Sunday, September 30, 2012

GI & Hepatology News Launches Website

GI & Hepatology News Launches Website
September 27, 2012
Readers of AGA’s official newspaper, GI & Hepatology News, can now receive the latest news in the field as soon as it breaks. The new website — — publishes new stories online in advance of the print edition. The site is also optimized for smartphones, enabling readers to easily browse the same breaking news on the go.

The GI & Hepatology News website offers more than just the latest news. Other features include a video library of interviews, reports and expert commentary on new research; summaries of important articles and podcast interviews with authors from the AGA journals; comprehensive DDW® coverage; and easy-to-navigate “Specialty Focus” article collections, making specific content instantly accessible.

Visit the GI & Hepatology News website often to stay abreast of the latest news affecting the practice of gastroenterology and hepatology. Select stories will also be featured in future editions of AGA eDigest.

Poster - "Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C

Bailey Presents at 2012 State of the Science Congress on Nursing Research

September 30, 2012
Friday, September 28, 2012

Chip Bailey presented a poster entitled "Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C (CHC)" at the Council for the Advancement of Nursing Science 2012 State of the Science Congress on Nursing Research in Washington, D.C., September 13-15. He co-authored the abstract with Shelly Epps, Trina Walker, Justin Levens, Karin Weissenborn, Richard Keefe, and Hans L. Tillmann.

Download PDF

Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C (CHC)

Donald E. Bailey, Jr. 1
Shelly Epps 2
Trina Walker 3
Justin Levens 2
Karin Weissenborn 4
Richard Keefe 3
Hans L. Tillmann 3

1 Duke University School of Nursing, Durham, NC;
2 Duke Office of Clinical Research, Durham, NC;
3 Duke University School of Medicine, Durham, NC;
4 Department of Neurology, Medizinische Hochschule, Hannover, Germany

Fatigue is a frequent complaint in CHC patients. CHC patients also often experience problems with cognitive function: difficulties with attention, concentration, memory.

Study Aims
Describe cognitive processing difficulties in adults with CHC. Explore relationship of cognitive function in these patients with fatigue, sleep quality, and disease stage.

Sample (n=29)
Adult patients with CHC:
*18 with fatigue
*11with no fatigue
*Convenience sample
* Recruited at Duke University Medical Center, Gastroenterology Clinic
*Baseline data for sample demographic and clinical characteristics are shown in tables

Fatigue: Revised Piper Fatigue Scale (PFS).
*22-item scale (each item scaled 0-10); use summary score.
*Summary score scaled 0-10 (higher score indicates more fatigue).
*Administered only to patients reporting fatigue (n=18)

Sleep Quality:
*Sleep Timing & Sleep Quality Screening Questionnaire: 1 item
Disease Stage and Disease Grade :
*Clinical data abstracted from medical record

Measures of Cognitive Function
*Brief Assessment of Cognition (BAC) includes 6 tasks:
List Learning -- Verbal Memory
Digit Sequencing Task -- Working Memory
Token Motor Task – Motor Spped Verbal Fluency
Semantic/Letter Fluency Tower of London
Reasoning & Problem Solving / Executive Function Symbol Coding
Attention and Processing Speed

B. Continuous Phase Trials – Identical Pairs (CPT – IP)
Measures Sustained Attention and Vigilance

* Standardized z-scores calculated for BAC cognitive function test (based on comparisons with normative healthy control sample). Separate z-scores for each of the 6 BAC measures; BAC composite z-score

*Means, 95% CI for BAC task & composite scores calculated for:
CHC patients with fatigue (n=18) vs. without fatigue (n=11) Patients at each disease grade (0-3; measures inflammation) Patients at each disease stage (I-IV; measures fibrosis)

*Mann-Whitney rank sum test used to compare z-scores on BAC and CPT-IP score for CHC patients with vs. without fatigue.

*Pearson correlation used to evaluate relationships between BAC z-scores and PFS fatigue scores, sleep quality ratings.


HCV patients in this study showed significant impairment independent of fatigue for 3 of the 6 BAC tasks.

In the graphs below, z-score for healthy controls on each task = 0.0 (shown in graphs below as a red dotted line)

Mean z-scores for all HCV patients were significantly lower than healthy control scores (no overlap of 95% CI with control line) for the 3 tasks identified by red star

These findings suggest HCV-related impairment of cognitive function in the 3 domains of verbal memory, working memory, reasoning/problem solving.


*No significant differences between HCV patients with fatigue vs. without fatigue on BAC composite scores (cognitive function) or CPT–IP (attention/vigilance).

*BAC composite scores of HCV patients lower than those of healthy controls.

*Disease stage (fibrosis) had no effect on BAC composite scores.

*Higher disease grade (liver inflammation) may be weakly associated with poorer cognitive function in patients with HCV.

Pearson correlation analysis of relationships between scores on 6 individual BAC tasks and: Level of Fatigue, Quality of Sleep:
Piper Fatigue Scale summary score (level of fatigue): No correlation with scores on any BAC cognitive task.

Sleep Quality Item: Poor sleep quality (high scores) was significantly correlated with impairment on three BAC tasks: Digit Sequencing, Symbol Coding, and Tower of London.

Examples below shows Pearson correlation analyses for symbol coding:

Findings of this study support previous reports of cognitive processing difficulty in patients with CHC. Differences in cognitive processing between CHC patients with vs. without fatigue at baseline were not significant in this sample, but merit further study in a larger sample.

This study was supported by a research grant from the National Institute of Nursing Research (NIH/NINR: 1 R15 NR 008794-01A1, Bailey, PI) and by a small grant from the Duke University School of Nursing Office of Research Affairs (Bailey, PI).

Audio- Why are baby boomers being urged to be tested for hepatitis C?

Hello folks,

In August the CDC recommended that all Americans born from 1945 through 1965 get a one-time test for hepatitis C, these tests and the importance of taking appropriate steps to avoid liver damage are discussed in an interview with Theresa Rohr-Kirchgraber, M.D., hosted by Barbara Lewis at Sound Medicine.

Why are baby boomers being urged to be tested for hepatitis C?

Air date: September 30, 2012
Host: Barbara Lewis

Interview: Theresa Rohr-Kirchgraber, Director of the IU National Center of Excellence in Women's Health. On medical staff at Riley and Wishard hospitals.

Saturday, September 29, 2012

Efficacy of telaprevir and boceprevir in treatment-naïve and treatment-experienced genotype 1 chronic hepatitis C patients : an indirect comparison using Bayesian network meta-analysis.

Also On The Blog
New Studies Investigate Boceprevir in Null Responders, Versus Telaprevir

Treatment of chronic hepatitis C genotype 1 with triple therapy comprising telaprevir or boceprevir

Curr Med Res Opin. 2012 Sep 27. [Epub ahead of print]

Efficacy of telaprevir and boceprevir in treatment-naïve and treatment-experienced genotype 1 chronic hepatitis C patients : an indirect comparison using Bayesian network meta-analysis.

Cure S, Diels J, Gavart S, Bianic F, Jones E.

To indirectly compare the efficacy of telaprevir (TVR) and boceprevir (BOC) combined with peginterferon/ribavirin α-2a/2b (PR) in achieving sustained viral response (SVR) in treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C virus (HCV) infection.

A systematic literature review was conducted to identify randomized controlled trials reporting the efficacy of PR-based treatment in genotype 1 chronic HCV patients. A Bayesian network meta-analysis was performed on the endpoint of SVR, assuming fixed study effects. For treatment-experienced patients, only previous relapsers and partial responders were included, as no results in prior null-responders were available for boceprevir.

11 publications were included. In treatment-naïve patients, the odds ratios (OR) (posterior median [95% credible interval]) for telaprevir (12 weeks + Response Guided Treatment (RGT) 24/48 weeks PR) and boceprevir (24 weeks + RGT 28/48 weeks PR) versus PR were respectively 3.80 [2.78-5.22] and 2.99 [2.23-4.01]. The OR between telaprevir versus boceprevir was 1.42 [0.89-2.25], with a probability for telaprevir being more effective (P[OR>1]) of 0.93. In treatment-experienced patients, the OR of telaprevir (12 weeks + 48 weeks PR) and boceprevir (32 weeks + RGT 36/48 weeks PR) versus PR were respectively 13.11 [7.30-24.43] and 5.36 [2.90-10.30]. The OR between telaprevir versus boceprevir was 2.45 [1.02-5.80], with telaprevir having a probability of 0.98 for being more effective. The main limitation of this study is the low number of trials included in the analysis, especially for the treatment-experienced patient population, which only allowed to explore random-effect models. We tried to identify potential biases due to study heterogeneity.

In the absence of direct comparative head-to-head studies between telaprevir and boceprevir for the treatment of chronic HCV genotype 1 patients, an indirect comparison based on Bayesian network meta-analysis suggests better efficacy for telaprevir than boceprevir in both treatment-naïve and treatment-experienced patients.

Does IL28B Genotyping Still have a Role in the Era of Direct-acting Antiviral Therapy for Chronic Hepatitis C Infection?

From Journal of Viral Hepatitis

Does IL28B Genotyping Still have a Role in the Era of Direct-acting Antiviral Therapy for Chronic Hepatitis C Infection?

J. A. Holmes; P. V. Desmond; A. J. Thompson

Posted: 09/28/2012; J Viral Hepat. 2012;19(10):677-684. © 2012 Blackwell Publishing

IL28B genotype has been shown to be the strongest pretreatment predictor of sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C infection (CHC) treated with pegylated interferon (peg-IFN) and ribavirin (RBV). Patients carrying the good response genotype have a two- to threefold higher chance of SVR than those with a poor response genotype, manifest as dramatically improved early viral kinetics. However, the treatment paradigm for CHC is changing with the introduction of potent direct-acting antivirals (DAAs). IL28B genotype remains relevant to both telaprevir and boceprevir treatment regimens, although the strength of association with virological response is attenuated. The association between IL28B genotype and outcomes of treatment regimens that involve peg-IFN plus combination DAA therapy, or IFN-free regimens, is currently being evaluated. IL28B genotype may remain relevant to individualizing the choice of treatment regimen in the future.

