October 8, 2013

Is 3 the New 1

Journal of Viral Hepatitis

Perspectives on Virology, Natural History and Treatment for Hepatitis C Genotype 3

E. B. Tapper, N. H. Afdhal

J Viral Hepat. 2013;20(10):669-677.

Abstract and Introduction


Affecting 2–3% of the world's population, hepatitis C is a common viral infection which is a significant cause of morbidity and mortality. Hepatitis C genotype 1 is the dominant viral genotype among Western patients. For the last 20 years, in the era of interferon-based therapy, it was far more difficult to treat relative to genotypes 2 and 3. Accordingly, a significant focus of research was on new antiviral agents for the dominant genotype 1 patient. Now, as promising specific treatments are being introduced for genotype 1, the attention of clinicians and researchers has turned back to the 50–70 million patients infected with a nongenotype 1 hepatitis C. Furthermore, 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.


Hepatitis C virus (HCV) affects an estimated 130–170 million persons (2–3% of the world's population).[1] HCV is an important cause of liver-related morbidity and mortality including the complications of cirrhosis and liver cancer. One of first steps in the diagnosis and management of chronic HCV infection is genotype determination. Six major genotypes have been identified. The proportion of patients infected with a given genotype varies from country to country, with genotype 1 (HCV-1) dominant in the United States and Western Europe closely followed by genotype 3 (HCV-3).[2]

Interferon (IFN) has been the major antiviral agent for the last 20 years, an era during which HCV-2 and HCV-3 were considered easy-to-treat genotypes with sustained virological response (SVR) rates approaching 70%. More recently with larger randomized trials of IFN and ribavirin (RBV) therapy, we have realized that HCV-2 is truly interferon sensitive with up to 80% SVR rates, whereas HCV-3 has an intermediate response at 65–70%. Because there was a belief that both HCV-2 and HCV-3 were easy to treat, a significant focus of research was on new antiviral agents for the dominant HCV-1 patient. Overall, HCV-1 response rates to PEG-IFN and RBV were between 40% and 50% and because 70% of patients in the United States are genotype 1, this represented a significant unmet need for new therapies. In 2011, new direct-acting antiviral agents (DAAs) against the NS3/4 protease were added to PEG-IFN and RBV and SVR rates reached 75%. In addition, newer DAA agents are being continuously introduced for HCV-1 disease with multiple different targets on the replication pathway and anticipated response rates are now between 80% and 90% and duration can be reduced to as little as 12 weeks of triple therapy.[3] As these new HCV-1-specific treatments are being introduced, the attention of clinicians and researchers has turned back to the 50–70 million patients infected with a nongenotype 1 HCV.[4] Herein, we will discuss how in this fundamentally altered landscape, HCV-3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development.


Discovered in 1989, HCV is an enveloped virus with a positive-sense, single-stranded RNA genome with about 9000 ribonucleotides in the genus Hepacivirus of the family Flaviviridae.[5] The genome is organized to include bookending untranslated RNA segments and a single large open-reading frame encoding several structural proteins (core and envelope glycoproteins E1, E2 and p7) as well as several nonstructural proteins (NS2, NS3, NS4A/B and NS5A/B). Numbered in order of their discovery, specific HCV genotypes are classified on the basis of their genetic similarity.[6] The genomic sequences of different HCV isolates vary by as much as 35%.[7,8] Certain proteins, namely the envelope proteins, are hypervariable resulting in intragenotype variability that, while significantly less than intergenotype variability, is still on the order of 20–25% of ribonucleotides. The genetic diversity of genotypes can be quite pronounced, albeit within fairly prescribed geography – for example, HCV-1 in Central Africa, HCV-2 in West Africa and HCV-3 in South and South-East Asia.[6] The proliferation of blood transfusion and unsterilized injection needles over the mid-twentieth century, however, led to the propagation of 'founder' viruses, for example, 1a and 3a in injection drug users in the west and 4a from schistosomiasis treatment in Egypt.[6, 9, 10] Today, HCV-2 and HCV-3 make up roughly 30% of the chronic HCV infections in the Western world.[4] HCV-3 itself accounts for 35–80% of chronic HCV infections in regions such as the Indian subcontinent, South-East Asia and Australia.[11,12]

HCV Genotype 3 and Lipid Metabolism

Hepatitis C viral proteins appear to interact with and interfere in the machinery of lipid metabolism and lipoprotein processing. Hepatitis C virus enters hepatocytes via the low-density lipoprotein receptor.[13] Once internalized within the hepatocyte, both HCV core protein and NS5A have been shown to interact with lipoproteins, while the core protein has been shown to inhibit microsomal triglyceride transfer protein activity and modify hepatic VLDL secretion (in a mouse model).[14–16] Similarly, it has been shown in cell culture that HCV-3 core protein expression induces significantly higher fatty acid synthetase promoter activity (in a SREBP-1-dependent manner) than does HCV-1 core protein, an effect that is directly linked to the genetics and protein structure of the HCV-3 core.[17] In vitro expression of HCV-3 core protein results in a 3-fold greater level of cellular triglyceride accumulation compared with other genotypes.[18] These basic insights underpin the readily confirmed finding that patients infected with HCV have lower serum cholesterol (particularly hypobetalipoproteinemia) and higher serum triglycerides, an effect most pronounced in patients with HCV-3.[19–21] The mechanisms behind this finding are becoming increasingly clear. Clark et al.[22] examined cholesterol synthesis in HCV-2 and HCV-3 treatment-naïve patients before and after therapy. This group was able to show that HCV-3 (not HCV-2) has specific effects on the distal – postsqualene – cholesterol synthesis pathway, an interference that resolved after SVR.

The degree to which hepatitis C viral processes interfere with hepatocellular lipid metabolism is dependent on the viral load and is clinically important for treatment success.[22–24] Rubbia-Brandt et al. were the first to show not only a correlation with intrahepatic viral load and steatosis but also a genotype-specific association, particularly HCV-3. Critically, this group was able to show that even in patients who had undergone orthotopic liver transplantation, post-transplant graft infection by HCV-3 reinstituted the pretransplant steatosis.[25] In turn, intrahepatic accumulation of steatosis leads to increased necroinflammatory activity vis-à-vis oxidative stress, an effect specific to HCV-3.[26] Accordingly, this infection-associated steatosis is considered a 'cytopathic effect' of chronic HCV-3.[25]

Steatosis is a cytopathic lesion induced by HCV-3 infection, whereas HCV-1 is not, in and of itself, steatogenic.[27,28] Adinolfi et al. compared 25 HCV-3- to 15 HCV-1-infected patients and found a disproportionate prevalence of steatosis (75% vs 22%).[27] This group also found that while steatosis is associated with advanced liver disease regardless of genotype, the grade of steatosis is independent of body mass index in patients with HCV-3. Indeed, here, as in other studies, there is a direct correlation between grade of steatosis and viral load for HCV-3 alone. The clinical significance of this is manifest most starkly by the finding that when comparing HCV-3- to non-HCV-3-infected patients and controlling for other variables, histological steatosis is associated with progression of fibrosis, mainly in HCV-3.[29] Treating the virus fortunately reverses this effect. First shown in a group of patients treated mainly with interferon-alpha monotherapy, those with HCV-1 experienced no change in hepatic steatosis after treatment, irrespective of the treatment response. Conversely, amongst those with HCV-3 infection, SVR significantly reduced steatosis but not amongst those without a SVR.[30] This effect was later confirmed in large-scale randomized trials.[31]

Natural History

As a function of its unique pathophysiology, chronic HCV-3 infection carries specific implications regarding its natural history. The most thorough evaluation of genotype-specific natural history comes from the Swiss Hepatitis C Cohort Study (SCCS) that evaluated 3412 treatment-naïve patients, 1189 of which had an assessable date of infection without comorbid disease and a pretreatment liver biopsy. In this study, independent risk factors for accelerated fibrosis progression included male sex and age at infection but the most significant effects in a multivariate model were histological activity (odds ratio = 2.03) and HCV-3 infection (odds ratio = 1.89). Furthermore, for any given stage of fibrosis at the time of index biopsy, HCV-3-infected patients were far more likely to advance at least one fibrosis stage compared with non-HCV-3-infected patients.[32] Bouchud et al. added the role of genotype, specifically HCV-3, to the list factors known to be associated with disease severity – duration of infection, age, male sex, alcohol consumption and coinfections.[32,33] The cytopathic effect of HCV-3-induced hepatic steatosis underlies the accelerated fibrosis observed in HCV-3 infection.[29] In their meta-analysis of patient data from a cohort of 3068 multi-institutional, geographically diverse multinational patients with chronic HCV infection, Leandro et al.[34] found steatosis significantly and independently associated with fibrosis while specifically HCV-3 infection was the most powerful driver of steatosis, even in obese patients.

