Long-term Outcome of Chronic Hepatitis C After Sustained Virological Response to Interferon-based Therapy

C. Koh, T. Heller, V. Haynes-Williams, K. Hara, X. Zhao, J. J. Feld, D. E. Kleiner, Y. Rotman, M. G. Ghany, T. J. Liang, J. H. Hoofnagle

Aliment Pharmacol Ther. 2013;37(9):887-894.

Abstract and Introduction

Abstract

Background Although the short-term benefits of a sustained virological response (SVR) to interferon-based therapies of chronic hepatitis C (CHC) are well known, the long-term consequences of SVR are less clear.

Aim To assess changes in markers of disease activity and fibrosis in patients followed up to 23 years post-SVR.

Methods The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE).

Results Of 103 patients, three subsequently relapsed 0.7, 6.3 and 6.5 years post therapy. The remaining 100 patients (56 men, mean age 56 years) maintained SVR at final follow-up. No patients developed hepatic decompensation, but one with pre-treatment cirrhosis died 12 years post SVR of hepatocellular carcinoma. In comparison to pre-treatment values, markers improved at follow-up, including mean ALT (152–27 U/L), AST (87–24 U/L), alkaline phosphatase (78–69 U/L), IgG (1463–1113 mg/dL), platelet count (209 000–239 000/μL) and AST to platelet count ratio index (APRI: 1.31–0.33). TE was performed in 69 patients and was normal (<7.0 kPA) in 60%, moderately elevated (7.1–13.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow-up correlated with fibrosis on pre-treatment liver biopsy (P < 0.001).

Conclusions In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre-treatment cirrhosis are at continuing low risk for hepatocellular carcinoma.

Introduction

Chronic hepatitis C virus (HCV) infection is estimated to affect 180 million persons worldwide and at least 3.2 million Americans.^{[1, 2]} This disease is the most common cause of chronic hepatitis and cirrhosis, end-stage liver disease and hepatocellular carcinoma in the United States and the developed world.^{[3, 4]} It is also the single most common reason for liver transplantation.^[4] Therapy for HCV has evolved during the last 20 years from use of interferon alone to the combination of interferon and ribavirin followed by the combination of peginterferon with ribavirin.^[5–7] Recently direct-acting antiviral agents have been developed for HCV that have increased the response rate substantially.^[8–13] The endpoint for assessing efficacy of antiviral therapy has been the loss of HCV RNA from serum which, if sustained for at least 6 months after stopping treatment, is referred to as a sustained virological response (SVR).^[14] The durability of a 6-month SVR is above 95%, but the long-term clinical benefits of this outcome have not been well defined.^{[15, 16]}

Although achievement of an SVR has been associated with clinical, laboratory and histological improvements in chronic HCV, this endpoint is a surrogate for the ultimate aim of therapy, which is prevention of progression to cirrhosis, end-stage liver disease, hepatocellular carcinoma and death from liver disease.^[17–26] These 'hard' endpoints, however, generally take years or decades to evolve and following patients randomised to treatment or observation with these dire outcomes has not been practical and has been considered ethically untenable. Thus, while SVR is associated with improvements in serum aminotransferase levels and liver histology, its role in preventing progression of disease and disability or death from chronic liver disease is uncertain and currently controversial.

At the Clinical Center of the National Institutes of Health (NIH), we have conducted a series of prospective controlled and uncontrolled studies of therapy of chronic HCV beginning in 1984.^[26–31] All patients who achieved an SVR as a part of these studies have been followed on a long-term basis to assess the natural history and outcome of this virological response. As a consequence, we have a cohort of SVR patients that have been followed up for up to 23 years. We report the follow-up of the initial 103 patients who achieved an SVR between the years 1986 and 2003.

Materials and Methods

Patients

All patients who achieved a 6-month post-treatment SVR in clinical research protocols conducted by the Liver Diseases Branch, NIDDK between 1984 and 2003 were included in this analysis. Of the 262 patients enrolled, 103 achieved an SVR. Thereafter, many patients were followed on a regular basis. Starting in 2007, patients who had not returned in the previous 2 years were asked to return for a medical evaluation, blood tests, abdominal ultrasound and ultrasound transient elastography. The initial protocols included studies of interferon alfa-2b alone for 6 or 12 months,^[26–29] escalating doses of interferon alfa-2b for 12 months, and the combination of standard interferon alfa-2b or peginterferon alfa-2a with ribavirin for 6–12 months.^[29–31] All patients gave written informed consent for the initial trials as well as for long-term follow-up and transient elastography in a protocol, which was approved by the NIDDK Institutional Review Board and registered in ClinicalTrials.gov (#NCT00001971). All authors had access to the study data and had reviewed and approved the final manuscript.

Laboratory Tests

At the time of last follow-up, patients were tested for liver biomarkers including alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase, gamma glutamyl-transpeptidase (GGT), immunoglobulin levels (IgG, IgA, IgM), rheumatoid factor, alpha-fetoprotein and platelet counts. Results of these markers before therapy were available from most patients. Serum HCV RNA was tested by quantitative and qualitative reverse transcriptase polymerase chain reaction (Amplicor; Roche Molecular Systems, Pleasanton, CA, USA) with a lower limit of sensitivity of 100 viral copies/mL (50 IU/mL). HCV genotyping was done using reverse hybridisation (INNO-LiPA; Innogenetics, Ghent, Belgium). HCV RNA testing before, during and immediately after therapy was performed using assays that were available at the time and were not always of similar specificity and sensitivity. Virological testing from the initial studies (done between 1984 and 1992) was done on serum samples, stored at −80 °C.^[29] In patients who relapsed, stored serum samples (−80 °C) were retrieved and retested for HCV RNA at the time of SVR using the Amplicor system to confirm the absence of HCV RNA.

All except three patients underwent a pre-treatment liver biopsy with interpretation by one hepatopathologist (DEK) using the Ishak modification of the HAI scoring system for activity and fibrosis.^[32]

Transient Elastography

Patients evaluated after 2007 underwent ultrasound transient elastography (TE) performed via FibroScan (Echosens, Paris) after informed consent.^[33] Elastography was done by individuals specifically trained in the technique. At least 10 determinations were made and median results were expressed in kilopascals (kPA). Values range from 2.5 to 75 kPA with values of <7.0 being normal and suggesting no or mild hepatic fibrosis, values of 7.1–13.7 suggesting moderate to advanced fibrosis and values of >13.8 suggesting cirrhosis.

Statistical Analysis

Continuous variables were reported as mean (±standard deviation), and categorical variables as percentages. Mean and proportion of abnormal values, differences of baseline ALT, AST, GGT, alkaline phosphatase, total and direct bilirubin, IgG, albumin, alpha-fetoprotein, rheumatoid factor and platelets and the most recent follow-up values were compared via paired student's t-test for continuous variables or McNemar's test for categorical variables. As a sensitivity analysis, regression analysis was used to explore the effect in time between baseline to follow-up and mean differences between baseline and follow-up values. Cumulative incidence of relapse was plotted using the Kaplan–Meier method. In comparing pre-treatment liver biopsy scores with follow-up TE, the McNemar's exact test for association was used. Significance was accepted at a P-value of less than 0.05. Data analysis was performed using sas, Version 9.1.3 (SAS Institute Inc., Cary, NC, USA) software.

Results

Among 262 patients treated in five clinical research protocols between 1984 and 2003, 103 had an SVR and comprised the analysis cohort for this study. These patients were followed up for a median time of 7.5 years (6 months to 23 years) after SVR and 89 were seen and evaluated after 2007. The duration of follow-up after SVR was less than 5 years in 27 patients, 5–10 years in 58 patients, and greater than 10 years in 12 patients. Of this cohort, three patients were found to be HCV RNA positive at the time of follow-up and were considered late relapsers. The estimated time to relapse was 0.67, 6.3 and 6.5 years after stopping therapy. Thus, the relapse free rate was 96% at an average of 7.6 years after therapy (Figure 1). The three HCV RNA positive patients appeared to have suffered a relapse rather than re-infection, as the recurrent virus was almost identical to the pre-treatment sequence strains (Supplemental Table S1, published online).^[34] None had ongoing risk factors for hepatitis C or a clear predisposition for relapse (i.e. corticosteroids, chemotherapy or immunosuppression).

Figure 1.

Kaplan–Meier analysis of proportion of patients without virological relapse. Three of 103 patients became HCV RNA positive after having achieved an SVR after interferon-based therapy. At 7.2 years, the relapse free rate was 96%.

The remaining 100 patients included 56 men and 44 women, 88 whites, 4 African Americans and 8 Asians, with an average age of 55.6 years (). Twenty-one received standard interferon alone, 55 interferon and ribavirin and 24 peginterferon and ribavirin.

Table 1. Clinical features of 100 patients with sustained virological response

Feature	Number
Number of men/women (%)	56(56%)/44(44%)
Median duration of follow-up in years (range)	7.5 (0.6–23.0)
Mean age at last visit (range) in years	55.6 (16.7–84.2)
Number of deaths/liver-related deaths	6/1
Race
Number of Caucasians (%)	88 (88%)
Number of African Americans (%)	4 (4%)
Number of Asians (%)	8 (8%)
Number of patients with HCV genotype (%)
1	45 (45%)
2	35 (35%)
3	18 (18%)
Others	2 (2%)
Number of patients with pre-treatment Ishak fibrosis score (%)
0–2	62 (64%)
3–4	25 (26%)
5–6	10 (10%)
Number of patients undergoing treatment (1985–2003) (%)
Interferon alfa-2b	21 (21%)
Interferon alfa-2b & Ribavirin	55 (55%)
Peginterferon alfa-2a & Ribavirin	24 (24%)

In follow-up, six of the 100 patients died but only one died of a HCV-related cause, hepatocellular carcinoma resulting in death 12.5 years after SVR. This patient had biopsy proven cirrhosis before the course of therapy with interferon and ribavirin that led to an SVR. The causes of death in the remaining five patients included Huntington's chorea, cerebrovascular disease, septicaemia from chronic osteomyelitis, pneumonia and cardiac arrest all of which occurred more than a year after therapy and none of which were considered related to hepatitis C or its treatment. No patient developed decompensated liver disease, jaundice, ascites, variceal haemorrhage, hepatic encephalopathy or required liver transplantation.

Follow-up testing was available from all patients 12–264 months after completion of therapy. Serum ALT levels were normal in 90% and the average value was 27 U/L, which was significantly less than before therapy (152 U/L) ( and ). Of the remaining 10% of patients with abnormal follow-up ALT levels, values were minimally or modestly elevated and were less than twice the upper limit of the normal range in nine. All 10 patients with ALT elevations had gained weight; four were overweight and five were obese. Abdominal ultrasound demonstrated steatosis in all six who underwent imaging during follow-up (Supplemental Table S2, published online).