Chronic infection with the hepatitis C virus (HCV) is a global epidemic affecting 130 to 170 million individuals, who are at risk of progressive liver fibrosis, decompensation and hepatocellular carcinoma. These complications have been shown to be reduced by viral eradication. Pegylated-interferon-alpha (peg-IFN) combined with ribavirin (RBV) has been the standard-of-care therapy for chronic hepatitis C (CHC) since 2003. However, the rate of response is suboptimal for genotype 1 HCV (HCV-1), with only 40–50% of patients being cured by dual therapy. Furthermore, the ability to identify which individuals would respond to treatment was limited. In the last 3 years, the field has made two major advances. In late 2009, genome-wide association studies (GWAS) identified genetic variants in the region of the IL28B gene that are strongly associated with the outcome of peg-IFN and RBV (PR) therapy.[1–3] In the IDEAL study pharmacogenetics cohort, carriage of the favourable IL28B genotype was associated with sustained virological response (SVR) rates of 70–80% in Caucasian patients treated with 48 weeks of PR, compared to 30–40% in patients carrying one of the unfavourable genotypes. Difference in population frequency of the favourable IL28B genotype explained much of the recognized ethnic disparity in PR response rates. IL28B genotyping immediately proved useful for pretreatment counselling for HCV-1 patients. However, PR is no longer standard-of-care for HCV-1 in many parts of the world. In 2011, the first direct-acting antivirals (DAAs) for HCV were approved for the treatment of HCV-1, increasing overall SVR rates almost twofold. 2011 also saw proof-of-concept that HCV could be cured using IFN-free regimens. DAA therapy clearly attenuates the association between IL28B genotype and HCV treatment response, but emerging data suggest that IL28B genotype will remain relevant to emerging treatment paradigms, including IFN-free therapy. In this article, we will discuss the clinical utility of IL28B genotyping for pretreatment counselling in the rapidly evolving era of DAA therapies for HCV.

IL28B Genotype and Response to Dual Therapy With peg-Interferon-A and Ribavirin
The first-generation DAAs are not yet universally available, and it is pertinent to briefly review the literature describing the association between IL28B polymorphism and response to peg-IFN and RBV therapy. IL28B genotype is the most important pretreatment predictor of response to peg-IFN and RBV therapy for HCV-1, where patients who carry the good response genotype (e.g. C/C at rs12979860) have reported SVR rates ≥70%, a two- to threefold increase over patients who carry one of the poor response genotypes (e.g. C/T, T/T at rs12979860).[4,5] The frequency of the good response IL28B genotype varies between individuals of different ethnic backgrounds, being >80% in certain Asian populations, 35–55% in Caucasians and <20% in patients of African ancestry. This variation explains much of the disparity in treatment response rates observed according to ethnicity. It is also relevant to discussion of the health economics of novel DAA therapies (see below). The mechanism explaining the association between IL28B genotype and IFN responsiveness is not known, but it manifests as profound differences in on-treatment viral kinetics. The good response IL28B genotype is associated with increased phase-1 and phase-2 viral kinetics,[5,6] resulting in increased rates of rapid virological response (RVR) and complete early virological response (cEVR) on-treatment (Table 1). In fact, most RVR patients carry the good response IL28B genotype.[5] It is important to note that all patients who achieve an RVR do well, and a high rate of SVR is observed even in the minority of patients who carry a poor response IL28B genotype. It is also important to note that the good response IL28B genotype is not sufficient to indicate short-duration PR therapy using response-guided protocols for HCV-1. Recent data have shown that short-duration therapy (24 weeks) is only sufficient for patients who carry the good response IL28B genotype and have a low baseline viral load (<400–800 000 IU/ml) and achieve an RVR.[7] Finally, the importance of IL28B genotype as a pretreatment predictor of IFN responsiveness should not discount other predictors of response, especially liver fibrosis stage. In the IDEAL study cohort, SVR rates in patients with advanced liver fibrosis were considerably lower (METAVIR F3-4, SVR in C/C = 41% vs C/T = 22% vs T/T = 11%).5]

IL28B Genotyping in the Setting of Telaprevir and Boceprevir Therapy
In the phase-3 registration studies of treatment-naïve HCV-1 patients, the addition of the NS3 protease inhibitors telaprevir (TVR) or boceprevir (BOC) to a PR backbone increased overall SVR rates from 40–45% to 68–79%.[8, 9] In the setting of such high SVR rates, the association between IL28B genotype and treatment response is attenuated (Table 2). However, it remains clinically relevant.

A retrospective analysis of the relationship between IL28B polymorphism (rs12979860) and treatment outcomes from the SPRINT-2 study of BOC-PR therapy for treatment-naïve patients has recently been published.[10] The analysis included 62% (653/1048) of the SPRINT-2 cohort who consented to genetic testing. Very high SVR rates were observed in all patients with the C/C genotype; in fact, SVR rates were equivalent in the BOC treatment arms and the PR control arm (Table 2). However, the C/C patients were much more likely to be eligible for short-duration therapy than the non-C/C patients (89% vs 52% non-C/C patients achieved undetectable HCV RNA levels at week 8). It was also notable that 97% of treatment-naïve C/C patients achieved ≥1 log10 IU/mL reduction in HCV RNA at the end of the 4 week lead-in phase of PR treatment.[10,11] A ≥1 log10 reduction in HCV RNA identifies good IFN responders, with SVR rates >80% and low risk of selection of resistance-associated variants. BOC therapy was associated with much more benefit in non-C/C patients, with rates of SVR of 55–71% compared to 27–28% with PR therapy alone in SPRINT-2 (Table 2). The lead-in phase of PR was more useful for stratifying IFN responsiveness in the non-C/C naïve population, in which 27% C/T and 46% T/T patients were identified to have poor IFN responsiveness, predicting for low SVR rate and higher risk of selecting resistant variants. Patients with poor IFN responsiveness might be considered for deferral of DAA exposure to minimize risk of selection of resistant variants, awaiting future quadruple therapy or combination DAA regimens. This should be an individualized decision, according to the urgency for antiviral therapy. IL28B genotyping can therefore identify patients in whom the lead-in has greatest clinical utility for stratifying IFN responsiveness.

Logistic regression modelling found that IL28B genotype was independently associated with the outcome of BOC-based therapy, OR = 2.6 (1.3–5.1) for C/C vs T/T and OR = 2.1 (1.2–3.7) for C/C vs C/T.[10] The other pretreatment predictors of SVR were low baseline HCV RNA level (< = 800, 000 IU/mL), the absence of cirrhosis, HCV-1 sub-type (1b vs 1a) and race (non-black vs black). IL28B genotype was the strongest predictor of good IFN response (≥1 log10 decline at week 4), OR = 26.5 (7.6–92.6) for C/C vs T/T and 16.4 (5.0–55.6) for C/C vs C/T.[10] When week 4 response was included in the SVR model, IL28B genotype was no longer independently associated with SVR. This is consistent with the observation from the PR literature that IL28B genotype informs IFN responsiveness, but once IFN responsiveness is defined in real-time by a trial of treatment, IL28B genotype is no longer clinically informative.[12]

IL28B genotyping has also been shown to be informative in the context of TVR therapy for treatment-naïve patients. Retrospective analysis of the association between IL28B polymorphism and treatment outcome was performed in a subset of the ADVANCE study population (n = 454/1088 [42%]).[13] The strength of association between IL28B genotype and treatment outcome was attenuated in the TVR treatment arms compared to the PR control arm. Rates of SVR were higher in the TVR treatment arms compared to the PR control arm among both C/C and non-C/C patients (it should be noted that the response rate among C/C patients in the PR control arm was lower than that observed in SPRINT-2, Table 2). SVR rates increased relatively more in non-C/C patients than C/C patients (Table 2). Similar to SPRINT-2, C/C patients were more likely to be eligible for short-duration therapy by achieving an extended rapid virological response (eRVR), defined as HCV RNA undetectable at weeks 4 and 12) with 12 weeks of TVR (C/C 78% vs C/T 57% vs T/T 45%).[13] SVR rates were very high in all patients who achieved an eRVR regardless of IL28B genotype (97% in CC patients and 88% in CT/TT patients). In patients who did not attain an eRVR, patients carrying the CC IL28B genotype had higher SVR rates (67% vs 38% for CT/TT patients). No data have yet been presented linking IL28B polymorphism to risk of resistance during TVR therapy, but given the key role for IFN responsiveness in controlling the emergence of resistance-associated variants (RAVs), this can be assumed.

In patients who have previously failed PR therapy, IL28B genotype is less informative for the outcome of TVR or BOC-based therapy. This was evaluated in retrospective analyses of the RESPOND-2 study of BOC therapy for prior relapsers and partial responders to PR therapy,[10] and the REALIZE study of TVR therapy for prior relapsers, partial responders and null responders (Table 2).[14] There was no significant association between IL28B genotype and treatment response noted in either study. This reflects again that IL28B genotype is no longer informative for SVR once IFN responsiveness is known, here defined by the prior course of PR therapy. IL28B genotyping may have a clinical role in real world patients where the prior treatment history is not well defined.

Can IL28B Genotype Identify HCV-1 Patients for Whom Dual Therapy With peg-IFN and RBV Should Remain First-line Therapy in the DAA Era?
The introduction of TVR and BOC represents a significant advance for the treatment of HCV-1. However, both drugs are very expensive. Modelling studies suggest that it may be possible to develop treatment algorithms in which PR is more cost-effective first-line therapy for a subgroup of patients. Patients who carry the C/C IL28B genotype achieve high rates of SVR, and a number of groups have suggested that in this population, PR is more cost-effective than universal triple therapy.[15–17] These patients also avoid the added morbidity of triple therapy, although this must be weighed against the need for an extra 24 weeks of total treatment time (most C/C patients will require 48 weeks of PR, but would be eligible for 24 weeks of triple therapy). There are a number of caveats to these modelling studies. They may be strongly influenced by underlying assumptions, as well as the set price for drug, and therefore may not be universally applicable to all patients and regions. One particular issue pertains to efficacy assumptions for patients with advanced liver fibrosis. In the IDEAL study, the rate of SVR was only 41% in C/C patients with F3-4 fibrosis,[5] and although there are little data concerning outcomes of triple therapy in this sub-population, it seems reasonable that triple therapy will be more effective, and cost-effective, for these patients.