Chronic HCV-3 infection is also associated with a disproportionately increased risk of hepatocellular carcinoma (HCC). Nkontchou et al. retrospectively compared 25 patients with chronic HCV-3 to 328 patients with other genotypes.[35] In a multivariate analysis, this group found that HCV-3 infection was the strongest predictor of HCC development (hazard ratio 3.54, P = 0.0002). In this French population, the rate of HCC occurrence after 5 years was 34% amongst those with chronic HCV-3 and 17% in patients with chronic non-HCV-3 infection (P = 0.013). These results added genotype – specifically HCV-3 – to an externally valid set of other significant covariates, including age, male sex, body mass index and low platelet count.[35] There also seems to be a significant regional variation in the natural history of HCV-3 with patients in South-East Asian countries developing significantly greater overall rates of cirrhosis and HCC compared with European patients.[36]

Treatment: Pegylated Interferon and Ribavirin (PEG-IFN/RBV)

Genotype has long been known to influence response to PEG-IFN and RBV therapy, with the potential for shorter durations of therapy and higher SVR rates for HCV-2 and HCV-3 compared with HCV-1 infection.[37,38] Historically, HCV-2 and HCV-3 have been lumped together as, relative to HCV-1, patients infected with these genotypes have responded best to interferon-based therapies. On closer inspection of treatment trials, however, HCV-3-infected patients clearly respond more poorly to interferon-based therapy than do patients with HCV-2. For much of the past decade, the focus on therapy has been the determination of therapy duration. There have been several landmark trials experimenting with duration of PEG-IFN and RBV for patients with chronic HCV-2 and HCV-3 infection examining 12, 14, 16 and 24 week treatment durations[39–48] (Table 1). These trials show consistent evidence of poorer therapeutic response in patients with HCV-3 compared with HCV-2, which might be explained by the concomitant steatohepatitis and more advanced fibrosis in HCV-3. Other issues that are important to consider are that not all HCV-3 patients are the same and that European patients with HCV-3 acquired from intravenous drug use may respond very differently from those from South-East Asia who are both older and have more advanced disease and where response rates are much closer to only 50%.[48]

Table 1.  Treatment outcomes in genotype 3 chronic hepatitis C – randomized trial data 372/(711)

Trial Therapy Patients with HCV-3 Duration of therapy (weeks) RVR (%) SVR (%) SVR in cirrhosis (%)
Zeuzem et al. [46] PEG-RBV 182 24 75.3% (137/182) 79% (144/182) N/A
Dalgard et al. [40] PEG-RBV 99 14 (24 without RVR) 74.7% (74/99) 80.1% (80/99) N/A
Mangia et al. [50] PEG-RBV 70 12 vs 24 58.6% (41/70) 65.7% (46/70) overall N/A
Von Wagner et al. [42] PEG-RBV 113 16 vs 24 92% (103/112) 76% (39/51) vs 75% (39/52) with RVR; 40% (4/10) without RVR N/A
Shiffman et al. [43] PEG-RBV 727 16 vs 24 52.3% (372/711) 62.2% (216/347) vs 67.0% (244/364) (ITT) 43% (35/81) vs 49% (37/75) – cirrhosis or bridging fibrosis
Dalgard et al. [39] PEG-RBV 343 14 vs 24 after RVR and 24 if no RVR 68.8% (212/308) 84% (86/102) vs 91.8% (101/110) after RVR; 56.3% (54/96) if no RVR N/A
Lagging et al. [45] PEG-RBV 276 12 vs 24 N/A 58% (79/137) vs 78% (108/139) – ITT 30% (7/23) vs 57% (13/23) – ITT
Mecenate et al. [44] PEG-RBV 94 12 vs 24 if RVR and 24 if no RVR 68.1% (64/94) 78.1% (50/64) if RVR, 43.3% (13/30) if no RVR N/A
Mangia et al. [59] PEG-RBV 414 24 vs 12 or 36 depending on RVR 63.3% (262/414) 71.5% (148/207) vs 74.9% (154/207) (ITT) N/A
Jacobson et al. [66] Sofosbuvir-RBV 98 12 N/A 61.2% (60/98) 21% (3/14)
Jacobson et al. [66] Sofosbuvir-RBV 129 12 vs 16 N/A 29.7% (19/64) vs 61.9% (39/63) 19.2% (5/26) vs 60.9% (14/23)
Lawitz et al. [3] Sofosbuvir-RBV versus PEG-RBV 359 12 N/A 55.7% (102/182) vs 62.5% (110/176) 34% (13/18) vs 30% (11/37)

Citations: 3, 39–46, 66. Abbreviations: HCV-3 (hepatitis C, genotype 3), RVR (rapid virological response), SVR (sustained virological response, PEG-RBV (pegylated interferon and ribavirin), ITT (intention-to-treat) and N/A (not available).

Two important early trials established shortened duration (24 weeks) therapy as a viable option. Mangia et al.[41] examined 12- and 24-week courses and found equal rates of SVR overall, 77% and 76%, respectively. There were, however, somewhat striking intergenotype differences. The rate of SVR was 80% for patients with HCV-2 and 66% for patients with HCV-3. Zeuzem et al.[46] treated 42 HCV-2-infected patients and 182 HCV-3-infected patients with PEG-RBV for 24 weeks. SVR was achieved in 93% of HCV-2 patients and 79% of HCV-3 patients.

In 2008, two trials were published comparing 24 weeks to 14 and 12 weeks of therapy. The North-C group found an overall SVR rate of 81.1% and 90.7% in 14- and 24-week courses following an RVR in the intention-to-treat analysis, respectively. Again, genotype-specific response was seen with SVR achieved in 97% of the 31 HCV-2 patients receiving 24 weeks of therapy compared with 92% of the 110 patients with HCV-3 experiencing RVR. Meanwhile, in the population who did not experience RVR, 75.0% (15 of 20) with HCV-2 and 56.3% (54 of 96) with HCV-3 experienced SVR.[39] The NORDynamic Study group saw a similar pattern of results after 24 weeks with HCV-3 patients achieving SVR 58% of the time after 12 weeks and 78% after 24 weeks.[45] More recently, in the PEG-RBV control arm of the FISSION trial, there was a significant difference in the attainment of SVR between genotype 2 and 3 patients, 77.6% vs 62.5%.[3]

ACCELERATE randomly assigned 1469 patients equally divided amongst HCV-2 or HCV-3 to receive 180 μg of peginterferon-alpha-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks.[43] 16 weeks of therapy was inferior to 24 with respect to SVR (62% vs 70%). SVR was achieved in 82% of HCV-2 patients receiving 24 weeks of therapy compared with 71% of HCV-3 patients in the per protocol analysis (67.0% in the intention-to-treat analysis). Amongst patients with a rapid virological response (RVR), SVR rates were 79% and 85% in the 16- and 24-week groups. Interestingly, there was no difference in the rate of SVR between genotypes for the patients that experienced RVR (85% vs 85%), confirming the findings of a prior, smaller trial.[42] ACCELERATE also showed that patients with advanced fibrosis fared poorly by comparison, achieving SVR 43% of the time after 16 weeks and 49% after 24 weeks. The major limitation of this trial is that it used fixed dose RBV 800 mg for all patients rather than weight based. The current consensus is that weight-based ribavirin is necessary for shortened treatment duration, particularly for HCV-3.[43]

