Genotype 3 - Archives
2014 - 2013 HCV Genotypes and Treatment
Treating HCV genotypes 1-6
Links to treatment options for all HCV genotypes is provided, using clinical research found published online in peer-reviewed journals and presented at conferences, as well as interactive learning activities.
HCV-Genotype 5 Or 6
Genotype 3 2013
AASLD-Gilead Announces New Sustained Viral Response Data for Sofosbuvir-Based Regimens in Genotype 3-Infected Hepatitis C Patients
CME Video: Emerging Treatment Options for Hepatitis C Genotype 3,2 and 1 Patients
Clinical Care Options (CCO) launched a series of video modules with three different case scenarios exploring treatment choices, duration, and outcomes in genotype 3, 2 and 1 patients.
For instance in the first module the panel weighs in on clinical trial data of investigational agents sofosbuvir and simeprevir in treatment naive and experienced genotype 3 patients. The text only for "Case 1" is provided below, an expert video discussion for each case is available in the module.
Prevalence of insulin resistance in chronic hepatitis C genotype 1 and 3 patients
Décio Passos Sampaio Péres, Hugo Cheinquer, Fernando Herz Wolf, Nelson Cheinquer, Maicon
Falavigna, Luciana Dornelles Sampaio Péres
In conclusion, our study did not show a difference on the prevalence of IR between chronic hepatitis C patients infected
with genotypes 1 or 3. Never the less, independent of HCV genotype, we found that IR was associated with greater
steatosis and liver fibrosis. This finding should lead health care providers involved with the management of chronic hepatitis C patients to consider measuring IR as part of the routine clinical evaluation, independent of the HCV genotype.
Is genotype 3 the New 1
Perspectives on Virology, Natural History and Treatment for Hepatitis C Genotype 3
After recent, larger randomized trials, we have realized that genotype 2 is truly interferon sensitive while genotype 3 patients are far less successful with therapy. In this fundamentally altered landscape, genotype 3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development. Herein we review the virology, natural history and the treatment of genotype 3 hepatitis C.
Drugs in Development: Genotype 2 and 3
Sofosbuvir/Ribavirin: Next Standard of Care
The next treatment for genotype 2 and 3 will be the combination of Gilead’s sofosbuvir (HCV polymerase inhibitor) and ribavirin. Sofosbuvir is dosed once a day. Ribavirin is dosed twice daily. The application with the clinical trial data has been submitted to the FDA. It is estimated that the two-drug combination will be approved by the FDA by the end of 2013 or early 2014. However, there is some controversy regarding the use of sofosbuvir/ribavirin for the treatment of HCV genotype 3 since the viral cure rates were generally less than optimal. But there are positive trade-offs in using the all-oral combination.....
Transcript - Morgan Stanley Global Healthcare Conference
Gilead Sciences' Management Presents at 2013 Morgan Stanley
In genotype 2 and 3 sofosbuvir could be used with ribavirin for either 12 or 16 weeks of duration and with those patients who are new therapy or patients who have failed other therapies or intolerant of other therapies have very high cure rates and that cure....
A New Subtype of Hepatitis C Virus Genotype 3: Analysis of Available Evidence
Currently, epidemiological data on the new HCV-3 subtype is lacking. The new subtype has been isolated from infected individuals residing in three provinces of Iran: Tehran (Central North), Lorestan (Central West) and Khouzestan (South
West). Considering these regions, it seems that the new subtype has a vast geographical distribution in Iran. However, isolation of this subtype from other countries has not been reported so far. Thus, it seems that this HCV-3 subtype
is endemic in Iran
COMMENTARY ON: Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.
We urge for studies in G4 HCV, naïve but also experienced patients. Third, for G2 HCV
naïve patients, sofosbuvir-RBV provide excellent results. We have to recall
obvious evidence: G2 HCV is not G3, and we need separate studies.
In past PegIFN/RBV dual therapy, for statistical issues, HCV G1 and G4, and HCV G2
and G3,were respectively pooled. For DAAs, we need individual study for each genotype.