IL28B Genotyping in Other Clinical Scenarios
Telaprevir and boceprevir are approved for the treatment of HCV-1 mono-infection only at present. The standard-of-care treatment for chronic infection with other HCV genotypes remains PR dual therapy. IL28B genotype is associated with the outcome of PR treatment for HCV-4, with a similar effect size to that seen in HCV-1.[18–20] IL28B genotype is less relevant to the outcome of PR treatment for HCV-2 and HCV-3.[21–26] HCV-2/3 are more IFN sensitive, and the data are conflicting. IL28B genotype may be most relevant for HCV-2/3 patients who are slow responders to PR (e.g. non-RVR patients).[21] IL28B genotype is associated with the outcome of PR therapy for HCV-1 in the setting of HIV co-infection, where HIV does not seem to attenuate the association.[27] IL28B genotype has been associated with the outcome of PR treatment for HCV-1 after liver transplantation, where both donor and recipient IL28B genotype influence outcome.[28–31] IL28B genotype is strongly associated with the outcome of acute HCV infection, where patients with poor response IL28B genotypes, particularly if anicteric, are unlikely to spontaneously clear infection and should be considered for early antiviral therapy.[32,33]

IL28B Genotyping and Next-generation Therapies Involving peg-Interferon
Emerging data suggest that IL28B genotype will remain relevant to the outcomes of DAA therapy when used in combination with a PR backbone. This has been the case for the emerging protease inhibitors (PIs), NS5A inhibitors (NS5I) cyclophilin inhibitors and non-nucleos(t)ide inhibitors (NNI) of the NS5B polymerase.[34–39] In general, rates of on-treatment response as well as SVR have been higher in patients with the good response IL28B genotype, and the good response genotype has predicted for short-duration therapy using response-guided regimens. Very recent interim data from the ATOMIC study suggest that the nucleotide inhibitor (NI) sofosbuvir (GS-7977) may overcome the IL28B effect. 90% of patients treated for 12 weeks with sofosbuvir plus PR achieved an SVR12 (n = 52).[40] Quadruple therapy regimens are also being evaluated. These involve the combination of two DAAs with PR. A small cohort of prior null responders was treated using the combination of daclatasvir (NS5I) plus asunaprevir (PI) plus PR.[41] 9/10 patients carried a poor response IL28B genotype. 10/10 patients achieved an SVR12; and 9/10 had a SVR24. Larger phase-3 studies are required in larger cohorts to confirm these encouraging results. Therefore, it seems likely that it will be possible to overcome the effect of IL28B polymorphism with the combination of PR plus either a high potency, high genetic barrier to resistance drug (sofosbuvir), or the combination of 2 DAAs. Even so, it may be that IL28B genotype might be used to individualize treatment strategies, such that patients who carry the good response IL28B genotype might be eligible for shorter, simpler or cheaper regimens, and conversely poor responder patients might require longer therapy with multiple DAAs. Such individualized treatment algorithms are yet to be explored in detail.

Finally, a brief note about IFN-lambda. IFN-lambda (IL29) is a type-3 IFN and member of the same family of IFNs as IL28B. The type-3 IFN receptor has a limited distribution of expression, and peg-IFN-lambda is being developed as a less toxic alternative to peg-IFNα. In a small phase-II dose escalation study, investigating the efficacy and safety of peg-IFN-lambda plus RBV, compared to peg-IFNα plus RBV, virological responses were similar, and similar associations between IL28B genotype and treatment response were observed comparing the two IFN preparations.[42]

IL28B Genotyping and IFN-free Therapy
Interferon-free therapy for HCV-1 is likely to be approved in the next 3–5 years. Recent data suggest that the good response IL28B genotype may represent an 'easy-to-cure' characteristic for certain IFN-free regimens also. The INFORM-1 study was the first study to demonstrate that IFN-free therapy could have a potent antiviral effect. Patients were treated with a combination of mericitabine (NI) and the danoprevir (PI) for 14 days, before follow-on PR therapy to 48 weeks. Analysis of the on-treatment viral kinetics in 15 patients during the 2 weeks of oral therapy revealed a significant difference in phase-II viral kinetics according to IL28B genotype,[43] suggesting that IL28B genotype influences the rate of clearance of infected hepatocytes during IFN-free therapy. This might be consistent with the association between IL28B genotype and spontaneous clearance of HCV.[44] SOUND-C2 is the largest study of IFN-free therapy to date (n = 362).[45] SOUND-C2 evaluated the combination of BI 201335 (PI), BI 207127 (NNI) ± RBV (Fig. 1a). Interim results demonstrated a clear difference in SVR12 according to IL28B genotype in HCV-1a patients (Fig. 1b,c). The low SVR rates observed in HCV-1a non-C/C patients resulted from virological breakthrough in most patients, suggesting that IL28B genotype influenced the emergence of RAVs. Future studies of this regimen plan to enrol only HCV-1a patients who carry the good response IL28B genotype. This IL28B effect may be overcome as more potent agents and combination regimens emerge. Analysis of the ELECTRON study observed SVR4 in 22/25 (88%) treatment-naïve HCV-1 patients treated with sofosbuvir plus RBV for 12 weeks.[46] 22 of the patients were infected with HCV-1a, and only 11/25 carried the good response IL28B genotype. Response rates with 'optimized' DAA combinations may be higher still. A recent study of the combination of sofosbuvir plus the daclatasvir reported SVR4 of 100% in 44 HCV-1 naive patients, with or without ribavirin.[47] Such optimized regimens are likely to be very expensive, however, and may not be necessary for all patients. IL28B genotype may continue to be useful to identify those patients for whom such regimens are most appropriate as first-line therapy.

Figure 1.
Interim results from the SOUND-C2 study 42. (a) Patients were randomized to one of five arms, involving variable durations of treatment with the protease inhibitor BI 201335 once daily, the NS5B non-nucleoside inhibitor BI 207127 BID or TID, plus or minus ribavirin. Interim analysis of SVR12 results was recently presented (with SVR4 results for the 40-week treatment arm). Overall results according to treatment arm: A – SVR12 = 59%, B – SVR12 = 61%, C – SVR4 = 56%, D – SVR12 = 68% and E – SVR 12 = 39% (treatment arm E was halted early because of concerns about RBV-free treatment); (b) SVR12 results in treatment arm D, according to HCV-1 subtype and IL28B genotype (rs12979860); (c) SVR results in treatment arms A–D, comparing non-C/C patients infected with HCV-1a (grey columns), with a composite group including C/C patients infected with HCV-1a and all HCV-1b patients (white columns).

IL28B genotype is the strongest pretreatment predictor of response to dual PR therapy for patients chronically infected with HCV-1. The approval of the first generation of NS3 protease inhibitors represented a significant advance for the field. The association between IL28B polymorphism and treatment outcome is attenuated in the setting of triple therapy, but IL28B genotyping continues to be useful for pretreatment counselling, with the good response IL28B genotype identifying the likelihood of an individual being eligible for short-duration therapy. IL28B genotype may also be relevant to strategies for maximizing cost-effectiveness. IL28B genotype is also associated with the response to IFN-free regimens, and C/C patients remain easier to cure, particularly in the setting of HCV-1a. Future regimens involving potent NI plus PR, quadruple therapy or combinations of best-in-class DAAs are likely to achieve very high SVR rates, and IL28B polymorphism will no longer predict treatment outcome. However, IL28B genotyping may remain useful if it can be used to individualize treatment strategies, identifying patients who can be successfully treated with shorter, simpler or cheaper regimens.

Risk for liver-related death higher with chronic HBV than HCV

Risk for liver-related death higher with chronic HBV than HCV

Falade-Nwulia O. Clin Infect Dis. 2012;55:507-513.

  • September 27, 2012
Patients with chronic HBV were at a greater risk for liver-related death than patients with chronic HCV, particularly among those with HIV coinfection, in a recent study.

Researchers evaluated 337 male patients with chronic HBV and 343 with chronic HCV, along with a subgroup of 472 patients coinfected with HIV-1, during 6,728 person-years. All participants had been members of the Multicenter AIDS Cohort Study (MACS). Incidence and causes of death were recorded, and mortality rates due to liver-related issues and all causes were calculated and compared between the groups.

Death from any cause occurred in 293 cases (43.5 per 1,000 person-years), including 51 because of liver-related issues (7.6 per 1,000 person-years). Most liver-related deaths (90.2%) occurred among patients coinfected with HIV, with mortality rates of 10.7 per 1,000 person-years among coinfected patients compared with 2.1 among those without HIV (P<.001).

All-cause mortality rates were similar between the two groups (41.2 per 1,000 person-years in the HBV group and 46.4 per 1,000 person-years in the HCV group, P=.5 for difference), but liver-related death was more common in the HBV group (9.6 per 1,000 person-years compared with 5.0, P=.027).

In the HIV coinfected subgroup, multivariate analysis indicated that liver-related death was more common among patients with HBV than those with HCV after adjusting for both potential confounders (IRR=2.2; 95% CI, 1.1-4.5) and competing risks (subhazard rate ratio=2.4; 95% CI, 1.14-5.04). Coinfected patients with CD4 cell counts less than 200 cells/mm3 (IRR=16.2; 95% CI, 6.1-42.8) and counts between 200 and 350 cells/mm3 (IRR=7.0; 95% CI, 2.4-20.1) were at significantly greater risk for liver-related death than those with counts more than 350. Older age also was associated with liver-related death in this subgroup (IRR=1.6; 95% CI, 1.1-2.3 per 10 years).

“This study clearly demonstrates that [chronic HBV] carries a greater risk of death from liver disease than does [chronic HCV],” the researchers wrote. “More emphasis needs to be placed on more-effective global HBV screening and increased efforts for vaccination and treatment of HBV infection worldwide.”

