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 inh