For IFN-based treatment, RVR and IL-28b are important predictors of response. While patients with RVR experience SVR at a rate that ranges from 69% to 100%, those without RVR achieve SVR from 30% to 60% of the time.[48] In a follow-up analysis from ACCELERATE, it was shown using multiple logistic regression that patients with low baseline viral load who achieve RVR were the best candidates for abbreviated (16 week) therapy.[49] Confirmatory results were obtained by Mangia et al.[50] in their randomized trial of 24 weeks of PEG-RBV compared with 12 or 36 variable duration ('personalized') course depending on the viral response at week 4. Their results demonstrated that RVR resulted in comparable rates of SVR for patients with HCV-3 (86.4% vs 83.7%) in those treated for 24 weeks or the 12 weeks in the variable duration arm. This study also showed that for HCV-3 patients who did not achieve RVR, 36 weeks of therapy resulted in a higher rate of SVR than 24 weeks (72.5% vs 63.0%). Similarly, in their analysis of data from 3 large studies,[38, 43, 51] Fried et al. showed that RVR on PEG-RBV therapy (achieved by 60% of those with HCV-3) was the most important on-treatment predictor of SVR. The proportion of patients with RVR subsequently achieving SVR was similar across genotypes (88–100%).[52] Meanwhile, the odds of achieving RVR were significantly associated with genotype. Compared to HCV-1, the odds ratio for RVR was 36.017 and 11.943 for HCV-2 and HCV-3, respectively.[52] Accordingly, it is accepted that for HCV-3-infected patients, a 24-week duration is standard with only potential shortening of treatment for patients with RVR for a total duration of 12–16 weeks.[53] The N-CORE study compared treatment duration in 188 HCV-3 patients without RVR on PEG-RBV. Preliminary results from this study suggest that amongst patients completing the study, SVR is achieved in 73% after 48 weeks compared with 54% after 24 weeks.[54] The results of this literature are summarized in the EASL guidelines[55] (Fig. 1).


Figure 1. Guideline based therapy for patients with chronic Genotype 3 Hepatitis C infection. Treatment decisions are based on the patient's viral load response to therapy with measurements at the beginning of therapy as well as 4 and 12 weeks into treatment. Abbreviations: HCV (hepatitis C), RNA (ribonucleic acid), RVR (rapid virological response), and EVR (extended virological response).

Guideline based therapy for patients with chronic Genotype 3 Hepatitis C infection. Treatment decisions are based on the patient's viral load response to therapy with measurements at the beginning of therapy as well as 4 and 12 weeks into treatment. Abbreviations: HCV (hepatitis C), RNA (ribonucleic acid), RVR (rapid virological response), and EVR (extended virological response).

The IL-28B gene codes for interferon (IFN)-k3 and has been shown to predict PEG-RBV treatment response in HCV-1.[56] Moghaddam et al. retrospectively reviewed 281 chronic HCV-3-infected patients who were treated with PEG-RBV to determine the role of IL-28b in post hoc prediction of response. They found that while IL-28b polymorphisms do not predict SVR, they do predict RVR; the odds ratio for RVR C/C versus T/T was 1.3 (95% CI: 1.0–1.6).[57] These findings were confirmed in a similar retrospective analysis..[58] On the other hand, in a retrospective evaluation of Mangia et al.'s 2005 trial, IL-28b polymorphisms were also predictive of SVR in the 55 patients with HCV-3 for whom RVR was not achieved.[59]

In summary, genotype 3 is an intermediate IFN responsive strain of HCV and should always be evaluated separately from genotype 2. Evaluating the data, overall genotype 3 has never been truly 'easy to treat' but has a larger subset compared with genotype 1 that attains RVR as a measure of viral response and can subsequently have shortened duration of therapy. Host factors such as Asian ethnicity, IL-28b status and presence of cirrhosis remain important factors in the response to IFN-based therapy.

New Direct-Acting Antivirals

Multiple targets are being developed for DAA therapy against HCV-1 but many of these particularly the protease inhibitors have limited activity against HCV-3.[60] There are some novel 2nd-generation NS5A inhibitors such as Achillion ACH-3102, IdenixIDX-719 and Gilead GS-5816 that have potent in vitro activity against HCV-3 and are moving into early-phase clinical trials in combination with other DAAs or IFN.[61–63] The class with the broadest pangenotypic activity to date is the NS5B nucleotide polymerase inhibitors, which includes merimepodib and sofosbuvir, which are in advanced clinical development and early-phase compounds such as Vertex VX-135. These compounds have the potential to be backbone agents for all oral DAA therapy for HCV-3 in combination with RBV or some of the newer NS5A or disease-modifying agents such as the cyclophilin inhibitors.

Mericitabine (also known as RG7128) is a nucleoside analogue with pangenotypic antiviral activity in vitro. Mericitabine was evaluated in HCV-2 and HCV-3 patients with prior PEG-RIBA treatment failure. After a 4-week triple combination, mericitabine at a twice-daily dose of 1500 mg was discontinued and PEG-RBV was resumed for 20–44 weeks. RVR was achieved in 95% of the mericitabine-treated patients versus 60% in the pegylated interferon ribavirin group. 68% of patients with RVR achieved SVR. SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%). Overall, SVR rates did not differ between HCV-2 and HCV-3 patients (63% and 67%, respectively).[64] Unfortunately, this strategy still requires IFN use for up to 48 weeks and will likely be replaced by all oral therapies.

Sofosbuvir, formerly GS-7977, is a uridine nucleotide analogue that inhibits the NS5B HCV polymerase with in vitro pangenotypic activity. The ELECTRON trial randomly assigned previously untreated, noncirrhotic patients with HCV-2 or HCV-3 to 6 groups receiving sofosbuvir at a daily dose of 400 mg.[65] Five of these groups received 12 weeks of therapy, 4 of which also received weight-based ribavirin and 3 of which received pegylated interferon (alpha-2a). These groups included 6 to 7 HCV-3 and 3–4 HCV-2-infected patients. A final 6th group of 10 HCV-3-infected patients received 8 weeks of sofosbuvir-PEG-RBV. All (100%) of the 50 previously untreated patients with chronic HCV-2 or HCV-3 infection who received 8 or 12 weeks of treatment with sofosbuvir and ribavirin, with or without peginterferon-alpha 2a, had a SVR at 24 weeks after therapy. Of the 10 patients treated with sofosbuvir monotherapy, 6 achieved SVR, while 4 (including two of the seven patients with HCV-3) had relapsed after the end of treatment.

Jacobson et al.[66] reported the results of two much larger trials of sofosbuvir in HCV-2 and HCV-3 patients: POSITRON (interferon intolerant/ineligible patients) and FUSION (interferon treatment failures). POSITRON randomized 207 patients to 12 weeks of sofosbuvir at a daily dose of 400 mg and weight-based ribavirin to be compared to 71 patients on placebo. SVR was achieved in 78% of treated patients, in 92.7% in HCV-2 and 61.2% of 98 HCV-3 patients. The superior performance of this therapy in HCV-2 compared to HCV-3 was also seen in patients without cirrhosis with a 92% SVR rate in HCV-2 and 68% in HCV-3. In a multivariate regression, genotype was the strongest predictor of response. Beyond that, it appears that cirrhotic patients with chronic HCV-3 fare particularly poorly, with an SVR rate of only 21%. FUSION randomized patients to receive sofosbuvir 400 mg once daily and weight-based RBV for either 12 (100 patients) or 16 weeks (95 patients). SVR was achieved in 50% after 12 weeks and 73% after 16 weeks. Again, genotype played a significant role. For patients with HCV-2, SVR was achieved in 86.1% after 12 weeks and 93.8% after 16 weeks of therapy. By contrast, HCV-3-infected patients achieved SVR in 29.7% and 61.9% after 12 and 16 weeks, respectively. In a multivariate regression, genotype was again the most significant predictor of response to sofosbuvir therapy. The only other predictor was the presence of cirrhosis where patients with HCV-3 cirrhosis achieved SVR in only 19.2% of cases.