Friday, September 28, 2012

The true costs of cancer in Europe revealed

European Society for Medical Oncology

The true costs of cancer in Europe revealed

The first ever estimate of the economic burden of cancer in Europe shows that it exceeds 124 billion euros

Vienna, Austria, 28 September 2012 – New studies that reveal for the first time the real economic and human costs of caring for cancer patients in Europe will be presented during the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.

"Here we have two studies of enormous importance," noted Prof Peter Boyle, President of the International Prevention Research Institute in Lyon, France, Member of the ESMO Faculty group on Cancer Prevention, who was not involved in the studies. "It is essential to have knowledge of the total costs of cancer and Dr Luengo-Fernandez and colleagues have performed a great service in preparing such a detailed report".

"The remarkable study of Dr Gilloteau and colleagues provides unique information on the impact of cancer on care-givers. This again is key information and is almost unique. These studies provide a background on which logical funding decisions can be made," Prof Boyle concluded.

Total cost 124 billion Euros each year... highest costs in Germany
Cancers cost the European Union 124 billion Euros each year, according to the first ever estimate of the economic burden of malignancies in the region. Lung cancer is responsible for the highest overall burden, the new study shows.

Dr Ramon Luengo-Fernandez from the University of Oxford, UK, and colleagues included direct health costs such as primary care, hospital care and medications, as well as the cost of informal care and losses in productivity in their calculations. Their data came from a variety of sources including the WHO, the OECD and national ministries of health.

"Cancer poses a considerable economic burden not only to healthcare systems but to other areas of the economy, including productivity losses through early mortality and time-off-work, and relatives who have to forego work/leisure to care for cancer patients," Dr Luengo-Fernandes said.

"Healthcare systems will have a good idea, I expect, of the healthcare costs of providing cancer care to their patients. However, the productivity losses and informal care costs associated with cancer will be less well understood and their magnitude less appreciated."

The researchers break their figures down by country, and by cancer. The lowest per-capita healthcare cost for cancer was 32 Euros per year in Lithuania, while the highest was in Germany where an average of 165 Euros was spent on healthcare for every person in the population. "The countries with the highest per-capita costs in terms of cancer healthcare tend to be Northern and Central European countries. Those with the lowest per-capita costs tend to be member states who joined the EU in 2004 and have lower national income levels," Dr Luengo-Fernandez said.

Breast cancer had the highest healthcare costs, at 6 billion Euros each year, accounting for 13% of the total cancer healthcare costs in the EU. However, the highest total economic burden was attributable to lung cancer, a total of 19 billion Euros, of which 10 billion due to premature mortality.

"One of the purposes of studies such as this one is to enable comparisons to be made between the burden of different diseases, aiding decision makers to prioritize scarce research funds," Dr Luengo-Fernandez said.

"In order to be in a better position to inform policy decisions there is a great need for improved information on epidemiology, healthcare resource use and unit costs across the EU."

Commenting on the report, Prof Peter Boyle said: "It is essential that the economic impact of cancer on a community is known, understood and placed in its perspective. The greatest single economic cost was 6 billion Euros for breast cancer. This should be placed in the perspective that the economic cost of pneumonia in the EU is 10 billion Euros each year. The cost of cancer is not just the cost of drugs and hospital stays and this has been taken into account by Dr Luengo-Fernandez."

Caregivers are hidden patients themselves
Looking after a person with cancer is associated with a variety of statistically significant impairments compared with non-caregivers.

Dr Isabelle Gilloteau from Bristol-Myers Squibb and colleagues obtained data from the 2010 and 2011 EU National Health and Wellness Surveys, self-administered online surveys of 105,581 adults in France, Germany, Italy, Spain and the United Kingdom.

They found that relative to non-caregivers, people who cared for cancer patients reported that they experienced worse physical (47.6 vs. 48.9) and mental health (43.7 vs. 46.9), were more likely to be absent from work (8.1 vs. 4.8), were more impaired in their activities (28.7 vs. 21.8), and had twice as many hospitalizations during the past 6 months (0.22 vs 0.11). The reports indicate that they were 50% more likely to be diagnosed with depression and had twice the odds of anxiety and insomnia, as well as higher odds of suffering from migraines (OR = 1.663), headaches (OR = 1.369), or gastrointestinal problems (OR = 1.626), compared with non-caregivers.

"The levels of burden seen in the current study for mental quality of life and absenteeism impairments are similar to those observed elsewhere among adults with hepatitis C virus in the EU, or adults with osteoarthritis pain in the US," Dr Gilloteau said. "They are also similar to mental quality of life impairments seen among adults with rheumatoid arthritis in the EU."

"The vital role played by unpaid caregivers in supporting cancer patients is well recognized, but the health burden and economic impact on these caregivers is poorly understood," Dr Gilloteau said.
"Caregivers of cancer patients reported statistically significantly poorer overall health status, physical and emotional health status, more healthcare resources use, and their work productivity and daily activity were also statistically significantly impaired. They were also at greater odds of being diagnosed with comorbidities. Importantly, this study specifically quantifies the extent of the burden attributable to each of the components mentioned above, and specifically examines comorbidities likely to have been affected by the caregiving experience. Estimating the financial impact of caregiving in cancer is essential as a future research step, especially given that the current findings indicate that this cost will be high."

The researchers call for greater recognition of the unmet caregiver needs. "This study underscores the importance of recognizing caregiver burden, not just because of the direct implications for the well-being and quality of care of the patient with cancer, but also due to the extra burden it brings to society overall," Dr Gilloteau said. "Because caregiving is a vital part of cancer patient management and providing this care incurs substantial burden for the caregiver, it is crucial to consider what can be done to minimize this burden, especially in the current context of containment, combined with an aging population and increasing incidence of cancer."

First Hand: The Surgeon and Hepatitis C

Journal of Hand Surgery
Volume 37, Issue 8 , Pages 1693-1694, August 2012
Veterans Administration Medical Center, Richmond, VA
Received 1 February 2012; accepted 23 April 2012. published online 25 June 2012.

First Hand: The Surgeon and Hepatitis C

Severe malaise, nausea, headache, and a look in the mirror showing that jaundice had colored my skin confirmed beyond denial that the tiny glove and skin puncture sustained about 2 weeks prior had, truly, been a notable happening. I was finished performing surgery on a hepatitis C–positive patient with a drug addiction when the inadvertent puncture occurred. I had been distracted while applying the dressing.

Fortunately, hospital rules require that all puncture wounds in the operating room must be reported. That report to the employee health department was the most positive action I took that day.

Consider the probability that a surgeon will acquire acute or chronic hepatitis C. As the old saw goes, with validity, if you are one of those surgeons who acquire the disease, for you it is 100%. So long as you do not contract hepatitis C, you can continue to deny that you are at risk and reassure yourself that you are careful and “it will not happen to me.” Centers for Disease Control and Prevention data from surveillance hospitals estimate that more than 380,000 exposures to blood occur annually to health care workers.1

A mistaken assumption that the incidence of hepatitis C in the general population is low might give surgeons a sense of invulnerability. Avoiding contact with patients who are drug addicted or hepatitis C–positive can help, but it is not ethical behavior.

Sadly, the distribution of hepatitis C is wide. (The most recent assessment by the Centers for Disease Control and Prevention is that 3.2 million people in the United States have the virus.2) The disease is commonly undiagnosed because it is chronic and indolent in most patients; therefore, the percentage who present with acute disease cannot be derived.

How do persons with chronic disease learn that they are afflicted? If one is fortunate, the clues will present during routine blood tests, at insurance physicals, and hospital admissions. It is late for others who learn the truth when they develop cirrhosis or primary liver cancer.

Despite the low chance of exposure to a patient with active hepatitis C and despite my vigilance and care, I acquired the hepatitis C genotype 1 virus, the most common of 6 genotypes in the United States, as well as the most difficult type to treat.

You, if so afflicted, are a patient, a supplicant looking to your favored hepatologist for advice and help. The obvious question is “should one treat or accept a symptom-free but active virus until cirrhosis or liver cancer intervenes?”

If you choose no treatment, you become a pariah to those to whom you can transmit the virus, such as patients, family, friends, and medical personnel who might be treating you. Inadvertent sharing of a toothbrush, for example, can transmit the virus. In addition, you cannot consume any alcoholic beverages or drugs that are metabolized in the liver.

End-stage cirrhosis and possible primary liver cancer often result from chronic hepatitis C, the leading cause of cirrhosis and primary liver cancer in the United States. The prospect of arriving at this state is often enough to cause one to consult a favorite hepatologist and choose drug treatment to try to eradicate the virus. That was the choice I made.

Treatment protocols do not vary much. They use 2 drugs. Neither of them attacks the virus directly. The hope is that Interferon alpha will stimulate the immune system to clear the virus, which has been crippled by ribavirin. Anyone who has prescribed these drugs or has been treated with them will describe the myriad unpleasant and often dangerous side effects. The standard treatment protocol continues for 48 weeks. The medications leave the patient in a weak, uncomfortable state for a year. That, in itself, is depressing. However, the drugs often cause dangerous, chemically induced depression. Careful monitoring of the psyche is essential if one is to avoid loss of life to suicide.
The weakened state during treatment is due to substantial depression of red blood cells, white blood cells, platelets, and other systemic effects. Growth hormones such as epoetin alfa (Procrit; Janssen Biotech, Horsham, PA) and filgrastim (Neupogen Amgen, Neuburg Park, CA) and, perhaps, transfusions are likely to be required to be able to continue treatment and have the patient survive.
The treatment protocol has been modified recently.3 A third drug is being added to the regimen. One of the new drugs has increased the chances of successfully eliminating the virus from 4 in 10 to 6 in 10, and it often makes it possible to reduce the treatment time from 48 weeks to 24 weeks.
One should not be reassured by the new treatment protocol. Twenty-four weeks on the drug regimen is still long, arduous, and dangerous.