Table 2. Mean results of routine laboratory values taken before therapy and at the time of last follow-up evaluation

Laboratory test	Initial value (range)	Final value (range)	P-value
ALT (U/L)	152 (16–459)	27 (10–72)	<0.0001
AST (U/L)	87 (18–296)	24 (14–44)	<0.0001
GGT (U/L)	47 (11–176)	28 (5–91)	<0.0001
ALP (U/L)	78 (37–237)	69 (28–238)	<0.0001
Total bilirubin (mg/dL)	0.7 (0.3–2.3)	0.8 (0.1–2.7)	0.055
Albumin (g/dL)	4.2 (3.0–5.0)	4.1 (3.1–5.2)	0.016
Alpha-fetoprotein (ng/mL)	4.6 (1.2–26.6)	2.9 (1.2–9.0)	<0.0001
IgG (mg/dL)	1463 (518–2580)	1113 (605–2090)	<0.0001
Platelets (×1000/μL)	209 (73–384)	239 (56–457)	<0.0001

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase.

Analysis by paired student's t-test.

Table 3. Proportion of patients with abnormal laboratory results before therapy and at the time of last follow-up evaluation

Laboratory test	Percentage abnormal		P-value
	Initial	Final
ALT	83	10	<0.0001
AST	79	5	<0.0001
Direct bilirubin	47	26	0.048
Rheumatoid factor	38	19	0.0043
Platelet count	24	10	0.001

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Analysis by McNemar's test.

At the time of final follow-up there were also significant improvements in mean AST (87–24 U/L), alkaline phosphatase (78–69 U/L), IgG (1463–1113 mg/dL), alpha-fetoprotein (4.6–2.9 ng/mL), GGT (47–28 U/L), platelet count (209 000–239 000/μL) and rheumatoid factor (38–19% positive). Based on sensitivity analysis using regression models, patients with longer duration of follow-up had greater mean changes of ALT, AST, total and direct bilirubin, IgG and albumin values between baseline and follow-up (data not shown). Serum total bilirubin and albumin levels did not change appreciably, but were largely normal even before therapy. Direct bilirubin improved slightly although not significantly overall. Before therapy, 47% of patients had a direct bilirubin level of greater than 0.2 mg/dL (range: 0.0–0.4 mg/dL); at the time of last follow-up testing, only 26% had abnormal values (range: 0.1–0.4 mg/dL) (). On follow-up evaluation, no patient had an abnormal prothrombin time. Because the methodology and normal range for the prothrombin time varied over the period of observation, a comparison of initial and final values was not possible.

Table 3. Proportion of patients with abnormal laboratory results before therapy and at the time of last follow-up evaluation

Laboratory test	Percentage abnormal		P-value
	Initial	Final
ALT	83	10	<0.0001
AST	79	5	<0.0001
Direct bilirubin	47	26	0.048
Rheumatoid factor	38	19	0.0043
Platelet count	24	10	0.001

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Analysis by McNemar's test.

The calculated APRI was elevated (>0.8) in 53% of patients before treatment and averaged 1.31. In follow-up, the APRI was normal in all patients and averaged 0.33, which was significantly less than pre-treatment values (P < 0.001) (Figure 2).

Figure 2.

Mean platelet counts (a) and AST-to-platelet ratio index values (APRI: b) before therapy (Pre-Tx) and at the time of last follow-up evaluation in 100 patients with a sustained virological response stratified by degree of hepatic fibrosis on pre-treatment liver biopsy. Patients were categorised into three groups based upon pre-treatment Ishak fibrosis scores of 0–2 (no fibrosis to portal fibrosis only), 3–4 (bridging hepatic fibrosis) and 5–6 (early and complete cirrhosis).

Transient elastography was attempted in 75 patients at follow-up, but was successful in only 69 (). In this group, 59% had stiffness scores of ≤7.0 kPA (considered normal), 32% had values between 7.1 and 13.8 (suggestive of moderate to advanced fibrosis), and 9% had values above 13.8 kPA (suggestive of cirrhosis).

Table 4. Association of initial Ishak fibrosis score from initial, pre-treatment liver biopsy and transient elastography stiffness score at the time of final follow-up evaluation

Baseline Ishak score	Number of patients	Fibroscan on follow-up			P-value
		≤7.0	7.1–13.8	>13.8
0–2	45	28 (62%)	16 (36%)	1 (2%)	0.0006
3–4	17	12 (71%)	4 (23%)	1 (6%)
5–6	7	1 (14%)	2 (29%)	4 (57%)
Total	69	41 (59%)	22 (32%)	6 (9%)

Analysis by McNemar's test.

Liver biopsy had been performed on 97 patients before therapy and demonstrated cirrhosis (Ishak fibrosis 5–6) in 10, bridging fibrosis (Ishak 3–4) in 25 and no fibrosis or portal fibrosis only (Ishak 0–2) in 62. Analysis of TE stiffness values by initial hepatic fibrosis scores demonstrated that most patients (6 of 7) with pre-treatment cirrhosis had high TE values at follow-up 3.1–23 years after an SVR. In contrast, abnormal TE values were found in only 38% of those with minimal fibrosis and 29% with bridging fibrosis before treatment.

Platelet counts were low (<160 000/μL) in 24% of patients before therapy including 80% of those with cirrhosis. In follow-up, the average platelet count in the 100 patients increased (from 209 000 to 239 000/μL) and was in the normal range in 90% ( and ). Platelet counts were generally normal in patients with no or mild fibrosis before therapy but even in these individuals, the average platelet count increased after SVR. Improvement in platelet count was most marked in patients with cirrhosis (123 000–164 000/μL) and also increased similarly in those with moderate to advanced fibrosis (204 000–241 000/μL) (Figure 2a). Importantly, the platelet count at the time of TE evaluation correlated with liver stiffness scores. Thus, the average platelet count in patients with normal TE scores was 219 902/μL, compared with 212 455/μL in those with TE scores between 7.1–13.8 and 147 333/μL in those with TE scores in the cirrhotic range of >13.8 kPA (P = 0.0248). In contrast, the APRI values correlated with the degree of hepatic fibrosis as assessed by liver biopsy before treatment, but were within the normal range in all patients at the time of follow-up evaluation regardless of initial Ishak scores or follow-up TE values (Figure 2b).

Table 2. Mean results of routine laboratory values taken before therapy and at the time of last follow-up evaluation

Laboratory test	Initial value (range)	Final value (range)	P-value
ALT (U/L)	152 (16–459)	27 (10–72)	<0.0001
AST (U/L)	87 (18–296)	24 (14–44)	<0.0001
GGT (U/L)	47 (11–176)	28 (5–91)	<0.0001
ALP (U/L)	78 (37–237)	69 (28–238)	<0.0001
Total bilirubin (mg/dL)	0.7 (0.3–2.3)	0.8 (0.1–2.7)	0.055
Albumin (g/dL)	4.2 (3.0–5.0)	4.1 (3.1–5.2)	0.016
Alpha-fetoprotein (ng/mL)	4.6 (1.2–26.6)	2.9 (1.2–9.0)	<0.0001
IgG (mg/dL)	1463 (518–2580)	1113 (605–2090)	<0.0001
Platelets (×1000/μL)	209 (73–384)	239 (56–457)	<0.0001

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase.

Analysis by paired student's t-test.

Table 3. Proportion of patients with abnormal laboratory results before therapy and at the time of last follow-up evaluation

Laboratory test	Percentage abnormal		P-value
	Initial	Final
ALT	83	10	<0.0001
AST	79	5	<0.0001
Direct bilirubin	47	26	0.048
Rheumatoid factor	38	19	0.0043
Platelet count	24	10	0.001

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Analysis by McNemar's test.

Discussion

The initial 5 of 10 patients treated with antiviral therapy in 1986 at the NIH for chronic HCV achieved an SVR and had both biochemical and histological evidence of improvement in the year following treatment.^[26] These five patients have now been followed up for more than 20 years and remain HCV RNA-negative and have normal or near-normal serum enzyme levels.^[28] Liver biopsies on these patients 10 years after initial therapy showed resolution of the disease activity and regression of fibrosis in some.^[35] After this initial study, patients at the NIH were enrolled in various therapeutic trials for chronic hepatitis C. As of 2003, a total of 103 patients had achieved an SVR, all in response to interferon-based therapy. The duration of subsequent follow-up in these 103 patients varied from a few months to as long as 23 years. In this cohort, three patients relapsed, and the remaining 100 patients had markedly improved liver tests at the time of follow-up evaluation and none had clinical evidence of advanced cirrhosis, hepatic decompensation or end-stage liver disease. These findings indicate that an SVR from interferon-based therapies for chronic HCV is usually durable and associated with improvement in biomarkers of disease, a favourable long-term prognosis and lack of evidence of progression of liver disease.

Similar findings after SVR in chronic HCV have been published in other cohorts.^{[15–20, 36–39]} However, the current analysis extends this experience to more than 20 years after therapy. Importantly, while patients who achieved an SVR did not develop progressive liver disease, at least one case of HCC still occurred. In this cohort, one patient who had cirrhosis before treatment developed HCC despite having had an SVR 12 years previously. The occurrence of HCC after SVR has been reported in several cohorts, although the rate of liver cancer appears to be far less than occurs among untreated patients with advanced fibrosis or cirrhosis due to chronic hepatitis C.^{[19, 20, 36, 37]} Such findings suggest that patients with an SVR should continue to have regular surveillance for HCC if they had histological evidence of cirrhosis before treatment.

A shortcoming of this study is the lack of a control group of patients with chronic hepatitis C who were not treated or a comparison group of patients who were treated but did not achieve an SVR. However, it was not feasible or considered ethical to randomise patients to therapy vs. no therapy and follow them for an indefinite period. In early controlled trials of interferon for hepatitis C, some patients were not treated for the initial 1–2 years after randomisation.^[27] However, the controls from those studies were subsequently offered therapy on an open-label basis and some achieved an SVR and are a part of this analysis. Since 1992 and the approval of interferon as therapy of hepatitis C, all large 'controlled' trials of treatment have compared one interferon-based regimen to another and patients were not given placebo or randomised to no therapy.

Another approach to assessment of the possible benefit of an SVR is to compare patients who achieve an SVR to those who relapse or do not respond. However, multiple studies have shown that patients who have an SVR have a durable loss of HCV RNA and are less likely to have advanced fibrosis or cirrhosis.^{[5–7, 27]} For these reasons, such comparisons require careful balancing of risk factors. Among the 262 patients treated in at this centre, the majority of the non responders were retreated at one time or another, with differing regimens and often at different institutions.

Use of transient elastography, a non-invasive marker for hepatic fibrosis, suggested that 41% of the cohort had residual evidence of fibrosis at the time of last follow-up 3–23 years after SVR. The elevated elastography scores were not associated with residual abnormalities of serum aminotransferase levels but were more likely to be abnormal in patients who had advanced fibrosis or cirrhosis before treatment. This suggests that some degree of fibrosis persists despite the resolution of disease activity as assessed by serum enzymes. Slight decreases in platelet counts at the time of final follow-up also correlated with the initial liver histology. Elastography scores were not available from before treatment, but improvements in other markers of advanced disease (platelet count, direct bilirubin, immunoglobulin levels) suggest that SVR may be associated with subsequent improvement in portal hypertension and perhaps partial regression of fibrosis. These findings suggest that the greatest benefit from successful eradication of HCV may be in non-cirrhotic patients, but that even patients with advanced disease, gain a benefit from treatment.

In summary, with continued follow-up of patients with chronic hepatitis C for up to 23 years after achieving sustained clearance of HCV RNA, progressive liver disease was not seen. Among patients who had advanced fibrosis and cirrhosis before being treated, evidence from platelet counts and transient elastography suggested the persistence of some degree of hepatic fibrosis and a low but continued risk for HCC.

