subanalysis of treatment response in Asian vs white subjects in the International Cohort only as it represented both ethnicities. Primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks after receiving last dose of therapy.

Results:

As in the overall REDD 2/3 population, the International Cohort was primarily G3 (84.8% vs 15.2% G2). Mean duration of HCV infection was 11.4 y, and 57% had baseline viral load ≥600,000 IU/mL. This cohort comprised 52.8% Asians and 47.2% whites. Overall SVR was 74.6% group A, 68.8% group B, and 66.1% group C. SVR was similar in Asian and white subjects (Table). Although not statistically significant, SVR was higher in group A vs groups B and C for both Asians and whites. Adverse event profile was consistent with that previously reported with PEG-IFN alfa-2b/RBV therapy.

Conclusion:

This study, consisting of >80% CHC G3 subjects, appears to be the largest study to date in Asian G3 subjects. SVR rates were similar in Asian and white subjects. This study demonstrates that PEG-IFN alfa-2b 1.5 µg/kg/wk plus WBD RBV is effective at treating Asian and white patients with CHC G2 or G3.

SVR According to Race

	Group A PEG 1.5/RBV (24 wk)	Group B PEG 1.0/RBV (24 wk)	Group C PEG 1.5/RBV (16 wk)
Overall Asian White	75.4% (43/57) 73.7% (42/57)	69.5% (41/59) 68% (34/50)	65.6% (40/61) 66.7% (34/51)
Genotype 2 Asian White	100% (1/1) 70% (7/10)	83.3% (5/6) 58.3% (7/12)	80% (4/5) 70.6% (12/17)
Genotype 3 Asian White	75% (42/56) 74.5% (35/47)	67.9% (36/53) 71.1% (27/38)	64.3% (36/56) 64.7% (22/34)

PEG=peginterferon alfa-2b; RBV=ribavirin.

HCV Populations: Injection Drug Users

891. Viral Hepatitis In IVDUs: A 14-Year Experience Of A Single Liver Unit - Epidemiological And Clinical Data.

M. Raptopoulou-Gigi; E. Sinakos; A. Sykja; E. Gigi; A. Bellou; I. Sidiropoulos; E. Orfanou

Background-Aims:

Intravenous drug users (IVDUs) are a group of patients with high prevalence of HBV and HCV infection. The aim of this study was to analyse epidemiological parameters, prevalence of HBV and HCV infection and treatment of hepatitis C in a large cohort of IVDUs followed- up between the years 1994-2008.

Methods:

893 IVDUs were analysed retrospectively concerning demographic, laboratory and clinical parameters. All patients were evaluated in our outpatient clinic. All patients were abstinent of use; none was receiving substitution therapy and 75% were members of a detoxification program without substitution.

Results:

The mean age of patients was 30,3 years old (17-55). Most of them were men (84,3%), 95,6% were Greeks and 4,4% immigrants. 64,2% of patients reported alcohol abuse and 6% had psychiatric co-morbidity. Mean age of drug use institution was 19,5 years old (11-45). Mean duration of illicit drug use was 10,6 years and mean duration of intravenous use was 7,8 years. 65% of patients had tattoos. HBV infection was present in only 4,2% of patients (26,4% had high viremia) and 18,9% had evidence of past HBV infection. Among HBsAg negative patients only 18,3% had undergone partial or complete immunization against HBV. HCV infection was present in 642/893 patients (72%). 493/642 (76%) had positive HCV-RNA. Most of them were infected with genotype 3 (59,7%) (G1 24,7%, G2 4,6%, G4 11%). 271/493 (54,9%) of our patients with chronic hepatitis C received antiviral treatment (31% standard IFN monotherapy, 18% IFN plus ribavirin combination and 51% PEG-IFN plus ribavirin). Premature discontinuation, mainly due to relapse to drug abuse, was higher in the standard IFN groups (76% for monotherapy and 79% for combination therapy), whereas it was 46% for the pegylated IFN group. The overall SVR rates were 89% for genotype 3, 59% for 1, 44% for 4 and 100% for 2.

Conclusions:

Our data show a) the majority of IVDUs in Greece have chronic hepatitis C and genotype 3 is the prevalent genotype. b) although many of them discontinue treatment, those that complete therapy have SVR rates similar to patients without drug dependence and c) therapy for chronic hepatitis C should be also offered in IVDUs not receiving substitution therapy.

