Review article: HCV genotype 3 – the new treatment challenge

Alimentary Pharmacology & Therapeutics

Volume 39, Issue 7, pages 686–698, April 2014

Review Article

You have free access to this content

J. Ampuero^1,2, M. Romero-Gómez¹ and K. R. Reddy^2,*

Article first published online: 20 FEB 2014

DOI: 10.1111/apt.12646

© 2014 John Wiley & Sons Ltd

Summary

Background

Over the past several years, hepatitis C therapy has been pegylated interferon and ribavirin based. Although protease inhibitor-based therapy has enhanced response rates in genotype 1, the recent advances in therapy have demonstrated a challenge in genotype 3, a highly prevalent infection globally.

Aim

To provide a comprehensive summary of the literature evaluating the unique characteristics and evolving therapies in genotype 3.

Methods

A structured search in PubMed, the Cochrane Library and EMBASE was performed using defined key words, including only full text papers and abstracts in English.

Results

HCV genotype 3 is more prevalent in Asia and among intra-venous drug users. Furthermore, it interferes with lipid and glucose metabolism, and the natural history involves a more rapid progression of liver disease and a higher incidence of hepatocellular carcinoma (HCC). New therapies with protease inhibitors have focused on genotype 1 largely and have demonstrated enhanced responses, but have limited activity against genotype 3. Thus far, in clinical trials, NS5B and NS5A inhibitors have performed more poorly in genotype 3, while a cyclophilin inhibitor, alisporivir, has shown promise.

Conclusions

As treatments for HCV have evolved, genotype 3 has become the most difficult to treat. Furthermore, genotype 3 has special characteristics, such as insulin resistance and alterations in lipid metabolism, which may partly explain the lower treatment responses. A great deal of emphasis on advancing therapy is needed in this population that appears to have a more rapid progression of liver disease and a higher incidence of HCC.

Introduction

Hepatitis C virus (HCV) infection is a global health problem that affects 170 million people worldwide, and approximately 55% (95 million) of the infected population is in South East Asia and Western Pacific countries.[1] Chronic hepatitis C is associated with significant morbidity and mortality, which result mainly from the progression towards cirrhosis and hepatocellular carcinoma (HCC).[2] Factors associated with rapid progression include: (i) host factors (i.e. older age at infection, male gender, Afro-American race, alanine aminotransferase level, liver fibrosis, genetic factors, metabolic factors); (ii) viral factors (i.e. genotype, viral load, viral kinetics); (iii) co-infections (i.e. hepatitis B virus or human immunodeficiency virus); (iv) exposure to toxic agents (i.e. alcohol, tobacco or cannabis).[3] Fibrosis progression in hepatitis C genotype 3 seems to be more rapid than in genotype 1 and is probably related to a higher degree of steatosis.

Hepatitis C virus does not integrate into the human genome. Thus, a sustained virological response (SVR), a feature strongly linked to reduced likelihood of progressive liver disease and mortality, is key to achieving cure.[4] Traditionally, genotypes 2 and 3 have been placed in the same group when making a decision on the dose of ribavirin or treatment duration. More recently, genotype 2, unlike genotype 3, has been found to be sensitive to various direct-acting anti-virals (DAAs), thus resulting in differences in SVR rates.[5] Therefore, genotype 2 and genotype 3 should not be grouped together for analyses of SVR rate or for therapeutic strategies. Given the recent approval of the DAAs for genotype 1 and with new imminent therapies, it is important that we recognise that genotype 3 is now the more difficult genotype to treat.[6] With the unique features and challenges in treatment in mind, we reviewed the literature and provide a perspective on chronic hepatitis C genotype 3.

Epidemiology

The hepatitis C virus, resulting from high-error rates of RNA-dependent RNA polymerase during the replication of the HCV genome, comprises six genotypes and several subtypes.[7] HCV genotype 1 (both 1a and 1b) is dominant in the US, Western Europe and Australia, representing up to 60% of global HCV infections. HCV-1b predominates in Japan, China and Russia.[8] Genotype 4a is the most common subtype in Egypt,[9] whereas other subtypes of HCV-4 are found in Central Africa.[10] Genotype 5a accounts for 50% of infections in South Africa, while HCV-3 and HCV-6 are common in Southeast Asia. Specifically, in populous countries such as India and Pakistan, HCV-3 is the predominant genotype.[11, 12] In addition, in certain European countries, such as Greece,[13] Poland[14] and the Netherlands,[15] HCV-3 can be found in up to 30% of all cases.

