Future hepatitis C virus treatment: interferon-sparing combinations

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 62–67, January 2011

Edward Gane

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02383.x
© 2011 John Wiley & Sons A/S

Author Information
New Zealand Liver Transplant Unit, Auckland, New Zealand
* Correspondence: Correspondence Edward Gane, New Zealand Liver Transplant Unit, 15th Floor Support Building, Auckland City Hospital, Park Road, Grafton, Auckland 92024, New Zealand Tel: 642 154 8371 Fax: 649 529 4061 e-mail: edgane@adhb.govt.nz

Keywords:
direct acting antiviral (DAA); Hepatitis C; pegylated interferon; polymerase inhibitor; protease inhibitor; standard-of-care (SOC)

Abstract

An estimated million people have chronic hepatitis C virus (HCV) infection. With current treatment success rates, by 2030, more than 40% will be cirrhotic and the number of cases with end-stage liver disease is projected to treble. Current standard-of-care is the combination of pegylated interferon plus ribavirin for 24–48 weeks. Unfortunately this is associated with poor efficacy (45% in HCV GT1; 75% in GT2 and 65% in GT 3) and tolerability. Many patients are either unsuitable for or decline current treatment infection because of the significant side-effects associated with this treatment, including those with decompensated cirrhosis or sever psychiatric illness. It is hoped that the development of direct acting antiviral agents (DAAs) will address this huge unmet medical need. The addition of a protease inhibitor to pegylated interferon plus ribavirin is associated with increase in efficacy and shortened duration of therapy in patients with HCV GT1 and is likely to become the new standard-of-care. However, triple therapy will not be suitable for patients with non-1 HCV infection, or contraindications to interferon. It is hoped that the combination of multiple DAAs which target different steps of HCV replication should provide interferon-free treatment regimen. Current and planned studies will determine which combination (protease, nonnucleoside polymerase, nucleoside polymerase, NS5A, cyclophyllin B inhibitors), how many DAAs and duration of therapy will be required to optimise cure. It will also be important to minimise the emergence of multi-resistance, which would jeopardise future retreatment options

Chronic hepatitis C is the global ‘epidemic’ of the new millennium, with an estimated 200 million people currently infected with the hepatitis C virus. The incidence of hepatitis C virus (HCV) infection has decreased by more than 50% over the last decade, reflecting reduced exposure risk (1, 2). Although the size of the population with chronic HCV infection has been stable since 2000 (3), this is an ageing cohort and the proportion of this cohort with cirrhosis will double over the next decade from 16 to over 35% (4). As a result, the annual rate of both HCV-related hepatocellular carcinoma and HCV-related-mortality is projected to triple again by 2030 (5–7). The only way to prevent this projected health burden is to reduce the pool of infected patients through successful antiviral therapy. However, <10% of the infected population has been treated, and less than half of these have been cured. It is estimated that these numbers would need to increase almost 10-fold to prevent the projected increase in HCV-related complications (1, 8).

Unfortunately, current treatment options are limited by both efficacy and tolerability. The current standard of care (SOC) treatment for chronic HCV infection is 48 weeks of combination therapy with subcutaneous injections of pegylated interferon (PEG-IFN) plus orally administered ribavirin. SOC achieves a sustained virological response (SVR) in only 45% of patients infected with HCV genotype (GT)1 and 65% of those infected with GT2 or 3 (9). HCV GT1 is the predominant genotype globally, accounting for between 55 and 95% of infections.

Baseline patient predictors of non-response to SOC other than HCV genotype include older age, advanced fibrosis, high body mass index, insulin resistance and African ethnicity. A specific inherited polymorphism on chromosome 19 at rs12979860, close to the interleukin (IL)28B gene, is strongly associated with SVR across all patient groups (T/T vs. T/C or C/C), independent of all other predictors including ethnic origin (10).

Subsequently, several other independent genome-wide association studies have also identified additional SNPs, in the IL28B region, associated with response to treatment (11–13).

In those patients with favourable baseline predictors of response, adherence to therapy is an important determinant of outcome. Both PEG-IFN and ribavirin are associated with significant adverse effects, from flu-like symptoms, fever, rash, anorexia, thyroid dysfunction, to dose-related life-threatening cytopaenias and mood disorders. Side effects result in a dose reduction in 60–80% of patients and treatment withdrawal in 5–10%. Another inherited polymorphism on Chromosome 20 at rs1127354, which determines the activity of inosine triphosphatase, reliably predicts protection from ribavirin-induced haemolysis (A/A and C/A vs. C/C) (14). In addition, many patients never start SOC because of real or perceived medical or psychosocial contraindications to either IFN or ribavirin. Many more defer therapy because of anecdotal stories about severe adverse effects.

Finally, there is a large and growing pool of largely GT1 patients who have not previously responded to PEG-IFN-a and ribavirin treatment, in whom retreatment no alternative treatment options are currently available.

New therapeutic approaches offering improvements in efficacy, safety and tolerability are urgently needed to address these unmet medical needs.

Direct-acting antivirals and triple therapy

The five steps in HCV replication that are potential targets for direct-acting antivirals (DAAs) include initial binding of HCV to hepatocyte surface receptors (via LDLR and CD81), translation and polyprotein processing (via the HCV protease complex), RNA replication (via the HCV RNA-dependent polymerase complex), virion assembly and maturation, followed by release from the hepatocyte (Fig. 1). To date, the most successful approaches have been targeting the HCV protease (via inhibition of NS3A4 protease) and the HCV polymerase complex (via inhibition of NS5A, NSAb and indirectly through NS3A4). The in vitro replicon and transgenic models for HCV replication and the application of rapid screening techniques for small molecules have triggered an explosion in drug development. Over the last 5 years, more than 90 protease and polymerase inhibitors have entered clinical development, of which several have halted because of toxicity (BILN2061, NM283, HCV796, R1626) and many more have been abandoned because of preclinical toxicity signals or lack of clinical efficacy.

Figure 1. Targets for direct-acting antivirals against the hepatic C virus (HCV).

The DAAs closest to being marketed are the protease inhibitors, boceprevir and telaprevir. Phase 3 global registration studies of both will be completed this year and these protease inhibitors are expected to be the first DAAs to gain regulatory approval as add-on therapy to current SOC PEG-IFN plus ribavirin. The benefits in terms of efficacy will be significant – 48 weeks of boceprevir plus SOC increased the SVR rates in treatment-naïve GT1 patients from 38 to 66%, while 12 weeks of telaprevir plus 24 weeks SOC increased the SVR rates from 43 to 75% (15, 16). Triple therapy may also offer hope in treatment-experienced patients, especially previous responder relapsers and partial responders (17– 19). However, both have specific toxicities (notably anaemia and dysgeusia with boceprevir and anaemia and rash with telaprevir), which increased the rate of treatment withdrawal in the DAA combination arms.
 
Although triple therapy (addition of either telaprevir or boceprevir to PEG-IFN plus ribavirin) is likely to become the new SOC in late 2011, this will not be suitable for patients either intolerant of or with contraindications to IFN or ribavirin, including patients with decompensated cirrhosis or following solid organ transplantation. Also, the efficacy of this triple therapy will probably be reduced in treatment-experienced patients, especially those who were non-responders to a previous treatment with SOC. Moreover, although telaprevir has similar antiviral activity against HCV GT2, this agent has no effect in patients with HCV GT3 infection (20, 21). All current protease inhibitors and most non-nucleoside polymerase inhibitors in development are active primarily against HCV GT1. PEG-IFN plus ribavirin will remain the SOC for non-GT1 HCV until nucleoside polymerase inhibitors and cyclophyllin inhibitors enter clinical practice.

Finally, the 30–40% of GT1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors, which will limit future treatment options.

Therefore, although the addition of a single DAA to PEG-IFN and ribavirin may improve cure and shorten the treatment duration of SOC, this approach will not meet the needs of many difficult-to-treat patient groups.

Towards an all oral regimen

The successful development of an all-oral, IFN-free regimen of multiple DAAs should address this current extensive unmet medical need and could potentially become the standard of care for all patients with chronic HCV infection. The rationale for this approach is based on the current human immunodeficiency virus (HIV) treatment paradigm, in which a combination of different DAA agents, which target different steps of viral replication, has been shown to increase viral suppression as well as delay or prevent the emergence of antiviral resistance. There is a rapidly increasing list of potential candidates for such a combination including NS3 helicase inhibitors, NS3/4A protease inhibitors, cyclophyllin B inhibitors, NS5A inhibitors, NS5B nucleoside inhibitors and NS5B non-nucleoside inhibitors (see Table 1). The primary criteria for a DAA combination should be to increase antiviral efficacy without increasing toxicity. The combination of DAAs should exhibit in vivo at least additive and preferably synergistic antiviral efficacy [i.e. rather than interference as observed with telbivudine plus lamivudine in patients with hepatitis B virus (HBV) infection]. The combination should lack cross resistance and should prevent virological breakthrough from the emergence of resistance mutants to either or both DAAs. Finally, the combination should lack direct drug interactions and overlapping toxicities.