HCV Populations

894. The impact of chemical dependency diagnosis and treatment on treatment of chronic hepatitis C (HCV) in patients in a stable insured population.

M. Pauly; M. Russell; C. Moore; C. Chia; S. Menenberg; G. L. Witt; S. E. Martin; B. H. Ruebner

Introduction:

It is estimated that 2.7-4 million in the US have HCV. The majority infected have a history of intravenous drug use and alcohol abuse is common in this cohort. Patients with recent drug abuse and active alcohol use are commonly excluded from clinical trials, and many clinicians discourage those consuming any alcohol or drugs from treatment with interferon therapy, increasing the risk of liver disease progression. As part of an ongoing study to evaluate the impact of past and current drug and alcohol use on sustained viral response (SVR) in patients with HCV, we conducted a retrospective analysis to examine the relation of patient characteristics, including a diagnosis of chemical dependency (CD) and records of CD treatment, to factors influencing compliance and SVR. We present data on the first 250 patients with complete data treated since Jan 2002.

Methods:

All patients treated for HCV with pegylated interferon alpha and ribavirin (PEG RBV) and followed at our Medical Center were invited to participate in the study. We have an integrated system of care headed by a HCV RN and hepatologist with back up from all sub-specialties, including psychiatry and CD treatment. Patient data collected by the treating RN and extracted from records included age, sex, HCV genotype, weight, liver biopsy grade and stage, pretreatment viral load (VL), premature treatment termination (PTT) and SVR. Data on a CD diagnosis and CD treatment since Jan 2000, were extracted from electronic records.

Results:

The average age was 54.3 (SD 6.7) years. 61.6% were male and 28.9% were obese. 67 (26.7%) had a CD diagnosis with no CD treatment since 2000 and 22 (8.8%) had CD treatment since 2000. Patients with recent CD treatment had a significantly higher VL (p=.019) and were twice as likely as patients without CD treatment to experience adverse reactions resulting in PTT. A positive response to HCV treatment was observed in 60.2% of patients with no CD diagnosis; 55.2% of those with a CD diagnosis and no CD treatment; and 45.5% of those with a CD treatment record.

Conclusion:

This study indicates treatment of HCV with PEG RBV can be successful in patients with CD in an integrated health system, including those with CD treatment history. This is important because of high incidence of CD in HCV population, high incidence of alcohol use in these patients, and its likely impact on fibrosis progression. We are limited by lack of details on specific CD diagnoses and recent and ongoing substance use in the medical records. To address these limitations we are currently interviewing our entire cohort regarding lifetime drinking and drug use patterns.

HCV Therapy: General

901. Impact of therapeutic education on the outcome of chronic hepatitis C treatment.

C. Renou; P. Lahmek; A. Pariente; J. Denis; J. Cadranel; Y. Giraud; R. Régine ; T. Morin; R. Faroux; B. Nalet; C. Wartelle-Bladou

The effects of adherence to treatment on patients’ sustained virological responses (SVRs) have been documented in several studies. However, the efficacy of therapeutic education (TE) is variable and may be correlated with the duration of the antiviral treatment.

Aim:

to compare 2 prospective groups of patients treated for chronic hepatitis C: the patients in the control group, which were recruited at several hospital centres, were not given TE (group C), whereas those in the second group, which were recruited at a single centre, were given TE (group TE).

Method:

the 2 groups studied included naive HCV patients treated with a peginterferon alpha-ribavirin association (EU recommendations). The patients in group 2 underwent a pre-therapeutic psychological assessment and a monthly follow-up by a TE nurse and a hepatologist. The impact of TE was assessed by performing multivariate analysis, adjusting to account for the usual factors involved in the therapeutic response (age, sex, genotype, viral load, fibrosis).