There has been an interesting and intriguing association between the mode of HCV transmission and HCV genotypes. Although HCV-1b has been encountered more often in patients who acquired HCV through blood transfusion[16] (the prevalence of HCV-1b has decreased concurrently with the implementation of screening of blood and blood products for HCV), HCV-3a has been associated with intravenous drug use (IVDU),[17] tattooing and piercing.[18] A unique worldwide epidemic among drug abuser communities has been proposed because nonstructural protein (NS) 5B of HCV-3a showed similar sequences in intravenous drug users across different countries,[19] suggesting a common origin (apparently emerged and diversified in Asia)[20] of the outbreak. Indeed, molecular evolutionary analysis suggests that a common ancestor of HCV subtype 3a strains existed approximately 200 years ago, and a Bayesian skyline plot suggested a spread to Thailand during the mid-1970s and early 1980s, partially overlapping with the Vietnam War (1955–1975), where the widespread use of injection drug use pervaded the US Army.[21] High rates of HCV transmission and prevalence among IVDUs are related to unsafe injecting practices, such as drug preparation materials, needles or syringe sharing, together with the social context of drug abuse.\

HCV genotype 3 and steatosis

HCV infection shares pathological features with metabolic syndrome, especially liver steatosis, due to HCV's effects on lipid and glucose metabolism,[22] and thus presents an increased cardiovascular risk.[23] The magnitude of HCV-3 infection-related steatosis correlates with the level of viral replication,[24] and it disappears after successful anti-viral therapy,[25] suggesting a cause and effect relationship between the virus and the genotype. HCV-3 genotype is associated with the highest rates of steatosis among all HCV genotypes, reaching up to 70%.[26] Rubbia-Brandt et al. assessed 101 HCV patients and demonstrated a significant correlation between steatosis and HCV RNA level in patients infected with HCV-3, but not in those infected with HCV-1, providing evidence that steatosis is the morphological expression of a viral cytopathic effect of HCV-3.[27] Furthermore, in patients with HCV cirrhosis, genotype 3 has been independently associated with an increased risk of HCC[28] (Figure 1).

Figure 1. Special issues related to HCV genotype 3.

Insulin resistance

Several studies have noted a direct role of HCV in altering glucose metabolism, leading to insulin resistance and diabetes.[29, 30] Of interest is the observation that achieving SVR with therapy has resulted in improvement in insulin resistance and a reduced incidence of diabetes mellitus.[31] An epidemiological overlap between HCV and glucose metabolism impairment could explain the impact of metabolic abnormalities on SVR,[32] independent of HCV genotype[33, 34] or IL28B genotype.[35]

HCV core protein promotes degradation of insulin receptor substrates 1 and 2 [by over-expressed tumour necrosis factor a (TNFa) and suppression of cytokine signalling-3 (SOCS)],[36] leading to defective downstream PI3K and Akt phosphorylation. As the PI3K/Akt pathway is critical for the inhibition of gluconeogenesis in the liver, this process could lead to increased glucose production.[37] HCV-3a core protein induces the expression of SOCS-7, which is partially involved in the development of insulin resistance, and downregulation of peroxisome proliferator-activated receptor γ expression.[38] The ability of insulin to decrease the plasma glucose level in HCV transgenic mice provides direct experimental evidence for the role of HCV in the development of insulin resistance in human HCV infection.[39]

Lipid metabolism

Low-density lipoprotein receptor facilitates entry of HCV into the hepatocyte.[40] Then, HCV core protein and NS5A interact with lipid droplets, which in turn may play a role in the pathogenesis of lipid metabolism and contribution to hepatic steatosis.[41] Clark et al. observed that HCV-3, but not HCV-2, selectively interfered with the late cholesterol synthesis pathway, which then resolved after achieving SVR.[42] Cram et al. observed that HCV-3a and HCV-1b core proteins up-regulated the fatty acid synthase promoter. However, HCV-3a core protein expression induced significantly higher fatty acid synthase promoter activity than HCV-1b core. Thus, it was concluded that the stronger effect of HCV-3a core protein was a plausible reason for the higher prevalence and severity of steatosis in HCV-3a infection.[43]

