Fighting an Uphill Battle': Experience With the HCV Triple Therapy

Fighting an Uphill Battle': Experience With the HCV Triple Therapy
What support is needed for patients undergoing the burdensome HCV triple therapy?

BMC Infectious Diseases

Available @ Medscape:

Fighting an Uphill Battle': Experience With the HCV Triple Therapy
Qualitative Thematic Analysis
Manuela Rasi, Patrizia Künzler-Heule, Patrick Schmid, David Semela, Philip Bruggmann, Jan Fehr, Susi Saxer, Dunja NiccaDisclosures

BMC Infect Dis. 2014;14(507)
December 05, 2014 

Discussion Provided Below

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• Abstract and Introduction
• Background
• Methods
• Results
• Discussion
• Conclusions

Discussion Only
This thematic analysis provides insights into HCV patients' experiences with PI based triple therapy. Before beginning their therapy, these patients were powerfully motivated to improve their health and achieve a cure. For dual therapy, patients have associated concerns regarding disease progression, loss of liver function and other potential health problems with treatment initiation.[43,44] However, this study group's homogeneously high motivation might not reflect the attitude of the majority of HCV patients in need for treatment. Studies have shown that large proportions of patients (10% - 44%) undergoing dual therapies typically discontinue treatment.[15,43,45] Although we included participants from three different outpatient clinics and used maximum variation sampling to ensure diverse characteristics and living circumstances, there might have been an earlier clinical selection of highly motivated patients treated with the then-newly-available triple therapies and the next generation of interferon-free treatments.

Soon after starting triple therapy, our highly-motivated study group found themselves struggling. The constitutive theme–"Fighting an uphill battle"–describes the patients' common existential experience of coping with the therapy's side effects and indirect negative consequences. Bell et al. describe similar existential treatment experiences among cancer patients receiving adjuvant chemotherapy.^[46] However, in contrast to cancer patients, who saw their symptoms as a means of tracking treatment effectiveness and increasing the possibility of remission, this study's HCV patients indicated beliefs congruent with research on triple therapy, i.e., that it numerous side effects, including possible life threatening adverse events, are to be expected, but that no associations exist between symptoms and success.^[18,47]

In this study, despite information from healthcare providers and research oriented treatment reports, the symptoms experienced surpassed the patients' expectations (as described in the "Encountering surprises" subtheme). Across chronic conditions, high symptom numbers, high symptom distress and low perceived symptom manageability have negative impacts on health outcomes including quality of life and medication adherence.^[48,49] Given the high number of HCV patients who commonly interrupt dual therapy and the high symptom burden of triple therapy, it can be hypothesized that mitigating patient distress via early symptom management support will increase successful completion of therapy and would decrease dropout rates in less persistent patient groups. And while even healthcare providers were occasionally surprised by the severity and diversity of the new treatment's side effects, the first step of effective symptom management is to assess patients' perceptions of their symptoms.^[50] However, our records illustrate very clearly that the participants' symptom experiences were often so foreign to them that only metaphoric language was sufficient to explain them. Therefore, standard biomedical symptom assessment by health care providers might not be sufficient to capture the details of symptoms or symptom clusters that impact safety, adherence and treatment persistence. And with the prospect of HCV treatment options appearing in the near future, a proactive and patient-oriented system of symptom assessment will remain an important component of clinical HCV management. On the one hand these treatments are expected to entail fewer and less severe adverse events; on the other, they will also be used in patients in advanced stages of the disease, suffering co-morbidities and living in more complex circumstances.
As described above in the subtheme "Reaching the limits of systems" the therapy's drastic physical and emotional effects fundamentally disrupted participants' everyday lives and severely limited their social interactions. Similar phenomena have been described for symptomatic but untreated HCV patients, as well as for other chronic conditions.^[51]

However, the radical social changes described by our study participants appeared heavily influenced by their fear of stigmatization. In order to protect themselves from negative social consequences, it is common for patients with stigmatized infectious diseases such as HIV and HCV to make careful disclosure decisions and in some cases conceal their conditions as fully as possible.^[52–54] Our illness-experienced study group described a range of selective disclosure management strategies that had apparently been effective before the start of their triple therapy. During treatment, though, the sudden appearance of visible symptoms led to isolation when support was most needed. In some cases, though, the perception of societal rejection might simply have been internalized, i.e., the fear of stigmatization may have led some to project it onto those around them. Recent evidence shows promising approaches to combatting internalized stigma (self-stigmatization) by improving both self-esteem and help-seeking behavior.^[55,56] To minimize stress and improve social support during HCV treatment, healthcare providers should discuss stigmatization fears and disclosure management strategies during consultations both before and during treatment.

The importance of social support is also apparent in the "Reaching the limits of systems" subtheme. Participants recalled both how their symptoms sometimes impaired their judgment and how, during these periods of diminished capacity, the support of family members and close friends was crucial. The positive effects of social support on chronically ill patients' health outcomes is well documented. For example, for patients living with HIV and receiving antiretroviral treatment, a stable partnership is associated with a slower progression to AIDS or death;^[57] and among patients living with HCV, those who are married are more likely to complete dual therapy.^[43] In addition to companionship, close social contact is known to have multifaceted benefits, including emotional, instrumental, informational support.^[34,58,59]

Since study patients revealed problems with judgment and efficacy concerning sometimes life threatening symptoms, a sound knowledge of HCV treatment and decision making skills is important not only for patients but for their close support persons. This requires healthcare providers to identify close support persons and integrate them into patient education programs. Where social contact with support persons is limited, professional support, e.g., community care, should be intensified.
Based on current evidence and clinical expertise, difficulties in adherence with the complex triple therapy regimens are to be expected.^[18,28,59] Surprisingly, this study's patients did not raise the issue of medication management. However, as some patients mentioned difficulties when asked, adherence issues may simply have been eclipsed by the intensity of the medications' side effects. Given that heavy symptom burdens (often much lighter than those described by this study's patients) are known to impact adherence, and that poor adherence to dual therapy is known to impact virological response,^[25–27] it is important to integrate non-judgmental adherence assessment into routine clinical care.