The first in vitro study of combination DAAs was performed in the replicon model (22). The addition of RG7128, a nucleoside polymerase inhibitor, to RG7227, a protease inhibitor, provided additive viral suppression and completely prevented the development of phenotypic resistance to the protease inhibitor. Similar in vitro effects have been demonstrated for other DAA combinations, including a protease inhibitor plus a non-nucleoside polymerase inhibitor and also the combination of two nucleoside polymerase inhibitors (23, 24). The in vivo efficacy of combining DAAs was first reported in chimpanzees treated with a combination of Merck NS3/4A protease inhibitor MK-7009 and non-nucleoside inhibitor MK-608 for 7 days, whereby both had rapid and sustained viral suppression and one animal eradicated the HCV infection (25). The first study of combination DAAs in patients was the proof-of-concept INFORM-1 study completed last year (26). In this randomised, placebo-controlled double-blind trial, 87 patients with HCV GT1 infection were randomised to receive up to 13 days of either oral combination therapy with RG7128, a nucleoside polymerase inhibitor, and RG7227/danaprevir, an NS3/4A protease inhibitor or with matched placebos. Both agents had already been administered to patients for 12 weeks in combination with SOC. Direct drug interactions between RG7128 and danaprevir were considered very unlikely, because of the different mechanisms of action and routes of elimination and the lack of overlapping toxicities identified in any of the preclinical or human clinical studies. This combination achieved profound antiviral suppression, greater than the additive effects of either treatment alone. The median reduction in HCV RNA from baseline was 5 logs, falling below the level of detection in 88% in the cohort who received the highest dose of both RG7128 (1000 mg b.i.d.) and danaprevir (900 mmg b.i.d.). No evidence of the emergence of resistance to either compound was observed during this study. This combination was well tolerated, with no serious adverse events, treatment-related dose modifications, discontinuations or study withdrawals. An important observation was that antiviral efficacy was similar in treatment-naïve and treatment-experienced patients including non-responders. Because the total duration of therapy was only 13 days, all patients rolled over into SOC. The rates of RVR, EVR and ETR were markedly increased by the 2 weeks of pretreatment. In the final cohort of patients who received the highest dose of RG7227 and RG7128, 100% achieved ETR after 24 weeks SOC. Although SVR results are still pending, the benefit of pretreatment with combination DAA on subsequent responses to SOC suggests that the strategy of combination of DAA lead-in before starting SOC could be an alternative strategy to IFN-free DAA therapy.

However, the primary goal of combination DAA therapy in HCV infection will be to provide a safe and effective substitute for IFN regimens in all treatment-naïve and -experienced patients.

Although the new treatment paradigm for HCV is based on HIV, the goals are very different. In HIV infection, a cure is not achievable because it is impossible to eradicate infection from lymphocytes and macrophage reservoirs and from nuclear integration. Therefore, lifelong combination DAA therapy is needed to maintain viral suppression and prevent disease progression. In HCV infection, however, replication is entirely cytoplasmic and limited to hepatocytes. Therefore, viral eradication should be possible with short-course combination DAA.

The duration of combination DAA necessary to eradicate HCV infection is unknown. The early viral kinetic profile of single DAA therapy demonstrates a rapid Phase 1 decline in serum HCV RNA levels of 3–4 log in the initial 36 h, attributed to the clearance of free virions from the circulation. The addition of a second DAA appears to increase this initial slope, suggesting at least additive effects of both agents. This is followed by Second Phase decline in serum HCV RNA of 1-1.2 log/week, attributed to the loss of infected hepatocytes (Fig. 2). This rate of viral decline continues until the infection is eradicated, unless DAA-resistant variants emerge. Therefore, based on the estimated total body viral burden of 1011 virions, between 8 and 12 weeks of DAA therapy should be sufficient to eradicate HCV infection in most patients. The addition of a second DAA targeting a different step of HCV replication and lacking cross resistance should both increase the slope of the Phase 1 decline as well as prevent virological breakthrough during Phase 2.

Figure 2. Early viral kinetic profile of combined direct-acting antivirals' therapy. HCV, hepatic C virus.

A finite duration of combination DAA therapy without IFN assumes that viral suppression alone will eradicate HCV, which seems reasonable in the absence of evidence of either viral latency or extrahepatic reservoirs of replication (as seen in HBV). Another important factor for the maintenance of end-of-treatment response may be the indirect effect of combination DAA therapy on host immune responses. In chronic HCV infection, the HCV NS3 protease may directly impair host IFN responses through the inhibition of phosphorylation of IFN regulatory factor-3 (27). Administration of the NS3/4A protease inhibitor should restore this immune responsiveness. Chronic HCV infection is also associated with high levels of IP-1(CXCL-10), a chemokine involved in lymphocyte chemotaxis, reflecting endogenous IFN activation levels. High levels of IP-10 during SOC are correlated with the risk of post-treatment relapse (28). In the INFORM study, the rapid and profound viral suppression achieved with 13 days of combination RG7128 and danaprevir (5 logs within 14 days) correlated with normalisation of IP-10 levels (29). Furthermore, it has been shown that in non-responders, some IFN-stimulated genes were highly expressed; thus, preactivation of the IFN system in patients appears to limit the effect of IFN antiviral therapy (30). Current and future studies will determine whether the IL28 genotype influences sustained response rates in an IFN-free DAA regimen.
 
Future studies of combination DAA therapy in chronic HCV should include the evaluation of HCV-specific and non-specific immune responses to determine whether immune reconstitution does occur and whether this is a prerequisite for the prevention of relapse after treatment withdrawal.
 
First studies with all-oral treatments
 
The shift from triple therapy (single DAA plus SOC) to IFN-free combination DAA studies has been impeded by the reluctance of regulatory authorities to approve the combination of two experimental compounds still in early-phase clinical development. However, such studies should be reasonable as long as safety data are available for each candidate DAA for the duration of the proposed treatment. The rapid emergence of resistant variants during monotherapy with either NS3/4a or NS5b non-nucleoside inhibitors has restricted the duration of DAA monotherapy studies to 3–5 days; thus, longer duration safety data must be obtained from studies of DAA in combination with SOC. An additional requirement before embarking on combination DAA studies in patients should be data from preclinical and human clinical studies for each candidate DAA, confirming lack of cross-resistance, lack of overlapping toxicities and a low likelihood of any drug–drug interactions, which could affect antiviral activity, bioavailability or clearance. INFORM-1 fulfilled all of these requirements but was performed in Australia and New Zealand, because the conservative regulatory environment of the FDA and EMEA did not allow this study to be performed in either Europe or the US at that time. The success of this proof-of-concept and widespread enthusiasm in the HCV field over these results will push the regulatory authorities to modify their previously conservative position.
 
Following the INFORM proof-of-concept study, seven Phase 2 studies of combination DAA studies are already entering Phase 2 clinical trials in patients with treatment-naïve HCV infection (see Table 2), with many more planned. All studies include an NS3/4a protease inhibitor with or without ritonavir boosting, combined with an agent targeting the HCV polymerase complex – either a non-nucleoside NS5b (n=4), nucleoside NS5b (n=1) or an NS5a inhibitor (n=2). The potential advantage of the nucleoside polymerase inhibitor is the relatively high genetic barrier to resistance and the low prevalence of pre-existing nucleoside polymerase resistance. In a recent survey, no treatment-naïve GT 1 patients had detectable signature S282T mutations, while the prevalence of mutations conferring resistance to either NS3/4a inhibitors or non-nucleoside polymerase inhibitors could be detected in more than 8% of treatment-naïve patients (31). However, it is not clear whether these pre-existing mutations will affect the response to combination DAA therapy. Most of these mutations are associated with decreased replicative fitness and none confer cross-resistance to either NS3/4a inhibitors or non-nucleoside polymerase inhibitors. Unlike INFORM-1, the aim of these studies is curative, with combination DAAs administered for 12–24 weeks. Most study designs incorporate response-guided therapy, with the 2-week rather than the 4-week RVR adopted as a predictor of efficacy (and shortened treatment duration). Although IFN-free, most studies have retained ribavirin as a third oral agent (based on observations of higher relapse rates in the ribavirin-sparing treatment arms in the telaprevir plus SOC studies) (32). However, the impact of ribavirin on the efficacy and tolerability of combination DAA therapy needs to be established.
 