Current treatment in HCV-3

Peginterferon (PEG-IFN) α-2b (1.5 mg/kg/week) plus ribavirin (RBV) (800–1400 mg/day) or PEG-IFN α-2a (180 mg/week) plus RBV (800 mg/day) for 24 weeks have been the established standard of care regimens for patients with HCV-3.[44] However, the optimal administration of PEG-IFN and RBV, especially the duration, has still not been clearly established. Manns et al.[45] and Fried et al.[46] carried out two randomised controlled trials that established a duration of 48 weeks of combination therapy with PEG-IFN and RBV as the standard of care for chronic hepatitis C. Mangia et al. observed that a shorter course of therapy over 12 weeks with PEG-IFN and RBV was as effective as a 24-week course for patients with HCV-3 who responded to treatment at 4 weeks (RVR).[47] Patients achieving RVR had similar SVR rates to HCV-3 patients treated for either 12 or 24 weeks (86.4% vs. 83.7%). However, in those without RVR, 36 weeks of therapy resulted in a higher rate of SVR compared with 24 weeks (72.5% vs. 63.0%). As such, it has been suggested that HCV-3 patients with RVR could be treated for 12 weeks, whereas in those without RVR, it was felt preferable to extend treatment to 36 weeks.[48] Therefore, virological response at week 4 of dual PEG-IFN and RBV therapy could be crucial in differentiating easy-to-treat from difficult-to-treat genotype 3 patients.[49] In contrast, the NORDynamIC trial observed that treatment for 12 weeks in HCV-3 was generally inferior to 24 weeks (SVR 58% after 12 weeks, 78% after 24 weeks).[50] Similarly, the N-CORE study showed that extended duration of treatment in non-RVR patients provided benefits in HCV-3 patients adherent to study protocol with SVR24 of 73% following 48 weeks of treatment and 54% after 24-week treatment duration. This was largely driven by differences in relapse rates (22% vs. 41%).[51] On the other hand, Hadziyannis et al. observed that 800 mg/d of RBV plus PEG-IFN for 24 weeks was enough to cure the majority of patients with HCV-3.[52]

In contrast, Zeuzem et al. enrolled 224 HCV-2 and HCV-3 patients, and evaluated PEG-IFN plus RBV administered for 24 weeks and noted higher rates of SVR in HCV-2 patients (93%) than in those with HCV-3 (79%).[53] These results were confirmed in a subsequent meta-analysis: 74% in HCV-2 in comparison with 69% in HCV-3.[54] The presence of steatohepatitis and more advanced fibrosis in HCV-3 could contribute to poorer therapeutic response in these patients.[55, 56] Shah et al. observed higher relapse rates in patients with steatosis (17.4% and 20.9% for low and high baseline levels of HCV RNA respectively) than in those without steatosis (2.5% and 8.8%).[57] Lastly, factors predictive of higher relapse rates in genotype 3 have included male gender (16% vs. 7%), age >55 years old (27% vs. 12%), high viral load (20% vs. 7%) and advanced fibrosis (20% vs. 6%).[58]

Factors reducing SVR in HCV-3

PEG-IFN and RBV achieve 70%–80% SVR among patients infected with genotype 3.[59] Prolongation of treatment duration in HCV-3 genotype has been controversial in recent years, so it is essential to identify difficult-to-cure patients to optimise disease management and prevent relapses. HCV-3 cirrhotic patients with high viral load (HVL) and those without RVR are the most difficult to treat.[60] Bridging fibrosis or cirrhosis was similarly predictive of reduced SVR for the standard 24-week treatment (76% and 60%) and for the short 16-week treatment (67% and 48%) in a post hoc analysis of the ACCELERATE study.[61] On the other hand, Dalgard et al. aimed to determine the efficacy of 14 weeks of treatment in HCV-3 patients who achieved early virological response, and observed that low viral load (LVL) (<600 000 IU/mL) was a strong predictor of SVR (98% vs. 79%).[62] Following 24 weeks of therapy, the same group achieved 80–90% SVR24 in HCV-3 patients with RVR compared to 56% in the absence of RVR.[63] Similarly, Diago et al. observed high SVR rates in those with LVL (<400 000 IU/mL) regardless of duration of treatment of 16 or 24 weeks (91% and 95%, respectively), while patients with HVL achieved SVR of 79% and 89% respectively.[64] Von Wagner et al. encountered a significantly lower SVR rate (59% vs. 85%) in HCV-3 patients with HVL (>800 000 IU/mL) than in those with LVL.[65] Ferenci et al. demonstrated that viral kinetics, primarily in genotype 1 patients, as noted by the decline in HCV level on treatment, correlated with the probability of SVR. In those with ≤2 log₁₀ suppression of virus at week 12, the probability of SVR was approximately 10%, thus leading to the concept of a ‘stopping rule’ in such null responders.[66]