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36. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology (Baltimore, MD) 2007; 45: 579–87.

37. Giannini EG, Basso M, Savarino V, Picciotto A. Sustained virological response to pegylated interferon and ribavirin is maintained during longterm follow-up of chronic hepatitis C patients. Aliment Pharmacol Ther 2010; 31: 502–8.

38. Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010; 8: 280–8.

39. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007; 147: 677–84.

Guarantor of the article
Christopher Koh.

Author contributions
Study concept & design: CK, TH, JHH; Acquisition of data: CK, TH, VH, JJF, YR, MGG, TJL, JHH; analysis/interpretation: CK, DEK, KH, TH, JHH; Drafting: CK; Critical revision: TH, VH, KH, JJF, XZ, DEK, JHH, MGG, YR, TJL; Statistical analysis: CK, XZ; Technical Support: None; Supervision: JHH, TH, TJL.

All authors approved the final version of the manuscript.

Aliment Pharmacol Ther. 2013;37(9):887-894. © 2013 Blackwell Publishing

Source

A risk for hepatocellular carcinoma still persists long-term after sustained virological response in patients with hepatitis C associated liver cirrhosis

Clin Infect Dis. (2013) doi: 10.1093/cid/cit234 First published online: April 24, 2013

Soo Aleman1,2, Nogol Rahbin1, Ola Weiland2, Loa Davidsdottir1, Magnus Hedenstierna2, Nina Rose1, Hans Verbaan3, Per Stål1, Tony Carlsson2, Hans Norrgren4, Anders Ekbom5, Fredrik Granath5, and Rolf Hultcrantz1

+ Author Affiliations

Correspondence to: Soo Aleman, Department of Gastroenterology and Hepatology, and Infectious Diseases, Karolinska University Hospital, at Karolinska Institute, 171 76 Stockholm, Sweden, Phone: +46 8 517 72741, Fax: +46 8 517 700 00, E-mail: soo.aleman@ki.se

Alternate corresponding author: Rolf Hultcrantz, Department of Gastroenterology and Hepatology, Karolinska University Hospital, 171 76 Stockholm, Sweden, Phone: +46 8 517 00 00, E-mail: rolf.hultcrantz@ki.se

Abstract

Background. The long-term effect of sustained virological response (SVR) to antiviral therapy on the risk to develop hepatocellular cancer (HCC), liver complications, liver-related deaths and overall death in hepatitis C (HCV) infected patients with liver cirrhosis is not fully known.

Methods. These risks were evaluated during long-term follow-up in in 351 patients with HCV related cirrhosis. 110 with SVR, 193 with non-SVR and 48 untreated patients were included in a multi-center cohort which was initiated 2001 and prospectively followed-up for a mean 5.3 ±SD 2.8 years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up.

Results. Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4 and 7.6 years after achieving SVR. The incidence of HCC, any liver complication, liver-related and overall death per 100 person-years was significantly lower in SVR time with 1.0, 0.9, 0.7, 1.9, compared to 2.3, 3.2, 3.0, 4.1 and 4.0, 4.9, 4.5, 5.1 in non-SVR and untreated time, respectively. The long-term consequences did not decline significantly after more than 3-year versus during the first 3-year of follow-up.

Conclusions. The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk to develop HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

Received October 28, 2012. Accepted February 11, 2013.

Source

AbbVie's Investigational HCV Regimen Receives Breakthrough Therapy Designation from the U.S. Food and Drug Administration

- Interferon-free, direct-acting antiviral combination therapy currently in Phase 3 development

May 6, 2013

NORTH CHICAGO, Ill., May 6, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that its investigational direct-acting antiviral (DAA) combination with and without ribavirin for the treatment of genotype 1 (GT1) hepatitis C virus (HCV) infection has been designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA).

The designation is based, in part, on positive data from AbbVie's clinical development program, including the Phase 2b clinical trial M11-652, known as "Aviator." The Aviator study was conducted in 571 patients infected with HCV GT1. Results from the treatment arms evaluating ABT-450/r + ABT-267 + ABT-333 with and without ribavirin demonstrated that the regimen provided high sustained viral response rates (SVR) with 12 weeks of therapy in patients who had not been previously treated (treatment naive) and in those who had failed prior therapy with pegylated interferon and ribavirin (null responders), regardless of sex, HCV subtype, stage of fibrosis, viral load or IL28B genotype.

According to the FDA, Breakthrough Therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy designation includes preliminary clinical evidence demonstrating a drug may have substantial improvement on at least one clinically significant endpoint compared to available therapy. A Breakthrough Therapy designation conveys all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.⁽¹⁾

"AbbVie is pleased that the FDA has granted Breakthrough Therapy designation to our 3-DAA combination with and without ribavirin. We feel it reflects the potential of this regimen to be important in the treatment of HCV," said John M. Leonard, M.D., senior vice president and chief scientific officer, AbbVie. "Our HCV program is one part of our advancing pipeline which is focused on delivering innovative therapies to address pressing areas of unmet clinical need."

New results from Aviator were recently presented at the 2013 International Liver Congress® in Amsterdam. These results continued to demonstrate high SVR rates against GT1 HCV with the 12-week, triple-DAA regimen with ribavirin, across patient types. Specifically,

• 99 percent of treatment-naive patients (n=79) achieved SVR₁₂, 96 percent achieved SVR₂₄ in an intent-to-treat analysis
• 93 percent of prior null responders (n=45) achieved SVR₁₂ and SVR₂₄
• A single relapse with this regimen occurred at post-treatment week two
• Of the 247 patients treated for 12 and 24 weeks with triple DAA with ribavirin, four patients (1.6 percent) discontinued the study because of drug-related adverse events. Serious adverse events were noted in four patients (1.6 percent), with one (arthralgia) considered possibly drug-related. Other events reported in more than 10 percent of patients included headache, fatigue, nausea, insomnia, and diarrhea. Grade 3-4 laboratory abnormalities in total bilirubin (six patients) and ALT (one patient) were noted; all resolved with continued dosing.

AbbVie's all-oral, triple-DAA combination is currently being studied in Phase 3 clinical trials. The Phase 3 program includes more than 2,000 patients with HCV genotype 1, with trial sites in 29 countries. The DAAs in the studies include ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor). Treatment durations under investigation are 12 weeks in non-cirrhotic patients, and 12 or 24 weeks in cirrhotic patients. All patients will be followed for 48 weeks post-treatment. Co-formulated tablets of ABT-450/r and ABT-267 are being used in the Phase 3 trials.

About the Hepatitis C Virus

Across the world, about 160 million people are chronically infected with hepatitis C.⁽²⁾ Hepatitis C is an inflammation of the liver caused by an infection with the hepatitis C virus (HCV).⁽³⁾ HCV is transmitted when an infected person's blood enters the bloodstream of another person.⁽⁴⁾

For the hepatitis C virus, there are six major HCV genotypes (GT1-6).⁽⁵⁾ Presently, there is no vaccine for the hepatitis C virus (HCV) infection.⁽⁵⁾ Decision to treat is dependent on a number of factors such as the amount of liver damage present, other conditions the patient may have, amount of virus in the body, and viral genotype.⁽⁵⁾ If treatment is needed, a hepatitis C infection is typically treated with a combination of antivirals.⁽⁵⁾

About AbbVie's HCV Development Programs

AbbVie's HCV portfolio includes investigational medicines with three different mechanisms of action, including protease (ABT-450/r), polymerase (ABT-333) and NS5A (ABT-267) inhibitors, currently being studied in clinical trials. ABT-450 is being developed with low dose ritonavir which enhances the pharmacokinetic properties of ABT-450. The use of ritonavir 100mg with ABT-450 for the treatment of HCV is investigational.

ABT-450 was discovered during the course of a collaboration between AbbVie and Enanta Pharmaceuticals for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV. AbbVie is well-positioned to explore combinations and co-formulations of these medicines.

Ritonavir Use in the Treatment of HIV

Ritonavir is in a class of medicines called the HIV protease inhibitors. Ritonavir is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. Ritonavir is for adults and for children greater than 1 month in age and older.

Ritonavir does not cure HIV infection or AIDS and does not reduce the risk of passing HIV to others. People taking ritonavir may still get opportunistic infections or other conditions that happen with HIV infection. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.

Ritonavir Safety in Treatment of HIV

Patients should not take ritonavir with certain medicines, as these can cause serious or life-threatening problems such as irregular heartbeat, breathing difficulties, or excessive sleepiness. Patients should not take ritonavir if they have had a serious allergic reaction to any of its ingredients. Some patients taking ritonavir may develop liver and pancreas problems, which can cause death.

Patients may develop large increases in triglycerides and cholesterol, diabetes, high blood sugar, changes in body fat, increased bleeding in people with hemophilia, allergic reactions, and/or changes in heart rhythm. Patients may develop signs and symptoms of infections that they already have after starting anti-HIV medicines.

For more information, please see Important Safety Information and Full Prescribing Information.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

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1.U.S. Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. 2013. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm. Accessed April 19, 2013.

2.Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.

3.World Health Organization. Global Alert and Response (GAR): Hepatitis C. 2003. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index1.html. Accessed April 9, 2013.

4.World Health Organization. Hepatitis C Fact Sheet 2012. http://www.who.int/mediacentre/factsheets/fs164/en/ Accessed April 9, 2013.

5.European Association for the Study of the Liver. Clinical Practice Guidelines: Management of hepatitis C virus infection. Journal of Hepatology. 2011; 55: 245-264.

SOURCE AbbVie

For further information: Media, Tracy Sorrentino, +1 (847) 937-8712, or Roseanne Durril, +1 (847) 938-6114, or Investors, Larry Peepo, +1(847) 935-6722, or Liz Shea, +1 (847) 935-2211

Source

Some liver transplants 'avoidable'

4 May 2013 Last updated at 19:08 ET

Some patients with severely damaged livers may not need a transplant as their own organ is actually regrowing, say doctors at a hospital in London.

They made the discovery by looking at a rare group of patients given a transplant while their own damaged liver is left in the body.

Sometimes the original liver recovers.

A study, in the American Journal of Transplantation, suggests doctors can predict which patients do not need a transplant as their liver is healing.

King's College Hospital has a leading liver transplant centre and is one of few places to perform "auxiliary transplants".

They are performed in sudden cases of liver failure caused by overdoses or viral infections, rather than the long-term damage caused by alcohol abuse.

Normally in organ transplants one organ comes out and a new one goes in. However, in this complex operation the transplant is put in beside the old liver.

After any transplant a patient needs to take a lifetime of drugs to suppress the immune system in order to avoid rejection. The drugs leave the body vulnerable to infection.

However, if the patient's liver does eventually recover then they can come off the immunosuppressant drugs and their body will get rid of the transplant.

The transplant is used to get the patient past the critical stage of the illness.

But the recovery happens only in some patients. In the study, the transplant was no longer needed in seven out of 11 patients.

So doctors analysed the detailed chemistry inside the liver cells of patients and looked for differences between those who recovered and those who did not.

Dr Varuna Aluvihare told the BBC: "There was a big difference right from the point of transplantation in the expression of some very small molecules between the group that would, three years down the line, regrow their liver versus the group that never did."

Those molecules regulated the way cells in the liver grow.