FISSION was a randomized, open label, active-control noninferiority study of 12 weeks of sofosbuvir plus ribavirin versus PEG-RIBA in an international cohort of untreated patients with HCV-2 and HCV-3. This trial included 183 HCV-3-infected patients in the sofusbuvir-RIBA arm and 176 HCV-3-infected patients in the PEG-RIBA arm. RVR was achieved in all but one patient in the sofusbuvir-RIBA arm compared with 67% in the PEG-RIBA arm. Both arms achieved SVR in 67% of cases. However, response rates in the sofosbuvir–ribavirin group were again lower amongst patients with HCV-3 infection than amongst those with HCV-2 infection (56% vs 97%).[3]

How can we best interpret these responses in HCV-3? Certainly with over 90%, SVR HCV-2 is now truly an easy-to-treat genotype with a simple all oral DAA regimen of sofosbuvir and RBV. However, this same combination was not superior to PEG-IFN and RBV for treatment-naïve HCV-3 patients and the SVR was somewhat disappointing at 67% in all HCV-3 groups studied but still very acceptable as a treatment for our patients in clinical practice. We need to also realize that in the presence of RBV as the 2nd agent, duration may be a critical factor. The studies were designed with 12-week treatment arms except for FUSION, which had a 16-week arm. Just increasing treatment by 4 weeks more than doubled SVR including patients with cirrhosis, where it went from 19% to 61% with just a 4-week increase in duration. Because all patients had RVR and all were negative at the end of treatment, the issue with sofosbuvir/RBV is clearly one of relapse, and as in prior studies with IFN, increasing duration prevented that relapse. The aetiology of the relapse is unclear, but its response so dramatically to duration does suggest that it is a reservoir effect. This level of relapse is not seen in therapies with sofosbuvir for genotype 1 and suggests that there may be something unique about the ability of genotype 3 to avoid complete eradication. To answer the relapse question, there is a large European trial that is looking both at 24 weeks of sofosbuvir and RBV and also combining these two agents with IFN for 12 weeks. An alternative is to add a 2nd more powerful genotype 3 active NS5A to sofosbuvir to see whether that can replace RBV and improve SVR rates.

An alternative approach has been taken with alisporivir, a host-targeting antiviral (HTA) with pangenotypic anti-HCV activity and high barrier to viral resistance. VITAL-1 randomized 340 treatment-naïve HCV-2 and HCV-3 patients (ratio 3:7) to five arms: alisporivir monotherapy (1 g daily), alisporivir (600 or 800 mg) and weight-based ribavirin, alisporivir (600 mg) and pegylated interferon, or PEG-RBV. Patients in alisporivir-containing arms that achieved RVR continued on their initial treatment for 24 weeks. Those without RVR continued with alisporivir and rescue PEG-RBV from week 6 to week 24. Of the interferon-free treatments, alisporivir and ribavirin achieved greater early HCV clearance at week 6 than alisporivir monotherapy: 49% (600 mg and ribavirin), 46% (800 mg and ribavirin) and 32% (1 g monotherapy). Of the 70 patients receiving any interferon-free alisporivir/ribavirin regimens, 88% achieved SVR. Of 177 patients receiving combined regimen – interferon-free alisporivir/ribavirin from baseline and alisporivir/ribavirin/interferon add-on, 90% had SVR versus 72% with standard pegylated interferon and ribavirin. There was no difference in HCV-2 and HCV-3 responses to alisporivir treatment.[67] Host-targeting agents with their high-resistance barrier and efficacy have more potential in combination with other DAAs for treatment of HCV-3.


Genotype 3 HCV is an important healthcare problem with its large global distribution, relatively unique pathophysiology and potentially more aggressive disease. It has also become the most difficult to treat based on SVR rates, not just because of any real host or viral issues but because of the neglect of the research hepatology community in developing novel agents against genotype 3. The polymerase inhibitors with only RBV are moderately effective, and this effect seems clearly duration dependent but the advent of newer DAAs moving rapidly into clinical trials have put a 'bullseye' on the head of genotype 3 HCV. We anticipate that with the renewed interest and targeting of genotype 3, the same success of 90% SVR will soon become attainable as we are seeing with the other HCV genotypes. Genotype 3 may be the new 1, but it will only stay there for a short time before innovative research, drug development and novel combinations make the concept of a hard-to-treat HCV genotype a historical footnote in our battle against chronic HCV.


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  17. Jackel-Cram C, Babiuk LA, Liu Q. Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype-1b core. J Hepatol 2007; 46(6): 999–1008.

  18. Abid K, Pazienza V, de Gottardi A et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J Hepatol 2005; 42(5): 744–751.

  19. Hui JM, Kench J, Farrell GC et al. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol 2002; 17(8): 873–881.

  20. Serfaty L, Andreani T, Giral P, Carbonell N, Chazouill_eres O, Poupon R. Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. J Hepatol 2001; 34(3): 428–434.

  21. Corey KE, Kane E, Munroe C, Barlow LL, Zheng H, Chung RT. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology 2009; 50: 1030–1037.

  22. Clark PJ, Thompson AJ, Vock DM et al. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotypespecific manner. Hepatology 2012; 56(1): 49–56.

  23. Gastaminza P, Whitten-Bauer C, Chisari FV. Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection. Proc Natl Acad Sci U S A 2010; 107: 291–296.

  24. Harrison SA, Rossaro L, Hu KQ et al. Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy. Hepatology 2010; 52: 864–874.

  25. Rubbia-Brandt L, Quadri R, Abid K et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 2000; 33: 106–115.

  26. Vidali M, Tripodi MF, Ivaldi A et al. Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C. J Hepatol 2008; 48(3): 399–406.

  27. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33: 1358–1364.

  28. Hezode C, Roudot-Thoraval F, Zafrani ES, Dhumeaux D, Pawlotsky JM. Different mechanisms of steatosis in hepatitis C virus genotypes 1 and 3 infections. J Viral Hepat 2004; 11: 455–458.

  29. Westin J, Nordlinder H, Lagging M, Norkrans G, Wejst_al R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol 2002; 37: 837–842.

  30. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002; 36: 1266–1272.

  31. Poynard T, Ratziu V, McHutchison J et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003; 38(1): 75–85.

  32. Bochud PY, Cai T, Overbeck K et al. Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol 2009;51(4):655–666.

  33. Massard J, Ratziu V, Thabut D et al. Natural history and predictors of disease severity in chronic hepatitis C. J Hepatol 2006; 44(1 Suppl): S19–S24. Epub 2005 Nov 21.

  34. Leandro G, Mangia A, Hui J et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 2006; 130: 1636–1642.

  35. Nkontchou G, Ziol M, Aout M et al. HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis. J Viral Hepat 2011; 18: e516–e522.

  36. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132(7): 2557–2576.

  37. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa- 2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001 Sep 22; 358(9286): 958–965.

  38. Hadziyannis SJ, Sette Jr H, Morgan TR et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140(5): 346–355.

  39. Dalgard O, Bjøro K, Ring-Larsen H et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008; 47: 35–42.

  40. Dalgard O, Bjøro K, Hellum KB et al. Treatment with pegylated interferon and ribavirin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004; 40: 1260–1265.

  41. Mangia A, Santoro R, Minerva N et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352: 2609–2617.

  42. von Wagner M, Huber M, Berg T et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522–527.

  43. Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. NEJM 2007; 357 (2): 124–134.

  44. Mecenate F, Pellicelli AM, Barbaro G et al. Short versus standard treatment with pegylated interferon alfa2A plus ribavirin in patients with hepatitis C virus genotype 2 or 3: the CLEO trial. BMC Gastroenterology 2010; 10: 21.