Taking into account RVR, baseline viral load, cirrhosis, metabolic abnormalities and 12-week virological response, EASL guidelines[67] recommend that in HCV-3: (i) in patients with RVR and baseline low viral load (<400 000–800 000 IU/mL) treatment duration could be shortened to 16 weeks at the expense of a slightly higher chance of post-treatment relapse; (ii) in the presence of advanced fibrosis, cirrhosis or cofactors affecting response (insulin resistance, metabolic syndrome, nonviral steatosis), the treatment duration should not be shortened to 16 weeks even if the patient has baseline low viral load and achieves RVR, and at least 24 weeks of therapy should be administered; (iii) patients with early or delayed virological response should be treated for 48 or 72 weeks, provided their HCV RNA is undetectable at week 24; (iv) patients with non-RVR and ≤2 log₁₀ drop or positive RNA at 24 week should discontinue therapy (Figure 2).

Figure 2. Peginterferon plus ribavirin treatment in HCV-3 genotype.

The addition of a protease inhibitor (telaprevir[68] and boceprevir[69]) to the standard of care has substantially improved the treatment response in HCV-1 patients, but not in HCV-3. Telaprevir as monotherapy had minimal activity against HCV-3, as noted by a mild decrease in HCV RNA levels (−0.54 log₁₀ IU/L at day 15),[70] while boceprevir has been found to be slightly more active than telaprevir against HCV-3 in cell-based assays, and to decrease HCV RNA levels comparable to those observed with the same dose in HCV-1 treatment-experienced patients in a phase 1 study.[71] As we have advanced in HCV therapy, even second wave protease inhibitors simeprevir, asunaprevir, faldaprevir and danoprevir have demonstrated limited activity against HCV-3.[72]

Advances in therapy

The main mechanism of action of most DAAs is the inhibition of an enzyme (protease or polymerase),[73] although some inhibit the assembly of the replication complex (NS5A inhibitors) or target the host factors that the virus uses (cyclophilin inhibitors)[74] (Table 1). Such all-oral therapy regimens appear to be very well tolerated and achieve high response rates even without the backbone of pegylated interferon.

Table 1. Characteristics of HCV DAAs and host targeting anti-virals

Characteristics	Protease inhibitors	Protease inhibitors	Polymerase inhibitors	Polymerase inhibitors	NS5A inhibitors	Cyclophilin inhibitors
a Ledipasvir has low activity against genotype 3. b No data available.
	First generation	Second generation	Nucleoside analogues	Non-nucleoside analogues
Potency	Variable among HCV genotypes	Variable among HCV genotypes	Consistent across genotypes	Variable among HCV genotypes	Multiple HCV genotypes	Multiple HCV genotypes
Barrier to resistance	Low	Low	High	Very low	Low	High
Drugs	Telaprevir Boceprevir	Simeprevir Asunaprevir Faldaprevir Vaniprevir Danoprevir ABT/rb	Sofosbuvir Mericitabine	BMS-791325 Tegobuvir ABT-333b	Daclatasvir MK-8742 Ledipasvira GS-5816 ABT-267b	Alisporivir
Efficacy in HCV-3	No	No	Yes	No	Yes	Yes

IFN-based regimens (Table 2)

NS3/4A protease inhibitors

NS3/4A is a serine protease essential for viral replication. Inhibitors of NS3/4A have a high potency but a low barrier to resistance, and are not effective against all HCV genotypes (i.e. telaprevir and boceprevir are only effective for HCV-1). Apart from telaprevir and boceprevir, other NS3/4A protease inhibitors have been developed to overcome the current limitations of first-generation drugs, with regard to the pharmacokinetic profile, barrier to resistance, adverse events and activity among other genotypes.[75] Simeprevir (TMC-435), the next line protease inhibitor, demonstrates good tolerability even with the infrequent mild and asymptomatic hyperbilirubinaemia (reversible at the end of the therapy).[76, 77] It is effective against HCV-1, but also against HCV-2, HCV-5 and HCV-6. However, it has shown limited efficacy against HCV-3.[78]