Summary
 
The addition of a protease inhibitor to PEG-IFN plus ribavirin will increase the cure rate in both treatment-naïve and treatment-experienced patients and is likely to become the new SOC. However, there will still be a large ‘unmet need’, including patients unable to or unwilling to receive IFN or ribavirin therapy and previous non-responders to SOC. The rationale for combining different DAAs is to increase viral suppression and prevent or delay the emergence of antiviral resistance. The ultimate goal is to develop a short-duration, IFN-free oral combination, with excellent tolerability and efficacy in both treatment-naïve and treatment-experienced patients.
 
Conflicts of interest
 
Edward Gane is a member of local or international Advisory Boards and Invited Speaker for GSK, Roche, Pharmasset, Abbott, Novartis and Merck.
 
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Source 

The role of genetic markers in hepatitis C virus therapy: a major step for individualized care

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 29–35, January 2011

John G. McHutchison

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02389.x
© 2011 John Wiley & Sons A/S

Author Information
Gilead Sciences, Foster City, CA, USA
* Correspondence: Correspondence John G. McHutchison, MD, 333 Lakeside Blvd, Foster City, CA, USA Tel: +1 650-522-5302 Fax: +1 650-522-1975 e-mail: john.mchutchison@gilead.com

Keywords
Genetics; HCV; IL28B;treatment response

Abstract

It has been understood for some time that the treatment outcome of hepatitis C virus (HCV) infection is influenced by host genetic factors. Three independent genome-wide association studies have recently identified that a genetic variation in the IL28B gene [interferon-λ3 (IFN-λ3)] determines the outcome of IFN-α-based therapy in patients with genotype 1 chronic hepatitis C infection. This genetic polymorphism is also strongly associated with a higher likelihood of spontaneous clearance following acute hepatitis C infection. These results confirm the importance of specific host genetic markers in predicting outcome and treatment response. They also provide the framework and potential for a clinically relevant and meaningful pharmacogenomic approach to personalizing anti-HCV treatment.

Host genetics have long been suspected to play a role in determining response to interferon-α (IFN-α)-based therapy for chronic hepatitis C virus (HCV). The current standard of care (SOC) therapy is pegylated IFN (PEG-IFN) and ribavirin (RBV) combination therapy. The sustained virological response (SVR) rate is approximately 40–45% in patients with genotype 1 HCV (1–4). Predictors of treatment response are poorly defined for any individual patient and do not allow personalization of therapy; both host (e.g. gender, age and liver fibrosis) and viral factors (e.g. genotype and viral levels) are recognized to be important, but do not adequately explain the variation in response that is observed. African-American ancestry is strongly associated with a poor response, and the SVR rate is half that observed in Caucasians (5, 6). These ethnic differences cannot be explained by the severity of disease, compliance, viral kinetics or more basic immunological or other parameters. Hispanic ethnicity has also been associated recently with lower response rates compared with Caucasians (7). In contrast, Asian populations appear to have the highest response rates (8, 9). Taken together, these ethnic or racial differences in the treatment response rates strongly suggest a genetic basis.

Technology that can screen the entire human genome for variants associated with human diseases has recently become widely available. Although they are not yet ready for large-scale clinical use, these tools could potentially define polymorphic sites that might translate into clinical diagnostics, as well as provide an insight into systems biology. Three published genome-wide association studies (GWAS) have been published recently that link a genetic variation in the IL28B gene region to response to PEG-INF-α plus RBV in patients with genotype 1 chronic HCV (10–12). Here, we explain these technologies and principles and summarize the publicly available data as well as discuss future directions and potential applications.

Genetic association studies

A case/control genetic association analysis involves a comparison of the frequency of a particular allele(s)/genotype(s) in a sample of affected patients compared with a control group of unaffected individuals. The existence of stretches of linkage disequilibrium (LD) in the human genome and the wealth of data that have been generated by the HapMap Project (http://www.hapmap.org) make it possible to assess common genetic variation (i.e. variants that are present in at least 5% of a given population) on a genome-wide scale using ‘tag’ SNPs. GWAS are therefore a hypothesis-free method for systematically testing the association between all common variants in the human genome and any polymorphic trait, notably clinical phenotypes (disease, drug response, drug toxicity and others). An important note about the use of tag SNPs is that GWAS are only able to identify a region within the genome that is associated with a phenotype. They do not usually identify the polymorphism itself that is directly responsible for the effect (the causal or the functional variant), although this may occur by chance. Follow-up of a discovery involves fine sequencing of the associated region, as well as more basic biological studies. As GWAS involve hundreds of thousands of association tests, the threshold for statistical significance must be stringent and correction for multiple testing must be performed (e.g. Bonferroni correction, Table 1). This requires large, well-characterized cohorts to have enough power to detect real associations. Even then, unless the P-value of the association is clearly beyond the genome-wide significance, replication of the study in an independent cohort should be undertaken. For further discussion, readers are directed to a recent overview of the interpretation of GWAS (13).

Before genome-wide approaches became available, most studies used a candidate gene approach, in which polymorphisms affecting plausible biological pathways are chosen to be tested for association with a particular phenotype. A limited number of SNPs are selected, minimizing cost. The threshold for statistical significance is lower, although correction for multiple testing should still be performed. Unfortunately, such statistical vigilance has not always been the case. Another limitation of these targeted studies is the difficulty of correcting for population stratification: invalid associations can be created by systematic differences due to shared ancestry between subgroups of study subjects. Panels of ancestry markers, or informative markers extracted from genome-wide genotyping data, can be used to address this issue. Consequently, many candidate gene findings have not been replicated in follow-up studies, and this is also true for candidate gene studies of HCV treatment response (14–26). All have been limited by a small sample size and borderline significance in the setting of multiple testing. Results have been inconsistent and reproducibility limited.

Genome-wide analyses of genotype 1 hepatitis C virus treatment response

Genetic variation in the IL28B gene region has recently been shown to be strongly associated with viral clearance following treatment with PEG-IFN and RBV in patients with chronic genotype 1 HCV infection.

Ge and colleagues: the first genome-wide association analysis to investigate genetic predictors of treatment response used patients from the IDEAL study, a large randomized-controlled trial that confirmed the similar efficacy of the two commercially available PEG-IFN preparations (PEG-IFN α-2b vs PEG-IFN α-2a) in North American patients with chronic genotype 1 HCV infection (1). One thousand six hundred and four patients consented to genetic testing. An additional 67 patients were enrolled from a second randomized clinical trial that compared the efficacy of PEG-IFN-2b/RBV in Caucasians vs African Americans (5). This study therefore had the advantage of an extremely well-characterized patient phenotype, defined within the context of clinical trials. Genome-wide analysis was performed using the Illumina Human 10-quad BeadChip (610 000 SNPs on chip/565 759 passed QC and were used for the association analysis). The primary analysis for treatment outcome compared SVR with true biological non-response in 1137 patients, in three independent ethnic groups – Caucasians, African Americans and Hispanics, defined by genetic ancestry (336 patients who did not attain SVR were excluded on the basis of <80% compliance to PEG-IFN or RBV; a further 198 were excluded for technical reasons).

Seven SNPs on chromosome 19 in the region of the IL28B gene (coding for IFN-λ3) met the threshold for Bonferroni-corrected significance in the GWAS, adjusting for other clinical factors known to affect the treatment response, including baseline HCV RNA level, hepatic fibrosis stage and steatosis grade, age, body mass index, baseline ALT level, blood sugar levels and weight-adjusted RBV dose (1). The P-value for association of the top discovery SNP, rs12979860, located 3 kb upstream of the IL28B gene, was 1.06 × 10−25 in Caucasians (P=1.37 × 10−28, combined across the three ethnic populations). The six other SNPs displayed different degrees of LD with rs12979860 (Table 1), and their effects were largely explained by rs12979860. Another two SNPs, not present on the genome-wide chip, were shown to be highly associated with rs12979860 by fine sequencing studies. These were both putative functional variants, rs28416813 lying in the promoter region 37 base pairs upstream of the IL28B start codon and rs8103142 a non-synonymous polymorphism in exon two (Lys70Arg). Given the high degree of correlation, it was not possible to resolve which of these three polymorphisms might be solely responsible for the association signal. A validation cohort was not required, given the strength of the association signal (exceeding genome-wide significance by a factor of 10−20).