For G2HCV treatment experienced and cirrhosis, we need more data.....
Management of Treatment-Naïve Genotypes 2 and 3 HCV Infection
Advanced fibrosis is not a negative pretreatment predictive factor for genotype 2 or 3 chronic hepatitis C
June 17 2013
Telaprevir - Analysis of Genotype 2/3 Hepatitis C Virus Variants
Genotype 3 HCV: The Next Hurdle in Hepatitis C Therapy
Effect of Functional Interleukin-10 Polymorphism on Pegylated Interferon-α Plus Ribavirin Therapy Response
in Chronic Hepatitis C Virus Patients Infected With 3a Genotype in Pakistani Population
Both Simeprevir and Sofosbuvir Likely Approved by 2014-Clinical/Ethical/Pharmacoeconomic Dilemmas Loom
For those not following this field closely, here’s the deal: If approved, both simeprevir and sofosbuvir will be indicated for treatment of HCV genotype 1, but only in combination with pegylated interferon/ribavirin. (Sofosbuvir
approval is also expected for genotype 2/3, just with ribavirin.)
Sofosbuvir -FDA Grants Priority Review, Approval Set For December
Following successful late stage Phase III clinical trials of sofosbuvir, the FDA has
granted a priority review designation for Gilead's new hepatitis C drug. If successful during the
abbreviated approval process, Gilead expects the drug to be approved by December 8 of
this year, making it the first, in a new generation of drugs that target the virus itself, to hit
The oral pill will be prescribed for those with genotype 2 and 3 of the virus in combination with
ribavirin. In patients who have never received treatment for hepatitis C, or naïve patients,
and have genotypes 1, 4, 5 and 6, the oral drug would be used in combination with peg-interferon and
In Vitro Efficacy and Resistance Profiling of Protease Inhibitors Against a Novel HCV Genotype 3a Replicon
Watch Dr. Andrew Muir Discuss the latest Hepatitis C research presented at DDW 2013
Sofosbuvir Works for Patients Who Cannot Take Peginterferon
Two phase III studies confirm the efficacy of a sofosbuvir and ribavirin therapy
in patients with HCV genotype 2 or 3 infection for whom peginterferon
is not an option.
EASL: Treatment With Sofosbuvir + Ribavirin for 12 Weeks Achieves SVR12 of 78% in GT 2/3 Interferon-Ineligible, -Intolerant, or -Unwilling Patients: Results of the Phase 3 POSITRON Trial -
EASL: Phase 3 Randomized Controlled Trial of All-Oral Treatment With Sofosbuvir + Ribavirin for 12 Weeks Compared to 24 Weeks of PEG + Ribavirin in Treatment-Naïve GT 2/3 HCV-Infected Patients (FISSION)
EASL: All Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment-Experienced Genotype 2/3 HCV-Infected Patients: Results of the Phase 3 FUSION Trial
Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options
Sofosbuvir + Ribavirin Cures Most Genotype 2 Hepatitis C, but Genotype 3 Response Is
A ‘Killer’ of a Reason to Treat Hepatitis C
Dr. David Johnson stresses the importance of treating patients with hepatitis C and advanced hepatic
fibrosis, given that those with sustained treatment response have a lower all-cause mortality rate
Interestingly, they also found a cofactor that was a subset risk, which was genotype 3. If you are genotype
3 and not treated, then you are 2 times more likely to have all of these consequences. We do know that
genotype 3 tends to be a much more rapidly progressive disease, although genotypes 2 and 3 are easier to treat.
If you don't treat them, they tend to more rapidly progress to fibrosis and cirrhosis....
Hepatitis C Virus Diversity and Hepatic Steatosis
Jan 10 2013
Telaprevir - Analysis of geno 2 and 3 hepatitis C virus variants demonstrates a consistent resistance profile across
Retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3
Research Article: HCV genotype 1 and 6 had significantly higher viral loads than genotype 2 and 3
July 28 2012- Hepatitis C Therapy in Non-genotype 1 Patients: The Near Future
July 13 2012 - Geno 1-4: Hepatitis C Drug Development Goes from Pony
Ride to Rocket Launch
Viral Hepat. 2012 May;19(5):346-52. doi: 10.1111/j.1365-2893.2011.01555.x.