"Some of them were already starting to regrow. So what we may be able to do is come up with a better set of tests to allow us to identify those patients who are already regrowing and may not need transplantation.

"So we may be able to remove a group from the transplant list."

The liver does have a phenomenal ability to regenerate. In healthy people it will recover in the space of months even if a large amount is taken away.

People who need a transplant because of acute liver failure are seriously ill. Even if doctors could tell which patients' livers were already on the path to recovery, they would still need to keep those patients alive long enough for the liver to return to form.

Dr Aluvihare argued this would be possible as a small amount of restored liver function would be enough for patients to leave hospital.

He said there are cases at King's of patients recovering while they were on the waiting list.

"I would say five to 10 patients a year we seriously consider for emergency transplantation and then they start recovering.

"That tells us there probably is a pool there and there is probably quite a lot of mileage in identifying people would would recover."

Whether this would work is still uncertain. The team have received funding to look for those chemical differences in the blood of patients.

Source

New antiviral treatment could significantly reduce global burden of hepatitis C

Press release issued 6 May 2013

Scientists show potential impact of therapy in reducing transmission in UK, Canada and Australia

Around 150 million people globally are chronically infected with the hepatitis C virus (HCV) – a major cause of liver disease and the fastest growing cause of liver transplantation and liver cancer.¹ New prevention strategies are urgently required as people are continuing to be infected with HCV. Findings, published in Hepatology, reveal the impact of a new antiviral treatment that could potentially reduce HCV rates in some cities affected by chronic HCV prevalence by half over 15 years.

In Europe, the US and other developed countries the majority of HCV infections occur among people who inject drugs (PWID). Although current prevention strategies, which are based on needle and syringe programmes and opiate substitution therapy, can avert HCV infections and have reduced its prevalence in some cities from the very high levels that occurred in the 1980s, these interventions are unlikely alone to achieve further substantial reductions.

HCV treatment as prevention has been proposed as a possible solution. However, while current HCV antiviral treatment of pegylated-interferon and ribavirin can cure approximately 60 per cent of people treated, they are poorly tolerated, long in duration (five to 11 months), and have a low take-up among PWID.

Several new interferon free direct-active antivirals (DAAs) treatment are emerging with very promising results in trials suggesting that treatment is shorter (12 weeks) with fewer complications and side effects, and around a 90 per cent cure rate.

Using a mathematical model, researchers at the University of Bristol and London School of Hygiene and Tropical Medicine in collaboration with researchers and clinicians in the UK, Australia and Canada projected the potential impact of these new DAAs treatment among PWID in three cities with similar PWID prevalence (~1 per cent among adults) but very different levels of chronic HCV prevalence among PWID. The cities were Edinburgh, UK (25 per cent chronic HCV), Melbourne, Australia (50 per cent chronic HCV) and Vancouver, Canada (65 per cent chronic HCV).

In Melbourne and Vancouver, where current annual HCV treatment take-up rates and other interventions are around one per cent of PWID with chronic HCV, the findings show that switching to the new DAA treatment is likely to have very little impact on reducing HCV prevalence over the next 15 years. But in Edinburgh where chronic HCV prevalence is lower and current treatment rates already at three per cent of PWID with chronic HCV, then once the new DAA become available HCV prevalence is projected to reduce by 25 per cent over the next 15 years.

The researchers predict that chronic HCV prevalence among PWID could be halved in 15 years by doubling HCV treatment in Edinburgh to six per cent among PWID with chronic HCV and increasing HCV treatment by 13 to 15 fold in Melbourne and Vancouver respectively.

The findings strengthen the evidence that achievable levels of HCV antiviral treatment for PWID, particularly with the new emerging DAAs treatment, can substantially reduce prevalence across a range of global settings.

Clinicians, patient groups and policy-makers will be able to plan for large-scale population reductions in HCV and chronic liver disease. However, an important consideration will be how to make HCV treatment scale-up affordable — especially for lower and middle income settings but possibly also for developed countries that require very high treatment rates to achieve population goals.

The researchers estimate that if the cost of the new DAAs are equivalent to other new HCV antiviral drugs then treatment rates would require an annual treatment budget of US $3.2 million in Edinburgh and approximately $50 million in Melbourne and Vancouver.

Matthew Hickman, Professor in Public Health and Epidemiology at the University of Bristol's School of Social and Community Medicine and lead author of the study, said: “Scaling up HCV treatment is critical to the prevention of HCV in the population to support and enhance traditional harm reduction measures — opiate substitution treatment and needle exchange. The new direct-active antivirals treatment offer many sites the opportunity to achieve substantial reductions in HCV and future liver disease in the population, and the chance to demonstrate empirically that our model projections are right.”

Professor David Goldberg, lead of the team implementing Scotland’s hepatitis C Action Plan (2008-2011), said: “This study demonstrates that, in a country like Scotland which has a Government seriously committed to the improvement of hepatitis C services, increasing patient access to antiviral therapy could potentially have a major impact in the prevention of transmission of infection.”

Professor Greg Dore, Head of the Viral Hepatitis Clinical Research Program, Kirby Institute for infection and immunity in society at the University of New South Wales Australia, said: "The development of highly effective simplified new HCV treatments has the potential to greatly enhance existing HCV prevention strategies. Access to affordable HCV direct acting antiviral regimens for people who inject drugs should be a major focus to harness this potential prevention capacity."

Professor Margaret Hellard from the Burnet Institute in Australia added: “This research suggests that with the advent of new direct-active antivirals treatment there is a real opportunity to achieve substantial reductions in HCV and future liver disease in the population. Although the cost of these treatments appear to be expensive, economic models by Martin et al in the UK and Burnet researchers in Australia suggests that scaling up HCV treatment in people who inject drugs is highly cost effective. It is also important that the scale up of HCV treatment occurs in combination with traditional harm reduction measures — opiate substitution treatment and needle exchange which have previously also been shown to be highly cost effective.”

Further information:

1. World Health Organisation: http://www.who.int/mediacentre/factsheets/fs164/en/

2. About hepatitis C

Hepatitis C is a blood-borne virus that predominantly infects the cells of the liver. This can result in inflammation and significant damage to the liver. It can also affect the liver’s ability to perform its essential functions. Although it has always been regarded as a liver disease - ‘hepatitis’ means ‘inflammation of the liver’ - recent research has shown that the hepatitis C virus (HCV) affects a number of other areas of the body. These can include the digestive system, the lymphatic system, the immune system and the brain. Source: The Hepatitis Trust - http://www.hepctrust.org.uk/Hepatitis_C_Info/About+Hepatitis+C/About+Hepatitis+C

3. Paper

‘Hepatitis C Virus Treatment for Prevention Among People Who Inject Drugs: Modeling Treatment Scale-Up in the Age of Direct-Acting Antivirals’ by Natasha K Martin, Peter Vickerman, Jason Grebely, Margaret hellard, Sharon J Hutchinson, Viviane D Lima, Graham R Foster, John F Dillon, David J Goldberg, Gregory J Dore and Matthew Hickman is published in Hepatology.

The draft online paper (ahead of print) available to download from the below URL: http://onlinelibrary.wiley.com/doi/10.1002/hep.26431/pdf

4. Funders

UK: Scottish HCV Action plan; NIHR postdoctoral research training fellowship; MRC New Investigator Award G0801627; NIHR SPHR; MRC Addiction Cluster; UKCRC DeCipher

Australia: NHMRC Career Development Fellowship, Project Grant & Practitioner Research Fellowship.

US: National Institute on Drug Abuse Michael Smith Foundation for Health Research Scholar Award.

Source

Survey Reveals Discrimination Experienced by People with Hepatitis C

New survey from hepatitiscnews.com finds that almost two thirds of people with hep C have experienced stigma and discrimination.

(PRWEB) May 05, 2013

“Greater awareness and understanding about hepatitis C will not only reduce the stigma experienced by so many people but also reduce the risk of transmission”

The survey, conducted by the online community hepatitisCnews.com, also found low awareness of the virus, and four out of ten respondents admitted that they had never heard of hepatitis C until they were diagnosed.

While 87% told their family and friends about their diagnosis, over 70% said that people they told had a limited understanding of how the virus is transmitted.

One respondent said: “Education and open discussion is needed within the media, much as there has been with mental illness and depression.”

Almost eight out of 10 felt there is not enough help or support for people living with the hepatitis C virus.

Often called a silent disease, as it often does not result in any symptoms, hepatitis C is most commonly transmitted through contact with an infected person’s blood. The hepatitis C virus can cause serious damage to the liver and, if it is not treated, can result in scarring of the liver, cancer and even death. According to the World Health Organization, an estimated 150 million people are living with the virus worldwide.

Dr Matthew Foxton, consultant hepatologist at Chelsea and Westminster Hospital and King’s College Hospital said: “While it is encouraging that there is an increased openness about hepatitis C, there are still many misconceptions as to how it is transmitted. Greater awareness and understanding about hepatitis C will not only reduce the stigma experienced by so many people but also reduce the risk of transmission.”

The survey was carried out by hepatitiscnews.com, an online community and news resource for people living with hepatitis C. The site features tips on living well with the virus, details of resources and support groups worldwide, expert advice and regular news and features on hepatitis C and liver disease.

For further information, visit http://www.hepatitiscnews.com.

ENDS

Contact Tudor Reilly Health
Christine Lydon at Tudor Reilly
Tel: +44 (0) 20 7034 3200

Source

Feds: Health providers with hepatitis B are no threat to patients, covered by disability law

By Associated Press,

May 05, 2013 02:46 PM EDT

APUpdated: Sunday, May 5, 10:46 AM

Peter Nguyen was a promising medical student when his school learned that he had tested positive for the hepatitis B virus. He said he was blackballed by school administrators and forced to halt his studies.

“I knew the stigma” that came with a hepatitis diagnosis, Nguyen said. But he thought that a medical school, of all places, would understand. “I came there expecting help. Instead, I was greeted with discrimination.”

Nguyen’s prospects of becoming a physician are a lot brighter today. The U.S. Department of Justice recently declared in a legal settlement that hepatitis B patients are protected by federal disability law. And, separately, federal health officials have issued a revised set of guidelines that make it clear that health care workers and students who carry the hepatitis B virus — HBV for short — generally pose little or no risk to patients.

Taken together, advocates say, the new health guidelines and the Justice Department settlement remove barriers to practice, handing HBV-positive health professionals and students a pair of powerful tools to combat discrimination.

“It gives us so much more leverage. We no longer have to wring our hands,” said Joan Block, executive director and co-founder of the Hepatitis B Foundation, a nonprofit in Doylestown, Pa. She said Nguyen was among several students who contacted the foundation in 2011 to report they’d either been forced out of school, or had their admissions rescinded, because of an HBV diagnosis.

Hepatitis B is a contagious and potentially fatal liver disease spread through blood and other bodily fluids. The virus that causes it is most commonly transmitted through unprotected sex. Intravenous drug use is another major risk factor.

It can also be passed from an infected mother to her baby at birth, which is how Nguyen contracted it. Even though he’d been vaccinated as a child, the virus was already in his body.

As many as 1.4 million Americans have chronic hepatitis B. It’s not clear how many of them are health practitioners. But some 25 percent of medical and dental students — and many practicing doctors, surgeons and dentists — were born to mothers from countries in Asia and other regions of the world where the virus is endemic, according to the U.S. Centers for Disease Control and Prevention.