In this compliant cohort, the IL28B polymorphism was associated with a two-fold increase in the SVR rate in all ethnic groups. In a multivariable logistic regression model, ‘IL28B-type’ was a stronger independent predictor of SVR than viral load (±600 000 IU/ml), hepatic fibrosis stage or ethnicity [adjusted odds ratio (OR) for SVR in Caucasians=7.3 (5.1–10.4)]. Furthermore, the favourable CC genotype was more common in Caucasians than African Americans, and it was estimated that this difference in genotype frequency was responsible for approximately half of the recognized discrepancy in the treatment response rates between the two populations. Random sampling of a healthy population then identified the rs12979860 CC genotype to be most common in Asian patients, suggesting that this genetic variant may also contribute to the high response rates that have been reported in this group (8). Finally, the frequency of the C allele in the study population was found be lower than that of an ethnically matched population of unknown HCV status, suggesting that the genetic variation in the IL28B gene region may be relevant to the natural clearance of HCV. This last point was subsequently confirmed in a separate study that examined the association between rs12979860 and the spontaneous clearance of HCV (28).

Tanaka and colleagues: a second GWAS, conducted in a Japanese population, also identified an important role for the IL28B gene region in HCV treatment response (11). A two-stage design was used with a GWAS discovery stage in 154 patients, using Affymetrix SNP 6.0 genome-wide SNP typing array (900 000 SNPs/621 220 SNPs passed QC), followed by a subsequent validation stage in 172 patients. The association analysis used null virological response as a phenotype (NVR, defined as a <2log10 IU/ml reduction in serum HCV RNA by week 12 of therapy and detectable HCV RNA at week 24) rather than SVR. Adherence >80% during the first 12 weeks was required for inclusion. Two SNPs in the IL28B gene region showed strong associations in the GWAS phase I, rs8099917 and rs12980275 (P=3.11 × 10−15 and P=1.93 × 10−13 respectively). These two SNPs were validated in the replication phase [combined P=2.68 × 10−32, OR 27.1; (14.6–50.3) and P=2.84 × 10−27, OR 17.7 (10.0–31.3) respectively]. Six other SNPs were associated beyond the genome-wide threshold, found either on the basis of LD and haplotype structure (HapMap release 23a, Japanese ancestry), or by fine resequencing studies. All were in the IL28B gene region, in strong LD, and it was concluded that the association signal was driven by one of the identified SNPs, although again it was not possible to conclude which, if any, was the causal variant. Logistic regression modelling confirmed a strong independent role for SNP rs8099917 in predicting NVR. In a secondary analysis, Tanaka and colleagues also observed that SNPs rs8099917 and rs12980275 were significantly associated with SVR vs no SVR [unadjusted OR 12.1 (6.5–22.4), P=1.18 × 10−18 and 8.8 (5.1–15.4), P=1.17 × 10−16 respectively]. This study therefore confirmed that genetic variation in the IL28B gene region was associated with viral clearance, as well as null response (an expected finding, given the recognized role of NVR in strongly predicting overall non-response).

Suppiah and colleagues: a third GWAS was conducted in genotype 1 HCV-infected patients of European ancestry (Australian/western Europe) (12). The investigators tested for polymorphisms associated with SVR. Adherence to therapy was not defined. A two-stage approach was adopted. The initial GWAS was performed in an Australian cohort (n=293) using the Illumina Infinium HumanHapMap300 or the CNV 370-Quad genotyping BeadChip (311 159 SNPs used for the association analysis). One hundred and seventy-two SNPs were taken forward to the second stage, based on a P-value for association <10−5, or P<10−3 and immune-regulatory/antiviral function. The replication cohort included patients from the UK, Germany, Italy and Australia. The polymorphism rs8099917 exceeded the threshold for genome-wide significance in the GWAS stage and replication phases [OR 1.98 (1.57–2.52), P=9.25 × 10−9]. Seven other SNPs in the IL28B gene region were noted to be associated with SVR in a subsequent haplotype analysis using tagging SNPs identified within the distinct IL28B haplotype block (Table 1). Although only one of these seven SNPs reached genome-wide significance, it was notable that six of the seven were common to the Ge/Tanaka papers (Table 1). Several other SNPs were described as being of interest in this study, on the basis of suggestive but not genome-wide significance (P<10−4)±biological plausibility. These included SNPs related to the genes IL21R and CASP1. However, given the absence of these association signals in the other two studies, it is reasonable to conclude that they probably represent false-positive associations.

Summary

Three independent original GWAS have now identified variants within the IL28B gene region that are strongly associated with response to PEG-IFN plus RBV combination therapy in patients chronically infected with genotype 1 HCV. Furthermore, a strong association of rs12979860 with both an early virological response and an SVR in IFN-naïve patients treated with PEG-IFN and RBV was also reported. In particular, the association of rs12979860 with virological response appeared to be stronger in the naïve patients' population compared with prior non-responders (27).

There are now more than 10 independent validations of the importance of this genetic variant related to HCV treatment response in different populations of chronically infected individuals (other HCV genotypes, HIV coinfected patients and in the setting of transplantation, among others). Another study has also shown that the SNP rs12979860 is strongly associated with the spontaneous clearance of HCV. Most probably, studies have detected the same genetic signal. The fact that multiple SNPs have been identified, with differing effect sizes, almost certainly reflects the differences between the studies with respect to ethnicity, phenotype definition and SNP genotyping platform, and also suggests the existence of a strong LD in the region. The causal variant(s) have yet to be defined.

Genome-wide analysis of spontaneous clearance of hepatitis C virus

Data supporting a role for IL28B genetic variations in spontaneous clearance of HCV followed rapidly after the treatment response discovery. Thomas and colleagues used a candidate gene approach to investigate the potential role of rs12979860 variation in determining the natural clearance rate following acute HCV, in cohorts of individuals who spontaneously cleared the virus (n=388) or had persistent infection (n=620) (28). Patients with the CT/TT genotypes at rs12979860 were three times less likely to spontaneously clear HCV [clearance rate: CT/TT=28% vs CC=53% vs OR 0.33 (0.25–0.45), P=10−13, overall cohort]. Similar effects were found in individuals of European or African American ethnicity. Nineteen per cent of the cohort was co-infected with HIV, and 10% were HBsAg-positive; neither infection altered the effect of this locus on the outcome of an acute HCV infection. These data were extended by a second group that performed a GWAS for spontaneous clearance in a Swiss/German cohort (chronic hepatitis C, n=1015; spontaneous clearance, n=347; n=448 were co-infected with HIV). They confirmed that variants of the IL28B gene region are the only common genetic variants associated with the spontaneous clearance of HCV infection, using a genome-wide approach [top association SNP=rs8099917, OR 2.31 (1.74–3.06), P=6.7 × 10−9] (29).

Mechanism

The mechanism by which genetic variation in the IL28B gene region influences the treatment response is unknown. None of the identified variants has an obvious effect on gene function (e.g. non-sense mutation). But even without a dramatic impact on protein production or structure, polymorphisms may exert a functional influence through gene expression, mRNA splicing, protein stability/half-life or, for cytokines like IFNs, receptor binding and activation. The data available to date are limited to studies of gene expression, with conflicting results. Ge and colleagues did not identify any association between the polymorphism rs12980275 and IL28B RNA expression in peripheral blood mononuclear cells from 80 HCV-negative individuals. In contrast, Suppiah and colleagues observed a weak association between rs8099917 and IL28B/IL28A expression in 49 healthy volunteers, where a higher expression was noted in the responder genotype (P=0.044); this effect was largely driven by lower expression in three patients homozygous for the non-responder genotype. Tanaka and colleagues were the only group to examine expression in HCV-infected patients. In a small cohort (n=20), higher expression levels of IL28B mRNA in patients with the responder genotype were observed. Further studies are required. Finally, although the association signals in all three studies were mainly due to IL28B gene variants, an effect from the nearby IL28A gene cannot be excluded.

We have to recall that in non-responders, some IFN-stimulated genes were highly expressed before treatment; thus, pre-activation of the IFN system in patients appears to limit the effect of IFN antiviral therapy (30, 31). Further ongoing studies evaluating the inter-relationships between IL28B polymorphisms and intrahepatic gene expression (in particular, the IFN pathway and immune response) may also shed some additional light.