Table 2. Summary of DAA studies in HCV-genotype 3 patients

Author	Year	Drug	Patients characteristics	Study design	Outcome	Comments
Dore[81]	2013	Daclatasvir	80 HCV-3 patients All treatment-naïve 22.5% cirrhotics	DCV 60 mg/day and PEG-IFN/RBV 12 weeks DCV 60 mg/day and PEG-IFN/RBV 16 weeks placebo and PEG-IFN/RBV 24 weeks	SVR24 rates a) 85% b) 82% c) 69%	HCV-3 patients showed higher relapse rates than HCV-2
Yeh[82]	2013	MK-8742	48 HCV-1/HCV-3 Noncirrhotics	50 mg 5-day monotherapy 100 mg 5-day monotherapy	HCV RNA levels were reduced −3.4 log10 IU/mL in HCV-3	More sustained virological suppression in the 100 mg group
Lawitz[83]	2013	GS-5816	20 HCV-3 patients Treatment naïve Noncirrhotics	25 mg 3-day monotherapy 50 mg 3-day monotherapy 150 mg 3-day monotherapy	HCV RNA levels were reduced −3.25 log10 IU/mL −3.12 log10 IU/mL −3–14 log10 IU/mL
Lawitz[86]	2013	Sofosbuvir	25 HCV-2/HCV-3 Treatment naïve Noncirrhotics	SOF 400 mg/day plus PEG-IFN and RBV for 12w	SVR12 rate: 92%
Lawitz[87]	2013	Sofosbuvir	24 HCV-3 patients Treatment failure 55% cirrhotics	SOF 400 mg/day plus PEG-IFN and RBV for 12w	SVR12 rates: 83% in noncirrhotics and cirrhotics	HCV-2 achieved higher SVR12 rates (100% and 92%, respectively)
Gane[88]	2013	Sofosbuvir	40 HCV-2/HCV-3 Treatment naïve Noncirrhotics	SOF 400 mg/day plus RBV 12w SOF 400 mg/day plus RBV 12w and PEG-IFN 4w SOF 400 mg/day plus RBV 12w and PEG-IFN 8w SOF 400 mg/day plus RBV 12w and PEG-IFN 12w SOF 400 mg/day plus PEG-IFN/RBV for 8w SOF 400 mg/day 12w	SVR24 rates 100% 100% 100% 100% 100% 60%
Lawitz[89]	2013	Sofosbuvir	359 HCV-3 patients Treatment naïve 20% cirrhotics	SOF 400 mg/day plus RBV for 12w PEG-IFN/RBV for 24w	SVR12 rate in SOF 400 mg/day plus RBV for 12w was 67%	PEG-IFN/RBV for 24w achieved also 67% SVR12
Jacobson[93]	2013	Sofosbuvir	135 HCV-3 patients for whom treatment with PEG-IFN was not an option 20% cirrhotics	SOF 400 mg/day plus RBV for 12w Placebo	SVR12 rates Overall SVR 61% (68% noncirrhotics, 21% cirrhotics)	Overall SVR12 rate in HCV-2: 93% (92% noncirrhotics, 94% cirrhotics)
Jacobson[93]	2013	Sofosbuvir	127 HCV-3 patients Treatment failure 30% cirrhotics	SOF 400 mg/day plus RBV for 12w SOF 400 mg/day plus RBV for 24w	SVR12 rates 62% 30%	SVR12 was achieved in 19% HCV-3 cirrhotics In HCV-2, SVR12 was 86% after 12 weeks and 94% after 16 weeks
Zeuzem[94]	2013	Sofosbuvir	250 HCV-3 patients 58% treatment failure 21% cirrhotics	SOF 400 mg/day plus RBV for 24w Placebo	Overall SVR12 rate with sofosbuvir was 85%	SVR12 rates 94% treatment-naive patients without cirrhosis 92% treatment-naive cirrhotics 87% treatment-experienced noncirrhotics 60% treatment-experienced cirrhotics
Gane[90]	2010	Mericitabine	25 HCV-2/HCV-3 Treatment failure Noncirrhotics	Mericitabine 1500 mg/12 h plus PEG-IFN/RBV 24w Mericitabine 1500 mg/12 h plus PEG-IFN/RBV 48w Placebo plus PEG-IFN/RBV	SVR12 rates: 67% 90% 60%	SVR12 rates did not differ between HCV-2 and HCV-3 patients (63% and 67% respectively)
Fisiak[91]	2008	Alisporivir	7 HIV/HCV-3-coinfected patients Noncirrhotics	Alisporivir 1200 mg 14 days Placebo 14 days	HCV RNA levels were reduced −3.63 log10 IU/mL −0.73 log10 IU/mL
Fisiak[92]	2009	Alisporivir	HCV-1/2/3/4 patients Treatment naïve Noncirrhotics	ALV 200 mg/day plus PEG-IFN for 4w ALV 600 mg/day plus PEG-IFN for 4w ALV 1000 mg/day plus PEG-IFN for 4w ALV 1000 mg monotherapy for 4w PEG-IFN monotherapy for 4w	The 600- and 1000-mg combinations reduced HCV RNA levels HCV-1: −4.61 ± 1.88 HCV-2: −5.91 ± 1.11 HCV-3: −5.89 ± 0.43 HCV-4: −4.75 ± 2.19
Pawlotsky[95]	2012	Alisporivir (ALV)	194 HCV-3 patients Treatment-naïve Noncirrhotics	ALV 1000 mg/day for 24w ALV 600 mg/day plus RBV for 24w ALV 800 mg/day plus RBV for 24w ALV 600 mg/day plus PEG-IFN for 24w PEG-IFN/RBV for 24w	SVR24 rates 90% in ALV plus RBV 72% ALV 1000 mg 70% PEG-IFN/RBV	Late relapse was not observed after ALV plus RBV in contrast to PEG-IFN/RBV or ALV monotherapy
Sulkowski[97]	2012	Daclatasvir plus Sofosbuvir	18 HCV-3 patients Treatment naïve Noncirrhotics	SOF 400 mg/day for 7 days then add DCV 60 mg/day for 24w DCV 60 mg/day plus SOF 400 mg/day for 24w DCV 60 mg/day plus SOF 400 mg/day plus RBV for 24w	SVR4 rates 88% 100% 86%	Virological response did not vary by IL28B status or with the use of RBV