  45. Lagging M, Langeland N, Pedersen C et al. Randomized comparison of 12 or 24 weeks of peginterferon-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection. Hepatology 2008; 47: 1837–1845.

  46. Zeuzem S, Hultcrantz R, Bourliere M et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients with HCV genotypes 2 or 3. J Hepatol 2004; 40: 993–999.

  47. Manns M, Zeuzem S, Sood A et al. Reduced dose and duration of peginterferon alfa-2b and weightbased ribavirin in patients with genotype 2 and 3 chronic hepatitis C. J Hepatol 2011; 55(3): 554–563.

  48. Mangia A, Mottola L, Piazzolla V. Update on the Treatment of Patients With Non–Genotype 1 Hepatitis C Virus Infection. Clin Inf Dis 2013; 56: 1294–1300.

  49. Diago M, Shiffman ML, Bronowicki J-P et al. Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin. Hepatology 2010; 51: 1897–1903.

  50. Mangia A, Bandiera F, Montalto G et al. Individualized treatment with combination of peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3. J Hepatol 2010; 53: 1000–1005.

  51. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. NEJM 2002; 347: 975–982.

  52. Fried MW, Hadziyannis S, Shiffman ML, Messinger D, Zeuzem S. Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection. J Hepatol 2011; 55: 69–75.

  53. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 2006; 355: 2444–2451.

  54. N-Core Study Group. 48 Weeks of Peginterferon Alfa-2a/Ribavirin Improves SVR24 and Decreases Relapse across HCV Genotype 2/3 Patient Subgroups Not Achieving a Rapid Virological Response: N-CORE Study. AASLD 2012.

  55. Crax_ı A, Pawlotsky JM, Wedemeyer H et al. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 55(2): 245–264.

  56. Lai M, Afdhal NH. Clinical utility of interleukin-28B testing in patients with genotype 1. Hepatology 2012; 56(1): 367–372.

  57. Moghaddam A, Melum E, Reinton N et al. IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection. Hepatology 2011; 53(3): 746–754.

  58. Sarrazin C, Susser S, Doehring A et al. Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 2011; 54: 415–421.

  59. Mangia A, Thompson AJ, Santoro R et al. An IL28B polymorphism determines treatment response of patients with hepatitis C genotypes 2 and 3 who do not achieve a rapid virologic response. Gastroenterology 2010; 139: 821–827.

  60. Foster GR, H_ezode C, Bronowicki JP et al. Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011; 141: 881–889.

  61. McCarville JF, Seifer M, Standring DN, Mayers DL. Treatment-Emergent Variants Following 3 Days Of Monotherapy With IDX719, A Potent, Pan-Genotypic NS5A Inhibitor, In Subjects Infected With HCV Genotypes 1–4. Amsterdam: EASL, 2013. #1209

  62. Muir A, Hill J, Lawitz E et al. ACH- 3102, A Second Generation NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients with Genotype 1A HCV Infection Despite the Presence of Baseline NS5AResistant Variants. Amsterdam: EASL, 2013. #876.

  63. Cheng G, Tian Y, Yu M et al. GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier. Amsterdam: EASL, 2013. #1191

  64. Gane EJ, Rodriguez-Torres M, Nelson DE et al. Sustained virologic response following RG7128 1500 mg BID/PEG-IFN/RBV for 28 days in HCV genotype 2/3 prior non responders. J Hepatol 2010; 52: S16.

  65. Gane EJ, Stedman CA, Hyland RH et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368: 34–44.

  66. Jacobson IM, Gordon SC, Kowdley KV et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867–1877.

  67. Pawlotsky JM, Sarin SK, Foster GR et al. Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 Phase 2b study. EASL, 2012.


OxyElite Pro: Health Advisory - Acute Hepatitis Illness Cases Linked To Product Use


AUDIENCE: Health Professional, Consumer

ISSUE: The FDA, along with the Centers for Disease Control and Prevention (CDC) and the Hawaii Department of Health (DOH), are investigating a growing number of reports of acute non-viral hepatitis in Hawaii. The Hawaii DOH has reported that 24 of these cases share a common link to a dietary supplement product labeled as OxyElite Pro.

BACKGROUND: OxyElite Pro is distributed by USPlabs LLC of Dallas, Texas, and is sold nation-wide through a wide range of distribution channels, including the internet and retail stores that sell dietary supplements. There have been 29 cases of acute non-viral hepatitis with an unknown cause identified in the state of Hawaii.  Eleven of the 29 cases have been hospitalized with acute hepatitis, two cases have received liver transplants and one person has died. CDC is also looking at other cases of liver injury nationwide that may be related. Symptoms of all types of hepatitis are similar and can include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay or gray-colored bowel movements, joint pain, yellow eyes, and jaundice.

The epidemiological investigation is being conducted by the Hawaii DOH and the CDC. As part of FDA’s associated investigation, the agency is reviewing the medical records and histories of patients identified by the Hawaii DOH. The FDA is also analyzing the composition of product samples that have been collected from some of these patients. Additionally, the FDA is inspecting the facilities involved in manufacturing the product and reviewing production and product distribution records. Because USPlabs LLC has informed FDA that it believes counterfeit versions of OxyElite Pro are being marketed in the US and have been on the US market for some time, FDA is also investigating whether counterfeit product is related to any of the cases of acute  hepatitis.

RECOMMENDATION: The FDA advises consumers to stop using any dietary supplement product labeled as OxyElite Pro while the investigation continues. Consumers who believe they have been harmed by using a dietary supplement should contact their health care practitioner.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

  • Complete and submit the report Online: www.fda.gov/MedWatch/report.htm1Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch Safety Alert, including links to the FDA Recalls, Outbreaks and Emergencies page at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm370857.htm

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Three-Drug Combo Knocks Out HCV

Published: Oct 8, 2013

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • A triple-drug regimen without interferon and ribavirin achieved very high success rates in treatment-naive hepatitis C genotype 1 patients.

SAN FRANCISCO -- A triple-drug regimen for hepatitis C (HCV) led to a cure in about 90% of patients without using elements of the standard therapy for the disease, a researcher said.

In a randomized phase II trial, the combination of so-called "direct-acting agents" completely knocked out the virus in between 89% and 94% of patients 12 weeks after the end of therapy, according to Maribel Rodriguez-Torres, MD, of the Fundación de Investigación in San Juan, Puerto Rico.

The combination of investigational drugs was "generally well tolerated" in patients with the difficult-to-treat genotype 1 of the virus, Rodriguez-Torres reported at the IDWeek meeting here.

For years, standard HCV therapy has included pegylated interferon alfa and ribavirin, drugs that are both difficult to take and in some cases dangerous.

And that therapy leads to sustained virologic responses in no more than half of patients with genotype 1, although adding either of the approved direct-acting agents – telaprevir (Incivek) and boceprevir (Victrelis) – improves those outcomes markedly.

So researchers are seeking regimens that both target the virus directly -- interferon and ribavirin do not -- and have better outcomes.

In this case, they are testing once-daily daclatasvir, an NS5A replication complex inhibitor; twice daily asunaprevir, an NS3 protease inhibitor; and the as-yet-unnamed non-nucleoside NS5B polymerase inhibitor, BMS-791325, given twice a day.

The study is encouraging for those hoping that interferon- and ribavirin-free regimens will soon be approved, according to Arthur Kim, MD, of Massachusetts General Hospital in Boston, who was not involved in the study but who moderated the session at which it was presented.

"Once you are able to attack multiple viral targets," he told MedPage Today, "it seems that even if there is baseline resistance or some poor prognostic indicators, the multiple targeting works to eradicate the virus and overcome the barriers."

As the new regimens work their way through the clinical trials process, he said, he and other doctors are trying to delay treatment "unless it is absolutely necessary."

But he cautioned that so far the "novel paradigms" are still being tested. "We're still waiting for the phase III trials and larger numbers," Kim said.

The study so far includes 66 patients in four treatment arms differing by the length of therapy and the dose of BMS-791325, Rodriguez-Torres reported.