Results:

the 326 patients in group C and the 98 patients in group TE (p=NS) were matched in terms of age, the sex ratio, the BMI, alcohol consumption, genotype distribution (2, 3 vs 1, 4, 5), viral load, histological lesions (F0F1F2 vs F3F4) and the presence of cirrhosis. The end-of-treatment virological response rate was 68.1% in group C and 81.6% in group TE (p=0.009) and the rate of SVR was 53.3% and 71.4%, respectively in the 2 groups (p=0.001). After stratification by genotype, the rate of SVR was found to be higher in group TE with genotypes 1, 4 and 5 (41.3% vs 66.7%, p=0.001) whereas it was similar in both groups with genotypes 2 and 3 (69.2% vs 78%, p=0.268). The relapse rate between the 2 groups was barely significant in genotypes 1, 4 and 5 (25% vs 11.6%, p=0.06) and non significant in genotypes 2 and 3. The rate of early cessation of treatment was 29.9% in group C and 17.8% in group TE (p=0.02). The rate of cessation because of side effects was identical in both groups (13% vs 12.2%, p=NS), whereas the rate of cessation because of ineffectiveness was higher in group C (16.9% vs 5.6%, p=0.02). Based on multivariate analysis, the main factors associated with the SVR were age under 40 years (p=0.02; OR=1.9), genotype 2 or 3 (p=0.004; OR=2.2), fibrosis stage < 2 (p=0.001; OR=2.6) and TE (p=0.003; OR=2.7).

Conclusion:

TE was found to be associated with a significant increase in the SVRs but only in patients with genotypes requiring a 48-week treatment. A suboptimum level of observance may have been responsible the higher rate of premature cessation of treatment for non virological response occurring in patients treated without TE.

Experimental Therapies: Alinia

904. Effects of High Dose Ribavirin (RBV), Alinia (Nitazoxanide) and Pegylated Interferon (PEG) alfa-2a in Attaining Sustained Viral Response (SVR) in Treatment of Chronic Hepatitis C (ERAIS-C trial) - Interim Results in Naïve Genotype 1 Patients.

P. Basu; K. Rayapudi; N. Shah; T. Pacana; R. S. Brown

Purpose:

Pegylated interferon alfa (PEG IFN-α) and Ribavirin(RBV) are the backbone of therapy of Chronic Hepatitis C with Sustained Virological Response (SVR) ~50%, globally in all genotypes. A recent study reveals correlation of rapid viral response(RVR) to SVR. Alinia (Nitazoxanide) is an interferon(IFN) inducer that may increase SVR when used in combination with pegylated interferon and ribavirin. More rapid response or Very Rapid Viral Response (VRVR) defined as undetectable viral load at 14 days after initiation of therapy may predict even higher SVR rates. We assessed Nitazoxanide(NTZ) in combination with high dose RBV and PEG IFN-α 2a in achieving VRVR, RVR and Early Viral Response (EVR) in treatment naïve Chronic HCV genotype 1(GT1) patients.

Methods:

Prospective, open-label pilot trial of naïve hepatitis-C GT1 patients.

Exclusions: Uncontrolled diabetes mellitus (A1c>7.5), decompensated cirrhosis, active use of illicit drugs, excessive alcohol intake (>40 g/day), poorly motivated patients and co-morbid conditions (i.e. severe depression, anemia, thrombocytopenia, HIV).

Dose:

● NTZ 500 mg BID x 2 weeks

● then NTZ + RBV 1400 mg/d x 2 weeks

● then NTZ + RBV + PegIFN 180 mcg weekly x 12 weeks

● then RBV + PegIFN x 12 weeks (continued for a total of 48 weeks if HCV RNA (-) after week 24)

VRVR, RVR, EVR and viral load at the end of 24 weeks were assessed (COBAS TaqMan HCV Test v2.0, Roche Diagnostics).

Hematologic growth factors were used as needed to minimize dose reductions.

Results:

Total patients: N=23: Caucasians(n=9) 39%, Hispanic(n=4) 17%, blacks(n=5) 21% and Asians(n=5) 21%.

Study patients had mean BMI of 27.9% and a mean viral load <600,000 IU/ml. Most had fibrotic score-F2 (57%).

Epoetin (52%), Elthrombopag (8.6%) and filgrastim (30%) were used to minimize dose reductions.See table.

● 11/23 (47.8%)- neutropenia requiring Filgrastim

● 12/23 (52%) - anemia requiring epoetin

● 9/23(39%) - got both Filgrastim and Epoetin

● Using a novel regimen with a NTZ and RBV lead-in phase prior to PegIFN/RBV/NTZ triple therapy, we report rates of VRVR, RVR, and complete EVR of 39.1%, 47.8%, and 60.9%, respectively.