NS5A inhibitors

NS5A is a zinc-binding phosphoprotein that plays an important but currently unclear role in HCV replication. Daclatasvir (BMS-790052) is an HCV NS5A inhibitor that has been demonstrated to have anti-viral activity across all genotypes.[79] Daclatasvir-resistant variants have been shown to remain sensitive to interferon and other HCV protease and non-nucleoside polymerase inhibitors. Consequently, the addition of interferon or other DAAs to daclatasvir would enhance response to therapy, while minimising the risk of emergence of viral resistance.[80] The COMMAND study included 80 treatment-naïve HCV-3 patients, who were treated with daclatasvir and PEG-IFN/RBV (12 or 16 weeks) vs. placebo and PEG-IFN/RBV (24 weeks). SVR24 was achieved by 85%, 82% and 69% in HCV-3 patients in the 12-week, 16-week and placebo groups, respectively.[81]

In a phase 1b, randomised, placebo-controlled study, MK-8742, an NS5A inhibitor, was administered as 5-day monotherapy in 48 HCV-1 and HCV-3 patients without cirrhosis. Plasma HCV RNA declined rapidly from baseline by 3.4 log₁₀ IU/mL in HCV-3 patients, and mean viral load reductions were similar in 50- and 100-mg dose groups with more sustained virological suppression after cessation of dosing in the 100-mg group.[82] On the other hand, GS-5816, a second-generation NS5A inhibitor, with anti-viral activity against all HCV genotypes, is well tolerated and has demonstrated potent anti-viral activity against HCV genotypes 1-4.[83]

NS5B polymerase inhibitors

NS5B is an HCV RNA-dependent RNA polymerase that plays a crucial role in HCV replication. Nucleotide inhibitors have been found to be pan-genotypic and possess high potency and high barrier to resistance, as the active site of NS5B is highly conserved across all HCV genotypes. Non-nucleoside inhibitors allosterically target the NS5B region, and inhibit the initiation stage of RNA synthesis. This class of inhibitors displays a low barrier to resistance, mild potency and limited effectiveness across all HCV genotypes.