The CDC last issued guidelines for management of health workers and students with hepatitis B in 1991. A lot had changed in two decades. Universal infant vaccination had slashed the number of new cases by more than 80 percent. New drug therapies had proved effective at reducing the amount of virus in a carrier’s blood to very low or undetectable levels, greatly minimizing the risk of transmission.

And there had been only a single case of hepatitis B transmission from a health provider to a patient at least since 1991 — an orthopedic surgeon who was unaware of his hepatitis infection and had a very high amount of the virus in his body. He infected two to eight patients, according to the CDC.

While the old guidelines stated that a hepatitis B diagnosis by itself shouldn’t preclude doctors, dentists, nurses and other health professionals from seeing patients, “we were concerned that with a 20-year-old set of guidance, it was not really considered as relevant as it could be,” said Dr. John Ward, director of the CDC’s Division of Viral Hepatitis.

He said the new guidelines offer a “powerful message that in the great majority of clinical encounters between a health care provider and a patient, there is minimal or no risk of hepatitis B virus transmission.”

Released last summer, the updated CDC guidelines were cited by the Justice Department in March as the agency announced a settlement with a New Jersey medical school over claims it violated the Americans with Disabilities Act by excluding two applicants with hepatitis B. While the state-run University of Medicine and Dentistry of New Jersey denied liability, it agreed to admit qualified HBV-positive students and provide training to staff.

It was the first case in which the Justice Department pursued an ADA complaint on behalf of people with hepatitis B.

“This is a historic decision,” Block said. “We can now pull out the DOJ settlement and really guide these people: ‘What you’re facing is discrimination, and here are the tools to help.’ That’s powerful.”

Nguyen said he had no idea he was a carrier until he started medical school. That’s when he began to feel persistently tired and lost the ability to concentrate. Given a family history of liver cancer — of which hepatitis is the leading cause — his doctor had him tested. It came back positive.

Nguyen alerted the school and said he was told by an administrator that he would never be able to complete the required surgical rotation because “no operating room in the country will let you in.”

“That’s when I started almost panicking,” Nguyen said. “To this point I had been a good student. All the sudden my world was crashing, with all this debt and all the things I had worked for in jeopardy.”

He said the school began making life more difficult for him, to the point where he felt he had no choice but to leave.

With successful treatment, the virus is now undetectable in his blood and Nguyen said he is feeling better — and plotting a return to his medical studies. He said he’s leaning toward a career in hepatology, so he can help others like him.

The specialty is “definitely at the top of the list,” Nguyen said. “I understand the risk and the mental strain. I have a lot of compassion for those individuals.”

Source

HIV Treatment as Prevention -- Across an Entire Community

Shira Berman, Salim S. Abdool Karim, MBChB, PhD

DisclosuresMay 03, 2013

Editor's Note: In 2011, the HIV Prevention Trials Network (HPTN) 052 study of serodiscordant couples demonstrated that lowering viral load through the use of antiretroviral therapy (ART) in an infected partner could lower the risk for HIV acquisition by the uninfected partner.^[1] In early 2013, using data on more than 16,000 people in the Hlabisa HIV Treatment and Care Programme in rural KwaZulu-Natal, South Africa, investigators demonstrated a real-world setting application of this principle: Individual HIV acquisition risk in KwaZulu-Natal declined significantly with increasing ART coverage in the surrounding local community.^[2]

In an interview with Medscape, Salim S. Abdool Karim, MBChB, PhD, Professor at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) at the University of KwaZulu-Natal in Durban, South Africa, reviewed the findings from this study and considers what more we need to learn about treatment as prevention strategies moving forward.

Medscape: The report in Science focused on the real-world application of how increased ART coverage changes the demographics of HIV acquisition. Why was a study like this important?

Dr. Karim: When the HPTN 052 results were published, we had, for the first time, a clear idea of the very high efficacy that is possible with the use of ART to suppress viral load and lower the risk for HIV transmission to HIV-negative partners. But even before the HPTN 052 results, there was a study by Donnell and colleagues^[3] published in The Lancet that showed a very low incidence of HIV infection in serodiscordant couples in which the HIV-positive partner was receiving ART.^[4] Mathematical models have also provided some indication of the potential impact of "treatment as prevention." However, it was not known what the impact would be if this strategy were implemented in the real world.

The data from the study published in Science provide, for the first time, a compelling picture of the effects that ART scale-up within a community can have not only in terms of its treatment impact but also in terms of its prevention potential.

Why is it that they were able to show this in this particular community?

The circumstances are unique in that population. The first and very important issue to understand is that ART was simply not available for many years in that community. It was official government policy not to provide ART during South Africa's "denialist" era. Eventually, when the government did decide to provide antiretrovirals, it took them quite a while to establish health systems capabilities to initiate therapy. So, in this community, the researchers were dealing with a huge backlog of patients who needed treatment.

In essence, then, this Hlabisa community was experiencing a rapidly advancing HIV epidemic associated with a very high mortality rate because of the absence of treatment. With the increasing prevalence and the concomitant large number of infected individuals in this community, it was also experiencing a very high HIV incidence rate within the population.

In this kind of situation, introducing ART and providing it to scale puts a spotlight on the substantial impact it can have on such areas as the huge improvement in life expectancy. The HIV epidemic wiped out almost 10 years of life expectancy; with the introduction of ART, we're now regaining those lost years of survival. So what we're seeing in this community in Hlabisa in northern KwaZulu-Natal is a return in life expectancy to the pre-HIV era. That's a very substantial impact. If you add 10 years of life expectancy in that community of nearly 100,000 people, you've got a million new years of peoples' lives. These are potentially productive life-years gained to be able to contribute toward society. It's just amazing when you think about that scale of impact.

But it was not only that those who were treated who benefited -- those who were HIV-negative also benefited from HIV-infected people getting treatment. In communities in which the rollout of ART was highest, we saw a substantial impact on HIV transmission and declines in HIV incidence.

This demonstrates the real-world impact of treatment as prevention -- where HIV-positive people are getting the intervention, but HIV-negative people are benefiting from the intervention.

To me, it highlights how we've come full circle. On the basis of data from the Rakai Project Study Group,^[5] we thought that if someone doesn't have a detectable viral load, they would probably not transmit HIV. The Rakai study provided the initial discovery of the central role of viral load in HIV transmission when its data showed that transmission among couples was dependent on viral load. The next step in the sequence was the observation of the effects of ART in cohorts.^[3] In this secondary analysis of serodiscordant couples, the data provided observational evidence of the potential impact of ART on HIV transmission. Then came the HPTN 052 randomized controlled trial in discordant couples that showed convincingly that treatment of HIV-infected partners is highly efficacious.^[1] Now we've gone to the final step, where we have evidence of an impact in the real world.

On a note of caution, these data do not mean that the effect observed in Hlabisa will be necessarily present in every community. Owing to the unique circumstances in that community, where they were deprived of ART for such a long period and the epidemic was able to progress to such an advanced stage, when ART was introduced and scaled up, you could see a substantial impact. But it has shown us that with real-world implementation, treatment both to improve the HIV-infected patient's health and as prevention for the partners of HIV-infected patients is of benefit.

Medscape: On that point about the applicability of these findings to other communities, the investigators showed this tremendous impact in communities that had coverage rates of 30%-40%. That's a fairly low coverage rate, but obviously, in this community, that was a huge step forward.

Dr. Karim: Absolutely. When coverage goes from 0% to 30%, a big difference can be observed. But when there is a slow incremental growth of coverage, it is much less likely to lead to this kind of impact.

But there's another factor that is affecting outcomes: We're identifying key populations and treating them at the earliest stages. In other words, the 30%-40% that are being treating in that community are the important 30%-40% -- the ones with the low CD4 counts and the highest viral loads. So they're not just lowering each individual's viral load, but also lowering the overall mean community-level viral load. That's probably one of the mechanisms leading to the impact that was observed.

It is not clear whether such dramatic and large benefits would be readily observed in other communities where ART scale-up has been more incremental. Observing a large effect within this specific community was feasible due to its unique circumstances.

Medscape: Moving forward, having measured such a dramatic impact in this community, is it reasonable to think that we might see continued benefit if coverage is higher but increases at a slower, incremental rate?

Dr. Karim: These kinds of interventions can reach a point where substantial increases in coverage may be required for smaller additional benefits. So although the initial intervention had a very substantial effect at relatively low coverage rates, to improve on that and to get a marginal increase above the currently observed effect may require substantially higher coverage rates.

One way to assess the potential impact of increased coverage is to model the different coverage levels and the impact on the community base on the Hlabisa data -- to essentially ask such questions as, "If you achieved 80% coverage, what would that do?"

Three community-based randomized controlled trials being conducted by the National Institutes of Health, USAID, and the Centers for Disease Control and Prevention with the President's Emergency Plan for AIDS Relief (PEPFAR) funding^[6] are asking a more direct question: If we can scale up ART from the current coverage rate, which is around 30%, and achieve 60% or 80% coverage, what is the magnitude of the impact on survival and on HIV transmission to HIV-negative people?

These 3 studies will help us determine how incremental increases in treatment coverage through active scale-up strategies may or may not continue to show a prevention benefit.

References

Source

Silymarin for HCV infection - Review

Download the PDF here

Antiviral Therapy April 2013
Stephen J Polyak1,2,3,*, Nicholas H Oberlies4, Eve-Isabelle Pecheur5, Harel Dahari6,7,8, Peter Ferenci9, Jean-Michel Pawlotsky10,11

Silibinin Is a Potent Antiviral Agent in Patients With Chronic HCV not Responding to Pegylated Interferon/Ribavirin Therapy
http://www.natap.org/2008/HCV/090808_01.htm.........After 7 days of silibinin monotherapy the 5-mg/kg dose was marginally effective (n = 3; log drop, 0.55 ± 0.5), whereas the 10 mg/kg (n = 19 [including the patients in protocol 1], log drop 1.41 ± 0.59), 15 mg/kg (n = 5; log drop, 2.11 ± 1.15), and 20 mg/day doses (n = 9; log drop, 3.02 ± 1.01) led to a highly significant decrease in viral load (P < .001

Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C
http://www.natap.org/2011/HCV/021611_06.htm

Silymarin for HCV infection

Antiviral Therapy April 2013

Stephen J Polyak1,2,3,*, Nicholas H Oberlies4, Eve-Isabelle Pecheur5, Harel Dahari6,7,8, Peter Ferenci9, Jean-Michel Pawlotsky10,11

1Department of Laboratory Medicine, University of Washington, Seattle, WA, USA 2Department of Microbiology, University of Washington, Seattle, WA, USA 3Department of Global Health, University of Washington, Seattle, WA, USA 4Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA 5UMR INSERM 1052/CNRS 5286, Lyon, France 6Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA 7Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA 8Present address: Department of Medicine, Division of Hepatology, Loyola University Chicago, Maywood, IL, USA 9Internal Medicine 3, Medical University of Vienna, Vienna, Austria 10National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Henri Mondor Hospital, University of Paris-Est, Creteil, France 11INSERM U955, Creteil, France

Abstract

Silymarin, an extract of milk thistle seeds, and silymarin-derived compounds have been considered hepatoprotective since the plant was first described in ancient times. Hepatoprotection is defined as several non-mutually exclusive biological activities including antiviral, antioxidant, anti-inflammatory and immunomodulatory functions. Despite clear evidence for silymarin-induced hepatoprotection in cell culture and animal models, evidence for beneficial effects in humans has been equivocal. This review will summarize the current state of knowledge on silymarin in the context of HCV infection. The information was collated from a recent workshop on silibinin in Germany.