The insights provided by this study illustrate the need to assess patient perspectives of new treatment options in 'real-life' settings–as opposed to those of clinical trials. In clinical care, clinicians routinely treat patients who would have been excluded from clinical trials due to medical, social or behavioral problems. Research shows that exactly such medical or socio-behavioral challenges impair results in patients with HCV.^[42,60,61] Therefore, despite the availability of new HCV treatment options, it remains important to assess patients' treatment experiences with various other regimens where, based on information from clinical trials, these treatments offer higher tolerability and manageability. Furthermore, considering the extremely high cost of the currently-available IFN-free regimes with improved tolerability, it can be expected that they will not be used in all countries.

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Hepatitis C Cure

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by Katharin Czink
Medical Watch Producer

Once considered a chronic and often deadly disease, now doctors are using a powerful word to describe the results of a new treatment for Hepatitis C.

Dr. Donald Jensen, University of Chicago Medicine: “This is a curable disease.”

It is news University of Chicago Medicine’s Dr. Donald Jensen is happy to spread. For 25 years he’s treated patients with hepatitis c, a virus that attacks the liver and causes inflammation. Over time, tissue in the organ turns to scar, cirrhosis sets in.

Dr. Jensen: “It’s like marbling in beef. It’s throughout the liver.”

Patients can develop liver cancer. More commonly, they end up in liver failure and require a transplant. But many don’t realize they have the virus.

Dr. Jensen: “The most common symptom is fatigue, which is pretty common for all of us.”
Judy Palmer knew something was wrong six weeks after she received a blood transfusion due to complications following the birth of her daughter.

Judy Palmer: “I started turning jaundiced and having abdominal pain.”

That was years before doctors even had a name for the virus that was attacking Judy’s liver. In the early 1990s, doctors used interferon alone – an injectable medication that suppresses the virus. But the medicine’s severe side effects, lengthy 12-month course and low success rates deterred many patients. But Judy forged ahead.

Judy Palmer: “My response was always the same … as soon as I was off treatment the virus came back.”

Dr. Jensen: “In 1999 we added another medication called ribavirin and that boosted the success rate from in the teens and 20s to around 40%. In 2011 we added a third drug.”

A protease inhibitor, an oral medication that turns off a genetic switch and stops the virus from replicating.

Dr. Jensen: “Adding a protease inhibitor to a backbone of interferon and ribavirin then boosted the success rate to up to 75%, which is a huge step up.”

Dr. Jensen tested the new combination as part of a clinical trial. Judy signed on. Since that time she’s been virus free.

Judy Palmer: “I tell people this is my miracle. After 30 years I never thought I’d see this day.”

Dr. Jensen: “When we follow those patients out beyond six months and out to 10 years, 98% of those people remain virus undetectable, their liver goes back toward normal, there’s no virus in their liver.

At the very least it freezes the disease at the stage they were cured.”

Fifty-seven year old Michael Marcotte is hoping the new drug combination will help him, too. Diagnosed in the early 1990s, he put off treatment, waiting for a more promising therapy.

Michael Marcotte: “It’s scary, when you hear those words that you’re that close to cirrhosis, you can only imagine what goes through your mind. This is like a new lease on life to me.”

Doctors say 75% of Hep C patients are likely baby boomers born between 1945 and 1965, but most don’t now they have the virus. Now the CDC is recommending one-time screening, which will likely uncover 800,000 new cases.

University of Chicago Medicine doctors are looking for more patients to enroll in drug trials. Go to http://www.uchospitals.edu/news/features/hepatitisc-cure.html to learn more.

If you’d like information about the HCV Cure support group for patients, call (773) 834-3634 or (312) 377-9030.

Read more: http://wgntv.com/2013/03/07/hepatitis-c-cure/#ixzz2MxGQZTJI
Read more at http://wgntv.com/2013/03/07/hepatitis-c-cure/#g2g8Vql14B5hrOEs.99

Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection in Adults: A Systematic Review

Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection in Adults: A Systematic Review

Roger Chou, MD; Daniel Hartung, PharmD, MPH; Basmah Rahman, MPH; Ngoc Wasson, MPH; Erika Barth Cottrell, PhD, MPP; and Rongwei Fu, PhD

[+-] Article and Author Information

Full Text Available @ Annals Of Internal Medicine

Abstract
Background: Multiple treatments are available for chronic hepatitis C virus (HCV) infection.

Purpose: To compare benefits and harms of antiviral regimens for chronic HCV infection in treatment-naive adults.

Data Sources: English-language literature from MEDLINE (1947 to August 2012), the Cochrane Library Database, Embase, Scopus, PsychINFO, and clinical trial registries.

Study Selection: Randomized trials of antiviral treatments and cohort studies examining associations between sustained virologic response (SVR) after therapy and clinical outcomes.

Data Extraction: Several investigators abstracted study details and quality by using predefined criteria.

Data Synthesis: No trial evaluated effectiveness of treatment on long-term clinical outcomes. Dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a lower likelihood of SVR than was pegylated interferon alfa-2a plus ribavirin (absolute difference, 8 percentage points [95% CI, 3 to 14 percentage points]) on the basis of 7 poor- to fair-quality trials. For genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood of SVR than was therapy for 24 weeks, and lower doses of pegylated interferon alfa-2b were less effective than standard doses (2 to 4 fair-quality trials). For genotype 1 infection, fair-quality trials found that triple therapy with pegylated interferon, ribavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was associated with a higher likelihood of SVR than was dual therapy (absolute difference, 22 to 31 percentage points). Compared with dual therapy, boceprevir triple therapy increased risk for hematologic adverse events and telaprevir triple therapy increased risk for anemia and rash. A large well-designed cohort study and 18 smaller cohort studies found that an SVR after antiviral therapy was associated with lower risk for all-cause mortality than was no SVR.