Nevertheless, the finding that polymorphisms in genes of the IFN-λ family, also known as type III IFNs, are important for both spontaneous and treatment-related clearance of genotype 1 HCV has significant biological plausibility. Three members of the type III IFN family have been described, IFN-λ1/2/3 (IL29, IL28A, IL28B). IFN-λs appear to be ubiquitously expressed in response to the same viral stimuli that induce type 1 IFN (TLR ligands, double-stranded RNA) (34, 35). The IFN-LR is made up of two subunits – IFN-λ receptor 1 (IFN-LR1=IL28RA) and interleukin 10 receptor 2 (IL10R2=IL10RB); all three members of the IFN-λ signal via this receptor. The IFN-LR is believed to share a common downstream signalling pathway with the type 1 IFN receptor, activating the complex IFN-stimulated gene factor 3 (ISGF3=STAT-1/2·IRF-9), which binds to the IFN-stimulated response element to induce the transcription of IFN-stimulated genes. The major distinction recognized between type 1 and type III IFN appears to be the tissue distribution of the receptor. Whereas the type 1 IFN receptor is expressed by all cells, the type III IFN receptor (specifically, the IFN-LR chain) is more restricted. It is expressed on epithelial cells, including hepatocytes, but not on haemopoietic cells that therefore have an impaired response to IFN-λ. IFN-λs have been shown to inhibit HCV in cell culture models: it was less potent than IFN-α, but also at least additive with IFN-α. More recently, a subcutaneous preparation of IFN-λ1 has shown antiviral activity in HCV patients. Importantly, it remains unclear how IFN-α and IFN-λ interact in vivo, and the relevance of genetic variation in the IL28B gene region to IFN-λ1 therapy is not known.

Clinical applicability

Genotyping of one of the IL28B polymorphisms has great potential as a clinical diagnostic tool to aid in assessing the probability of response to current therapy. To test for a single polymorphism is not technically difficult or time consuming (the PCR-based assay uses the same technology as the current test used for haemochromatosis). A licensed assay has been available in the USA since July 2010. The SNP rs12979860 appears to be the most suitable simple genetic predictor of treatment outcome, because it has the strongest association signal in the largest cohort studied to date, thus explaining the lower observed response rates in AA patients. Knowledge of host IL28B type could help in the clinical decision-making process. The use of this genetic predictor might allow genotype 1 HCV-infected patients to be divided into 2 groups in the future: (i) those with the good response genotype, who might be managed in the same way as patients with genotypes 2/3 HCV, and (ii) those with the less favourable genetic response genotypes, in whom the decision about starting therapy must be evaluated in light of the expected availability of direct antivirals in the near future.

Future studies

A number of important clinical and more translational questions now must be addressed. These include whether IL28B type can be used to personalize the duration of therapy with SOC. That is, will rs12979860 CC ‘good responder’ patients only require 24 weeks of PEG-IFN and RBV therapy? Will direct antivirals overcome or attenuate the IL28B-type effect? It is likely that they will, at least to some degree, with fixed-duration regimens. However, perhaps IL28B type will allow a shortened duration of therapy, minimizing toxicity and drug resistance. Is IL28B type relevant to non-genotype 1 HCV infection and treatment outcomes? And is this relevant for those with HIV/HCV co-infection or for the rapidity and severity of post-transplant HCV recurrence [which might also depend on IL28B type of both the donor and the recipient liver as reported recently (40)]? What is the future for IFN-λ as a therapeutic, and will the IL28B type be relevant? And how will the geographical differences in the favourable IL28B allele frequency relate to treatment response, as well as to newer therapeutic regimens and durations? Is this a marker of IFN response above and beyond HCV infection, and if so, do other diseases with IFN-based regimens (such as hepatitis B, some malignancies, multiple sclerosis and others) interact differentially with IL28B types? And finally, the functional underpinnings of this genetic marker should, once unravelled, provide greater biological insight into treatment response in this disease and potential novel therapeutic approaches.

Should IL28B typing be included in hepatitis C virus clinical trials?

Because of the effect of the IL28B on treatment outcomes and early viral kinetics (Thompson A. J., personal communication), it seems very relevant that this factor, like HCV genotype, race, viral load and ethnicity, be incorporated into clinical trial designs. This is particularly relevant for new small-molecule studies, where an imbalance in IL28B type could be associated with significant numbers of patients, with the favourable IL28B type being randomized unequally into different arms of a particular study. This is especially true in small proof-of-concept studies (with less than 100 patients) and to a lesser degree in studies with approximately 250 subjects (Fig. 1). If this factor is not taken into account in trials of this size, there is an approximately 25–50% chance of a mismatch in terms of the proportion of patients with a favourable IL28B type randomized into each arm of any trial. Because of these discrepancies, the results of these trials could be incorrectly interpreted as favouring one treatment arm or dose of a drug, while in fact it is due to this factor alone.

What important clinical trials should now be performed?

It seems clear that many opportunities now exist to segment our HCV patients into groups of patients who are highly and less likely to respond to PEG-IFN and RBV therapy. Being able to determine the IL28B type before treatment makes it possible to position and perform certain trials:

1 A trial comparing PEG-IFN and RBV for 24 and 48 weeks in IL28B C/C favourable patients. Similar to genotype 2- and 3-infected patients, who only require 24 weeks of therapy, IL28B favourable patients might also only require a shorter duration of therapy. This is particularly relevant to East Asia, where the higher prevalence of the favourable C/C alleles and higher response rates might make a shorter duration of therapy possible for most patients.
 
2 A trial comparing PEG-IFN and RBV for 48 and 72 weeks (or longer) in IL28B unfavourable patients.
 
3 Evaluation of shorter triple therapy direct antiviral combination regimens (12 and 24 weeks) in IL28B C/C patients.
 
Conclusions
 
In conclusion, the identification of the genetic variation in the IL28B gene region as a predictor of genotype 1 chronic HCV treatment outcome is an exciting discovery. It sheds new light on virus–host interaction, and appears to have immediate clinical use as a diagnostic tool, providing potentially helpful information to both patients and clinicians considering therapy with PEG-IFN plus RBV. It is therefore a step towards a personalized approach to anti-HCV therapy. However, the treatment paradigm for genotype 1 HCV is about to change with the introduction of direct antivirals. The role of the IL28B variation in this setting as well as determining the duration of therapy required in these favourably genetically determined individuals with both current two-drug and future three-drug regimens requires semi-urgent investigation.
 
Conflicts of interest
 
John McHutchison is an employee of Gilead. He has received funding for research and acted as a consultant and advisor for Schering Plough and Merck. He is co-inventor of patents relating to the IL 28B and ITPA discoveres.

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Source

Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study

Journal of Viral Hepatitis
Early View (Articles online in advance of print)

J. Fung, C.-L. Lai, D. K.-H. Wong, W.-K. Seto, I. Hung, M.-F. Yuen

Article first published online: 7 JAN 2011
DOI: 10.1111/j.1365-2893.2010.01428.x
© 2011 Blackwell Publishing Ltd

Author Information
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
*Correspondence: Prof Man-Fung Yuen, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. E-mail: mfyuen@hkucc.hku.hk

Abstract

Keywords:
chronic hepatitis B;fibroscan;liver stiffness;longitudinal;transient elastography

Summary.  For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty-six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e-antigen (HBeAg)-positive, 293 (69%) were HBeAg-negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow-up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow-up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow-up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow-up ALT levels were independent significant factors associated with a decline in LSM.

Source

The liver-cytokine-brain circuit in interferon-based treatment of patients with chronic viral hepatitis

Journal of Viral Hepatitis
Early View (Articles online in advance of print)

C. Stasi, A. L. Zignego, G. Laffi, M. Rosselli

Article first published online: 7 JAN 2011
DOI: 10.1111/j.1365-2893.2010.01418.x
© 2011 Blackwell Publishing Ltd

Author Information
Department of Internal Medicine, University of Florence, Florence, Italy
*Correspondence: Cristina Stasi, MD, Dipartimento di Medicina Interna, Viale G.B. Morgagni, 85, 50134 Firenze, Italy. E-mail: cristina.stasi@unifi.it

Abstract

Keywords:
chronic viral hepatitis;cytokines;interferon;interleukins;psychological disorders

Summary.  Psychiatric symptoms are commonly identified in patients with viral hepatitis. They may have been present prior to the onset of disease and may include symptoms related to addiction issues. Furthermore, the virus and antiviral therapy, in particular interferon, may induce or modify psychiatric symptoms. Recent data support chronic hepatitis C replication in the brain and subsequent changes of cerebral metabolite spectra and magnetic resonance alterations. In chronic viral hepatitis and in other chronic inflammatory diseases, an alteration of the neuro-endocrine-immune system response has been observed. Catecholamines and glucocorticoids modulate this immune/inflammatory reaction. Psychiatric assessment and monitoring before, during and after antiviral therapy can identify patients whose psychiatric symptoms preclude therapy, and those who may benefit from psychopharmacological therapy and counselling, thereby improving therapeutic results. This review will discuss current insights into the complex interplay between cytokines, liver and brain in chronic viral hepatitis closely associated with psychiatric issues, especially in the case of antiviral therapy, with the aim of indicating future research and possible treatments.