Remember, I said that having followed the mandatory reporting requirement was a useful thing to have done. Of course, getting statistical data recorded is the obvious rationale, but because my incident was recorded, it was relatively easy to confirm that my disease was an acquired on-the-job injury. This meant that I received medical care and medications from the insurance program. At the end of the treatment, I added up the costs of the Interferon, ribavirin, epoetin alfa (Procrit), filgrastim (Neupogen), the antidepressant, and drugs used to treat the skin manifestations and other symptoms.

The cost approached US$70,000. Of course, this is not the whole cost story. There were charges for expensive viral tests and other blood tests. There were costs for travel, parking, and doctor's visits. My estimate for the total approaches US$100,000. Add that to lost time from a productive occupation, and the economic losses stagger. Providentially, I was among the 40% cured by treatment.

Upon having read this, you will properly infer that the best outcome is to avoid acquiring the virus.

Henderson DK. Management of needlestick injuries; a house officer who has a needlestick . JAMA. 2012;307:75–84
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Department of Health & Human Services, Centers for Disease Control and Prevention, Division of Viral Hepatitis. The ABCs of hepatitis .
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Hepatitis C and the Hand Surgeon: What You Should Know
Journal of Hand Surgery
Volume 37, Issue 8 , Pages 1711-1713, August 2012

Chronic hepatitis C has recently become the number one cause of liver-related mortality in the United States.1 A blood-borne infection, it is most commonly spread by intravenous drug use. However, health care workers such as hand surgeons can be exposed through “sharp” injuries (eg, accidental needle sticks) both in clinic and in the operating room. If one acquires hepatitis C, there is approximately an 80% chance that it will develop into a chronic infection.2 Hepatitis C infection is deemed chronic if detectable hepatitis C virus (HCV) ribonucleic acid (RNA) is present for at least 6 months. After hepatitis C has developed into a chronic infection, there is roughly a 30% chance that cirrhosis will manifest within the next 20 years.3 Cirrhosis develops because the HCV targets hepatocytes, causing damage to them through a mechanism not completely understood.4 There is no vaccine for the prevention of hepatitis C infection. In this article, we review the transmission, diagnosis, treatment, and prevention of hepatitis C as it pertains to practicing hand surgeons.

The prevalence of hepatitis C in the United States is estimated5 to be around 1% to 1.6%. Unfortunately, sharp injuries are relatively common in hand surgery, perhaps owing to the confined working area of the hand.6, 7, 8 Studies have shown that up to 19% of all gloves used during hand procedures sustain a perforation, which is often undetected.7 It is estimated that 97% of hand surgeons in practice for more than 10 years have sustained a sharp injury, most frequently from a suture needle.6, 7 Hollow-bore needles (eg, syringes) are believed to be more likely to successfully transmit disease than their solid-bore counterparts (eg, suture needles) because the former often contain blood in their lumens, which can result in greater inoculation after a needle stick.9 Historically, the transmission rate for a needle stick injury involving an infected hepatitis C patient has been quoted10 as 3% to 5%. However, more recent studies11 have shown that the actual rate of transmission might be much lower, about 0.3%.

Whenever a needle stick injury occurs with a contaminated needle, the individual sustaining the injury should report it immediately to occupational medicine, regardless of the index of suspicion for hepatitis C or human immunodeficiency virus (HIV) transmission. Studies show that only about a third of surgeons always report such injuries.12 It is important to have the blood of both the individual who sustained the needle stick and the patient tested, to establish a baseline for the former and test for a disease such as hepatitis C in the latter (hepatitis B and HIV are also typically tested). Consent from the patient is required before testing. In determining hepatitis C status, a rapid enzyme-linked immunoassay (ELISA) test is often used as an initial screening tool. It is a sensitive test (> 95% sensitivity) and can detect antibodies to hepatitis C in the blood.13 If the ELISA test is positive, the result is usually confirmed with an HCV polymerase chain reaction (PCR) test, a slightly less sensitive but more specific test (> 95% specificity) that detects the presence of HCV RNA in blood.14, 15, 16 The HCV PCR test is considered the gold standard for confirming a diagnosis of HCV infection. A positive ELISA can also be confirmed with a recombinant immunoblot assay test, which is comparable in specificity to the HCV PCR test (Fig. 1). Of note, false-positive ELISA test results can occur; however, they are relatively rare and tend to happen in patients with autoimmune diseases.14, 15, 16 It generally takes from 3 to 7 days for each of these test results to come back, depending on how frequently the laboratory runs each test. The price of an ELISA test is approximately $60, whereas the recombinant immunoblot assay averages $140, and the HCV RNA test averages $170.14

Although it varies by institution, any individual who sustains a needle stick from a patient with known hepatitis C should not only be tested initially but again at 6 weeks, 3 months, and 6 months from the event. Repeat testing is necessary because even infected patients are frequently asymptomatic, and it can take months for the virus to become detectable in the blood. It is important to diagnose an hepatitis C infection in a timely fashion so that treatment can be initiated.2

After a diagnosis of hepatitis C has been established, the next question is whether to begin treatment, with the goal being to prevent chronic hepatitis from developing. Some patients choose to forego treatment because of the numerous side effects of the drugs that must be administered. Treatment generally consists of interferon with or without ribavirin for 24 to 48 weeks. In a recent study involving 15 patients treated during the acute phase of hepatitis C with interferon with or without ribavirin for 24 weeks, all became HCV RNA negative within 4 to 8 weeks.17 Unfortunately, the side effects of the interferon therapy are numerous and often debilitating. Flu-like symptoms, fatigue, and depression are common throughout treatment. Ribavirin also has negative side effects, most notably hemolytic anemia. As part of the treatment for hepatitis C, patients are also encouraged to protect their livers from both alcohol and acetaminophen.

All medical personnel should protect themselves from their patients' bodily fluids at each and every encounter. Operating room staff should always wear protective eyewear, because reports of transmission of blood-borne diseases such as hepatitis C exist in the literature.18 Safety needles should also be available, for several authors have reported a 70% to 100% reduction in needle stick injuries after switching to safety-engineered devices.8, 19 A recent study by Tosini et al analyzing different types of safety syringes showed that passive (ie, fully automatic) devices are associated with the lowest incidence of needle stick injury.20 However, in a more recent study by Sibbit et al, some passive devices (eg, automatically retractable syringes) were shown to be ineffective in performing certain basic orthopedic procedures such as arthrocentesis, in which longer needles and larger syringe volumes might be required.8 The authors ultimately concluded that shielded safety needles and manually retractable syringes (as opposed to automatic) were most appropriate for orthopedic procedures.8

Double gloving for surgeons and scrub technicians can also decrease the chances of an accidental exposure. In a 2009 Cochrane Review, the authors concluded that double gloving was effective in preventing perforation of the innermost glove without interfering with surgeon performance.21 A study by Sebold et al has shown that wearing outer gloves that are cut-resistant (eg, those made of Kevlar or other similar materials) versus wearing outer gloves of either the thick “orthopedic” type or standard latex variety notably reduces the rate of inner glove perforation.22 A more recent study by Louis et al on the same subject found that cut-resistant gloves might not be as effective as the Sebold study suggests.23 Louis showed that wearing cut-resistant outer gloves only slightly decreased the frequency of inner glove perforation.23 Other basic measures to reduce the risk of intraoperative sharp injuries include announcing the transfer of all sharp instruments, transferring all sharp instruments in a basin, and avoiding having several surgeons close one wound at the same time.

Kim WR. The burden of hepatitis C in the United States . Hepatology. 2002;36(Suppl 1):30–34
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Centers for Disease Control and Prevention. Hepatitis C information for the public . December 18, 2011
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Liang TJ , Rehermann B , Seeff LB , Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C . Ann Intern Med. 2000;4:296–305
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Zeisel MB , Fofana I , Fafi-Kremer S , Baumert TF. Hepatitis C virus entry into hepatocytes: molecular mechanisms and targets for antiviral therapies . J Hepatol. 2011;54:566–576
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Armstrong GL , Wasley A , Simard EP , McQuillan GM , Kuhnert WL , Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002 . Ann Intern Med. 2006;144:705–714
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Lopez RA , Rayan GM , Monlux R. Hand injuries during hand surgery: a survey of intraoperative sharp injuries of the hand among hand surgeons . J Hand Surg. 2008;33E:661–666
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Maffulli N , Testa V , Capasso GJ. Glove perforation in hand surgery . J Hand Surg. 1991;16A:1034–1037
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Sibbitt WL , Band PA , Kettwich LG , Sibbitt CR , Sibbitt LJ , Bankhurst AD. Safety syringes and anti-needlestick devices in orthopaedic surgery . J Bone Joint Surg. 2011;93A:1641–1649
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Thorburn D , Roy K , Cameron S , Johnston J , Hutchinson S , McCruden E , et al. Risk of hepatitis C virus transmission from patients to surgeons: model based on an unlinked anonymous study of hepatitis C virus prevalence in hospital patients in Glasgow . Gut. 2003;52:1333–1338
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Arai Y , Noda K , Enomoto N , Arai K , Yamada Y , Suzuki K , et al. A prospective study of hepatitis C virus infection after needlestick accidents . Liver. 1996;16:331–334
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De Carli G , Puro V , Ippolito G Studio Italiano Rischio Occupazionale da HIV Group. Risk of hepatitis C virus transmission following percutaneous exposure in healthcare workers . Infection. 2003;31(Suppl 2):22–27
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Wallis G , Kim W , Chaudhary B , Henderson JJ. Perceptions of orthopaedic surgeons regarding hepatitis C viral transmission: a questionnaire survey . Ann R Coll Surg Engl. 2007;89:276–280
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World Health Organization. Hepatitis C information .
Accessed December 18, 2011
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Carithers RL , Marquardt A , Gretch DR. Diagnostic testing for hepatitis C . Semin Liver Dis. 2000;20:159–171
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Courouce AM, Barin F, Botte C, Lunel F, Maisonneuve P, Maniez M, et al. A comparative evaluation of the sensitivity of seven anti-hepatitis C virus screening tests . Vox Sang. 1995;69:213–216
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Huber KR , Sebesta C , Bauer K. Detection of common hepatitis C virus subtypes with a third-generation enzyme immunoassay . Hepatology. 1996;24:471–473
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Loomba R , Rivera M , McBurney R , Haynes-Williams V , Rehermann B , Alter HJ , et al. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes . Aliment Pharmacol Ther. 2011;33:559–565
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Hosoglu S , Celen MK , Akalin S , Geyik MF , Soyoral Y , Kara IH. Transmission of hepatitis C by blood splash into conjunctiva in a nurse . Am J Infect Control. 2003;31:502–504
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Adams D , Elliott TS. Impact of safety needle devices on occupationally acquired needlestick injuries: a four-year prospective study . J Hosp Infect. 2006;64:50–55
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Tosini W , Ciotti C , Goyer F , Lolom I , L'Hériteau F , Abiteboul D , et al. Needlestick injury rates according to different types of safety-engineered devices: results of a French multicenter study . Infect Control Hosp Epidemiol. 2010;31:402–407
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Tanner J , Parkinson H. Double gloving to reduce surgical cross-infection . Cochrane Database Syst Rev. 2006;19:3
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Sebold EJ , Jordan LR. Intraoperative glove perforation (A comparative analysis) . Clin Orthop Relat Res. 1993;297:242–244
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Louis SS , Steinberg EL , Gruen OA , Bartlett CS , Helfet DL. Outer gloves in orthopaedic procedures: a polyester/stainless steel wire weave glove liner compared with latex . J Orthop Trauma. 1998;12:101–105
View In Article