Epub 2011 Nov 9.
Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12
weeks of pegylated interferon-α-2a plus ribavirin and RVR.
Restivo L, Zampino R, Guerrera B, Ruggiero L, Adinolfi LE.
Source Internal Medicine & Hepatology, Second University of Naples, Naples, Italy.
HCV genotypes 2- or 3-infected patients with a rapid virological response (RVR) to therapy with pegylated
interferon and ribavirins who have a low viral load, noncirrhotic and nonobese may be considered for a shorter course of
treatment. However, no studies have assessed host-viral factors associated with relapse in
genotype 2 and 3 separately.
Accordingly, we assessed whether 12 weeks of pegylated interferon and ribavirin was an optimized regimen
for treatment of HCV genotype 2 and 3 with positive predictors of response.
Power and sample size were a priori calculated and 96 consecutive chronic hepatitis C patients (53, genotype 2 and 43, genotype 3) without cirrhosis who were not obese and who achieved a RVR to therapy with peg-IFN-α-2a and
ribavirin were enrolled. Fibrosis, steatosis, homeostatic model assessment-insulin resistance and HCV RNA
were predefined variables to be evaluated in relapse. An intention-to-treat analysis was performed. SVR
rates were 98% and 84% for genotype 2 and 3, respectively. Analysis of genotype 3 patients who had relapse showed a negative correlation with steatosis (P < 0.0001) and HCV RNA (P < 0.015).
Multivariate analysis showed that steatosis was the independent predictor of relapse (OR, 0.988; 95% CI, 0.981-0.993; P < 0.001). Genotype 3 patients with steatosis had a relapse rate of 36.4% and 15.8% in those with high and low
viral load, respectively, whereas there was no relapse in those without steatosis. In conclusion, a 12-week course of therapy is sufficient for patients without cirrhosis, not obese and infected with HCV genotype 2 achieve a RVR. This is not the case for genotype 3. Steatosis is the independent predictor of relapse. New therapeutic strategies are necessary for this subgroup of HCV genotype 3.
© 2011 Blackwell Publishing Ltd.
Hepatitis C, insulin resistance and fatty liver: Bad things come in threes
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study
Treatment of patients with genotype 3 chronic hepatitis C- current and future therapies
Genotype 3 is a common type of HCV infection, and standard therapy using pegylated interferon (PEG-IFN) and ribavirin (RBV) is quite effective in these patients. While a short course of 16 weeks may result in comparable end of therapy responses, relapse rates are often high. A 24-week course is therefore preferable, and is expected to result in sustained virological response (SVR) rates of more than 70%. The 24-week course is especially recommended in the presence of steatosis (often associated with Genotype 3 infection), fibrosis stage two or more, high BMI and high viral load. In patients who do not achieve a rapid viral response (RVR) with combination therapy, an extended course up to 48 weeks should be considered. While not as definite as for genotype 1 patients, the presence of the CC variant of IL28b could help in the initial prognosis and the need for additional treatment, if an RVR is not achieved. The role of directly acting antiviral agents (DAA) has not been fully evaluated in treatment naïve, non-responders and relapsers in genotype 3 patients. Initial results with the cyclophilin inhibitor Debio-025 are quite encouraging. There is an urgent need for large clinical trials using DAA and host modulators in patients with G3 infection.
PSI-7977 plus ribavirin -A 'Newer' Era of HCV Therapy Begins?
Dawning of Another New Era
In an editorial appearing in the New England Journal of Medicine  in March of this year, Jensen suggested that a new era of therapy for hepatitis C virus (HCV) infection was dawning with the development of 2 effective protease inhibitors -- telaprevir and boceprevir. These direct-acting antiviral (DAA) agents, used in combination with peginterferon and ribavirin, were shown to be effective in patients infected with HCV genotype 1. Now an even newer era may be on the horizon!