The primary endpoint is the so-called SVR12 – viral levels too low to be quantified 12 weeks after the end of treatment.

Outcomes appeared similar regardless of the doses and length of treatment, Rodriguez-Torres reported -- in three arms, 94% of patients (or 15 out of 16) reached the primary endpoint.

In the fourth arm -- with 12 weeks of treatment and a higher dose of BMS-791325 -- 16 of 18 patients (89%) reached SVR12. One patient had viral breakthrough while on therapy and another relapsed during follow-up, she said.

Investigators saw only one serious adverse event -- a case of renal calculus that was judged not to be related to the study drugs, she reported.

There were no adverse events that led to patients stopping treatment and only one clinical adverse event that reached grade 3 or 4 -- a headache that resolved as treatment continued.

Investigators did not see any grade 3 or 4 laboratory abnormalities, Rodriguez-Torres said.

Follow-up is continuing and the study is being expanded to include other patient populations, Rodriguez-Torres said, adding: "We call it the study that never ends."

The study was supported by Bristol-Myers Squibb. Rodriguez-Torres reported financial links with the company and several authors are employees of BMS.

Primary source: IDWeek
Source reference: Rodriguez-Torres M, et al "Interim analysis of an interferon (IFN)- And ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients" IDWeek 2013; Abstract 1828.


Also See: Interim Analysis of an Interferon (IFN)- And Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 In Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients

Researchers Launch Hepatitis Research Network in Africa

Released: 10/8/2013 1:55 PM EDT
Source Newsroom: Loyola University Health System

Newswise — MAYWOOD, Il. – Although it does not receive as much attention as AIDS, hepatitis has long been one of Africa’s most serious health problems.

To study how to better prevent and control hepatitis, physicians and researchers from Africa, the United States and Europe recently launched the Africa Collaborative Hepatitis Network, known as HepNet http://stritch.luc.edu/hepnet/

The initiative is led by Jennifer E. Layden, MD, PhD, and colleagues from Loyola University Chicago Stritch School of Medicine.

HepNet is an outgrowth of a study Dr. Layden and colleagues are conducting in Africa. The researchers hope to estimate the prevalence of hepatitis C in Ghana and Nigeria; determine the major ways hepatitis C is transmitted; and identify the genetic factors in patients and in the virus that influence outcomes.

An estimated 12 percent to 15 percent of the population of Africa has chronic infection of Hepatitis B, and 3 percent to 6 percent have hepatitis C. In the United States, by comparison, about 2 percent of the population has hepatitis C and less than 1 percent has hepatitis B. In Gambia, 62 percent of all cancers are liver cancer, which is almost always due to the hepatitis virus.

Hepatitis C has been infecting people in Africa for the last 500 to 1,000 years. But hepatitis often receives less attention from public health officials and the general public than other serious infectious diseases such as AIDS, tuberculosis and malaria, Dr. Layden said.

Dr. Layden and colleagues from Loyola’s Public Health Sciences Department organized the inaugural HepNet meeting August 12-13 in Kumasi, Ghana. Several studies already are being organized.

The inaugural meeting included physicians and scientists from the University of Ibadan in Nigeria, Kwame Nkrumah University of Science and Technology in Ghana, the U.S. Centers for Disease Control and Prevention, Duke University, Johns Hopkins University and the University of Cambridge. In addition to Dr. Layden, representatives from Loyola’s Department of Public Health Sciences and Department of Medicine included Amy Luke, PhD; Lara Dugas, PhD; Nallely Mora, MD; Steven Scaglione, MD; and Thomas Layden, MD.

HepNet will provide an infrastructure for researchers to communicate with one another, share resources, find other investigators, standardize studies, publicize findings, etc. The multidisciplinary network will include public health specialists, physicians, geneticists and virologists.

Researchers and scientists from the United States and Europe will collaborate closely with local physicians and public health officials. Both sides will benefit. Africa will get added resources to fight hepatitis. Researchers, in turn, will gain a better understanding of the host-virus biology, which could lead to better treatments and new vaccines, Dr. Layden said.

“HepNet is facilitating a functioning group of dedicated investigators who are working to understand and control hepatitis,” Dr. Layden said.

Dr. Layden is an infectious disease specialist and epidemiologist. She is an assistant professor in the Departments of Medicine and Public Health Sciences of Loyola University Chicago Stritch School of Medicine.


Janssen Acquires Investigational NS5A Inhibitor for the Treatment of Hepatitis C from GlaxoSmithKline


TITUSVILLE, N.J., Oct. 8, 2013 /PRNewswire/ -- Janssen Pharmaceuticals, Inc. (Janssen) announced today the acquisition of the investigational compound GSK2336805, an NS5a replication complex inhibitor in Phase 2 development for the treatment of chronic hepatitis C, from an affiliate of GlaxoSmithKline plc. Janssen has acquired all rights to develop and commercialize GSK2336805, including in combination with other drugs. Financial details of the agreement have not been disclosed.

Janssen plans to initiate Phase 2 studies to evaluate the use of GSK2336805 in interferon-free combinations with the investigational protease inhibitor simeprevir (TMC435) and TMC647055, Janssen's non-nucleoside polymerase inhibitor, for the treatment of chronic hepatitis C in adult patients with compensated liver disease.

"We're excited to add GSK2336805 to our existing portfolio of direct-acting antivirals (DAAs). This addition will broaden our clinical development program as we continue to look for new investigational interferon-free treatment combinations to combat the hepatitis C virus," said Gaston Picchio, Hepatitis Disease Area Leader, Janssen. "Janssen is dedicated to working with the hepatitis C community to investigate our portfolio of DAAs in a number of different treatment combinations and hepatitis C patient populations."  

About GSK2336805
GSK2336805 is an investigational once-daily NS5a replication complex inhibitor in Phase 2 development for the treatment of chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis.

About Simeprevir
Simeprevir is an investigational NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB for the treatment of genotype 1 and genotype 4 chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir works by blocking the protease enzyme that enables the hepatitis C virus to replicate in host cells.

Janssen is responsible for the global clinical development of simeprevir and has acquired exclusive, worldwide marketing rights, except in the Nordic countries. Medivir will retain marketing rights for simeprevir in these countries. Simeprevir has been submitted for regulatory approval in the United States, Canada and Europe, and was approved in September 2013 in Japan. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.

Additionally, simeprevir is being studied in combination with several DAAs with different mechanisms of action, with and without ribavirin, as part of interferon-free regimens. These include:

  • The Phase 2 COSMOS study of simeprevir and Gilead's nucleotide inhibitor sofosbuvir (GS-7977) in treatment-naive and previous null-responder genotype 1 hepatitis C patients, including patients with cirrhosis; 
  • A Phase 2 study of simeprevir and Bristol-Myers Squibb's NS5A replication complex inhibitor daclatasvir in treatment-naive and previous null-responder genotype 1 hepatitis C patients;  and
  • The Phase 2 HELIX-1 study of simeprevir and Idenix's once-daily pan-genotypic NS5A inhibitor samatasvir (IDX719) in treatment-naive genotype 1b and genotype 4 hepatitis C patients.

For additional information about simeprevir, please visit www.clinicaltrials.gov.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is the focus of a rapidly evolving treatment landscape. Approximately 150 million people are infected with hepatitis C worldwide – including approximately 3.2 million people in the United States – and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Janssen
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in infectious diseases and vaccines, oncology, immunology, neuroscience, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Pharmaceuticals, Inc. and Janssen R&D Ireland are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit http://www.janssenrnd.com for more information.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995.  The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events.  If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Pharmaceuticals, Inc., any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson.  Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; impact of business combinations; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies.  A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2012.  Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson.  None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)

Media Contact: Daniel De Schryver 
Mobile: +49 173 76 89 149

Media Contact: Craig Stoltz 
Mobile: +1 (215) 325-3612

Investor Contact: Stan Panasewicz
Office: +1 (732) 524-2524

Investor Contact: Louise Mehrotra
Office: +1 (732) 524-6491

SOURCE Janssen Pharmaceuticals, Inc.