Don't rule out IFN/ribavirin for HIV patients with hep C cirrhosis: study

NEW YORK (Reuters Health) - In HIV patients with hepatitis C, compensated cirrhosis should not be considered a contraindication to therapy with pegylated interferon (peg-IFN) and ribavirin, researchers say.

As is the case in patients without HIV, peg-IFN plus ribavirin is more effective against hep C in HIV patients who are free of cirrhosis, the researchers reported online September 5th in Clinical Infectious Diseases.

"In spite of that, this antiviral combination still leads to an appreciable rate of sustained virological response in cirrhotic patients carrying HCV genotype 3," Dr. Jose A. Mira and Dr. Juan A. Pineda of Hospital Universitario de Valme in Seville, Spain, who helped conduct the new study, told Reuters Health.

While compensated liver cirrhosis is known to predict worse response to IFN plus ribavirin in patients who are only infected with HCV, the researchers note, just one small study has looked at the issue in individuals who are co-infected with HIV. That study, which included 41 patients, found similar rates of sustained viral response (SVR) for patients with and without cirrhosis.

To investigate further, Dr. Mira, Dr. Pineda and their colleagues looked at 629 HIV/HCV co-infected patients receiving treatment with peg-IFN and ribavirin, all of whom had undergone a liver biopsy or liver stiffness measurement within a year of beginning treatment. Twenty-eight percent had cirrhosis.

Intention-to-treat analysis showed SVR in 25% of patients with cirrhosis and 39% of cirrhosis-free patients (p=0.001). Among the patients with cirrhosis, SVR occurred in 14% of those with HCV genotype 1; 47% of patients with HCV genotype 2-3; and 30% of patients with HCV genotype 4.

Part of the difference in response could have been due to the fact that 17% of the cirrhotic patients discontinued treatment due to adverse events, compared to 8% of those without cirrhosis, the researchers note.

"We think that the efficacy of pegylated interferon plus ribavirin in HIV/HCV co-infected patients with HCV genotype 4 depends primarily on other known predictors of response to HCV therapy in these patients, specifically the IL28B genotype," Dr. Mira and Dr. Pineda said via email.

"In fact, in another study carried out in our research group (Mira JA et al. AIDS 2012; 26:1721-1724), we found that only IL28B genotype CC was associated with sustained virological response in this population," they continued. "There are data supporting that interferon-mediated immune response against HCV, which is associated with IL28B genotype, has a different impact depending on HCV genotype. To confirm this hypothesis, a study with a higher number of HCV-4-infected patients would be required."

Despite the fact that patients co-infected with HIV and HCV who have compensated cirrhosis are a "hard-to-cure population," the researchers add, HCV therapy should be a priority in these patients, "given that once decompensated cirrhosis emerges, death due to liver failure occurs in the short-term."

Clin Infect Dis 2012.

Copyright © 2012 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

The Next Big Thing in Biotech: Hepatitis Drugs

Investment Commentary

The Next Big Thing in Biotech: Hepatitis Drugs

Adam Feuerstein, Sr. Columnist for TheStreet, says heptatitis drugs are the next big things to watch in biotech.
Fri 09/28/12 02:00 AM EST -- Adam Feuerstein & Gregg Greenberg

Gilead Begins Single Pill Hepatitis C Study for 2014 Approval

AASLD 2012: The Liver Meeting: 63rd Annual Meeting of the American Association for the Study of Liver Diseases
Boston, Massachusetts, United States  
November 9-13, 2012

The Liver Meeting® 2012
Published on Aug 22, 2012 by
Dr. Bezerra explains why the plenary, parallel, and poster sessions are the "essence" of The Liver Meeting® and how attendees can access those sessions through AASLD's LiverLearning® portal free of charge for one year.

AASLD - Liver Learning
"Liver Learning" @ the AASLD website includes meeting webcasts, video podcasts, abstracts....

The Liver Meeting® 2012
AASLD Website

Protease Inhibitors - Maximizing Treatment Benefit in HCV

Alimentary Pharmacology & Therapeutics

Despite Poor Interferon Response in Advanced Hepatitis C Virus Infection, Models of Protease Inhibitor Treatment Predict Maximum Treatment Benefit

I. A. Rowe; D. D. Houlihan; D. J. Mutimer
Posted: 09/28/2012; Aliment Pharmacol Ther. 2012;36(7):670-679. © 2012 Blackwell Publishing



Background Protease inhibitors have improved sustained virological response (SVR) rates for subjects with genotype 1 hepatitis C virus infection (HCV). There is however uncertainty regarding how, and in whom, these agents should be used. In previously treated subjects, prior response to interferon has a major effect on SVR rates with protease inhibitor therapy.
Aim To assess the benefits of treatment and to understand the utility of a stopping rule for subjects with a poor interferon response following a 4-week lead-in with pegylated interferon and ribavirin.
Methods Treatment responses and long-term outcomes were modelled using hypothetical 1000 subject cohorts with 5 years of follow-up. Treatment strategies were compared with number needed to treat (NNT) and comparative effectiveness approaches.
Results Over 5 years of follow-up the NNT to prevent liver-related mortality for subjects with advanced fibrosis was substantially lower than that for subjects with all fibrosis stages (18 vs. 60) indicating particular benefit in this high-risk population. The use of a stopping rule for subjects with advanced fibrosis and a poor interferon response after a 4-week lead-in reduces the number of subjects exposed to a protease inhibitor by 55%. However, 33% fewer liver-related deaths are prevented using this strategy, indicating that there is unacceptable harm associated with this approach over a 5-year follow-up period.
Conclusions Subjects with advanced fibrosis should be prioritised for triple therapy on the basis of need. Treatment should be continued regardless of initial interferon response to maximise the early prevention of hepatitis C virus-related mortality.

Hepatitis C virus (HCV) infection affects up to 200 million individuals worldwide and is an important cause of both morbidity and mortality.[1] Indeed up to 30% will develop cirrhosis with the attendant risks of liver failure and the development of hepatocellular cancer (HCC).[2, 3] Antiviral treatment has improved during the last two decades, but sustained virological response (SVR) rates remained below 50% for individuals infected with genotype 1 HCV who were treated with pegylated interferon and ribavirin. Since these were until recently the only available treatments many patients have been treated and not cured. Many of these individuals have cirrhosis, are at significant risk from liver related mortality and are prime candidates for more efficacious treatments that will reduce this mortality risk. To estimate this risk reduction it is crucial to understand the impact of the surrogate outcome of SVR on liver-related morbidity and mortality. This understanding permits well-informed discussion with patients who are considering retreatment.[4]

In the last year, the first generation of directly acting antiviral (DAA) agents has been licensed for treatment of patients with genotype 1 HCV infection. These are NS3 serine protease inhibitors that, when used with pegylated interferon and ribavirin, substantially improve response rates and have the potential to cure many individuals who would not have been cured with the previous standard of care.[5, 6] This increased cure rate comes at the expense of increased adverse events and an increased pill burden. Furthermore, DAAs have the potential to cause drug resistance, analogous to that seen with antiviral treatment for human immunodeficiency virus and hepatitis B virus (reviewed in).[7]

Resistant species are associated with antiviral treatment failure, but the long-term ramifications of resistance are not known. It is possible that resistance to these agents will compromise the chance of treatment success with regimens that contain similar agents in the future. To limit the development of resistance, all of the phase II and III studies employed strict stopping rules to prevent futile drug exposure. Despite this up to 50% of those treated and who were not cured still developed drug resistant variants although these were frequently short-lived in the plasma.[8]

In the boceprevir development programme and in the phase III study of previously treated subjects with telaprevir, a 4-week lead-in phase with pegylated interferon and ribavirin was employed.[8–10] This strategy confirmed that interferon responsiveness was a key determinant of successful treatment. It has been suggested that the lead-in could be used to identify individuals with poor interferon response where treatment with first-generation protease inhibitors should be avoided, thus eliminating the risk of drug resistance and reducing the frequency and severity of treatment-associated adverse events.[11–13] Indeed, some experts would use the 4-week lead-in with both telaprevir and boceprevir where poor interferon response might be expected to aid decision making.[14] This approach is the subject of intense debate as some patients with poor response during the lead-in phase are subsequently cured with DAA containing treatment.

The aims of this study were therefore twofold: first to quantify the benefit associated with protease inhibitor treatment in previously treated subjects to aid patient selection for treatment, and second to evaluate the benefits and risks of using a lead-in phase with interferon and ribavirin dual therapy to identify patients who will benefit from addition of a protease inhibitor. The comparative effectiveness of treatment strategies was assessed using hypothetical patient cohorts over a clinically relevant 5-year follow-up period.