New Compounds, New HopeSeveral investigational drug trials were presented at The Liver Meeting 2011 -- the annual meeting of the American Association for the Study of Liver Diseases. Two groups reported the apparently remarkable preliminary results of an investigational agent for the treatment of infection with HCV.[2,3] An interferon-free regimen of PSI-7977 plus ribavirin achieved strikingly high rates of sustained viral response (SVR); this drug offers the potential solution to a long sought after goal -- the ability to delete noisome interferon injections from treatment strategies.
PSI-7977 is a uridine nucleotide analog polymerase inhibitor that is administered orally once daily. This agent has previously demonstrated robust activity in patients infected with HCV genotype 1 when used in combination with pegylated-interferon and ribavirin, and activity when used as a monotherapy has also been reported.
Promising Antiviral Activity
Two phase 2 studies of this investigational compound were presented at The Liver Meeting 2011.
The aim of the first (ELECTRON) trial was to determine the shortest duration of interferon, if any, that was required to achieve SVR when PSI-7977 plus ribavirin are coadministered. Forty treatment-naive, noncirrhotic patients infected with HCV genotype 2 or 3were randomly assigned to receive PSI-7977 400 mg plus ribavirin for 12 weeks -- this was combined with either no interferon or interferon for 4, 8, or 12 weeks. All patients achieved a rapid virologic response (RVR); more then 80% had nondetectable HCV RNA at 2 weeks and all patients had undetectable levels at 3 weeks. All patients achieved an end-of-treatment (ETR) response and normalization of alanine aminotransferase levels. No serious adverse events were attributed to PSI-7977, and as expected, safety and tolerability were highest in the interferon-free treatment group. Buoyed by these results, the investigators carried out a small trial of open-label PSI-7977 monotherapy for 12 weeks; the response rates were similar to the combination therapy results.
A similar study (PROTON), a double-blind, placebo-controlled, dose-ranging study of PSI-7977, enrolled 121 treatment-naive patients with HCV genotype 1. Patients were randomly assigned to receive either 12 weeks of interferon/ribavirin plus PSI-7977 (200 mg or 400 mg), or placebo. Duration of therapy was response guided. The control group received the interferon/ribavirin standard combination for 48 weeks. The RVR for the 200 mg and the 400 mg dose was 98%, with an ETR at 24 weeks of 91%. The RVR in the placebo group was 19%, and the ETR was 50%. Of specific note, all patients with the difficult-to-treat interleukin 28B single-nucleotide polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3 and 100% went on to achieve an SVR.
The studies suggest that PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes and has a high barrier to resistance; the agent reduced the duration of therapy for HCV clearance in half. The impact may be significant -- offering a shorter, interferon-free regimen that is effective even in difficult-to-treat patients. A newer era indeed!
The potent antiviral efficacy in association with a promising safety profile, support the continued exploration of PSI-7977 with abbreviated interferon duration, as monotherapy, or with other DAA in patients with all HCV genotypes. These further studies will hopefully confirm this optimism and document the spectrum of potential adverse effects of this drug.
AASLD:PSI-7977- New HCV Drug Promising, Cuts Out Interferon
But in a small phase II study conducted in New Zealand, Gane and colleagues asked whether interferon was actually necessary. To find out, they enrolled 40 patients with genotype 2 and 3 virus and randomly assigned them to one of four arms in which the duration of interferon treatment varied from 12 weeks – the full length of the trial – to none at all.
The other component of standard therapy – ribavirin – was given to all patients throughout the 12-week trial.
The researchers selected genotypes 2 and 3 because they are easier to treat than genotype 1, offering the possibility of "rescue" with interferon and ribavirin if the treatment failed, Gane said.
The primary endpoint was sustained virologic response – undetectable hepatitis C RNA -- at week 12.