Investigational interferon-free regimen demonstrates undetectable hepatitis C virus in all patients reaching end of treatment in ongoing Phase II trial


08 October 2013

• Collaborative trial from Boehringer Ingelheim and Presidio Pharmaceuticals investigates triple-DAA regimen of faldaprevir, deleobuvir and PPI-668
• 97% (28/29) of patients achieved rapid virologic response at 4 weeks and 100% of patients (13/13) who have completed all 12 weeks of the investigational regimen had undetectable levels of hepatitis C virus at the end of treatment
• Of the 36 genotype-1a patients, the majority have a non-CC IL28B genotype and many have pre-existing HCV mutations that had been difficult-to-cure in previous studies

For media outside of the U.S.A., UK and Canada only

INGELHEIM, 8 October, 2013 – Boehringer Ingelheim today announced that interim data from its Phase II hepatitis C (HCV) clinical collaboration with Presidio Pharmaceuticals have been accepted for presentation as a late breaker poster at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), taking place 1-5 November in Washington, D.C.1 The poster presentation will be on Monday 4 November.

This ongoing study evaluates a new 12-week interferon-free regimen of Boehringer Ingelheim’s protease inhibitor, faldaprevir*, and non-nucleoside NS5B polymerase inhibitor, deleobuvir*, in combination with Presidio’s pan-genotypic HCV NS5A inhibitor, PPI-668*, with and without ribavirin.1,2 The trial is fully enrolled (36 patients) and to date, 97% of patients (28/29) have achieved undetectable levels of virus at week 4 of treatment, also known as rapid viral response (RVR). Additionally, 100% of patients who have completed treatment (13/13) achieved undetectable levels of virus at the end of treatment.

"These results are promising particularly because they show the potential to evaluate harder-to-treat populations; all patients studied were genotype-1a and the majority of patients had the non-CC IL28B genotype," said Jacob Lalezari, M.D., Director of Quest Clinical Research in San Francisco, CA.

Two thirds of patients in the study have the difficult-to-cure non-CC IL28B genotype1; previous studies have shown that presence of this genotype led to a reduced likelihood of achieving viral cure.3 In addition, of the 29 patients who have completed 4 weeks treatment, 11 had HCV NS5A and/or NS5B resistance substitutions which are mutations in the hepatitis C virus that can impact treatment response with some antiviral therapies.1 Ten of these patients achieved RVR and one patient had a partial response to treatment but developed viral breakthrough and was discontinued.

Professor Klaus Dugi, Senior Vice President Medicine at Boehringer Ingelheim

"This collaboration is part of our ongoing commitment to develop interferon-free treatment options for a broad range of real-world patients, including the difficult-to-cure who currently have few treatment options," said Professor Klaus Dugi, Senior Vice President Medicine at Boehringer Ingelheim. "This data adds to the growing body of evidence for faldaprevir* which is the foundation of both, our interferon-based and interferon-free treatment regimens. We are encouraged by the data so far and look forward to further results at AASLD next month and the final results in Q2 2014."

To date, there have been no treatment discontinuations for adverse events in this study. Adverse events overall have been mild to moderate, with the incidence and severity of skin rashes and gastrointestinal side effects similar to those observed in previous trials studying faldaprevir* and deleobuvir*.1

In March 2013, Boehringer Ingelheim and Presidio Pharmaceuticals entered a non-exclusive collaboration to evaluate the three direct acting antivirals (DAAs) in combination regimens. Both companies will retain all rights to their respective compounds. Presidio has operational responsibility for this collaborative trial, with oversight by an intercompany project team. Post-treatment sustained response data will be presented at the AASLD Congress next month and final results are expected in Q2 2014.

As part of the company’s long-term commitment to developing new therapeutic options for patients with HCV, Boehringer Ingelheim recently completed enrolment for its pivotal Phase III interferon-free HCVerso™ 1 and 2 trials. The trials are evaluating the treatment regimen of faldaprevir*, deleobuvir* and ribavirin in genotype-1b infected patients.


About the Phase IIa Presidio collaboration trial
The trial includes 36 treatment-naïve patients with genotype-1a HCV treated for 12 weeks with an all-oral DAA regimen, with 24 weeks of post-treatment follow-up. There are three arms in this study:2

  • The first enrolled 12 patients and is evaluating faldaprevir* 120 mg once-daily (QD), PPI-668 200mg once-daily (QD) and deleobuvir* 600mg twice-daily (BID) with ribavirin
  • The second enrolled 12 patients and is evaluating faldaprevir* 120 mg QD, PPI-668 200mg QD and deleobuvir* 400mg BID with ribavirin
  • The third arm enrolled 12 patients and is evaluating the same regimen as arm 1, but without ribavirin

The primary endpoint of the trial is viral cure 12 weeks after treatment completion (SVR12).2

The Boehringer Ingelheim NewsHome: An innovative resource for journalists
The Boehringer Ingelheim hepatitis C www.NewsHome.com is the one-stop-shop for clear, concise and easy to understand information about hepatitis C for the media.

About Boehringer Ingelheim in hepatitis C
Through pioneering science, Boehringer Ingelheim is striving to find answers to the pressing challenges still faced by the diverse population of hepatitis C patients. The company’s comprehensively designed hepatitis C clinical trial programme includes a broad range of patients, including the challenging to cure, that clinicians see every day in clinical practice.

Boehringer Ingelheim is developing faldaprevir*, an optimised second generation protease inhibitor, as the foundation for both interferon-based and interferon-free treatment regimens.

Interferon-based therapy with faldaprevir* has the potential to improve cure rates with the added convenience of once-daily dosing and no dietary requirements for intake. Faldaprevir* has proven efficacy in a broad range of genotype-1a and 1b hepatitis C patients. The Phase III STARTVerso™ trial programme, which includes treatment-naïve, treatment-experienced and HIV co-infected patients with hepatitis C virus, is nearly complete.4,5,6,7

Deleobuvir* is a potent investigational non-nucleoside NS5B polymerase inhibitor to treat patients with genotype-1b hepatitis C virus. Phase III HCVerso™ trials, investigating the interferon-free regimen of twice-daily deleobuvir in combination with once-daily faldaprevir* and ribavirin, are well underway.8,9

As part of Boehringer Ingelheim’s long-term commitment to hepatitis C, the company is also evaluating other combinations of investigational hepatitis C compounds that work in different ways. Boehringer Ingelheim’s recent collaboration with Presidio Pharmaceuticals, Inc. for a Phase II clinical study investigating an interferon-free, all-oral, potentially ribavirin-free combination is part of the company’s continued exploration to discover and develop innovative options for the treatment of HCV.

About Hepatitis C
Hepatitis C is a blood-borne infectious disease caused by the hepatitis C virus which lives and replicates in the liver. Hepatitis C is a leading cause of chronic liver disease, liver cancer and transplantation.10 Chronic hepatitis C is a major public health issue and one of the most prevalent infectious diseases worldwide, affecting around 170 million people,11 with 3-4 million new cases occurring each year.12

It is common for hepatitis C patients to remain undiagnosed due to the initial unspecific symptoms of the disease. Consequently, a large number of patients first present to their physician when they experience symptoms or already have liver disease.13 Patients with advanced liver disease are challenging to cure, yet have the greatest need for more effective and better tolerated treatments.

Of patients with chronic hepatitis C, 20 percent will develop liver cirrhosis, of which 2-5 percent will die every year.14 Advanced liver disease due to hepatitis C currently represents the main cause for liver transplantation in the western world.14

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

About Presidio in HCV
Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company focused on the discovery and development of oral pan-genotypic therapeutics for HCV patients. Efforts are currently focused on novel inhibitors of both the HCV NS5A and NS5B genes. PPI-668 is an investigational, pan-genotypic, once daily, NS5A inhibitor. In earlier clinical studies in healthy volunteers and HCV-infected patients, PPI-668 has been well-tolerated to date with no serious or severe adverse events and no apparent pattern of treatment-related clinical side effects or laboratory abnormalities. PPI-668 achieves plasma concentrations high enough to inhibit most pre-existing resistant variants and achieves steady-state levels after a single dose. In a clinical study of PPI-668 monotherapy in GT1 HCV-infected patients, viral load reductions of 3.5 to 3.7 log10 HCV were achieved in 1-2 days. Activity was also noted in GT3 HCV-infected patients.