Maximizing Treatment Benefit in HCV: Methods

Treatment Strategy
All patients who had previously failed treatment with interferon and ribavirin were considered suitable for treatment. The proportions of subjects with previous null response (<2log10 decline in plasma HCV RNA during 12 weeks of dual therapy), partial response (>2log10 decline in plasma HCV RNA but without achieving plasma HCV RNA PCR negativity) and relapse (PCR negativity at end of antiviral treatment, but subsequent relapse) were estimated at 45%, 20%, 35% respectively.[15–17] There is no head-to-head comparison of boceprevir and telaprevir, and treatment responses appear comparable.[8–10, 18] As patients with prior null response to dual therapy were not included in the registration studies of boceprevir we planned treatment using a prototypic protease inhibitor modelled on telaprevir. Sustained virological response rates were estimated from studies in previously treated subjects and their subgroup analyses (Table 1, and supplementary information).[9, 19] The utility of treating subjects with advanced fibrosis (defined as METAVIR F3/F4) was first determined using these SVR estimates and by comparison with treatment of subjects with all stages of fibrosis.

Treatment regimens with and without a stopping rule after the 4-week pegylated interferon and ribavirin lead-in phase (<1log10 reduction in HCV RNA) in subjects with advanced fibrosis were then assessed. The variables included in this analysis are shown in Table 2 (and are summarised in Supplementary Figure S1). Standard stopping rules to avoid futile treatment were left in place (i.e. HCV RNA greater than 1000 IU/mL at either 4 weeks or 12 weeks after the start of triple therapy[20]) but were not explicitly modelled. In each case, analyses were done containing only those showing previous partial or null response since it was considered likely that previous relapsers would receive full treatment regardless of response to lead-in pegylated interferon and ribavirin (SVR rates in this population are very high regardless of baseline fibrosis stage).[9] Frequency of poor interferon response was extracted from a subgroup analysis of the REALIZE trial.[9, 19]

Table 1. Calculation of estimated rates of sustained virological response (SVR) for previously treated subjects

Prior treatment responseTreat allAdvanced fibrosis only
Measured SVR (%)Number of subjects with SVR per 100 subjectsMeasured SVR (%)Number of subjects with SVR per 100 subjects
Partial responder56.711.3428.4
Null responder31.314.12511.3
Total (%)55.449.4

Pooled measured SVR rates of protease inhibitor treated subjects9 were used to estimate SVR rates from an unselected, previously treated, HCV-infected population. Frequency of prior responses was determined as above: relapse 35%, partial response 20% and null response 45%.

Outcomes After Treatment
Estimations of the rates of liver-related mortality, hepatic decompensation, and for the development of HCC were reported in a meta-analysis of previously treated patients,[21] and more recently in a prospective study of patients entered into clinical trials in a single centre.[22] These data allow the calculation of the absolute risk reduction (ARR) for each of these clinical events with successful treatment. For instance in the meta-analysis,[21] in previously treated subjects with advanced fibrosis and who do not achieve SVR the annual risk of liver-related mortality is estimated at 2.7%. For individuals with SVR the annual risk reduction is estimated at 0.19, or an annual mortality risk of 0.5% thus giving an ARR of liver-related mortality of 2.2% in those with SVR. The ARR for each outcome is given in Table 2. Adverse outcomes were calculated considering a follow-up duration of 5 years as it is unlikely that additional classes of DAAs will be licensed in that timeframe, and since it is interferon failure in this group that governs poor treatment response this is likely the minimum time until interferon-free regimens are licensed.

Table 2. Variables included in the analysis of a stopping rule after a 4-week lead-in with pegylated interferon and ribavirin

VariableBase case (%)Sensitivity (%)Reference
Previous treatment response[15–17]
Partial response2920–40
Null response7160–80
Interferon sensitivity: <1log10 After 4-week P/R lead-ina[9, 19]
Previous partial response3730–40
Previous null response6260–75
SVR with protease inhibitor[9, 19]
Previous partial response
<1log10 After 4-week P/R lead-in5650–60
>1log10 After 4-week P/R lead-in5950–65
Previous null response
<1log10 After 4-week P/R lead-in1510–20
>1log10 After 4-week P/R lead-in5450–60
Annual ARR following SVR[21, 39]
Liver related mortality2.22–4
Hepatocellular carcinoma2.22–5
Risk of treatment emergent adverse events[27–29]

ARR, absolute risk reduction; P/R, pegylated interferon and ribavirin; SVR sustained virological response.

*Estimate includes all subjects receiving pegylated interferon and ribavirin for 4 weeks, i.e. control group and lead-in arm.

Comparison of Treatment Regimens
Calculations were based on hypothetical cohorts of 1000 subjects, and were compared using a decision analysis and comparative effectiveness approach.[23–25] These cohorts were assigned to receive treatment according to the regimens defined above. Treatment benefit was estimated using a number needed to treat (NNT) approach.[26] The NNT was calculated using the formula below accounting both for the ARR associated with successful treatment (i.e. the SVR) and also the relative probability of that success.

Since the ARR is expressed per annum, to account for 5-year follow-up, the NNT was divided by 5 to give a 5-year NNT for each outcome.
The rate of clinical events in each cohort was then calculated using the NNT and compared by treatment regimen. The rate of the treatment related serious adverse events of hepatic decompensation (2%) and death (1%)[27–29] were also compared using this approach.

Sensitivity Analyses
Selected parameters in the base case analysis were varied within plausible limits (Table 2). For instance, rates of ARR for liver-related mortality and HCC varied from 2% to 4%, and 2% to 5%, respectively, in line with recently published data.[21, 22] As relatively few subjects with advanced fibrosis were included in the phase III studies, and those that were had well-preserved liver function, SVR rates varied from 10% to 20% in previous null responders and from 40% to 60% in partial responders. The proportion of subjects not achieving a 1log10 reduction at 4 weeks also varied from 32% to 45% in partial responders and from 55% to 70% in null responders. The relative proportion of null and partial responders included varied from 80/20 to 60/40 splits. Finally, the rate of treatment emergent adverse events varied between 1% and 3% for hepatic decompensation and 0.5% and 2% for treatment-related death.

Maximizing Treatment Benefit in HCV: Results

Mortality Reduction After Treatment
The effect of antiviral treatment on mortality has been assessed in relatively few studies due to the slowly progressive nature of HCV infection and the consequent use of SVR as a surrogate endpoint. To assess the treatment benefit of protease inhibitor containing triple therapy in previously treated subjects, we calculated the 5-year NNT for two groups: those with any stage of liver disease, and those with advanced fibrosis.[30] For those treated with a protease inhibitor, the 5-year NNT for those with any stage of liver disease is 60 to prevent one liver-related death whereas it is 18 when considering those with advanced fibrosis, despite a reduced SVR (Table 3). The impact of the NNT is highlighted when the number of deaths prevented in each treatment strategy is calculated in hypothetical patient cohorts: more than threefold more deaths are prevented when treating only subjects with advanced disease. These data highlight the importance of considering treatment in this high-risk group and indicate that this group should be prioritised for treatment on the basis of need.

Table 3. Comparison of liver-related mortality benefit in treatment of previously treated subjects with HCV infection stratified by fibrosis stage

Treatment groupAnnual ARR in liver-related mortality (%)21SVR (%)a95-year NNT to prevent 1 deathHCV deaths prevented per 1000 patient cohort over 5 years
Treat all0.655.46017
Advanced fibrosis only2.249.41854

ARR, annual risk reduction; NNT, number needed to treat; SVR, sustained virological response.
*Calculated SVR based on estimated proportion of prior null and partial responders as described.

Comparative Effectiveness of Including a Stopping Rule After the 4-week Lead-in
The outcomes of subjects treated with protease inhibitor containing triple therapy are shown in Figure 1. The strategy of treating all patients regardless of response after the 4-week lead-in with pegylated interferon and ribavirin results in the maximal prevention of death (Figure 1a). Employing the virological response to a 4-week lead-in with dual therapy as a stopping rule (Figure 1b) allows treatment to be stopped in the majority of this difficult-to-treat population thus reducing protease inhibitor exposure, and reducing the total number of treatment emergent adverse events. However, there is a notable increase in the efficacy of protease inhibitor containing therapy if treatment is stopped in subjects not achieving a >1log10 reduction in HCV RNA. As those with unfavourable responses are excluded from protease inhibitor containing treatment SVR rates for subjects treated with triple therapy are increased from 37.9% in the treat all strategy to 56.1% when the 4-week stopping rule is applied (Figure 1a,b).

Figure 1.
Flow diagram of the hypothetical 1000 subject cohort based on two strategies. (a) All 1000 subjects were treated with protease inhibitor containing triple therapy regardless of initial interferon response, and (b) after a 4-week lead-in treatment was stopped in subjects not achieving >1log10 reduction in HCV RNA. The number needed to treat for each scenario of completed treatment was calculated. After 5-year follow-up the number of deaths prevented was also assessed. F/U, follow-up; NNT, number needed to treat; P/R, pegylated interferon and ribavirin; SVR, sustained virological response.

There is however a significant reduction in overall clinical effectiveness associated with using the 4-week stopping rule. The number of patients achieving SVR is reduced by 37% as a result of excluding those subjects who would otherwise have been cured by continued treatment (SVR 'missed', Figure 1b). As this is a high-risk group and subjects who are not cured remain at significant risk of liver related morbidity and mortality we calculated the effects of the 4-week stopping rule on these parameters (Table 4). For subjects treated with triple therapy but without a stopping rule at week 4, 42 deaths are prevented over 5-year follow-up. However, only 28 deaths are prevented when the 4-week stopping rule is applied, a reduction of 33%. This indicates that by using the 4-week stopping rule 14 premature deaths occur that would have otherwise have been prevented by treating in the absence of the stopping rule.

