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

Abstract

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.

Introduction

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.

Virology

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).

811158-fig1

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.

Conclusion

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.

References

  1. World Health Organization. Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol 2004; 44: 20–29.

  2. Cornberg M, Razavi HA, Alberti A et al. A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. Liver Int 2011; 31: 30–60.

  3. Lawitz E, Mangia A, Wyles D et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878–1887.

  4. Wartelle-Bladou C, Le Folgoc G, Bourli_ere M et al. Hepatitis C therapy in non-genotype 1 patients: the near future. J Viral Hepat 2012; 19: 525–536.

  5. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA derived from a bloodborne non-A, non-B hepatitis genome. Science 1989; 244: 359–362.

  6. Simmonds P, Alberti A, Alter HJ et al. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology 1994; 19(5): 1321–1324.

  7. Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 2000; 13(2): 223–235.

  8. Okamoto H, Kurai K, Okada S et al. Full-length sequence of a hepatitis C virus genome having poor homology to reported isolates: comparative study of four distinct genotypes. Virology 1992; 188: 331–341.

  9. Pybus OG, Charleston MA, Gupta S, Rambaut A, Holmes EC, Harvey PH. The epidemic behaviour of Hepatitis C virus. Science 2001; 22: 2323–2325.

  10. Pybus OG, Drummond AJ, Nakano T, Robertson BH, Rambaut A. The epidemiology and iatrogenic transmission of hepatitis C virus in Egypt: a bayesian coalescent approach. Mol Biol Evol 2003; 20: 381–387.

  11. Hissar SS, Goyal A, Kumar M et al. Hepatitis C virus genotype 3 predominates in North and Central India and is associated with significant histopathologic liver disease. J Med Virol 2006; 78: 452–458.

  12. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5: 558–567.

  13. Agnello V, Abel G, Elfahal M, Knight G, Zhang Q-X. Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA 1999; 96: 12766–12771.

  14. Shi ST, Polyak SJ, Tu H, Taylor DR, Gretch DR, Lai M. Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins. Virology 2002; 292: 198–210.

  15. Perlemuter G, Sabile A, Letteron P et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J 2002; 16: 85–94.

  16. Moriya K, Yotsuyanagi H, Shintani Y et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 1997; 78: 1527–1531.

  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.

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