Sofosbuvir (GS-7977) is a pyrimidine nucleotide analogue with high anti-viral activity against all genotypes and shows a high genetic barrier to resistance.[84] Regardless of HCV genotype, although in relatively small cohorts of genotype 3, sofosbuvir-based triple therapy resulted in SVR rates of 83–100%.[85] In the PROTON study, a total of 121 patients with HCV-1 were randomised to three cohorts: PEG-IFN/RBV plus sofosbuvir 200 mg, sofosbuvir 400 mg or a placebo once daily for 12 weeks; in addition, a fourth arm was included with HCV-2 and HCV-3 patients who received sofosbuvir 400 mg plus PEG-IFN/RBV for 12 weeks. The combination of sofosbuvir (200 mg or 400 mg once daily) and PEG-IFN/RBV for 12 weeks demonstrated efficacy, reaching SVR12 of 91% in HCV-1 and 92% in HCV-2/HCV-3, while it was 58% in placebo plus PEG-IFN/RBV group.[86] Recently, the LONESTAR-2 study assessed the combination of sofosbuvir plus PEG-IFN/RBV in 47 previous treatment-failure HCV-2 and HCV-3 patients (55% with compensated cirrhosis) treated for 12 weeks. HCV-2 achieved 100% and 92% of SVR12 in those without and with cirrhosis, respectively, while the response rates were lower and at 83% in both groups of HCV-3 patients.[87] Additional studies evaluated the safety and efficacy of sofosbuvir and RBV in various IFN-based and IFN-free regimens in HCV-1, HCV-2 and HCV-3 patients, but in small cohorts. In HCV-2 and HCV-3 treatment-naïve patients, 100% of patients treated with sofosbuvir and PEG-IFN/RBV achieved SVR (30/30), as well as the all-oral regimen of sofosbuvir and RBV (10/10), vs. 60% (6/10) with sofosbuvir monotherapy. On the other hand, only 68% of all treatment-experienced patients with HCV-2 and HCV-3 receiving a combination of sofosbuvir and RBV achieved SVR12.[88] The FISSION trial, a randomised study of 12 weeks of sofosbuvir plus RBV vs. PEG-IFN/RBV during 24 weeks in untreated HCV-3 patients achieved an identical SVR12 rate of 67% in HCV-3 patients with both regimens.[89]

Mericitabine (RG7128) is a nucleoside polymerase inhibitor, with anti-viral activity demonstrated in vitro against all HCV genotypes. In HCV-2 and HCV-3 treatment-failure patients, mericitabine-treated patients (plus PEG-IFN/RBV) achieved a higher RVR rate of 95% vs. 60% in the PEG-IFN/RBV arm, as well as higher SVR when treated with mericitabine 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).[90]

Cyclophilin inhibitors

Alisporivir (DEB025) is able to inhibit HCV viral replication by interfering with the interaction between cyclophilin A and NS5. A proof of concept study was done with alisporivir monotherapy in HIV/HCV-coinfected patients. The conclusion was that alisporivir at a dose of 1200 mg twice daily for 15 days had a significant viral inhibitory effect against HCV-1, HCV-3 and HCV-4.[91] In another study in treatment-naïve patients, alisporivir had potent activity against the four most prevalent genotypes of HCV (HCV-1: −4.61 ± 1.88; HCV-2: −5.91 ± 1.11; HCV-3: −5.89 ± 0.43; HCV-4: −4.75 ± 2.19 log₁₀ IU/mL at week 4), when it was combined with PEG-IFN.[92]

IFN-free regimens

Combination of DAAs with RBV (Table 2 and Figures 3 and 4)