Introduction

Despite clear evidence for silymarin-induced hepatoprotection in cell culture and animal models [1], evidence for beneficial effects in humans has been equivocal. This may be attributable to a relative dearth of well-designed and controlled clinical trials and a generalized pervasiveness of inadequate attention to silymarin nomenclature and composition. The potential of silymarin-derived natural products for hepatitis C originated from cell-culture-based studies showing that silymarin blocked HCV infection [2,3].

However, recent reports exemplify a bipolarity of silymarin action. On one hand, there is the striking observation by Ferenci et al. [4] that Silibinin-C-2', 3-dihydrogen succinate, disodium salt (Legalon SIL), an intravenous, aqueous soluble formulation of silybin A and silybin B (synonymously called silibinin A and B; Figure 1) that collectively comprise the mixture known as silibinin, reduces viral load in HCV-infected patients. This has led to other studies showing that Legalon SIL prevents re-infection of the graft during liver transplantation through its pretransplant antiviral effect [5-7]. At the opposite end of the spectrum is the report from the randomized double-blind placebo-controlled SyNCH trial using the highest oral doses of silymarin to date (700 mg per day) that showed lack of any demonstrable effect of orally administered silymarin in reduction of HCV viral loads and alanine aminotransferase in infected patients [8]. In the last few years, new investigators have entered the field with the goals of understanding how silymarin, silibinin, Legalon SIL and other silymarin-derived flavonolignans inhibit HCV infection, as well as defining other potential clinical applications of Legalon SIL.

With these goals in mind, the first workshop on silibinin was held on 10 February 2012, in Cologne, Germany. Organized by Ralf-Torsten Pohl from Madaus Rottapharm in Cologne, Germany, the manufacturer of Legalon SIL, and an affiliate of the international Rottapharm-Madaus-Group headquartered in Monza, Italy, the workshop was chaired by Peter Ferenci and Jean-Michel Pawlotsky, and attracted an international group of researchers in this small but growing field.

History and composition of silymarin and silibinin

Ralf Torsten-Pohl (Madaus Rottapharm) gave a brief overview of the history of silymarin and silibinin, stressing the ancient origins of silymarin, where the herbal extract has been referenced in early medical texts. He discussed briefly the taxonomy of milk thistle (Silybum marianum [L] Gaertn [Asteraceae]). Dr Pohl's talk also highlighted how silymarin is extracted from the seeds (achenes), purified to form the mixture of the two isomeric silybin components, and then esterified with succinic acid to form the disuccinate disodium salt, Legalon SIL. Moreover he reviewed the large body of published studies on silymarin components that describe their pleiomorphic biological and pharmacodynamic behaviour in different preclinical and clinical settings covering diverse fields of medicinal use.

Nicholas Oberlies (University of North Carolina at Greensboro, Greensboro, NC, USA) presented an overview of the components of silymarin, with particular emphasis on the structures and nomenclature of the various mixtures of flavonolignans. Focusing on the most well-studied mixtures, silymarin and silibinin, he compared and contrasted these through a series of structural diagrams, chromatograms and lists.

The mixture silymarin constitutes major flavonolignans silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin and silydianin. These flavonolignans are likely derived from the parent flavonoid, taxifolin, which represents the left-hand side of all those compounds, condensing with coniferol alcohol. The various ways in which coniferyl alcohol combines with taxifolin imparts a fair degree of molecular diversity. By contrast, silibinin is a two-component mixture, made up of only silybin A and silybin B, and as noted by Pohl, Legalon SIL results from a synthetic addition of two succinic acid moieties to both silybin isomers. Dr Oberlies also showcased some of the chromatographic methods his group has developed to purify the individual components to >98% purity [9]. In the structural descriptions, Dr Oberlies stressed the importance of proper nomenclature of silymarin-derived compounds [10]. Indeed, the literature is rife with misnaming of compounds, and this lack of attention to detail likely adds to the confusion surrounding the biology of these compounds in the literature. He stressed that in the interest of furthering the medical potential of these compounds, scientists should strive to be clear, correct, and consistent in the nomenclature of silymarin-derived compounds and mixtures. Please refer to Table 1 for a guide to milk thistle nomenclature.

Human clinical experience

Over 400 subjects have received oral silymarin in multiple clinical trials [8,11-17]. In approximately half of these studies, some improvement in liver histology or reduction in liver enzymes was observed [11-13,16]. In the HALT-C trial, approximately one-quarter of the 1,145 patients were using silymarin at baseline [18]. In a follow-up study of 1,049 HALT-C subjects [19], 34% of subjects were consuming silymarin at baseline, which was associated with lower hepatic collagen content on study biopsies and less histological progression. However, no effect was seen for clinical outcomes in this study. In all studies cited above, no reduction in HCV viral loads was observed.

Peter Ferenci (University of Vienna, Vienna, Austria) reviewed his pioneering studies on Legalon SIL administration to HCV-infected patients [4]. The first study demonstrated that Legalon SIL induced dose-dependent, log-fold reductions in HCV RNA level in 20 subjects. However, the virological response to Legalon SIL was heterogeneous from one patient to another. Particularly intriguing were his data showing that 2-3 weeks of daily Legalon SIL intravenous infusion may 'rescue' pegylated interferon plus ribavirin non-responders, obtaining 40% sustained virological response rates [20]. Similar data were recently described by Biermer et al. [21] who also successfully rescued patients ailing on treatment with protease inhibitor containing triple regimes. Thus, Legalon SIL (like other inhibitors of HCV replication) may be interferon-sensitizing, enabling the treatment of interferon non-responders with triple therapy. Moreover, Legalon SIL appears to suppress viral load in patients infected with genotypes 1, 3 and 4, whereas the effect of Legalon SIL on genotype-2-infected patients is currently unknown. Dr Ferenci also reviewed the cases in which Legalon SIL prevented re-infection of the graft following liver transplantation [5-7]. These data suggest that Legalon SIL may prove clinically valuable in the transplant setting, where therapeutic options are still limited.

Mechanisms of silibinin action based on in vitro investigations

Despite the clear reductions in viral load in HCV-infected patients treated with Legalon SIL, the mechanisms by which HCV suppression by silymarin, silibinin, and Legalon SIL occurs have not been fully characterized. In vitro studies have suggested multiple mechanisms may be operative.

Abdelhakim Ahmed-Belkacem, who is in Jean-Michel Pawlotsky's lab (INSERM U955, Henri Mondor University Hospital, Creteil, France), reviewed data showing that silymarin-derived compounds, Legalon SIL, and structurally related flavonoids can inhibit HCV RNA-dependent RNA polymerase (RdRp) activity in in vitro assays with recombinant HCV non-structural 5B (NS5B) protein with inhibitory concentrations 50% (IC50) in the range of 75-100 μM [22]. A focused screen of 44 compounds belonging to different subgroups of flavonoids, including flavones, flavonols, isoflavones, flavanols and flavonoid glycosides revealed that the flavonoid, quercetagetin, had the strongest RdRp inhibitory activity with IC50 of 6.7 ±1.0 μM and 4.3 ±0.7 μM against genotype 1a H77 and genotype 1b J4 NS5B isolates, respectively. Interestingly, quercetagetin was fivefold less efficient against RdRp from genotype 2a strain JFH1, with an IC50 of 20.5 ±2.8 μM. These data suggest that Legalon SIL may differentially modulate RNA polymerase of different HCV genotypes. Kinetic analyses showed non-competitive inhibition with nucleoside triphosphates. However, although the comparisons were made on key structural components of highly related flavonolignans, the compared structures differ in other regions of the molecules. Thus, it is not clear how changes at distant molecular positions affect overall structure and function of flavonoids.

Stephen J Polyak (University of Washington, Seattle, WA, USA) described the characterization of the hepatoprotective activities of silymarin and the seven major flavonolignans in silymarin using cell culture-based assays that measure antiviral, antioxidant and anti-inflammatory actions in liver cells, and immunomodulatory actions on T-cells [2,23]. A comparison of the effects of Legalon SIL versus the parent natural product mixture silibinin was also presented, focusing on the relationships between NS5B polymerase inhibition and antiviral activities. It was emphasized that Legalon SIL inhibits NS5B-1b better than silibinin, and silibinin is a poor inhibitor of NS5B-2a [24]. Regarding inhibition of HCV replication in subgenomic replicon cell lines, Legalon SIL inhibits genotype 1b but not 2a, while silibinin does not inhibit replication in 1b or 2a replicon cell lines. Since JFH-1 infection is more effectively inhibited by silibinin than by Legalon SIL, the data suggest that if indeed polymerase activity is involved in suppression of HCV infection by Legalon SIL, there may be genotype-dependent differential susceptibilities of NS5B polymerases to Legalon SIL. This is in line with the NS5B polymerase inhibition study described by Dr Ahmed-Belkacem, although in their study, silibinin and Legalon SIL had anti-HCV activity in both the genotype 1b subgenomic replicon and the JFH1 model [14]. These differences could be explained by different experimental conditions and/or cell lines. Moreover, Legalon SIL is by design soluble in aqueous solution while silibinin, silymarin, and all silymarin-derived flavonolignans are insoluble in aqueous solution and require organic solutions such as DMSO or methanol for solubilization. In this respect, Legalon SIL is thought to partition well into the membrane lipid-water interface [25]. Thus, the question arises as to whether differences in solubility contribute to the clear and demonstrable differences in HCV infection, replication, and polymerase inhibition between Legalon SIL and silibinin.

Julie Blaising, who is in Eve-Isabelle Pecheur's lab (UMR INSERM 1052/CNRS 5286, Lyon, France), presented exciting new data that continue the story on the silibinin inhibition of HCV entry at the fusion stage previously described by her group [3,24]. Using a variety of sophisticated techniques including spinning disk confocal microscopy, Ms Blaising showed that during HCV entry, cell culture-derived HCV virions (HCVcc) colocalize in clathrin-containing vesicles, and as a consequence of the interaction with vesicles that have markers of early endosomes, the virus particles transiently adopt low velocity movement. As the endosomes mature into late endosomes, the interaction with clathrin ceases, and HCVcc resume high velocity movement. Ms Blaising demonstrated that in presence of silibinin, HCVcc dissociation from clathrin vesicles does not occur, the particles become trapped in early endosomes, retain low velocity movement, and never become associated with late endosomes. Thus, silibinin inhibits key steps in the clathrin-dependent entry of HCV into hepatocytes. The data suggest that silibinin may impact fundamental cellular processes that could have profound influence on pathogens beyond HCV. These studies typify how one can use natural products or natural product containing mixtures to probe cellular functions to elucidate key biological processes and their effects on host-pathogen interactions.