But, regardless of the length of interferon treatment, the researchers found that 100% of the patients reached a sustained virologic response at week 12, Gane said. Moreover, all of the patients who have been followed for 24 weeks continue to show a 100% response rate...........rea
Role of HCV Genotype 3 in Liver Fibrosis Progression
This article explores some of the issues in the history and pathophysiology of chronic hepatitis C
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Viral factors have usually been considered to have limited influence on liver FPR in chronically infected HCV patients. However, recent studies highlighted a possible association between viral genotypes and rapid fibrosis progression. By pooling results from several, often small-sized studies, this meta-analysis provides a comprehensive summary of the published literature on the topic as well as new insights into the natural history of chronic HCV infection. The pooled analyses of eight single-biopsy studies clearly confirmed a significantly faster progression for genotype 3 patients compared with the other genotypes. Among them, five showed a significantly faster fibrosis progression or a clear trend towards faster progression for genotype 3-infected patients compared with others.[5–7,16,22] The failure of some studies to detect a significant effect for viral genotype 3 probably results from their insufficient sample size (i.e. 342 cases and 684 controls are necessary for 80% power to detect an OR of 1.5 for viral genotype 3 on fibrosis progression, considering a 30% prevalence of this genotype). Despite a much smaller observation time, the pooled analysis of eight paired biopsies studies showed a trend towards faster progression for genotype 3-infected compared with genotype non-3-infected patients.
A previous study assessing stage-specific FPR using a Markov model suggested that viral genotype 1 (compared with other genotypes) may influence fibrosis progression, but the estimation was performed using a meta-regression. It is known that such ecological associations may lead to incorrect estimates of the relation for individual patients.
The association of viral genotype 3 with FPR may have important practical implications. It has been reported that the uptake of antiviral therapy for hepatitis C has been declining during recent years. Apart from poor rate of diagnosis and lack of referral, two major factors may account for this trend: the widespread perception on the supposedly slow average progression rate of hepatitis C, coupled with the huge expectations surrounding novel, more effective direct antiviral agents (DAA), to be first marketed in 2011–2012. Genotype 3-infected patients should be aware of a potentially faster progression rate and may benefit from individualized counselling, with particular attention given to the controllable factors, such as alcohol consumption and overweight. While therapy with peginterferon alpha and ribavirin usually achieves 70–80% of sustained viral response among patients infected with HCV genotype 3, certain subgroups of patients still have high relapse rates, such as those with elevated baseline viral load (>800 000 copies/mL,[33,34]) and advanced fibrosis. Patients with chronic hepatitis C may be deferred from current treatment regimens just because more potent DAA will be licensed in the near future. However, this 'warehousing' attitude may not be justified in infections with genotype 3, given that the serine protease inhibitors, such as telaprevir, have very limited activity against genotype 3. DAAs with significant activity against genotype 3, such as the nucleoside RNA polymerase inhibitor R7128 or the cyclophilin-binding molecule Debio 025, are far from completing clinical development. These considerations argue against the indiscriminate deferral from antiviral therapy in patients infected with genotype 3.
Multiple reasons may explain why paired biopsies studies did not show a significant effect of genotype 3. First, confounding by indication is likely to be a major problem in paired biopsies studies, as only selected patients undergo a second biopsy (e.g. those with multiple comorbidities and potentially rapidly evolving liver disease). Second, paired biopsies studies have a smaller sample size than single-biopsy studies. Out of eight studies, none included more than 30 genotype 3 patients, and four included less then 7 genotype 3 patients, resulting in low power to detect a given ES. Third, paired biopsies studies have a much smaller observation time than single-biopsy studies (~5 years between 2 biopsies compared with ~13 years from the infection date to the first biopsy, Fig. S3). This short duration may not be sufficient to detect genotype-specific differences in terms of FPRs. Fourth, paired biopsies studies have used arbitrary cut-offs for dichotomizing the outcome into progression vs nonprogression, for instance a worsening of the score by one or several units[13–15,17,18,20,23] or reaching a specific fibrosis stage at the second biopsy. This method results in more information loss if one considers that the process of fibrosis is continuous. Finally, given that FPRs are not constant over time, paired biopsies studies may have included patients when the progression rate is the slowest (e.g. transition from Metavir scores F1–F2 or F2–F3), making it even more difficult to detect genotype-specific differences (Fig. S2).