Source

Hepatologists test drug on advanced liver cancer patients

2:03 p.m. EST, December 28, 2010

Hepatologists at the University of Florida have begun a new clinical trial in search of a better way to treat patients who have advanced, inoperable primary liver cancer but have trouble tolerating standard doses of the only drug available to help them.

Funded through a $650,000 grant from Bayer HealthCare Pharmaceuticals Inc. and Onyx Pharmaceuticals Inc., the makers and marketers of Sorafenib — the only FDA-approved drug for advanced liver cancer — the six-month, randomized pilot study will evaluate whether patients with a dual diagnosis of cirrhosis and liver cancer are better able to tolerate the drug if given doses that differ from the manufacturer's recommendation.

"The study will provide evidence for physicians about whether we can deliver more of the drug, improve tolerability and reduce adverse events by slowly introducing it," said study leader Roniel Cabrera, M.D., M.Sc., an assistant professor in the UF College of Medicine's division of gastroenterology, hepatology and nutrition.

UF and its Clinical and Translational Science Institute are coordinating the study, which will be carried out at 10 sites that include major Florida centers such as the University of South Florida, the University of Miami, the Florida Hospital, in collaboration with the University of Central Florida, and the Mayo Clinic in Jacksonville. The team hopes to develop a national academic consortium dedicated to advancing clinical and translational research efforts in hepatocellular carcinoma, the most common form of primary liver cancer.

"This study is very much targeting an unmet need in oncology, and it has the potential to clarify if we actually have the right dose for the medication," said Thom George, M.D., director of gastrointestinal oncology in the division of hematology/oncology at the UF College of Medicine, who is not directly involved in the study. "It may help answer the question of whether more patients will derive benefit from the treatment if we just go a little slower with the dosing."

Liver cancer, the fifth most common cancer and the third leading cause of cancer-related deaths, is a major global health problem. Despite new therapies, every year there are more than 600,000 new cases worldwide, and almost the same number of related deaths. Hepatocellular carcinoma is the leading cause of death among people who have chronic liver disease.

Many patients are diagnosed with advanced liver cancer at the same time they are diagnosed with cirrhosis, and that complicates treatment, since what works against one disease can worsen the other. When the cancer is advanced, treatment options are limited — surgery is impossible, and the most useful option left is the pill Sorafenib. It doesn't cure cancer, but in clinical studies, patients who took it survived for three to four months longer, on average, than untreated patients.

Manufacturers recommend a dose of two 200-milligram tablets twice a day. In practice, however, those doses are too high for patients with advanced disease to tolerate. The dosing recommendation is based on clinical studies in patients whose cirrhosis was under control. But "real life" patients show up at clinics with much worse cirrhosis and have negative reactions to the drug, including severe fatigue, skin rashes, gastrointestinal bleeding and worsening of liver function. That can be compounded by cirrhosis symptoms such as fatigue, confusion, fluid buildup in the abdomen and legs, and gastrointestinal bleeding.

"You can see how all those things can add up," Cabrera said.

In such patients, physicians have to discontinue therapy or give less than recommended.

Cabrera and colleagues will investigate whether a "ramp up" strategy that starts with one pill a day then adds a pill a week can improve how well patients tolerate the drug, the length of time they are able to remain on it, the amount they are able to handle overall without negative effects and the effect on the cancer being treated.

"This study will take patients who are not the most healthy, and see if there is a better way to still give them every chance to increase the benefits they receive from the medication and decrease the risk," George said. "That could potentially allow them to remain functional and be part of society and continue to work and provide for their families."

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Alcoholics Beware: Genetic Variation Linked to Liver Cirrhosis in Caucasians

Sunday, December 19th, 2010

Full findings are published in the January 2011 issue of Hepatology, a journal of the American Association for the Study of Liver Diseases.

Alcoholic liver disease (ALD) -- ranging from alcoholic fatty liver to alcohol induced liver fibrosis and cirrhosis -- accounts for more than 50% all chronic liver disease in industrialized countries and was responsible for over 25,000 deaths in the U.S. alone in 2005. Studies have shown that while all heavy drinkers display signs of hepatitis steatosis (fatty liver), only 10% to 35% of alcoholics develop hepatic inflammation, with up to 20% progressing to cirrhosis. Further medical evidence suggests a link between PNPLA3 gene variation and liver fat content; specifically the single nucleotide polymorphism (SNP) rs738409 was reported previously to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of European and Native American descent.

The German research team led by Jochen Hampe, MD, from Christian-Albrechts-Universität Kiel determined the genotype and allele frequencies of PNPLA3 rs738409 in 1043 alcoholics with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Cirrhosis and steatosis was determined by liver biopsy and standard diagnostic testing. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were established using routine clinical chemistry testing.

Participants were categorized as alcoholic liver cirrhosis (ALC); alcoholics with liver steatosis on ultrasound and elevation of ALT as alcoholic liver damage (ALD); alcoholic liver steatosis and normal liver enzyme levels as alcoholic fatty liver (AFL); and alcoholics with normal appearance of the liver on ultrasound and normal liver enzyme levels as alcoholic controls.

Researchers discovered that SNP rs738409 was strongly over-represented in patients with ALC and ALD compared to alcoholics without liver damage. Additionally, the frequency of allele PNPLA3 rs738409 in AFL participants was lower than in alcoholics without steatosis and normal liver enzymes. "Our findings show PNPLA3 rs738409 carriers represent a subpopulation of high risk individuals susceptible to progression from clinically silent alcoholic liver disease to obvious cirrhosis," Dr. Hampe concluded. "Carriers of this risk allele should be targeted for future pharmaceutical treatments and non-pharmacological interventions."

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Progress in the development of preventative and therapeutic vaccines for hepatitis C virus

Articles in Press

Joseph Torresiab, Doug Johnsonab, Heiner Wedemeyerc

Received 31 May 2010; received in revised form 27 August 2010; accepted 7 September 2010. published online 12 January 2011.
Accepted Manuscript

Abstract

Hepatitis C virus (HCV) is a blood borne disease estimated to chronically infect 3% of the worlds’ population causing significant morbidity and mortality. Current medical therapy is curative in approximately 50% of patients. While recent treatment advances of genotype 1 infection using directly acting antiviral agents (DAAs) are encouraging, there is still a need to develop vaccine strategies capable of preventing infection. Moreover, vaccines may also be used in future in combination with DAAs enabling interferon-free treatment regimens.

Viral and host specific factors contribute to viral evasion and present important impediments to vaccine development. Both, innate and adaptive immune responses are of major important for the control of HCV infection. However, HCV has evolved ways of evading the host’s immune response in order to establish persistent infection. For example, HCV inhibits intracellular interferon signalling pathways, impairs the activation of dendritic cells, CD8+ and CD4+ T cell responses, induces a state of T-cell exhaustion and selects escape variants with mutations CD8+ T cell epitopes. An effective vaccine will need to produce strong and broadly cross-reactive CD4+, CD8+ T cell and neutralising antibody (NAb) responses to be successful in preventing or clearing HCV.

Vaccines in clinical trials now include recombinant proteins, synthetic peptides, virosome based vaccines, tarmogens, modified vaccinia Ankara based vaccines and DNA based vaccines. Several preclinical vaccine strategies are also under development and include recombinant adenoviral vaccines, virus like particles and synthetic peptide vaccines. This paper will review the vaccines strategies employed, their success to date and future directions of vaccine design.

Keywords: Hepatitis C, vaccines, preventative vaccines, therapeutic vaccines, hepatitis C immunology.

a Austin Centre for Infection Research, Department of Infectious Diseases Austin Hospital, Heidelberg, Victoria 3084, Australia
b Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria 3084, Australia
c Department of Gastroenterology and Hepatology, Medizinische Hochschule, 30625 Hannover, Germany

PII: S0168-8278(11)00018-3
doi:10.1016/j.jhep.2010.09.040
© 2011 Published by Elsevier Inc.

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Noncirrhotic portal hypertension in HIV infection

Curr Opin Infect Dis. 2011 Feb;24(1):12-8.

Vispo E, Morello J, Rodriguez-Novoa S, Soriano V.

Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.