Limitations: Trials involved highly selected populations. Observational studies did not always adequately control for confounders.Conclusion: SVR rates for genotype 1 infection are higher with triple therapy that includes a protease inhibitor than with standard dual therapy. An SVR after antiviral therapy appears associated
with improved clinical outcomes

Discussion Only

Full Text Available @ Annals Of Internal Medicine

Antiviral therapy for chronic HCV infection continues to evolve. No study evaluated comparative effectiveness of current antiviral regimens on long-term clinical outcomes. Such trials are a challenge to carry out because of the long time course over which complications of HCV infection develop. 

In lieu of direct evidence on long-term clinical outcomes, SVR rates are the primary outcome measure with which to evaluate comparative effectiveness. For treatment-naive patients, dual therapy with pegylated interferon alfa-2b is associated with a lower likelihood of SVRpegylated interferon alfa-2a (absolute difference, about 8 percentage points). Although there was no difference between dual-therapy regimens in risk for withdrawals due to adverse events, pegylated interferon alfa-2b was associated with a lower risk for serious adverse events, suggesting potential tradeoffs between benefits and harms. However, serious adverse events were reported in only 2 trials (21,29), the absolute difference was only about 1%, and antiviral-related adverse events are generally self-limited.

For genotype 2 or 3 infection, standard doses and durations (24 weeks) of pegylated interferon as part of dual therapy are more effective than shorter regimens or lower doses, lending support to current dosing guidance (4,79 - 80). Evidence on differential effects of ribavirin dose is limited, although differences were small in most studies.

The relative ineffectiveness of dual therapy for genotype 1 infection has led to ongoing efforts to identify more effective treatments. Recent trials found triple therapy with boceprevir or telaprevir superior to dual therapy, with SVR approaching the 70% to 80% rates observed in trials of dual therapy for genotype 2 or 3 infection (20,22,31,55 - 59). This has important implications for treatment, as well as for screening, because screening benefits depend in part on the effectiveness of available treatments (81).

Triple therapy for genotype 1 infection is also associated with shorter duration of treatment, an important consideration given the high frequency of adverse effects associated with interferon-based therapy. However, triple therapy is also associated with increased risk for hematologic adverse events with boceprevir (neutropenia, anemia, and thrombocytopenia) and anemia and rash with telaprevir (including severe rash in less than 10% of patients), although there was no clear increase in risk for serious adverse events overall. Across all antiviral regimens, absolute treatment response rates are lower in older patients; black patients; and patients with higher baseline viral load, genotype 1 infection, or more advanced fibrosis. 

The strongest evidence on the association between virologic and clinical outcomes is a large Veterans Affairs cohort study that found SVR to be associated with a 30% to 50% reduction in mortality risk, after adjustment for many confounders (61). The rapid separation of mortality curves in this study suggests possible residual confounding, given the typically protracted course of HCV infection. Therefore, estimates of benefit may be exaggerated, although it is not possible to determine to what degree. Eighteen other cohort studies also found that SVR was associated with decreased risk for serious complications of chronic HCV infection, but these studies had more methodological shortcomings than did the Veterans Affairs study.

Our study has limitations. We excluded non–English-language articles. We did not perform formal analyses for publication bias because of the small numbers of trials, but analyses of abstracts and searches of clinical trials registries did not suggest publication bias. Meta-analyses were performed by using the DerSimonian–Laird random-effects model, which results in CIs that are slightly too narrow when heterogeneity is present, so that pooled estimates with 95% CIs close to 1.0 should be interpreted cautiously (82). Estimates and conclusions based on small numbers of trials should also be interpreted cautiously. For example, pooled estimates based on 2 trials can be unreliable, particularly when statistical heterogeneity is present. The trials generally met criteria for efficacy studies, which could limit their applicability because of exclusion of patients with comorbid conditions, and greater adherence than typically observed in clinical practice. Almost all of the randomized trials were funded by pharmaceutical companies (83 - 84).

Additional research would help clarify the comparative effectiveness of antiviral treatments. Studies are needed to understand the long-term clinical outcomes associated with different antiviral treatments, the long-term harms of telaprevir and boceprevir, the comparative effectiveness of triple therapy with telaprevir versus boceprevir, and effective strategies to improve adherence (85). Other direct-acting antiviral agents, including second-generation protease inhibitors, polymerase inhibitors, NS5A inhibitors, and others, are in active development, with all-oral, interferon-sparing regimens expected within the next few years (86).

 

Full Text Available @ Annals Of Internal Medicine

 

 

HCV: second-generation protease inhibitors

Liver International

Special Issue: Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis

Volume 33, Issue Supplement s1, pages 80–84, February 2013

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New therapeutic strategies in HCV: second-generation protease inhibitors

Virginia C. Clark,
Joy A. Peter,
David R. Nelson*

Article first published online: 3 JAN 2013

DOI: 10.1111/liv.12061

Keywords:
Hepatitis C;
protease inhibitors;
ACH 2684;
MK 5172

Abstract
Telaprevir and boceprevir are the first direct-acting antiviral agents approved for use in HCV treatment and represent a significant advance in HCV therapy. However, these first-generation drugs also have significant limitations related to thrice-daily dosing, clinically challenging side-effect profiles, low barriers to resistance and a lack of pan-genotype activity. A second wave of protease inhibitors are in phase II and III trials and promise to provide a drug regimen with a better dosing schedule and improved tolerance. These second-wave protease inhibitors will probably be approved in combination with PEG-IFN and Ribavirin (RBV), as well as future all-oral regimens. The true second-generation protease inhibitors are in earlier stages of development and efficacy data are anxiously awaited as they may provide pan-genotypic antiviral activity and a high genetic barrier to resistance.