As in many systematic reviews, the limitation of this study results from the limitation of the original studies themselves. Those include the inability to precisely determine the date of infection, the variability in the assessment of fibrosis staging, the nonlinearity of fibrosis progression over time, the failure to account for multiple risk factors. However, several studies addressed these issues. In three studies, the role of viral genotype 3 in fibrosis progression was confirmed in multivariate analyses, accounting for different covariates such as age, alcohol consumption and steatosis.[5–7] In one of them, the authors suggested that cannabis use, which may be more prevalent among genotype 3-infected patient, may have been a confounding factor for the role of genotype 3. However, this study clearly identified cannabis use, genotype 3, age at infection, alcohol intake and steatosis all as independent risk factors for rapid fibrosis progression (greater then 0.74 U/year) in a stepwise logistic regression model of 267 patients. In another study, the association of genotype 3 with faster progression remained significant among patients infected by blood transfusion (for whom the date of infection is certain), among different age groups, or among different periods of infection, and when using different methods to assess the progression rate.
Owing to our stringent selection criteria, the number of studies included in the meta-analysis is relatively small. Therefore, it was not possible to perform a meta-regression analysis and explore the role of potential confounders. We could not include a large confirmatory study (N = 327, N genotype 3 = 80), showing that patients infected with HCV genotype 3 had shorter time to infection than others, because it did not provide FPR rates.
This study provides new insight into the natural history of HCV infection. The evidence for a role of genotype 3 in fibrosis progression may have important implications for the management of patients infected with this genotype.
AASLD-Novartis’ alisporivir may become first interferon-free oral for hepatitis C G2/G3
The clear conclusion from a clinical trial of alisporivir (DEB025, from Swiss drug major Novartis [NOVN: VX]), an oral host-targeting cyclophilin inhibitor, is that treatment based on it may be an effective, interferon (IFN)-free alternative for individuals with genotype 2 or 3 (G2/G3) hepatitis C virus (HCV) infections. The finding was presented by Jean-Michel Pawlotsky, a professor at the Henri Mondor Hospital, University of Paris-Est, Creteil, France, at a late-breaking poster session on November 7, 2011 at the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) held last week in San Francisco.
HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis
In multivariate analysis, infection with a genotype 3 was independently associated with an increased risk of hepatocellular carcinoma occurrence, even after adjustment for prothrombin activity and alcohol abuse. For patients with hepatitis C virus cirrhosis and ongoing infection, infection with genotype 3 is independently associated with an increased risk of hepatocellular carcinoma development.
Hepatitis C; Response To Treatment Geno 3-fibrosis but not race encourages relapse
"Telaprevir Alone or W-Peg/Riba Reduces HCV RNA in Patients With Geno 2 But Not Geno 3
Individualizing Treatment Duration in Hepatitis C Virus Genotype 2/3-infected Patients
The drugs currently licensed for the treatment of hepatitis C are Peg-Interferon (PEG-IFN) and ribavirin. In recent years, the recommendation to treat hepatitis C virus genotype 2- and 3-infected patients with a fixed 800 mg/day dose of ribavirin in combination with PEG-IFN and for just 24 weeks has been challenged by the concept of tailoring the length of therapy according to on-treatment viral response. Therefore, the objective of the present review was to highlight the different designs of the studies on short treatment duration and the role of wk4-R as a predictor of sustained virological response after an abbreviated course of treatment. The secondary aim was to verify whether we had enough evidence to support the implementation of a short treatment course in subsets of patients with genotype 2 and 3 infection. We will also focus on how drug dosing may have influenced the outcome of treatment. To clarify reasons for discrepant results in the studies so far published, the recently discovered genetic variant near the interleukin 28B gene will be presented and its predictive role will be discussed. Finally, we will face the debated issue of whether the subset of patients with genotype 2 or 3 requires an extended treatment duration...Continue Reading..