Application of HCV kinetics to understanding how Legalon SIL works

Harel Dahari (University of Illinois, Chicago, IL, USA; Los Alamos National Laboratory, Los Alamos, NM, USA) reviewed the principles of mathematical modelling of HCV dynamics during antiviral treatment and examined the kinetics of HCV RNA changes observed during directly-acting antiviral (DAA) drug administration that might be relevant to understanding the modes of action of Legalon SIL against HCV. The original model published in 1998 [26] posits that HCV RNA decline is biphasic, consisting of an early, rapid phase lasting approximately 2 days that reflects the direct antiviral effects of interferon-α (IFN) in blocking virus production/release. The second phase is protracted in time (days-weeks), has a slower viral RNA decline, and presumably reflects the loss/death of infected cells. Dr Dahari reviewed the current state of modelling HCV kinetics and the challenges to the original biphasic viral decline model that arise when fitting HCV kinetics during DAA treatment [27].

Jeremie Guedj (Los Alamos National Laboratory) [28] described a recent publication presenting a modelling analysis of HCV RNA kinetics from 25 patients infected with HCV genotype 1 or 4, who were treated for 7 days with monotherapy of 10, 15 or 20 mg/kg/day of Legalon SIL. Drs Guedj, Dahari and colleagues attempted to resolve the controversy in the field of whether Legalon SIL inhibits viral production, which is expected if the RdRp activity is inhibited [3,22,24,29], or whether Legalon SIL blocks other components of the HCV lifecycle such as virus entry or release [3,24]. Interestingly, the antiviral profile of Legalon SIL resembles that of IFN during the first phase, characterized as a rapid, dose-dependent decrease in viral RNA levels in serum.

The second-phase decline induced by Legalon SIL is not dose-dependent and resembles that of an RdRp inhibitor [30]. Moreover, half of Legalon-SIL-treated patients had biphasic RNA decay profiles, while the other half had monophasic decay patterns. Thus, Legalon SIL appears to induce two classes of viral RNA decay profiles, suggesting the possibility that blocking both virus production/release (probably by RdRp inhibition and later steps in virion release) and virus entry mechanisms contribute to the anti-HCV effects of Legalon SIL.

Pharmacokinetics and pharmacodynamics of silymarin preparations

A recent study by Schrieber et al. [31], indicated that patients with non-alcoholic fatty liver disease show biphasic and in some cases triphasic plasma concentrations of silymarin flavonolignans. This may be due to enterohepatic recycling of silymarin flavonolignans, which involves the circulation of parent and conjugated (by glucuronidation and/or sulfation) versions of silymarin flavonolignans. The metabolized (that is, conjugated) flavonolignans are transported out of hepatocytes by hepatobiliary transporters into the bile. Upon encountering the small intestine, the parent flavonolignans can be reformed by deconjugation enzymes in intestinal flora. The deconjugated flavonolignans are then returned to the liver via the portal blood supply, where they are again taken up by hepatocytes. Thus, enterohepatic recycling can elicit profound differences in plasma flavonolignan pharmacokinetics, thereby influencing the hepatoprotective actions of Legalon SIL. Moreover, it has also been shown that patients with cirrhosis display higher plasma levels of silymarin flavonolignans [32]. Future studies should formally characterize flavonolignan metabolism following Legalon SIL versus silymarin administration.

Key issues and areas for future research

First, a key issue involves differences between in vitro and in vivo dosing of silymarin-derived compounds. The in vitro antiviral activities of silymarin and silymarin-derived flavonolignans are observable at concentrations generally >20 μM. In healthy subjects, oral dosing of silymarin results in very low plasma concentrations of major flavonolignans in the range of 50-300 ng/ml due to their rapid metabolism to glucuronide and sulfate conjugates [8,32-37]. The key point is that silymarin as an oral formulation is not highly bioavailable, with a pharmacokinetic profile that achieves peak plasma concentrations 1-2 h post-dosing, with elimination in 4-6 h. However, in HCV patients with advanced liver disease, three- to fivefold higher plasma concentrations of flavonolignan conjugates are achieved compared to healthy subjects [38], while in patients with prostate cancer, plasma levels of silybin A and B up to 40 μg/ml (approximately 80 μM) are achieved with high oral doses of silipide, a formulation of silibinin with phospholipids [39]. Thus, it is possible that with the correct formulation for oral dosing, plasma levels of flavonolignans that approach in vitro concentrations can be achieved. However, results from the SyNCH trial, which administered the highest oral doses of silymarin to date, were presented at the AASLD meeting in 2011 and recently published [40]. The patients achieved 2-2,000 ng/ml of silymarin flavonolignans and there was no significant change in serum alanine aminotransferase activity or RNA levels in the silymarin treatment arms [8]. While it is logical to assume that intravenous dosing of Legalon SIL leads to higher serum levels of silybin A and B as compared with oral dosing, it is not clear how much higher. Thus, there is a need for additional clinical trials of Legalon SIL administration to patients.

The effects of Legalon SIL on different HCV genotypes should also be evaluated. These studies should have frequent sampling so that pharmacokinetic profiles can be accurately assessed. The investigators at the workshop also urged the company to publish existing Legalon SIL pharmacokinetic data. Although the SyNCH trial provided the highest oral silymarin dosing to date and was shown to be well-tolerated and safe, it will likely be impractical to increase pill burden to increase dose in future studies. Therefore, improved formulations of silymarin and silibinin for oral dosing that overcomes the bioavailability limitations are also urgently needed.

Second, hepatic levels of silymarin flavonolignans following oral and intravenous dosing in humans are unknown. Historically, liver biopsies have not been performed in patients receiving Legalon SIL and in the recently completed SyNCH trial [41]. However, it might be possible to justify studies in future trials, especially if Legalon SIL is used as a rescue therapy for previous non-responders to interferon-based therapies.

Third, despite the clear antiviral effects of silymarin and silymarin-derived compounds on HCV in vivo and in vitro, the mechanism(s) remain incompletely understood. While polymerase inhibition is demonstrable in vitro using purified NS5B proteins, the activity is modest. Cumulatively, the data support an important role for inhibition of virus entry in inhibition of HCV infection.

Silymarin, Legalon SIL, and silibinin also appear to inhibit release of progeny viruses [3,24], so it is possible that these compounds target other steps in the virus lifecycle that are dependent on host cell functions. Thus, additional studies should be performed to more clearly elucidate the mechanisms of antiviral action of silymarin. In doing so, these studies may reveal whether one or multiple mechanisms predominate.

Fourth, it is not known if Legalon SIL, which is the disuccinate versions of silybin A and silybin B, or silybin A and silybin B are the bioactive components. It is likely that the succinate moities on Legalon SIL could be cleaved by intracellular esterases, meaning that the parent silybin A and silybin B flavonolignans are the actual intracellular biological effectors of Legalon SIL. This issue is quite important because if it turns out that Legalon SIL is cleaved into silybin A and silybin B in cells, it likely means that the bioactivity of silibinin is more relevant than that of Legalon SIL, and as such, this information might help to settle the controversy over antiviral mechanisms of action of Legalon SIL versus silibinin. The situation becomes even more complex considering that silymarin flavonolignans are metabolized primarily through glucuronidation and also by sulfation [8,42], with multiple possible sites available for modification on each compound. Thus, metabolic studies on liver tissue are required to resolve these issues.

Fifth, Legalon SIL has shown promise in prevention of HCV infection during orthotopic liver transplantation [5-7]. Additional studies with recently FDA-approved protease inhibitors and other emerging (DAA) compounds are required to formally demonstrate the efficacy of Legalon SIL in conjunction with new antivirals.

Sixth, at present, Legalon SIL is administered daily for only 1-2 weeks before treatment is stopped. Despite having robust anti-HCV activity, this dosing regimen could conceivably create a scenario for development of resistance to Legalon SIL. Indeed, a recent study shows resistance to SIL can be selected both in vitro and in vivo [43]; thus, further studies on SIL resistance should be conducted.

With the recent approvals of new DAA compounds and second-generation drugs on the horizon, the renewed excitement and interest in compounds derived from the ancient botanical medicine known as silymarin may, at first glance, seem to be 'too little too late'. For patients who can afford and tolerate standard of care therapy, this statement may be true. However, many patients experience side effects that require cessation of therapy, and Legalon SIL may be useful as salvage therapy for prior interferon non-responders. Moreover, many developing countries may be unable to afford DAA combination therapy, let alone pegylated interferon plus ribavirin therapy. Thus, silymarin-derived compounds may provide clinical utility in these situations. Moreover, if hepatoprotective mechanisms of action and molecular targets for silymarin flavonolignans can be identified, this may lead to the structure-based development of potent new compounds that are orally bioavailable. The efficacy of Legalon SIL in orthotopic liver transplantation has been demonstrated, so continued research into this area may lead to identification of biomarkers of silymarin treatment and efficacy, novel targets for antiviral and anti-inflammatory drug design, and guide refinements in natural product-derived treatments for liver diseases in HCV- and HCV-HIV-coinfected patients. In this regard, we have recently shown that Legalon SIL inhibits in vitro HIV-1 infection of multiple cell types [44]. Furthermore, the antioxidant and anti-inflammatory effects of silymarin [45,46] may reduce pathogenesis of liver diseases of non-viral origin, as well as show efficacy in inflammatory diseases including cancer.

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Medivir: Webcast Presentation of Simeprevir Phase III Clinical Data

May 3, 2013
8:30 AM ET

Simeprevir Phase 3 Clinical Data Presented at The International Liver Congress of the European Association for the Study of the Liver (EASL)

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Shorter Treatments for Hepatitis C Patients on Their Way

By Brian Orelli
May 2, 2013

We're quickly transitioning from a battle to see which company will get an all-oral hepatitis C treatment approved to one in which the length of treatment will likely dictate which company wins the war.

Gilead Sciences (NASDAQ: GILD ) fired off a solid warning shot over AbbVie's (NYSE: ABBV ) bow on Thursday. The biotech released phase 2 data today, demonstrating that a combination of sofosbuvir and ledipasvir works extremely well, perhaps even better, when a third generic drug ribovarin is added.

Eight weeks after treatment, all 21 patients taking the three-drug regimen for just eight weeks had undetectable virus levels in their system. When just sofosbuvir and ledipasvir were given for eight weeks, 19 of 20 patients appear to be cured. The results look even better -- 19 out of 19 -- when the two-drug combination was given for 12 weeks, although the results measured the presence of virus just four weeks after treatment, so they could change if patients relapse.

The trial also tested hepatitis C patients who had failed a previous treatment. Both the two-drug and three-drug combinations taken for 12 weeks produced 95% interim cure rate, again measured just four weeks after treatment.

Current treatments, Vertex Pharmaceuticals' Incivek, which Johnson & Johnson sells overseas as Incivo, and Merck's Victrelis, require at least 24 weeks of treatment -- Vicrelis requires at least 28 -- and need to be taken with peginterferon, which must be injected. If patients don't respond initially, both drug regimens recommend continuing the treatments for a total of 48 weeks. That's nearly a year.

AbbVie has solid data testing a 12-week course of a four-drug combination -- ABT-450/r, ABT-267, ABT-333, and ribovarin -- where 99% of patients showed no detectable virus 12 weeks after treatment. But when that combination was tested for eight weeks, just 88% of patients had undetectable virus levels after 12 weeks.

The Gilead and AbbVie data isn't directly comparable, because they didn't measure the response at the same time after treatment; Gilead's number could go down a little if patients relapse. But given what we know now, it appears that Gilead's drug combination works better than AbbVie's when used for just eight weeks.