Presidio’s NS5B inhibitor, PPI-383, is a novel pan-genotypic non-nucleosidic inhibitor with potential to inhibit all of the major HCV genotypes.This compound is currently in Phase 1 studies in healthy subjects. For more information, please visit our website at: www.presidiopharma.com.

* Faldaprevir, deleobuvir and PPI668 are investigational compounds and not yet approved. Their safety and efficacy have not yet been fully established.


1 J. Lalezari. Rapid and Consistent Virologic Responses in a Phase 2 Trial of a New All-Oral Combination of Faldaprevir, Deleobuvir, and PPI-668, with and without Ribavirin, in Patients with HCV Genotype-1a Infection
2 ClinicalTrials.gov. Study of PPI-668, BI 207127 and Faldaprevir, With and Without Ribavirin, in the Treatment of Chronic Hepatitis C. May 2013.
3 A. Thompson. Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus. 2010.
4 ClinicalTrials.gov. Efficacy and Safety of BI 201335 in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Genotype 1 Hepatitis C Infected Patients. http://clinicaltrials.gov/ct2/show/NCT01343888?term=bi+201335&rank=4 [Last accessed 17/09/13]
5 ClinicalTrials.gov. BI 201335 Used in Treatment Naive Patients Infected With Genotype 1 Chronic Hepatitis C Infection. http://clinicaltrials.gov/ct2/show/NCT01297270?term=bi+201335&rank=5 [Last accessed 17/09/13]
6 ClinicalTrials.gov. Pivotal Trial Treatment Experienced Patient Infected With Hepatitis C Virus (HCV) Genotype 1 (GT1). http://clinicaltrials.gov/ct2/show/NCT01358864?term=bi+201335&rank=14 [Last accessed 17/09/13]
7 ClinicalTrials.gov. Phase III Trial of BI 201335 in Treatment Naive (TN) and Relapser Hepatitis C Virus (HCV)- Human Immunodeficiency Virus (HIV) Coinfected Patients. http://clinicaltrials.gov/ct2/show/NCT01399619?term=bi+201335+HIV&rank=1 [Last accessed 17/09/13]
8 ClinicalTrials.gov. IFN-free Combination Therapy in HCV-infected Patients Treatment-naive: HCVerso1. http://clinicaltrial.gov/ct2/show/NCT01732796?term=faldaprevir+bi+207127&rank=3 [Last accessed 17/09/13]
9 ClinicalTrials.gov. Phase 3 Study of BI 207127 in Combination With Faldaprevir and Ribavirin for Treatment of Patients With Hepatitis C Infection, Including Patients Who Are Not Eligible to Receive Peginterferon: HCVerso2. http://clinicaltrial.gov/ct2/show/NCT01728324?term=faldaprevir+bi+207127&rank=2 [Last accessed 17/09/13]
10 World Health Organisation. Hepatitis C. 2002 http://www.who.int/csr/disease/hepatitis/Hepc.pdf [Last accessed on 23/09/13
11Centers for Disease Control and Prevention (2012) Hepatitis C available at: http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c.htm [Last accessed on 23/09/13]
12 World Health Organisation. Hepatitis C Fact Sheet. Updated July 2012 http://www.who.int/mediacentre/factsheets/fs164/en/index.html [Last accessed on 16/09/13]
13 Chen S.L., Morgan T.R. The Natural History of Hepatitis C Virus (HCV) Infection. Int J Med Sci 2006; 3:47-52. Available from http://www.medsci.org/v03p0047.htm [Last accessed on 16/09/13]
14 Soriano, Vincent et al. New Therapies for Hepatitis C Virus Infection. Clinical Infectious Disease 2009; 48:313–20


National Coverage Analysis for Screening for Hepatitis C Virus (HCV) in Adults

October 4, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Office of Clinical Standards and Quality
600 Security Boulevard
Mailstop S3-02-01
Baltimore, MD 21244

Re:  National Coverage Analysis for Screening for Hepatitis C Virus (HCV) in Adults

Dear Dr. Jacques:

The National Minority Quality Forum (The Forum) is pleased to submit this comment regarding the CMS National Coverage Analysis for Hepatitis C Virus (HCV). The Forum strongly recommends that CMS provide to Medicare beneficiaries coverage of HCV screening in a manner that is consistent with the U.S. Preventive Services Task Force (USPSTF) Recommendation for screening for Hepatitis C Virus Infection in Adults, which was issued on June 25, 2013.

The Forum welcomes this focus by CMS on HCV screening in order to prevent the ravages of this disease that can include cirrhosis, end-stage liver disease and hepatocellular carcinoma. The Forum is a Washington, DC-based not-for-profit, non-partisan, independent research and education organization founded in 1998 that is dedicated to improving the quality of healthcare that is available for and provided to all populations. The Forum has launched the Hepatitis C Index to help health-care practitioners, policy makers, advocacy groups and industry identify and quantify Hepatitis C geographically and by age, gender and race/ethnicity.

As with many amendable conditions that lead to devastating illness and death, early diagnosis and treatment is key. Accordingly, in the update of their 2004 recommendation on screening for and treatment of hepatitis C virus (HCV) infection in asymptomatic adults, “The USPSTF recommends screening for HCV infection in persons at high risk for infection. The USPSTF also recommends offering 1-time screening for HCV infection to adults born between 1945 and 1965.”[i]

In 2010, the overall incidence rate of acute HCV infection was 0.3/100,000, and varied by race or ethnicity. Persons born between 1945 and 1965 are more likely to be diagnosed with HCV infection than other birth cohorts, possibly because they received blood transfusions before the introduction of screening in 1992, or were exposed decades earlier as a result of other risk factors.[ii] The incidence rate for acute hepatitis C was lowest among persons of Asian or Pacific Islander descent, and highest among American Indians and Alaskan natives. Black/African American persons had the highest mortality rates from HCV, at 6.5 to 7.8 deaths per 100,000.[iii]

Hepatitis C is the most common chronic bloodborne pathogen in the United States. Hepatitis C-related end-stage liver disease is the most common indication for liver transplants among U.S. adults, accounting for more than 30% of cases. Studies suggest that approximately one-half of the recently observed 3-fold increase in the incidence of hepatocellular carcinoma is related to acquisition of HCV infection 2-4 decades earlier.[iv]

Given the importance of early detection, and the increased availability of effective treatments, improved screening and surveillance of HCV will not only increase the potential for successful intervention for the patient and the physician, but also stimulate additional research and innovation.

The Forum strongly encourages CMS to take this critical step toward preventing the avoidable morbidity and mortality associated with the Hepatitis C virus.


Gary A. Puckrein, PhD
President and Chief Executive Officer

[i] Moyer, V, on behalf of the U.S. Preventive Services Task Force. Screening for Hepatitis C Virus Infection in Adults:  U.S. Preventive Services Task Force Recommendation Statement, Clinical Guideline, Annals of Internal Medicine, June 25, 2013.

[ii] Smith BD, Patel N, Beckett FA, Jewett A, Ward JS. Hepatitis C virus antibody prevalence, correlates and predictors among persons born from 1945 through 1965, United States, 1999-2008 [Abstract], Hepatology, Supplement 1, 2011.

[iii] Moyer, V, op. cit.

[iv] Chou R, Cottrell EB, Wasson N, Rahman B, Guide JM. Screening for Hepatitis C Virus Infection in Adults, Comparative Effectiveness Review no 69. AHRQ publication no. 12-EHC090-EF, Agency for Healthcare Research and Quality, 2012.