Abstract

PURPOSE OF REVIEW: Liver disease in the HAART era is one of the leading causes of morbidity and mortality in HIV-infected individuals in Western countries. Even if the majority of cases rely on identifiable causes (viral hepatitis, steatohepatitis, alcohol abuse, drug toxicity, etc.), the cause of liver abnormalities remains unknown for a subset of patients, some of whom present with noncirrhotic portal hypertension (NCPH).

RECENT FINDINGS: In 2006, the first reports of NCPH in HIV-infected patients attracted special attention. Typically, individuals unaware of any underlying liver illness presented with variceal bleeding, occasionally fatal. Interestingly, severe portal hypertension occurred in the absence of liver function impairment in most cases. Liver biopsy revealed a distinctive histological feature characterized by massive absence of portal veins along with focal obliteration of small portal veins. After extensive ruling out of other causes, the role of antiretroviral toxicity (particularly didanosine exposure) emerged as the major contributor to this condition. Other potential factors could be an enhanced microbial translocation from the gut and prothrombotic conditions.

SUMMARY: NCPH is an uncommon condition, although increasingly being reported in HIV-infected individuals. It generally presents as a clinical episode of decompensated portal hypertension, generally with gastrointestinal bleeding. Long-lasting HIV infection and prolonged antiretroviral exposure are universally recognized in these patients. The involvement of didanosine has been highlighted in most series. Removal of this drug and prevention of variceal bleeding episodes are currently the most effective prophylactic and therapeutic interventions.

PMID: 21157331 [PubMed - in process]

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Antibody Dynamics and Spontaneous Viral Clearance in Patients with Acute Hepatitis C Infection in Rio de Janeiro, Brazil

Published on: 2011-01-12

The anti-HCV antibody response has not been well characterized during the early phase of HCV infection and little is known about its relationship to the clinical course during this period.

Methods: We analyzed serial anti-HCV antibodies longitudinally obtained from a prospective cohort of 65 patients with acute HCV infection by using a microparticle enzyme immunoassay AxSYM HCV 3.0 (Abbott Diagnostics) during the first 12 months from HCV acquisition in Rio de Janeiro, Brazil. Spontaneous viral clearance (SVC) was defined as undetectable HCV RNA in serum, in the absence of treatment, for three consecutive HCV PCR tests within 12-months of follow-up.

Results: Baseline antibody values were similar among patient groups with self-limiting HCV evolution (n=34) and persistent viremia (n=31) [median (interquartile range) signal/cut-off ratio (s/co) 78.7 (60.7-93.8) vs. 93.9 (67.8-111.9), p=0.26]. During 12-months follow-up, patients with acute spontaneous resolving HCV infection showed significantly lower serial antibody response in comparison to individuals progressing to chronic infection [median (interquartile range) s/co 62.7 (35.2-85.0) vs. 98.4 (70.4-127.4), p<0.0001]. In addition, patients with self-limiting HCV evolution exhibited an expeditious, sharp decline of serial antibody values after SVC in comparison to those measured before SVC [median (interquartile range) s/co 56.0 (25.4-79.3) vs.79.4 (66.3-103.0), p<0.0001].

Conclusion: Our findings indicate a rapid short-term decline of antibody values in patients with acute spontaneous resolving HCV infection.

Author: Alexander StrasakArthur KimGeorg LauerPaulo de SousaCleber GinuinoCarlos FernandesCarlos VellosoAdilson de AlmeidaJaqueline de OliveiraClara YoshidaJulian Schulze zur WieschGlaucia Paranhos-BaccalaStefan LangLarry BrantHanno UlmerSusanne Strohmaie

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Gender Not Linked to Liver Disease Progression in HIV/HCV+ Canadians

1st International Workshop on HIV and Women, January 10-11, 2011, Washington, DC

Mark Mascolini

Canadian women coinfected with HIV and hepatitis C virus (HCV) did not differ from coinfected men in liver disease progression through 1 to 1.5 years of follow-up, though women and men did differ sociodemograpically and in risk behavior. The investigators noted that longer follow-up may be needed to identify potential gender-based progression differences in this cohort.

As people coinfected with HIV and a hepatitis virus live longer on antiretroviral therapy, liver disease progression poses a growing threat. Researchers established the Canadian Coinfection Cohort (CCC) to assess the impact of antiretroviral therapy and anti-HCV therapy on progression to end-stage liver disease. This analysis sought to determine whether gender affects progression of liver fibrosis in coinfected people.

The study involved coinfected people enrolled in the cohort from 2003 through 2009 at 16 centers across Canada. Study participants complete questionnaires on sociodemographics, drug use, and clinical care and give samples for biochemical, virologic, and immunologic studies every 6 months. CCC investigators determined the aspartate aminotransferase-to-platelet ratio index (APRI) as a fibrosis surrogate for all cohort members. An APRI at or above 1.5 has been validated as a marker of significant fibrosis and end-stage liver disease; that score corresponds to a biopsy score of F2 or higher. The investigators defined liver disease progression as reaching a score of 1.5 or higher during follow-up.

Of the 934 people enrolled, CCC researchers excluded 354 (38%) from this analysis because they already had an APRI of 1.5 or higher, already had end-stage liver disease, were transgendered, or had missing data. Of the remaining 580 cohort members, 422 (73%) were men and 158 (27%) women.

The study group had a median initial CD4 count of 396 (the same in women and men), 79% were taking antiretrovirals, and 54% had an HIV load below 50 copies. These measures, as well as distribution of HCV genotypes and initial APRI scores, were similar in women and men. However, women were younger (41 versus 45 years, P < 0.001) and more likely to be aboriginal (30% versus 10%, P < 0.001), to be heterosexual (87% versus 74%, P < 0.01), and to have a history of sex work (60% versus 40%, P < 0.001). A significantly lower proportion of women used alcohol (41% versus 52%, P < 0.05). A higher proportion of women than men had a history of injection drug use (88% versus 82%), but the difference was not statistically significant (P = 0.101).

Women had median HCV and HIV durations of 10.5 and 17.8 years, versus 11.8 and 18.8 in men. Median follow-up time was 1.0 years for women (interquartile range [IQR] 0.3 to 6.5) and 1.4 years (IQR 0.3 to 7.0) for men (P < 0.05). During follow-up the APRI score rose to 1.5 or higher in 71 people (12%) for an incidence of 9.7 per 100 person-years (95% confidence interval [CI] 7.4 to 11.9).

Among the 71 people whose APRI rose to 1.5 or higher, 23 were women and 48 were men. In an unadjusted analysis, liver disease progression by this measure appeared to be more frequent in women (11.5 per 100 person-years, 95% CI 8.0 to 19.1) than in men (8.5 per 100 person-years, 95% CI 6.1 to 10.9). But after statistical adjustment for age, duration of HIV and HCV, baseline APRI, HBV coinfection, active injection drug use, active alcohol use, nadir CD4 count, highest HIV viral load, prior treatment for HCV, and time-updated CD4 and HIV RNA, women did not have a significantly higher risk of progression (adjusted hazard ratio 1.53, 95% CI 0.90 to 2.67). Nineteen people died during follow-up, including 14 men and 5 women (difference not significant).

Two factors emerged as independent predictors of reaching an APRI at or above 1.5: An initial APRI below 0.5 more than quadrupled the risk (hazard ratio 4.6, 95% CI 2.5 to 8.4, P < 0.001). And every 100 cell higher time-updated CD4 count lowered the risk about 15% (hazard ratio 0.858, 95% CI 0.748 to 0.984, P < 0.05).

The CCO team concluded that sociodemographic and risk behavior patterns differ between HIV/HCV-coinfected women and men in Canada. But over the short term, there appeared to be no association between gender and liver disease progression. In HCV-monoinfected people, the investigators noted, liver disease has been reported to be milder in women than men. They stressed that the long gap between HCV infection and HIV infection--about 7 years in both women and men--point to a failure of HIV prevention in HCV-positive people. The link between higher CD4 count and slower liver disease progression indicates that improved immune function has liver-related benefits in coinfected women and men.

Reference
1. Pick N, Castillo E, Rollet K, et al. Gender and liver disease progression in HIV-hepatitis C co-infection. 1st International Workshop on HIV and Women. January 10-11, 2011. Washington, DC. Abstract O_21.