● By comparison, in the IFN alfa-2a arm of the IDEAL Study, the respective VRVR, RVR, and complete EVR rates were lower at 4.3%, 11.9%, and 45%.

● The percentage of patients with undetectable serum HCV RNA at week 24 was similar in ERAIS-C (65.2%) versus IDEAL (61.6%).

● The current pilot study is limited to the number of patients enrolled, the lack of a comparative study group,

Conclusion:

● This regimen of NTZ, high-dose RBV and PEG IFN-α2a enhances RVR over historical controls and offers promise for an accelerated SVR with this interim analysis.

● Precise efficacy of this regimen could be elucidated with SVR analysis.

Interim Virologic Response results
VRVR (week 6)	39.1 % (9/23)
RVR (week 8)	47.8% (11/23)
Complete EVR (week 16)	60.9% (14/23)
Partial EVR (week 16)	30.4% (7/23)
Undetectable (week 24)	65.2% (15/23)
Null Responder	8.7% (2/23)
Partial Responder	26.1 (6/23)

Current Therapy

969. PRELIMINARY OBSERVATIONAL STUDY ON EFFICACY AND TOLERABILITY OF PEG-IFN ON 151 PEDIATRIC AND ADOLESCENT CHRONIC HEPATITIS C PATIENTS

H. Zhang

Objective:

To assess the efficacy and tolerability of peg-IFNα2a or 2b (Peg-IFN) plus ribavirin (RBV) combination therapy in pediatric and adolescent chronic hepatitis C (CHC) patients.

Methods:

151 pediatric and adolescent CHC patients (5-7 years: 7; 7-12 years: 53; 12-18 years: 91) verified by liver biopsy, were treated by peg-IFNα2a (n=83) or 2b (n=68) plus ribavirin (RBV) combination therapy. The treatment course was determined by RGT (response guided treatment) principle. If rapid virological response (RVR) at week 4 was achieved, the treatment would last 48-52 weeks, and 72 weeks for early virological response (EVR) at week 12. The average treatment course was 68 weeks (24-96 weeks). The follow-up interviews were proceeding averagely 20.6 months (6-58 months. Dose determination: PegIFN-α2a: 104 ug/m2/week; PegIFN-α2b: 1.5 ug/kg; And adaptive adjustment of peg-IFNs individually varied from 10% to 50%. RBV:15-20mg/kg/d.

Results:

● About the baseline demographic and disease features, the mean age, weight and ALT were 12, 57Kg and 76 IU/L respectively.

● Male is predominant (80.8%).

● The median of HCV RNA load is 6.4 log10 IU/mL, and varied from 3.1 to 7.5 log10 IU/mL. HCV RNA detection is Roche COBAS system, quantification limit =< 100 IU/mL.

● About the HCV genotype, 82.1% cases were 1b, 6.6% were 2a, 4.0% were mixture of 2a and 1b, and 7.3% were undone.

Efficacy data

● (HCV RNA undetectable at week 4, 12, 24 and 48 and SVR) in details please see the table.

Side Effects

About the tolerability, totally there were 53.6% cases of influenza-like symptoms, 45.7% of fever (the most is low grade fever), 53.2% lack of power, 90.4% lack of appetite, erythema 3.3%, and 92.3% neutrophil <2.0×109/L (among them 37.85% cases <1.0×109/L), There were 2 recurrences of Hb decreasing need to adjust RBV dose. 6 recurrences of moderate depression and completed the treatment course by mental intervention. 1 hyperthyreosis and completed the treatment course under the isotope treatment.

Conclusions:

● This is the first attempt to observe the efficacy of individually response guided and reinforced (longer course and higher dose) antiviral therapy in pediatric and adolescent CHC patients.

● For them, peg-IFN plus RBV combination therapy is of high viral response, good tolerability and better compliance than adults.