It's more than just a convenience factor for patients to take drugs for the shortest amount of time possible. Viruses mutate as they replicate, so knocking them down, and keeping them down, is really important for the likelihood of a cure. The longer a patient is taking a medication, the more likely he or she will stop, or miss a couple of doses, allowing the virus to mutate in a way that it becomes resistant to the medication.

Safety first
Treatment time will be important, but safety will still trump it. Gilead's data included around 20 patients per treatment group. AbbVie's was around 80. Neither is enough to say much about the long-term safety of the drugs.

We'll have to wait until the companies complete phase 3 trials of the drug combinations to declare a clear winner of this war. AbbVie has already begun phase 3 trials testing its combination for 12 weeks, and after seeing this new data, Gilead just announced it will test the two-drug and three-drug combination for eight weeks in a phase 3 trial.

AbbVie needs its hep C program to succeed
In the pharma business, great success comes with a caveat. AbbVie is a perfect example, as investors in the new company are left wondering what the future holds once the company's golden goose, Humira, is cooked. The Fool's brand new premium report on the company answers the high-profile questions that AbbVie investors are asking. Simply click here now to claim your copy today.

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IL28B testing in a rapidly changing world: Still relevant?

Journal of Hepatology
Volume 58, Issue 5 , Pages 847-849, May 2013

Lindsay Y. King, Raymond T. Chung

Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, United States

Received 22 January 2013; received in revised form 8 February 2013; accepted 11 February 2013. published online 15 February 2013.

See Article, pages 883–889

In 2009, a now seminal genome wide association study led to the discovery of a nucleotide polymorphism, rs12979860, upstream of the interleukin 28B (IL28B) gene. The CC IL28B genotype was associated with an over twofold improvement in response to treatment with pegylated interferon and ribavirin (PR) in patients with genotype 1 chronic hepatitis C virus (HCV) infection [1]. In an intention-to-treat analysis evaluating on-treatment virologic response and sustained virologic response (SVR) in a large cohort of genotype 1 HCV infected patients, the CC IL28B genotype was associated with an improved SVR in Caucasians of 69% as compared to 33% for the CT and 27% for the TT genotypes. These findings were similar across other ethnic groups. The CC IL28B genotype was the strongest pretreatment predictor of SVR. Rapid virologic response (RVR) was a strong predictor of SVR regardless of IL28B genotype, and in non-RVR patients, the CC IL28B genotype was associated with a higher rate of SVR [2]. Given the lack of alternative therapies, the multiple side effects of dual therapy, and the prolonged course of treatment with overall low rates of cure, IL28B testing held promise as a prime example of applying pharmacogenomics to the planning of antiviral therapy. However, the discovery came at a time when HCV treatment was undergoing significant evolution with the development of direct acting antiviral (DAA) agents.

In 2011, the first generation HCV protease inhibitors, telaprevir, and boceprevir, were approved in combination with PR for genotype 1 HCV infection. With a nearly twofold increase in SVR compared to PR alone, the utility of IL28B genotyping could be called into question. Would the improved outcome for all comers accompanying telaprevir and boceprevir effectively nullify the predictive value of IL28B genotype? Or, could IL28B genotyping be used to determine which patients should succeed equally well receiving standard dual therapy versus triple therapy, especially given the cost of the DAAs? Could IL28B genotyping identify those patients who could receive an abbreviated course of therapy or could this question be answered with on-treatment virologic milestones alone? While IL28B genotyping was not available during the prospective randomized trials for the initial DAAs, retrospective analysis of those patients who consented for genetic testing has been performed.

In a retrospective analysis of those patients who consented to genetic testing in two large boceprevir trials for treatment naïve (SPRINT-2 [3]) and treatment experienced (RESPOND-2 [4]) patients, the main role for IL28B genotyping was in the prediction of those patients who could receive a shorter duration of therapy in the response guided therapy groups. In the SPRINT-2 trial, in which patients were randomized to 4 weeks of PR lead-in followed by 44 weeks of boceprevir and PR, a response guided therapy group, in which all patients received a 4 week PR lead-in and then boceprevir and PR for an additional 24 weeks, with an additional 20 weeks of PR if the viral load was detectable between weeks 8 and 24, or 48 weeks of PR alone, SVR rates for the favorable IL28B CC patients were high regardless of treatment arm (78% for PR alone, 82% for boceprevir response guided therapy group, and 80% for boceprevir/PR 48 week group). IL28B genotype was independently associated with the outcome of boceprevir based therapy. When interferon responsiveness, defined as a greater than 1 log₁₀ decline in HCV viral load at week 4 was added to the multivariable logistic regression model, IL28B genotype was no longer a significant predictor of SVR, indicating that on-treatment viral kinetics are the functional equivalent of IL28B genotype. Low baseline viral load, absence or cirrhosis, HCV subtype 1b, and lower BMI did remain significant predictors of SVR. For previously treated patients, IL28B genotype was not a significant predictor of overall SVR; only a greater than 1 log₁₀ decline in week 4 HCV viral load and prior response category, previous relapse versus previous non-response, were significant. Again, more patients in the CC category were eligible for a shortened duration of therapy [5].

There had been more limited data for the role of IL28B genotyping in patients receiving telaprevir. IL28B in telaprevir treatment naïve patients was evaluated retrospectively in 42% of patients in the ADVANCE [6] study population. Only Caucasians were included in this analysis. Since genotyping was performed in de-identified specimens, no formal statistical analysis was performed and other clinical and demographic data such as viral load and fibrosis stage were not evaluated. Rates of SVR in the telaprevir group were higher than in the PR group among all patients (CC and non-CC). Again, the presence of the IL28B CC genotype identified patients who were eligible for a shortened duration of therapy (those that achieved extended RVR (eRVR) as defined by undetectable HCV RNA at weeks 4 and 12). However, as with boceprevir, on-treatment viral kinetics were the main predictor of SVR, since SVR rates were excellent in all patients who achieved eRVR regardless of IL28B genotype. Ninety one percent of those telaprevir-treated eRVR patients achieved SVR (97% CC, 88% non-CC) with 24 weeks of therapy, whereas only 45% of non-eRVR telaprevir patients had SVR with 48 weeks of therapy. Among non-EVR patients, IL28B testing had more utility, as SVR was higher in CC (67%) as compared to non-CC (38%) patients [7]. In a sub analysis of the PROVE2 trial [8] in which non-cirrhotic treatment naïve HCV genotype 1 patients were randomized to 12 weeks of telaprevir and PR, 12 weeks of telaprevir, PR and an additional 12 weeks of PR, 12 weeks of telaprevir and PegIFN alone, or 48 weeks of PR, 100% (12/12) of the genotype CC patients achieved an SVR with only 12 weeks of telaprevir and PR [9], suggesting that patients with IL28B CC genotype may be eligible for an even shorter course of therapy than described in the ADVANCE trial.

In their sub analysis of the REALIZE study, Pol et al. provide us with the missing piece of the puzzle on the role of IL28B testing in the current era of triple therapy. They evaluated the impact of IL28B genotype on SVR in telaprevir-treated HCV genotype 1 infected patients who had previously failed treatment with PR, including null responders. In the REALIZE study, 662 patients were randomized to 12 weeks of telaprevir with or without a 4 week PR lead in or placebo, each with PegIFN-α-2a and ribavirin for 48 weeks overall [10]. Eighty percent of the subjects consented to genetic testing and were included in this retrospective analysis. Since the original trial showed no significant difference between the two telaprevir arms, these groups were pooled for this study. SVR rates were higher in patients who received telaprevir vs. placebo for all IL28B genotypes, CC 79% vs. 29%, CT 60% vs. 16% and TT 61% vs. 13%. SVR rates were similar irrespective of IL28B genotype for prior relapsers and prior partial responders. For prior null responders, SVR rates were slightly higher for the IL28B CC genotype than for non-CCs. In multivariable modeling, IL28B genotype did not significantly affect SVR. Prior response category, did however significantly affect SVR [11]. Thus, from this informative analysis, we can conclude that there is a limited utility for IL28B testing in treatment experienced patients being considered for telaprevir therapy, especially those patients who have well defined prior treatment courses.

Taken together, the results of the retrospective analyses of the REALIZE, ADVANCE, SPRINT-2, RESPOND-2, and PROVE2 trials indicate a limited role for IL28B genotyping. For treatment naïve patients, the role of genotyping would appear to be limited to encouraging those patients contemplating triple therapy to undertake treatment because they would have a high likelihood of requiring an abbreviated course of therapy. Interestingly, cost effectiveness modeling studies have suggested that for those with the CC genotype, dual PR therapy may be more cost effective [12], [13]. This, however, depends on the cost of the DAAs. For treatment experienced patients whose prior treatment courses have been well defined in terms of quantitative HCV reduction, there is no clear role for IL28B genotyping, since their interferon responsiveness has already been defined. IL28B genotyping may be more helpful in counseling those patients whose prior treatment courses have not been well defined. Overall, though, on-treatment kinetics will still be the most valuable predictor of response in addition to other known clinical variables, such as absence of cirrhosis and pretreatment viral load.

While these analyses are useful in clarifying the role for IL28B in triple therapy, as we enter 2013, they are about to again be supplanted by all oral interferon-free DAA regimens. What role will there be for IL28B genotyping in the era of interferon-free regimens? This question has been studied prospectively. In the SOUND-C2 study, the efficacy and safety of interferon-free combination regimens of faldaprevir, an NS3/4A protease inhibitor and BI207127, a non-nucleoside NS5B polymerase inhibitor, with or without ribavirin in 362 genotype 1 HCV treatment-naïve patients were evaluated. Of interest, IL28B genotype, genotype 1 subtype, and gender were identified as significant baseline predictors of SVR. The difference in response to therapy according to IL28B subtype was confined primarily to 1a, since 1b patients did uniformly well [14]. The finding of a predictive value for IL28B genotype indirectly suggests the contribution of the host innate immune response even to an IFN-sparing all-DAA regimen. Recently Poordad et al., evaluated ABT-450, an NS3 protease inhibitor, boosted with low-dose ritonavir, plus ABT-333, a non-nucleoside NS5B polymerase inhibitor, and ribavirin in genotype 1 HCV infected patients. For previously untreated patients, up to 95% of patients experienced an SVR 12 weeks after the end of treatment, and all previously untreated patients with CT/TT IL28B genotypes experienced SVR [15]. It was also recently shown that the combination of ABT-450/ritonavir with ABT-333 and another DAA, ABT-267, led to an SVR 12 weeks after therapy completion in 93% (42/45) of previous null responders despite a high frequency of the non-favorable IL28B non-CC genotype [16]. In a study of the nucleotide polymerase inhibitor sofosbuvir and ribavirin, 21/25 previously untreated patients with genotype 1 HCV achieved SVR 24 weeks after therapy. 11/25 patients were genotype CC [17]. Thus, while there may be a role for IL28B genotyping in genotype 1a patients for some DAA combinations, emerging data on regimens with very high SVR rates will likely limit IL28B testing to difficult-to-treat-patients or to justification of even more simplified regimens in uncomplicated patients. As treatment options for HCV rapidly unfold, so too must our ability to provide predictive tools that enable us to tailor therapy to the individual patient.

Conflict of interest

The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

References

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