Table 4. Effect of treatment emergent adverse events on clinical outcomes after antiviral treatment in previously treated HCV infected subjects with advanced fibrosis

Clinical eventTreatment strategyEvents incurred by using 4-week stopping rule*
Treat allStop if <1log10 reduction after 4 weeks
Prevented HCV death422814
On treatment death105-5
Prevented HCV decompensation473215
On treatment decompensation209-11
Prevented HCC422814
On treatment HCC000

HCC, hepatocellular carcinoma; HCV, hepatitis C virus.
Calculations are based on a hypothetical 1000 subject cohort with 5-year follow-up after antiviral treatment.
*Negative values indicate events that are reduced when the stopping rule is applied.

The Impact of Treatment Emergent Adverse Effects on Outcome
This difficult to treat population is at risk of treatment emergent adverse effects that can negatively impact on the outcome of treatment. In similar studies of dual therapy hepatic decompensation occurs in approximately 2% of those treated and death occurs in approximately 1%.[28, 29] These data are supported by the initial safety data reported in the early expanded access to protease inhibitor programmes in France.[27] The impact on these episodes is summarised in Table 4. For instance, treatment emergent hepatic decompensation (i.e. decompensation precipitated by treatment) decreases overall treatment effectiveness. In effect there is an approximately 40% reduction in the net number of decopmensation episodes prevented by treatment in the treat-all strategy. When the 4-week stopping rule is employed there is a reduction in treatment-related decompensation episodes, but the advantage of treating all subjects regardless of response at week 4 of treatment remains. The impact on death is similar and these data indicate that the development of treatment emergent adverse effects does not significantly reduce the comparative benefit that is achieved by treating subjects regardless of virological response at treatment week 4.

Sensitivity Analyses
In sensitivity analyses, the overall benefit of continued treatment despite poor virological response at treatment week 4 was maintained despite variation in the proportion of null and partial responders, low SVR rates to protease inhibitor containing treatment, and also in cohorts containing an increased frequency of subjects not achieving >1log10 reductions at treatment week 4. However, in scenarios where there was greater mortality associated with treatment, and particularly where this was associated with low treatment efficacy, there was no difference in overall mortality between those treated regardless of virological response and those treated according to the 4-week stopping rule (Table 5). These analyses support not using the 4-week lead-in as a universal stopping rule but rather individualising treatment where subjects at high risk of on-treatment mortality due to the presence of advanced cirrhosis and portal hypertension[28, 29] should have interferon sensitivity considered in treatment planning.

Table 5. Outcomes of sensitivity analyses

Sensitivity parameterNet deaths prevented by treatment strategyDeaths incurred by using 4-week stopping rule
Treat allStop if <1log10 reduction after 4 weeks
Base case32239
High ARR death765125
Low ARR death28217
Low SVR rates26206
Increased prior null response29227
Increased poor interferon response281810
High on-treatment mortality22193
Low SVR AND high on-treatment mortality16160

SVR, sustained virological response.
Calculations are based on a hypothetical 1000 subject cohort with 5-year follow-up after antiviral treatment. Outcomes presented here are based on the extremes of the sensitivity parameters provided in Table 2.

Maximizing Treatment Benefit in HCV: Discussion

The development of novel DAA agents targeting HCV has the potential to significantly improve outcomes for subjects with HCV infection.[5, 6] There are however a number of questions regarding how, and in whom, these agents should be used.[13, 14, 31] This analysis provides a clear rationale for prioritising subjects with advanced fibrosis who are at significant risk of liver-related morbidity and mortality for treatment. This group represents at least 25% of infected subjects at current estimates[32] and targeted treatment offers the potential to reduce liver-related mortality in a relevant timeframe. Our modelling cautions against the use of the 4-week lead-in phase as a universal decision point in subjects with advanced fibrosis as this strategy will disadvantage as many as 37% of subjects who would otherwise ultimately have derived benefit from continued treatment.

Recent licensing of DAA agents has brought further complexity to the management of genotype 1 HCV infection. In addition, the rapid development of new agents has led to uncertainty regarding which subjects to treat now, and which patients might be deferred from treatment.[33] Using the analyses presented here we have illuminated this difficult topic, particularly highlighting the benefits of treating subjects with advanced fibrosis. This population is in need of effective treatment and the benefit of this analysis is that it clarifies the clinical outcome that results as a consequence of treatment vs. no treatment in a clinically relevant timeframe. There is clinical heterogeneity in a group containing all subjects with advanced fibrosis (METAVIR F3/F4), however, the data included in the model are supported by clinical data drawn directly from this population. For instance, treatment responses are from randomised controlled data, and long-term follow-up data are from a meta-analysis of more than 1400 subjects.[9, 21] Using these analyses to support clinical decision making and the prioritisation of subjects for treatment should allow clinicians to maximise treatment benefit through mortality reduction in the next 5 years despite relatively low SVR rates and whilst further developments in therapy occur. Furthermore, the analyses provide critical information in the explanation of the potential benefits (and risks) of treatment for clinicians to share with subjects with advanced fibrosis who are considering treatment.

The rationale for using the 4-week lead-in phase for decision making has been based on concerns regarding increased toxicity in subjects with advanced disease, and also concerns about the evolution and persistence of drug resistant variants.[11–13] The registration studies for both boceprevir and telaprevir included patients with advanced fibrosis, albeit at a relatively low frequency, and these patients had well compensated liver disease. In subjects treated with pegylated interferon and ribavirin dual therapy there is evidence that the treatment emergent adverse effects of hepatic decompensation and death are more common in those with advanced cirrhosis and portal hypertension.[28, 29] Our analysis indicates that allowing for treatment-associated decompensation at a rate of 1 in 50 treated patients and mortality at 1 in 100 (in keeping with reports from early access programs),[27] there remains a benefit in continuing treatment regardless of treatment response at treatment week 4. The development of resistant variants is more difficult to model since the consequences of these frequently short-lived variants are uncertain. Whilst there is the potential for these variants to persist and to impact on future protease inhibitor containing treatment[7] and candidacy for future clinical trials of perhaps more effective therapies, the likelihood is that for many of the subjects included in this analysis this would be the last opportunity for treatment (prior to liver transplantation or death). This is especially apparent as it is interferon sensitivity that governs the poor responses to treatment in this group and that pegylated interferon is likely to remain a component of standard of care therapy for the next 5 years at least.

This analysis is limited by several factors. The data are extracted from several studies, none of which were intended to address this particular question. Furthermore, none of the studies contained large numbers of patients with advanced fibrosis and indeed the boceprevir development programme did not address treatment responses in prior null responders. The treatment responses for boceprevir and telaprevir appear broadly similar and we therefore considered a prototypic protease inhibitor based on the published data that were available. In sensitivity analyses, we varied the proportions of prior null and partial responders, the SVR rates and the rates of treatment emergent adverse effects to address the areas where there were uncertainty in the primary reports. These analyses indicated that there was benefit of continued treatment regardless of virological response at treatment week 4. There were however important exceptions to this, and that is in scenarios where there are high rates of treatment emergent mortality. In these situation there was no benefit to continued treatment following a <1log10 reduction in HCV RNA when considering 5-year follow-up. These scenarios might be represented by subjects with advanced cirrhosis and significant portal hypertension where treatment is already risky and where a failure to respond to the 4-week lead-in could be considered an indication to stop treatment. The analyses presented here therefore provide important evidence to support individualised treatment decision making in this difficult population. Further studies addressing this population should be carefully designed to ensure that stopping rules are implemented both for virological failure and to protect those included from excessive treatment related morbidity and mortality.

This analysis contains a relatively crude assessment of benefit and harm. Whilst this is based on important clinical outcomes of death, hepatic decompensation and the development of HCC rather than the surrogate measure of SVR it is likely that the lasting benefits of SVR are underestimated. Whilst several investigators have studied the effects of SVR on more relevant outcomes, such as serum biochemistry[34] and fibrosis stage,[35, 36] the overall clinical outcomes of SVR are seldom reported. We therefore utilised a meta-analysis of clinical outcomes after SVR.[21] A more recent prospective report suggests that both the annual risk of liver-related mortality, and the ARR in mortality might be greater than we considered[22] suggesting that the mortality reductions in the base case analysis might underestimate the true effect of treatment. Furthermore considering follow-up of only 5 years duration will underestimate the overall benefit of treatment. This parameter was however set at 5 years to permit decisions to be made in this clinically relevant timeframe. Additional data indicating that productivity is decreased and absenteeism is increased in HCV infected subjects suggests significant additional benefit from successful treatment.[37, 38] Although these outcomes are difficult to model the benefit we have highlighted in continuing treatment regardless of response at treatment week 4 is likely increased when all factors are considered. Of course, additional treatment emergent adverse events will also be incurred through continued treatment of this population regardless of virological response at week 4, and some of these will be severe. In those subjects with advanced disease these are likely to be more frequent, and to contribute to treatment emergent decompensation and death. These events, however, do not negate the benefit of treatment. A decision to wait for further treatment developments in this high-risk group therefore has the potential to cause the greatest harm when compared with any of the treatment strategies presented here and the mortality reduction noted with treatment strongly cautions against that approach.

These analyses describe previously treated subjects with prior null and partial responses. As the absolute risk reduction in mortality associated with successful treatment in the untreated population is likely to be similar[39] these findings are generalisable to all subjects with advanced fibrosis undergoing treatment with protease inhibitor containing treatment. The findings are however not applicable to subjects with early fibrosis where the harms of treatment manifest through treatment emergent adverse effects, or the development of resistant variants, may outweigh the benefits of continued treatment in poor interferon responders. Whilst information on the significance of resistance is emerging there are concerns that the harms relating to resistant variants may be significant and individualised decision making is appropriate until such data are available.

In summary, this analysis indicates that subjects with advanced disease should be prioritised on the basis of need. Furthermore, when considering protease inhibitor treatment of previously treated subjects with advanced fibrosis, this should be done without consideration of interferon responsiveness following the 4-week lead-in. This analysis provides critical information regarding both selection and on-treatment decision making for previously treated subjects that should be included in guidance for physicians using protease inhibitors to treat subjects with HCV infection.

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