The Efficacy of Peg-IFNs plus RBV Combination Therapy

Groups	N	HCV RNA undetectable* (N/total, (%))				Follow-up SVR (HCV RNA undetectable number /actual total number of follow-up (%))
		Week4	Week 12	Week 24	Week 48-72	=<6 m	6	>12m
HCVRNA 1b	130†	77/130 (59.2%)	102/130 (78.5%)	109/130 (83.9%)	112/130 (86.2%)	102/112 (91.1%)	102/112 (91.1%)	96/96 (100%)
HCVRNA2a	10	8/10 (80%)	9/10 (90%)	9/10 (90%)	9/10 (90%)	9/9 (100%)	9/9 (100%)	9/9 (100%)
Others	11	6/11 (54.6%)	8/11 (72.7%)	8/11 (72.7%)	9/11 (81.8%)	8/9 (88.9%)	8/8 (100%)	8/8 (100%)
Relapse	11	5/11 (45.5%)	7/11 (63.6%)	9/11 (81.8%)

*: HCV RNA detection: Roche COBAS system, quantification limit ≤ 100 IU/mL. †:6 mixture of HCVRNA 1b and 2a are included

Current Therapy

1554. Treatment of genotype 2 or 3 hepatitis C virus infection with pegylated interferon and weight based ribavirin: A meta-analysis comparing short term [12-16 wks] vs. regular duration [24 wks] treatment.

A. K. Singal; B. S. Anand

Background and aims:

Hepatitis C virus (HCV) infection is most common cause of liver disease in the United States. As per guidelines of the American Association for Study of Liver Diseases, patients with genotype 2 and 3 infection are treated with pegylated interferon (PEGIFN) and ribavirin (RBV) for 24 weeks. Recently, there are reports that the treatment duration can be reduced with rapid virologic response (RVR) defined as negative HCVRNA at 4 weeks. This systematic review and meta-analysis was performed comparing outcome of short term (12-16 wks) vs. regular duration (24 weeks) treatment in patients who achieve RVR.

Methods:

A detailed literature search was performed using Mesh terms: HCV, pegylated interferon, ribavirin, antiviral therapy, genotype 2 or 3, hepatitis c, rapid virologic response, RVR. Boolean logic was used to combine the words. Pubmed, Ovid, Cochrane reviews, EMBASE and ISI web of science databases were searched. Odds ratio [OR] was used as effect measure using random effects model. Publication bias was assessed by Egger’s test. Heterogeneity was assessed by I2 and Chi2 statistics. Studies which randomized patients after an RVR was achieved and used weight based RBV were included.

Results:

A total of 8 studies were obtained. Of these, 4 were excluded (3 for using fixed dose RBV including an abstract on a similar meta-analysis, and 1 which assessed factors for relapse after treatment with short duration), and 4 studies met the inclusion criteria. Data on end-of-treatment (ETR) response, sustained virologic response (SVR), and relapse rates were extracted from these studies (n=748). The ETR rates obtained with short-term (12-16 wks) treatment compared to the standard 24 wks treatment were similar 94.1% and 94.3% respectively with non significant pooled OR [1.18; 95% CI 0.37-3.74; p=0.77). However, the SVR rates were lower with 12-16 wks treatment compared to 24 wks therapy (89.7 % vs. 95.7 %), with pooled OR of 0.42 in favor of standard duration therapy [95% CI 0.21-0.82; p=0.01]. This was due to the higher relapse rates with short-term therapy (10.2% vs. 4.2%) with OR of 2.40 in favor of 24 wks therapy [95% CI 1.22-4.74; p=0.01). There was no publication bias and the data were homogenous for all the analyses.

Conclusions:

Short term treatment with pegylated interferon and weight based RBV for patients who achieve RVR is limited by a higher relapse rate and lower SVR. Based on these findings, short-term treatment is not recommended routinely. However, it may be considered in patients who are unable to tolerate the treatment well. Further studies are needed to identify factors predicting SVR in these patients.

Experimental Therapies: Boceprevir

1555. SVR Results in Chronic Hepatitis C Genotype 1 Patients Dosed with SCH 900518 and Peginterferon Alfa-2b for 2 Weeks, Followed by Peginterferon Alfa-2b and Ribavirin for 24/48 Weeks: An Interim Analysis.

J. de Bruijne; J. F. Bergmann; C. J. Weegink; R. Molenkamp; J. Schinkel; M. A. Treitel; E. A. Hughes; A. A. van Vliet; R. J. de Knegt; H. W. Reesink; H. L. Janssen

Background:

SCH 900518, a second generation hepatitis C virus (HCV) NS3 serine protease inhibitor, resulted in robust reductions of HCV RNA after 1 week of monotherapy and after 2 weeks of combination therapy with peginterferon alfa-2b (Peg-IFN) with or without ritonavir. At the end of this proof-of-concept (POC) study (i.e. after SCH 900518), all patients were offered standard of care (SOC) with Peg-IFN and ribavirin (RBV).