Abbreviations
AEs adverse effects
cEVR complete early virological response
PIs NS3-4A protease inhibitors
RVR rapid virological response
SVR sustained viral response

A large number of NS3-4A protease inhibitors (PIs) have reached clinical development, including two drugs, telaprevir and boceprevir, that have already been approved for use in combination with pegylated IFN-α (PEG-IFN) and ribavirin (RBV) in patients infected with genotype 1 hepatitis C virus. Telaprevir and boceprevir significantly improve virological outcomes in both treatment-naїve [1, 2] and -experienced genotype 1 patients [3, 4]. However, the clinical utility of these first-generation PIs is limited by a thrice-daily dosing schedule (with food), increased rates of adverse effects (AEs) (anaemia and rash), a low genetic barrier to resistance and extensive drug–drug interactions. These limitations highlight the opportunities for improvement in protease inhibitors. This review will discuss the newer protease inhibitors under late-stage development, which should be more potent, with higher barriers to viral resistance, and improved dosing regimens.

Second-wave protease inhibitors

 

Second-wave protease inhibitors offer several advantages over currently available drugs. Improved pharmacokinetics will allow a once-a-day dosing schedule and the side-effect profiles are more tolerable. However, these agents have similar genotype coverage and similar resistance profiles to telaprevir and boceprevir, and do not represent true second-generation PIs. The improved PIs have been referred to as second-wave PIs. They will probably replace first-generation PIs in combination with PEG-IFN/RBV to become the initial partners in the first generation of all-oral regimens. The following drugs are currently in phase II and III development (Table 1).

Table 1. HCV protease inhibitors
 

Telaprevir	Approved	First generation
Boceprevir	Approved	First generation
Simeprevir	Phase 3	Second wave
BI1335	Phase 3	Second wave
Asunaprevir	Phase 3 (all oral)	Second wave
Danoprevir/r	Phase 2	Second wave
Sovaprevir	Phase 2	Second wave
ABT450/r	Phase 2	Second wave
MK 5172	Phase 2	Second generation
ACH 2684	Phase 2	Second generation

Simeprevir (TMC435; Tibotec, Beerse, Belgium; Medivir Pharmaceuticals, Stockholm, Sweden; Janssen, Beerse, Belgium) is a once-a day-oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once-a-day dosing, and demonstrates potent antiviral activity and efficacy [5]. The final results of two phase IIb trials of TMC435 with PEG-IFN/RBV in naïve and treatment-experienced populations have been completed [6]. PILLAR study enrolled 368 treatment-naïve subjects with genotype 1 and compared two different doses (75mg vs 150 mg) and durations (12 weeks vs 24 weeks) of simeprevir therapy in combination with PEG-IFN/RBV for either 24 or 48 weeks. A sustained viral response (SVR) was achieved in 68–76% of patients with this triple therapy regimen and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy with very high SVR (93–96%). Adverse effects were similar to standard therapy, and the lowest rate of relapse was found in the study arm receiving 150 mg daily TMC435 in addition to PEG-IFN/RBV for 24 weeks (8%). In addition, SVR rates in the 150-mg dosing arms did not differ according to HCV subtype (1a vs 1b), but as expected, SVR was highest in the IL28B CC genotype.
 

ASPIRE was a randomized, double-blind, placebo-controlled phase IIb trial, which assessed the efficacy and safety of simeprevir in combination with PEG-IFN/RBV in 462 patients with genotype 1 HCV who had failed a previous PEG-IFN/RBV regimen. The ASPIRE study randomized patients to seven treatment arms, each of which was given simeprevir in combination with 48 weeks of PEG-IFN-2a/RBV. SVR rates were significantly higher in all simeprevir-containing treatment arms compared with PEG-IFN/RBV alone. The best results were obtained in the 150-mg dosing groups with a SVR of 85% vs 37% in prior relapsers, 75% vs 9% in partial responders and 51% vs 19% in prior non-responders. It is also important to note that higher 24-week SVR rates were observed with simeprevir-containing therapy in difficult-to-treat patient subgroups, including patients with cirrhosis and a previous non-response (31% SVR in non-response cirrhotics). As has been seen with most PI-based studies, breakthrough or relapse was associated with a resistant virus (42/43 people who experienced breakthrough and 34/36 who relapsed). Subjects with HCV genotype 1a were more likely to have the R155K mutation alone or with additional mutations, whereas people with HCV genotype 1b had the D168V mutation [7].
 

In both the naïve and treatment-experienced trials, TMC435 was generally well tolerated with no evidence of significant safety signals related to rash, anaemia or neutropaenia. However, transient elevations of direct and indirect bilirubin were seen in subjects who took a 150-mg dose of simeprevir. Elevations in bilirubin were not associated with an elevation of AST or ALT, returned to baseline with the cessation of therapy and are believed to be related to interference with bilirubin transporters.
 

Finally, simeprevir may also provide opportunities for use in non-genotype 1 patients. A phase IIa proof-of-concept trial provided evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes except for genotype 3 [8]. Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, no antiviral activity was seen against genotype 3. Thus, simeprevir seems to offer significant improvement over boceprevir and telaprevir: once-a-day dosing, improved safety profile (lack of rash and anaemia) and expanded antiviral activity across more genotypes.