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Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century

Vox Sanguinis
Volume 100, Issue 1, pages 92–98, January 2011

D. M. Dwyre, L. P. Fernando, P. V. Holland

Article first published online: 22 DEC 2010
DOI: 10.1111/j.1423-0410.2010.01426.x
© 2010 The Author(s). Vox Sanguinis © 2010 International Society of Blood Transfusion

Author Information
Department of Pathology, University of California Davis Medical Center, Sacramento, CA, USA
*Correspondence: Denis M. Dwyre, Department of Pathology, University of California Davis Medical Center, 4400 V Street, Sacramento, CA 95817, USA E-mail: denis.dwyre@ucdmc.ucdavis.edu

Abstract

Keywords:
hepatitis B;hepatitis C;HIV;pathogen inactivation;transfusion-transmitted infections

In the past, transfusion-transmitted virus (TTV) infections were not uncommon. In recent years with advanced technologies and improved donor screening, the risk of viral transfusion transmission has been markedly reduced. Hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have all shown marked reduction in transmission rates. However, the newer technologies, including nucleic acid technology (NAT) testing, have affected the residual rates differently for these virally transmitted diseases. Zero risk, which has been the goal, has yet to be achieved. False negatives still persist, and transmissions of these viruses still occur, although rarely. It is known that HBV serological testing misses some infected units; likewise, HBV NAT–negative units have also been known to transmit the virus. Similarly, HIV minipool NAT–negative units have transmitted HIV, as recently as 2007; likely, these transmissions would have been prevented with single-unit NAT testing. Newer technologies, such as pathogen inactivation (PI), will (ideally) eliminate these falsely test negative components, regardless of the original testing method used for detecting the viruses

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Noninvasive assessment of liver fibrosis†

Hepatology
Volume 53, Issue 1, pages 325–335, January 2011
Stella M. Martínez, Gonzalo Crespo, Miquel Navasa, Xavier Forns,‡

Article first published online: 29 NOV 2010
DOI: 10.1002/hep.24013
Copyright © 2010 American Association for the Study of Liver Diseases

Author Information
Liver Unit, Hospital Clínic, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer) and CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Barcelona, Spain

Email: Xavier Forns (xforns@clinic.ub.es)
*Correspondence: Xavier Forns, Liver Unit,Villarroel 170, Hospital Clinic, Barcelona 08036, Spain
†Potential conflict of interest: Nothing to report.
‡fax: (34)-93-451-55-22

Abstract

Liver biopsy has long been an important tool for assessing the degree of liver fibrosis. Information on the presence and degree of liver fibrosis is useful before making therapeutic decisions or predicting disease outcomes. The need to stage liver fibrosis, however, should decrease as treatment options become more successful (as has occurred with viral hepatitis). In recent years, noninvasive tests have demonstrated a reasonable ability to identify significant fibrosis, cirrhosis in particular, nor is it surprising that liver disease specialists and patients favor a noninvasive approach. However, only those tests with the highest diagnostic accuracy, cost-effectiveness, and availability should be implemented. Apart from their diagnostic accuracy, the potential ability of these tests to predict disease outcomes (a more relevant endpoint) should be compared with that of liver biopsy. Indeed, the use of a standardized system to evaluate the utility of biomarkers would facilitate their implementation in clinical practice. (HEPATOLOGY 2011.)

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Genotype differences in susceptibility and resistance development of hepatitis C virus to protease inhibitors Telaprevir (VX-950) and Danoprevir (ITMN-191)

Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)

Ingrid Imhof, Peter Simmonds,†

DOI: 10.1002/hep.24172
Copyright © 2011 American Association for the Study of Liver Diseases

Author Information

Centre for Infectious Diseases, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK
Email: Peter Simmonds (Peter.Simmonds@ed.ac.uk)

*Correspondence: Peter Simmonds, Centre for Infectious Diseases, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK
†Ph: 0131 650 7297; Fax: 0131 650 6511

Keywords: Phenotype;mutation;NS3 protease;antiviral;BILN 2061

Abstract

Protease inhibitors (PIs) have proven to be effective adjuncts to interferon / Ribavirin treatment of hepatitis C virus (HCV) infections. Little clinical or in vitro data exists however, on their effectiveness for non-type 1 genotypes that predominate in Europe, the Middle East, Africa and most of Asia.

NS3 protease and NS4A genes from genotypes 1-6 were inserted into the JFH clone to generate replication competent intergenotype chimaeras. Susceptibility to PIs was determined by replication and infectivity assays. To study resistance development, chimaeras were cultured in sub-inhibitory concentrations of PIs and mutations phenotypically characterised. Marked differences in susceptibility of different genotypes to Danoprevir (ITMN-191) and Telaprevir (VX-950) were observed. Genotypes 1, 4 and 6 showed IC50 values of 2-3 nM, >100-fold lower than genotypes 2/3/5 (250-750 nM). Telaprevir susceptibilities varied over a five-fold range, with genotypes 1 and 2 being most susceptible, and genotype 4 and 5 most resistant. Culture of genotypes 1-6 in PIs induced numerous mutations in the NS3 protease domain, highly variable between genotypes. Introduction of Danoprevir and BILN 2061-induced mutations into the original clones by site-directed mutagenesis (n=29) all conferred resistant phenotypes, with particularly large increases (1-2 log greater IC50 values) in the initially susceptible genotypes 1/4/6. Most introduced mutations, showed little or no effect on replicative fitness.

Major differences were found between genotypes in their susceptibility and resistance development to PIs. However, equal sensitivities of genotypes 1, 4 and 6 to Danoprevir and a broader efficacy range of Telaprevir between genotypes than initially conceptualised provide strong evidence that PIs might be effectively used beyond their genotype 1 target group. (HEPATOLOGY 2011.)

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Louisiana Outlines Appointments To HIV, AIDS, And Hepatitis C Commission

Source: Governor of Louisiana
Posted on: 12th January 2011

Governor Bobby Jindal has announced appointments to the HIV, AIDS, and Hepatitis C Commission.

The HIV, AIDS, and Hepatitis C Commission serves as an advisory body to the governor and the Department of Health and Hospitals on AIDS, HIV and Hepatitis C related matters.

The commission is responsible for coordinating forums on AIDS, HIV and Hepatitis C related matters among state agencies, local government, and other nongovernmental groups.

The commission researches and reviews all state regulations, guidelines, policies, and procedures relative to the prevention, treatment and care of HIV infection, AIDS, and Hepatitis C and, when appropriate, makes recommendations to the governor, the secretary of the Department of Health and Hospitals, and the legislature.

The HIV, AIDS, and Hepatitis C Commission consists of the following 29 governor’s appointments:

• Two persons infected with the human immunodeficiency virus (HIV), at least one of whom represents a racial or ethnic subpopulation.
• Two persons infected with hepatitis C, where one person is co-infected with HIV, and at least one of whom represents a racial or ethnic subpopulation.
• Two representatives from community-based provider organizations providing services to persons infected with the human immunodeficiency virus, one of which represents a racial or ethnic subpopulation.
• Two medically qualified representatives from a medical provider or community-based provider organizations providing services to persons infected with hepatitis C, one of which represents a racial or ethnic subpopulation.
• One representative from the Louisiana Primary Care Association.
• Two representatives from the Ryan White Consortia.
• Two representatives from the statewide HIV Prevention Community Planning Group.
• One physician representative from the Louisiana State Medical Society.
• One physician representative from the Louisiana Medical Association.
• One nurse representative from the Louisiana Nursing Association.
• One social worker representative from the Louisiana Chapter of the National Association of Social Workers. 
• One representative from the Louisiana Association of Substance Abuse Counselors and Trainers.
• Four Ryan White Care Act grantees consisting of one Title I grantee, one Title II grantee, one Title III grantee, and one Title IV grantee. 
• One representative of the Ryan White CARE Act Delta Region AIDS and Education Training Center.
• One representative from the Louisiana Dental Association.
• One representative from the Pelican Dental Association.
• One representative from the Louisiana State Board of Pharmacy.
• One representative from the Louisiana Psychological Association.
• One representative from the Louisiana Interchurch Conference.
• One representative from the Louisiana State University School of Dentistry.
• Appointments to the HIV, AIDS, and Hepatitis C Commission:

Leah Cullins, of Baton Rouge, is an assistant professor/family nurse practitioner at Southern University School of Nursing. Cullins will be appointed to serve as a nurse representative from the Louisiana Nursing Association, as required by statute.

Christina Eaton, of Metairie, is an HIV trainer for the Delta Region AIDS Education and Training Center. Eaton will be reappointed to serve as a representative of the Ryan White CARE Act Delta Region AIDS and Education Training Center, as required by statute.

Chris Melancon, of Carencro, is the owner of Melancon Pharmacy. Melancon will be appointed to serve as a representative from the Louisiana State Board of Pharmacy, as required by statute.

Enrique Moresco, of New Orleans, is the director of operations for the New Orleans AIDS Task Force. Moresco will be reappointed to serve as a person infected with the human immunodeficiency virus (HIV), whom represents a racial or ethnic subpopulation, as required by statute.

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