Methods:

Forty HCV genotype 1-infected patients (20 treatment-naïve and 20 treatment-experienced) completed the POC study of SCH 900518. These patients received SCH 900518 (n=32) or placebo (n=8) in combination with Peg-IFN for 2 consecutive weeks, immediately followed by SOC with once weekly 1.5 µg/kg Peg-IFN and daily weight-based RBV (800-1400 mg). Patients were treated for 24 or 48 weeks, provided standard stopping rules did not require premature discontinuation. HCV RNA measurements were centrally performed using Cobas® Ampliprep/Cobas® TaqMan® HCV Test (LLD 15 IU/ml). Patients with plasma viral load >1000 IU/mL at start of SOC were analyzed for known resistant mutations by sequence analysis.

Results:

All 40 patients began treatment with SOC (see table), 39 patients have completed follow-up and 1 patient (placebo) is still in follow-up. Premature discontinuation due to an increase of HCV RNA during SOC (>1 log10 from nadir) was seen in 10 patients who received SCH 900518 (treatment-naïve n=3 vs. treatment-experienced n=7) and in 1 patient who received placebo. Non-response at week 4, 12 or 24 was seen in 5 treatment-experienced patients (SCH 900518 n=2, placebo n=3). Virological relapse after SOC was observed in 2 treatment-experienced patients (SCH 900518 n=1 and placebo n=1). In total 15 patients had HCV RNA >1000 IU/mL at start of SOC; 7 patients received SCH 900518 and 8 patients received placebo. In 5 of 7 SCH 900518 dosed patients at least one of the following variants, associated with protease inhibitor resistance, within the NS3 protease were detected: R155K (n=5), A156T/S (n=2), V36M/L (n=4).

Conclusion:

This study demonstrates that administration of SCH 900518 for two weeks (with or without ritonavir) plus Peg-IFN followed by SOC for 24 weeks or 48 weeks resulted in 81% and 38% SVR in treatment-naïve and experienced patients, respectively. These results support further development of SCH 900518 in both treatment-naïve and treatment-experienced patients.

	SCH 900518 Treatment-naïve (n=16) n/N, (%)		SCH 900518 Treatment-experienced (n=16) n/N, (%)		Placebo (n=8) n/N, (%)
	RVR	No RVR	RVR	No RVR	RVR	No RVR
SVR	9/9 (100)	4/7 (57)	6/7 (86)	0/9 (0)	1/1 (100)	1/6 (17)
SVR overall	13/16 (81)		6/16 (38)		2/7 (29)
Discontinued SOC	3/16 (19)		9/16 (56)		5/8 (63)

Current Treatment: Pegasys

1556. Highly Effective Peginterferon Alpha-2a plus Ribavirin Combination Therapy for Chronic Hepatitis C in Patients with Hemophilia.

H. Lee; H. J. Kim; Y. Lee; S. Park; E. Baek; K. Kim; B. Cha; S. Lee; H. Oh; C. Choi; J. Kim; J. Do; J. G. Kim; S. Chang

Background and Aims:

Chronic hepatitis C (CHC) is becoming an increasingly common cause of mortality in patients with hemophilia. However, there are few published data on response to treatment and adverse events with peginterferon alpha-2a (PegIFN) plus ribavirin in hemophilic patients with CHC. We conducted an open prospective trial to assess the safety and efficacy of combination therapy with PegIFN plus ribavirin for the treatment of CHC in patients with hemophilia.

Methods:

95 CHC Patients with hemophilia were enrolled between March, 2007 and December, 2008. Genotype 1 patients (G1, n = 62) received PegIFN (180 mcg, weekly) plus ribavirin (1000/1200 mg, daily) for 48 weeks while genotype 2 and 3 patients (G2/3, n = 33) received PegIFN (180 mcg, weekly) plus ribavirin (800 mg, daily) for 24 weeks. We evaluated rapid virologic response (RVR), early virologic response (EVR), and end-of-treatment response (ETR). Safety evaluations included adverse events and laboratory tests. This analysis was conducted by intent-to-treat.