BI201335 (Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany) is another NS3/4A protease inhibitor with once-a-day dosing that has completed phase 2 testing. SILEN-C1 study reported the efficacy data from a randomized phase II trial with 429 genotype 1 treatment-naïve patients [9]. The treatment regimen included BI201335 in addition to PEG-IFN/RBV for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy. Response-guided therapy was evaluated and achievement of an eRVR (HCV-RNA negative at week 4 and week 12) resulted in randomization to stop therapy at week 24 or continue with PEG-IFN/RBV for a total of 48 weeks. The overall SVR rate was 83% for the 240-mg dose (lower for the 120-mg dose), and 92% of the patients with an eRVR achieved a SVR regardless of the subsequent duration of PEG-IFN/RBV. Adverse events (mostly gastrointestinal) resulted in drug discontinuation in 7.3% of subjects. SILEN-C2 study evaluated 288 partial or non-responders and evaluated the 240-mg dose, either once or twice daily in combination with PEG-IFN/RBV for 24 weeks [10]. The highest SVR was achieved in the once-a-day dosing groups: it was 50% in partial responders and 35% in non-responders. It should be noted that patients with cirrhosis were not included in this study. Both SILEN-C1 and C2 tested the efficacy of a 3-day lead-in with PEG-IFN/RBV. The expectation was that the lead-in would limit the development of resistance by providing better antiviral drug coverage when the PI was introduced. For unknown reasons, the lead-in arms in both trials showed a significant decrease in efficacy, and this strategy to limit resistance has been abandoned. SILEN-C3 evaluated treatment-naïve, genotype 1 patients and randomized them to either 12 or 24 weeks of once-a-day 120 mg BI 201335. Both groups received PEG-IFN/RBV for 24 weeks and patients who did not achieve an eRVR continued PEG-IFN/RBV until week 48. SVR rates were similar for both durations, 65% vs 73% overall and 82% vs 81% in those with eRVR respectively. Through all of the SILEN-C phase 2 trials, the adverse-event profile of BI 201335 appeared to be mild rash and photosensitivity along with some GI toxicity (nausea, diarrhoea and vomiting). As with a few other PIs under development, BI 201335 is associated with a transient rise in indirect or unconjugated bilirubin that is related to inhibition of the bilirubin transporter (inhibition of hepatic uptake of uridine diphosphate glucuronosyl transferase 1 family polypeptide A1, UGT1A1)[11]. The once-per-day dosing regimen that is moving forwards into phase 3 trials has fewer adverse events than the twice-per-day dosing regimen.

Danoprevir/r (RG7277; Roche, Basle, Switzerland; Intermune Pharmaceuticals, Brisband, CA) is a twice-a-day, ritonavir-boosted HCV protease inhibitor with good antiviral activity against genotypes 1, 4 and 6. Of note, the early hepatotoxicity signals of the drug were virtually eliminated by the addition of ritonovir boosting, which leads to strong inhibition of CYP3A and increased through concentrations of the PI. DAUPHINE is a large phase 2 trial in naïve patients that evaluated three different doses (50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, twice daily) and response-guided therapy in combination with PEG-IFN/RBV [12]. Twelve weeks after stopping therapy, antiviral negativity (SVR12) was 93% in the 200-mg dosing arm, 83% in the 100-mg arm and 67% in the 50-mg arm. At the 200-mg dose, the response was not influenced by either HCV subtype (1a vs 1b) or IL28B genotype (CC vs non-CC), suggesting that this regimen leads to potent viral suppression. Of note, genotype 4 patients had a 100% SVR 12 across all dosing arms. Danoprevir is also being evaluated in IFN-free regimens combined with the nucleoside inhibitor, Mercitabine (RG7128) [13].

 

Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor. Asunaprevir was initially studied at a dose of 600 mg twice per day, but was decreased to 200 mg twice per day because of increased liver enzymes. The combination of asunaprevir and daclatisvir was the first regimen to successfully cure HCV-infected patients without the use of IFN [14]. Despite potential approval in an IFN-free combination in genotype 1b patients and a potential quad regimen, asunaprevir is not likely to become the PI of choice for this second wave of PIs because of the twice-per-day administration and potential association with hepatotoxicity.
 

Sovaprevir (ACH-1625; Achillion Pharmaceuticals, New Haven, CT) is another NS3 protease inhibitor with very high potency, reporting a half-maximal inhibitory concentration of ~1 nm. A phase IIa study reported that ACH-1625, with PEG-IFN/RBV, resulted in a RVR in 75–81% of subjects compared with a RVR of 20% in patients receiving PEG-IFN/RBV alone [15]. A phase IIb study is under way at this time, but given the true second-generation PI also from Achillion (see below), it is less likely that this PI will be carried through to phase III trials.
 

ABT-450/r (Abbott, Abbott Park, IL; Enanta Pharmaceuticals, Watertown, MA) ABT-450 is being evaluated with ritonavir boosting to increase plasma concentrations and enable once-a-day dosing. A recent analysis included 35 treatment-naїve chronic hepatitis C patients randomly assigned to receive ABT-450/ritonavir or placebo [16]. Participants received ABT-450/ritonavir at doses of 50/100 mg, 100/100 mg or 200/100 mg once daily, or placebo, as monotherapy for 3 days, followed by 12 weeks of ABT-450/ritonavir or placebo at the same dose in combination with PEG-IFN/RBV. During the 3 days of monotherapy, the response was similar in all three ABT-450/ritonavir dose arms, with a mean maximum HCVRNA decrease of around 4 log IU/ml, compared with 0.36 log IU/ml in the placebo group. In an intent-to-treat analysis at 4 weeks, 88% of patients receiving ABT-450/ritonavir plus PEG-IFN/RBV had achieved a RVR (RVR; HCV RNA <25 IU/ml) compared with only 9% in the placebo arm. At 12 weeks, 92% receiving ABT-450/ritonavir vs 18% receiving placebo had achieved a complete early virological response (cEVR, again HCV RNA <25 IU/ml). HCV sub-genotype (1a or 1b), baseline HCV RNA and IL28B gene pattern were not associated with differences in virological response. ABT-450/r is also being studied in all-oral regimens and is more likely to receive approval in this IFN-free pathway.

Second-generation protease inhibitors

 

Two second-generation protease inhibitors, MK-5172 and ACH-2684, are in various stages of clinical development. These true second-generation PIs are expected to have broader genotype coverage and higher barriers to resistance, which represents a significant shift from the second-wave PIs.
 

MK-5172 (Merck & Co., Inc, Whitehouse Station, NJ) is a novel macrocyclic NS3/4a protease inhibitor under phase II clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major HCV genotypes, notably variants resistant to earlier protease inhibitors. R155 is the main overlapping position for resistance and different mutations at this amino acid site within NS3 protease confer resistance to nearly all protease inhibitors in development. However, MK-5172 exhibits potent antiviral activity against variants carrying mutations at position R155. Thus, based on its preclinical profile, MK-5172 is expected to be broadly active against multiple HCV genotypes, including genotype 3 as well as clinically important resistance variants making it highly suited for incorporation into newer all-oral regimens. MK-5172 was given in doses of 50–800 mg QD (monotherapy) to 48 men with HCV genotype 1 and 30 HCV genotype 3 patients for 7 days [17]. There were six arms (including a placebo arm). The maximum change in HCV levels was a decrease of −5.37 IU/ml in HCV genotype 1 and −4.41 IU/ml in genotype 3 patients. In the genotype 1 patients, 75% (30 of 40 pts) were below the level of HCVRNA quantification (25 IU/ml). The drug was generally well tolerated. In early-stage studies, MK-5172 in various doses has been shown to work across different genotypes [18] and can be dosed once a day, which makes it an attractive candidate for future clinical development.
 

ACH-2684 (Achillion Pharmaceuticals) is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and a safety profile at high drug exposures that strongly supports once-a-day dosing. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. It has preclinical activity against the six known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pm [19]. Achillion Pharmaceuticals, Inc reported proof-of-concept data from a Phase 1b clinical trial demonstrating that patients with HCV genotype 1 treated with ACH-2684 achieved a mean maximum 3.73 log¹⁰ reduction in HCV RNA after 3-day 400-mg monotherapy with once-a-day dosing. The compound also demonstrated good safety and tolerance both in healthy volunteers and in patients with HCV. This PI seems to represent an ideal partner for all-oral regimens that can help deliver pangenotypic activity with a high barrier to resistance.

Conclusion

 

The development of protease inhibitors represents a significant milestone in improving the efficacy of HCV treatment. However, the limitations of first-generation PIs have opened the door for continued drug development in this class. Several other direct-acting antivirals are under development [20]. Simeprevir, asunaprevir and BI are second-wave PIs in phase III trials, and will probably obtain approval with PEG-IFN/RBV in 2014. To be used in an all-oral regimen, second-wave PIs will need to be used in combination with other direct-acting antivirals to overcome the low genetic barrier to resistance. These combinations could include PIs and a nucleoside inhibitor with a high genetic barrier to resistance or PIs with a non-nucleoside inhibitor (or NS5A inhibitor) with a non-overlapping resistance profile. The future of protease inhibitors lies in the further development of second-generation drugs with a broad genotypic coverage and a high genetic barrier for resistance, which may be the ideal backbone for an all-oral HCV treatment regimen.

Disclosure

 

The authors have no disclosure.

References

 

• 1
  Pordada F, McCone Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 362: 1195–206.
• 2
  Jacobson IM, McHutchinson JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16.
• 3
  Zeuzem S, Andreone P, Pol S., et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–28.
• 4
  Bacon BR, Gordon SC, Lawitz E., et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207–17.
• 5
  Manns M, Reesink H, Berg T, et al. Rapid viral response of once-daily TMC435 plus peginterferon/ribavirin in hepatitis C genotype-1 pstients: a randomized trial. Antivir Ther 2011; 16: 1021–33.
• 6
  Fried M, Buti M, Dore GJ, et al. TMC435 in combination with peginterferon and ribavirin in treatment naïve HCV genotype 1 patients: final analysis of the PILLASR phase IIb study. 62nd Annual Meeting of the American Association for the Study of liver Diseases 2011; Novemeber 4-8; San Francisco, CA. Abstract LB-5.
• 7
  Lenz O, Fevery B, Vijgen L, et al. TMC 435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon/ribavirin treatment: virologic analysis of the ASPIRE trial. 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18-22; Barcelona, Spain. Abstract 9.
• 8
  Moreno C, Berg T, Tanwandee T, et al. Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study. J Hepatol 2012; 56: 1247–53.
• 9
  Sulkowski MS, Asselah T, ferenci P, et al. Treatment with the 2nd generation HCV PI BI 201335 results in high and consistent SVR rates-results from SILEN-C1 in treatment naïve patients across different baseline factors. Hepatology 2011; 54(suppl): 473A.
• 10
  Sulkowski MS, Bourliere M, Bronwicki JP, et al. Sustained viral response and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype 1 patients with non-response tp P/R. 46th Annual Meeting of the European Association for the Study of the Liver;2011March 30-April 3;Berlin, Germany; Abstract 66/330.
• 11
  Sane R, Podila L, Mathur A., et al. Mechanisms of isolated hyperbilirubinemia induced by HCV NS3/4A protease inhibitor BI201335. J Hepatol 2011; 54(suppl): S488.
• 12
  Everson G, Cooper C, Shiffman ML, et al. Rapid and sustained achievement of undetectable HCV RNA during treatment with ritonavir-boosted danoprevir/PEG-IFNa-2A/RBV in HCV genotype 1 or 4 patients: Dauphine week 36 interim analysis. 47th Annual Meeting of the European Association for the Study of Liver Disease; 2012 April 18–22; Barcelona, Spain. Abstract 1177.
• 13
  Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomized, double-blind, placebo-controlled, dose escalation trial. Lancet 2010; 376: 1467–75.
• 14
  Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 216–24.
• 15
  Poordad F, Lalezari J, Lawitz E, et al. Continued high virologic response rates with ACH-1625 daily dosing plus PEGIFN-alpha 2a in a 28-day and 12-week phase 2a trial. 47th Annual Meeting of the European Association for the Study of Liver Disease; 2012 April 18-22; Barcelona, Spain. Abstract 1151.
• 16
  Lawitz E, Gaultier I, Poordad F, et al. ABT-450/Ritonavir (ABT-450/r) Combined with Pegylated Interferon Alpha-2a and Ribavirin After 3-Day Monotherapy in Genotype 1 HCV-Infected Treatment-naive Subjects: 12-Week Interim Efficacy and Safety Results. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 252.
• 17
  Petry A, Brainard D, Van Dyck K, et al. Safety and antiviral efficacy of MK-5172, a novel HCV NS3/4a protease inhibitor with potent activity against known resistance mutants in genotype 1 and 3 HCV infected patients. 61st Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA 2010.
• 18
  Summa V, Ludmerer SW, McCauley JA. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012; 56: 4161–7.
• 19
  Huang M, Podos S, Patel D, et al. ACH-2684: HCV NS3 protease inhibitor with potent activity against multiple genotypes and known resistant variants. Hepatology 2010; 52(suppl): 1204A.
• 20
  Asselah T, Marcellin P. Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. Liver Int 2012; 32: 88–102.