Results:

Among 95 patients, 5 patients (5.3%) were withdrawn from treatment due to jaundice, periodontitis, general weakness, and dizziness. In 90 patients who treated more than 4 weeks, RVR was achieved in 53 patients (55.8%, G1=23/62, 37.1% vs. G2/3=30/33, 90.9%). In 90 patients who treated more than 12 weeks, EVR was achieved in 89 patients (93.7%, G1=58/62, 93.5% vs. G2/3=31/33, 93.9%). In 88 patients who completed the treatment schedule, ETR was achieved in 80 patients (90.9%, G1=49/55, 89.1% vs. G2/3=31/33, 93.9%). SVR was evaluable in 68 patients. SVR was achieved in 63 patients (82.9%, G1=34/44, 77.3% vs. G2/3=29/33, 90.6%). There was no severe adverse event. Hair loss and headache were common. Hematologic adverse events were neutropenia (ANC<1,000/mm2=39/95, 41.1%), anemia (Hgb<10 g/dL=22/95, 23.2%) and thrombocytopenia (Platelet<50,000=4/95, 4.2%). RVR was a only good predictive factor for SVR in multivariate analysis (odds ratio [OR], 15.851; 95% confidence interval [CI], 1.869-134.439; P = 0.011).

Conclusion:

Responses to antiviral therapy in patients with hemophilia appear to be superior to those in the general population. There were a few serious adverse events [Jaundice (n=1), periodontitis (n=1)] during the treatment and no bleeding associated adverse events

Experimental Treatment: Vaccines

1558. Significant continuous viral load decline in treatment-naive HCV genotype 1 patients after therapeutic peptide vaccination with IC41.

C. S. Klade; A. von Gabain; M. P. Manns

Background:

IC41 is a peptide vaccine with CD4 and CD8 T cell epitopes and poly-L-arginine as adjuvant. Safety, immunogenicity and occasional RNA responses in patients refractory to standard therapy have been described previously. Here we report data of an open label, controlled multicenter Phase II study in genotype-1 patients naïve to standard therapy. Fifty HCV infected subjects received an optimized IC41 dose and vaccination schedule.

Methods:

The regimen consisted of eight intra dermal vaccinations in biweekly intervals with topic application of the TLR7/8 agonist imiquimod (Group A). In Group B twenty one patients received an intensified schedule consisting of 16 subcutaneous vaccinations in weekly intervals without imiquimod. At Week 16 Group A (n=44, intent to-treat population) showed a statistically highly significant (p=0.0013) HCV viral load decline of 0.21 log. At Week 38 (n=34 subjects, 24 weeks after the last vaccination) the viral load decreased by 0.47 log (p<0.0001). The effect was more pronounced in patients with a high baseline HCV viral load (>2 million U/ml, n=17) with a 0.61 log decline at Week 38. In this subgroup significant p-values (p<0.02) were calculated continuously starting at Week 6, two weeks after the third vaccination. No apparent effect on HCV viral load was observed in Group B (n=21). In Group A at Week 38 eight patients (24%) showed a viral load response defined as a decline of >0.8 log. Nevertheless these patients were not alone responsible for the overall viral load decline seen in the total or high viral load sub population. HCV epitope specific immune responses were evaluated using ex vivo Interferon γ ELIspot, proliferation, and HLA-A2 tetramer assays. Overall, 40 to 60% of patients showed T cell responses during and up to 6 month after vaccination in both treatment groups. Nevertheless, significant correlations between the HCV viral load decrease and T cell immune response data were not detected.

Conclusions:

This is the first report showing a significant antiviral effect of a peptide vaccine in HCV infected patients. The time course with increased RNA decline 24 weeks after the last vaccination is encouraging and justifies further clinical studies potentially in combination with standard therapy or novel antiviral medications.

Experimental Therapies: Interferon

1560. ANA773, an Oral Inducer of Endogenous Interferons that Acts Via TLR7, Reduced Serum Viral Load in Patients Chronically Infected with HCV.

H. L. Janssen; J. de Bruijne; J. F. Bergmann; D. Hotho; R. J. de Knegt; C. J. Weegink; A. A. van Vliet; J. van de Wetering; S. P. Fletcher; L. A. Bauman; B. Eam; M. V. Sergeeva; T. W. Harding; M. H. Rahimy; J. R. Appleman; J. L. Freddo; H. W. Reesink

Background:

ANA773 is an oral p