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Hepatitis C-Interferon free therapy with direct acting antivirals:asunaprevir; daclatasvir; faldaprevir; simeprevir; NS5A inhibitors; NS5B polymerase inhibitors; protease inhibitors; ribavirin; sofosbuvir

Website Updates @ Hepatitis C New Drug Research and Liver Health

Interferon Free

Interferon free therapy with direct acting antivirals for HCV
asunaprevir; daclatasvir; faldaprevir; simeprevir; NS5A inhibitors; NS5B polymerase inhibitors; protease inhibitors; ribavirin; sofosbuvir.

The current treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct-acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen. Major progress has been made in the past few years: numerous ongoing trials with different compounds, increasing sustained virological response (SVR) rates with oral regimens and shortened treatment duration. Combinations of antivirals with additive potency that lack cross-resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN......

2013-HCV triple-therapy genotype 1: management of side-effects

How to optimize HCV therapy in genotype 1 patients: management of side-effects
Antiviral therapy for chronic hepatitis C has dramatically changed with the advent of triple therapy incorporating direct-acting antivirals (DAAs) such as the protease inhibitors (PI) boceprevir and telaprevir. Such triple-therapy is associated with a new spectrum of side-effects which can hamper quality of life. These may lead to dosage reduction and sometimes discontinuation of therapy. This review presents practical tips to help manage adverse effects appropriately and efficiently. The main adverse effects causing discontinuation of therapy are varied. Although the most common adverse effects are the ‘flu’-like symptoms of fatigue, myalgia, fever and lassitude, these are usually easily managed and do not lead to treatment discontinuation. Cytopaenia, particularly anaemia, has emerged as perhaps the most troublesome side-effect. Cirrhotic patients are especially prone to moderate or severe anaemia with boceprevir and telaprevir triple-therapy regimens. Aggressive ribavirin dosage reductions, erythropoietin and blood transfusions are effective for managing anaemia. Skin rash can be controlled with moisturization and corticosteroid ointment. Rarely, dermatology consultation is required for further management. Anal discomfort, with or without diarrhoea, sometimes responds to barrier creams and haemorrhoidal ointments. Dysgeusia is treated by sipping water frequently, oral ointments and mouth washes to maintain salivary flow and oral hygiene. Successful adherence to treatment can be enhanced by a strong support network for the patient, including specially-trained hepatitis nurses and a multidisciplinary team incorporating pharmacists, counsellors and social workers.........

Page Updates:

Index Of Current Hepatitis C Drugs In Development

2013 Stem Cell News and Research

2013 Interferon Free Combinations

2013 Sofosbuvir (GS-7977)

2013 News/Cirrhosis

2013 Transplant News

2013 News/Liver Cancer

Treatment of viral hepatitis: a new era

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2013-Interferon Free Combinations
Index Of Current Hepatitis C Drugs In Development

Special Issue: Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis

February 2013

Volume 33, Issue Supplements1 Pages 1–199

We are pleased to present the supplement for the 6th Paris Hepatitis Conference (PHC). This supplement of Liver International includes review articles with the most up-to-date information on the clinical care of patients with hepatitis B and hepatitis C, which was presented at this meeting.

Review Articles

 

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   Optimal treatment with telaprevir for chronic HCV infection (pages 3–13)Arun B. Jesudian and Ira M. Jacobson
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12079
   

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   Optimal treatment with boceprevir for chronic HCV infection (pages 14–22)Benjamin Maasoumy and Michael P. Manns
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12070
   

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   How to optimize HCV therapy in genotype 1 patients: predictors of response (pages 23–29)Salvatore Petta and Antonio Craxì
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12053
   

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   How to optimize HCV therapy in genotype 1 patients: management of side-effects (pages 30–34)Angeli Chopra, Patricia L. Klein, Thia Drinnan and Samuel S. Lee
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12080
   

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   How to optimize HCV therapy in genotype 2 patients (pages 35–40)Eleonora Grassi and Alessio Aghemo
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12056
   

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   How to optimize HCV therapy in genotype 4 patients (pages 41–45)Gamal Esmat, Mohamed El Kassas, Mohamed Hassany, Mohamed Esmat Gamil and Maisa El Raziky
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12059
   

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   How to optimize HCV therapy in genotype 1 patients with cirrhosis (pages 46–55)Marc Bourlière, Astrid Wendt, Hélène Fontaine, Christophe Hézode, Stanislas Pol and Jean Pierre Bronowicki
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12067
   

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   Current management and perspectives for HCV recurrence after liver transplantation (pages 56–62)Audrey Coilly, Bruno Roche and Didier Samuel
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12062
   

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   HCV therapy in HIV-infected patients (pages 63–67)Mark S. Sulkowski
   Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12082
   

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    Best strategies for global HCV eradication (pages 68–79)Liesl M. Hagan and Raymond F. Schinazi
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12063
    

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    New therapeutic strategies in HCV: second-generation protease inhibitors (pages 80–84)Virginia C. Clark, Joy A. Peter and David R. Nelson
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12061
    

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    New therapeutic strategies in HCV: polymerase inhibitors (pages 85–92)Ludmila Gerber, Tania M. Welzel and Stefan Zeuzem
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12068
    

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    Interferon free therapy with direct acting antivirals for HCV (pages 93–104)Tarik Asselah and Patrick Marcellin
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12076
    

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    Patients with HCV and F1 and F2 fibrosis stage: treat now or wait? (pages 105–110)Mitchell L. Shiffman and Yves Benhamou
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12066
    

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    Impact of therapy on the outcome of chronic hepatitis B (pages 111–115)Yun-Fan Liaw
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12057
    

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    Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance (pages 116–124)Fabien Zoulim and Stephen Locarnini
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12069
    

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    The role of HBsAg quantification for monitoring natural history and treatment outcome (pages 125–132)Michelle Martinot-Peignoux, Martine Lapalus, Tarik Asselah and Patrick Marcellin
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12075
    

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    Why do I treat HBeAg-positive chronic hepatitis B patients with a Nucleoside analogue (pages 133–136)Hong Ma and Jidong Jia
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12065
    

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    Treatment of HBeAg positive chronic hepatitis B: interferon or nucleoside analogues (pages 137–150)Geoffrey Dusheiko
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12078
    

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    Why do I treat HBeAg-negative chronic hepatitis B patients with nucleos(t)ide analogues? (pages 151–156)George V. Papatheodoridis
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12054
    

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    Why do I treat HBeAg-negative chronic hepatitis B patients with pegylated interferon? (pages 157–163)Pietro Lampertico, Mauro Viganò and Massimo Colombo
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12064
    

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    Management of acute hepatitis B and reactivation of hepatitis B (pages 164–175)Ankur Jindal, Manoj Kumar and Shiv K. Sarin
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12081
    

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    Treatment of HBV related cirrhosis (pages 176–181)Florian van Bömmel and Thomas Berg
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12074
    

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    Management of HBV in immunocompromised patients (pages 182–187)Stanislas Pol
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12055
    

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    Optimal management of HBV infection during pregnancy (pages 188–194)Teerha Piratvisuth
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12060
    

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    Current management of delta hepatitis (pages 195–197)Mario Rizzetto
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12058
    

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    Hope for the eradication of HCV worldwide (pages 198–199)Jean-François Delfraissy
    Article first published online: 3 JAN 2013 | DOI: 10.1111/liv.12077
    

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Treatment of viral hepatitis: a new era

Patrick Marcellin, Tarik Asselah

Article first published online: 3 JAN 2013

DOI: 10.1111/liv.12086

Dear Colleagues,

We are pleased to present the supplement for the 6th Paris Hepatitis Conference (PHC). This supplement of Liver International includes review articles with the most up-to-date information on the clinical care of patients with hepatitis B and hepatitis C, which was presented at this meeting.

This meeting will once again provide state of the art information on the management of patients with hepatitis B and hepatitis C by outstanding international experts who will present the most recent data as well as the clinical applications in this area. The PHC 2013 includes a full day dedicated to hepatitis C and a full day dedicated to hepatitis B. Approximately, 170 million people have been infected with HCV worldwide. There are about 350 million carriers of HBV.
 

The goal of the PHC is to encourage interaction with the audience during the plenary sessions (round table discussions). In addition, several interactive luncheons are held every day for discussions between experts and participants. Since the first edition of the meeting in 2004, attendance has steadily increased. More than 1000 specialists (most of them key national opinion leaders) from more than 60 countries and all continents have participated in this year's PHC meeting. Rapid progress, the availability of many new drugs and new therapeutic strategies are increasing the complexity and individualizing the management of patients with viral hepatitis. Therefore it is extremely important to educate and advise clinicians, so that available information can be exploited to optimize management of these patients.
 

Last year, the meeting was specifically devoted to hepatitis C and the recent spectacular innovations made in the management of this disease thanks to the development of new therapies. At present, the treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the combination of direct-acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) with the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen [1-3]. The primary goal of treatment is to achieve a sustained virological response (SVR), which is usually defined as undetectable serum or plasma HCV RNA 24 weeks after the end of treatment. A SVR corresponds to a cure [4]. Twelve weeks post-treatment follow-up appears to be as relevant as 24 weeks to determine SVR [5]. Some IFN-stimulated genes have been shown to be highly expressed in non-responders; thus, pre-activation of the IFN system in patients appears to limit the effect of IFN antiviral therapy [6, 7].
 

Hopefully, second-generation protease inhibitors (simeprevir and faldaprevir) once a day will soon be available with PEG-IFN and RBV, making treatment easier. Thus, DAA with different viral targets, including NS3 protease inhibitors, nucleoside/nucleotide analogues and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A inhibitors are under development [8-10]. Early data have demonstrated that antiviral combinations with additive potency that lack cross-resistance and have a good safety profile may provide new regimens in the near future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN [8]. Thus, clinicians have turned their attention to an exciting new direction: finding interferon-free therapy that will be effective in all genotypes. This raises an important issue that will be at the heart of discussions during the PHC conference in 2013: which patients should be treated in 2013 and how can we increase their chance of a cure? Which patients can be treated later based on future options?
 

At the same time, the PHC 2013 conference, as in the past, will address and focus upon Hepatitis B. We will spend a full day discussing results on the long-term outcome of patients receiving the most potent available antiviral drugs. We will also assess the issue of quantifying HBsAg and its role as a new tool for predicting the severity of disease and response to therapy. The optimal management of special populations and difficult situations will be extensively discussed: pregnancy, co-infections, cirrhosis. As in previous PHCs, we will privilege interactive discussions and many specific working luncheons addressing the management of real-life patients. Finally, the ultimate goal of PHC 2013 is to review the most current knowledge and discuss their therapeutic applications with the most experienced experts to provide optimal therapy and the best chance of cure to as many patients as possible, worldwide.
 

All the reviews from these outstanding international experts have been published in this issue of Liver International, which is available during the meeting. This up-to-date issue covers every aspect of hepatitis C and hepatitis B management.

References

1. Top of page
2. References

• 1
  Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 25: 2405–16.
• 2
  Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 13: 1195–206.
• 3
  EASL. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 2: 245–64.
• 4
  Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 3: 821–9.
• 5
  Martinot-Peignoux M, Stern C, Maylin S, et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin. Hepatology 2010; 4: 1122–6.
• 6
  Sarasin-Filipowicz M, Oakeley EJ, Duong FH, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci USA 2008; 19: 7034–9.
• 7
  Asselah T, Bieche I, Narguet S, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008; 4: 516–24.
• 8
  Asselah T, Marcellin P. Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. Liver Int 2012; 32 (Suppl 1): 88–102.
• 9
  Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 3: 216–24.
• 10
  Zeuzem S, Asselah T, Angus P, et al. , Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 2011; 6: 2047–55.