POSITRON and FUSION trials evaluated all-oral therapy regimens of sofosbuvir and RBV in genotypes 2 and 3 IFN ineligible, IFN intolerant, and prior-pegylated interferon and RBV failures for 12 or 16 weeks with the longer duration being in prior failures. The POSITRON trial observed that sofosbuvir and RBV resulted in 78% overall SVR12, with 93% in HCV-2 and 61% in HCV-3 of patients for whom IFN treatment was not an option. Those with genotype 3 and cirrhosis fared poorly, with an SVR12 rate of only 21%. The FUSION trial compared sofosbuvir 400 mg plus RBV for 12 or 16 weeks, and there were better SVR12 rates after 16 weeks (73% vs. 50%). There were differences between genotypes: SVR12 was achieved in 86% after 12 weeks and 94% after 16 weeks in HCV-2, while SVR12 was 30% and 62% after 12 and 16 weeks in HCV-3. Again, patients with HCV-3 cirrhosis achieved SVR12 in only 19% of cases.[93] The VALENCE trial was conducted in Europe, and assessed the safety and efficacy of sofosbuvir plus RBV, administered for 12 or 24 weeks in treatment-naïve or treatment-experienced patients infected with HCV-3. Eighty-five per cent (n = 212/250) of treatment-naïve or treatment-experienced patients with HCV-3 who received a 24-week regimen achieved SVR12. However, it was noted that only 60% of prior treatment-experienced patients with cirrhosis achieved SVR with sofosbuvir plus RBV for 24 weeks.[94]

Figure 3. Response rates, in treatment-naïve patients, with all oral DAAs in HCV-3.

Figure 4. Response rates, in treatment-experienced patients, with all-oral DAAs in HCV-3.

The VITAL-1 study evaluated alisporivir, randomising 340 treatment-naïve patients infected with HCV-2 and HCV-3 to five arms (ALV 1000 mg; ALV 600 mg plus RBV; ALV 800 mg plus RBV; ALV 600mg plus PEG-IFN; PEG-IFN/RBV). Combination of alisporivir and RBV achieved higher SVR24 rates (90%) in comparison with patients receiving alisporivir monotherapy (72%) and those receiving PEG-IFN and RBV (70%). Late relapse was not observed after alisporivir and RBV treatment in contrast to PEG-IFN treatment or alisporivir monotherapy.[95] In a post hoc analysis, IFN-free alisporivir treatment was well tolerated compared to IFN-based treatment.[96]

Combination of DAAs without RBV

Combination of daclatasvir and sofosbuvir, with or without RBV, has been assessed in HCV-1, HCV-2 and HCV-3 patients and such therapy, for 24 weeks, achieved SVR in more than 95% of the overall cohort: the SVR rate was 100% in HCV-1 patients, while it was 91% in both HCV-3 and HCV-2 patients. The data demonstrated that virological response did not vary by IL28B status, genotype, HCV genotype 1 subtype or with the administration of RBV.[97] Garcia-Rivera investigated if alisporivir showed synergistic, additive or antagonist effects with other DAAs in the human hepatoma cell line Huh 7.5. They found that combining alisporivir and boceprevir had an additive effect in inhibiting HCV replication, while the combinations of alisporivir and NS5B inhibitors (mericitabine or sofosbuvir) and NS5A inhibitors (daclatasvir) exhibited greater synergistic effects in HCV-3.[98]

Future directions

The landscape of therapy for hepatitis C virus infection is changing rapidly. Currently, the standard of care for HCV infection is a combination of a protease inhibitor (telaprevir or boceprevir) plus PEG-IFN and RBV for HCV-1, and only PEG-IFN and RBV for HCV-2/6. Recently, newer DAAs (simeprevir and sofosbuvir) in combination with PEG-IFN and RBV have become available for genotype 1 patients.[76, 77, 99, 100] The advent of protease inhibitors has improved the likelihood of cure, but with a number of inherent limitations: (i) they do not have anti-viral activity in HCV genotypes other than HCV-1; (ii) they need to be administered with PEG-IFN and RBV, which have extensive and well-established side-effect profiles that are currently aggravated by the addition of telaprevir or boceprevir.

On the other hand, a multitude of DAAs are being developed in clinical trials with or without PEG-IFN and RBV.[101] The tremendous improvement in SVR rates in genotype 1 and genotype 2 has rendered genotype 3 HCV the major challenge, as it continues to globally afflict a large population of patients. Based on SVR rates with these new drugs, HCV-3 has become the more difficult genotype to treat. Special characteristics of HCV-3, such as insulin resistance or disturbances in lipid metabolism, could be closely related to these suboptimal responses. A better mechanistic understanding of the reasons for suboptimal response, which appears to be mediated by a higher relapse rate, at least partly, needs to be explored. In addition, the clear association between HCV-3 and liver progression, as well as increased incidence of HCC, should be the focus of attention in this genotype. The low incidence of side effects, the relatively short duration of treatment and the pan-genotypic properties of new drugs are compelling reasons to opt for these regimens, while effective new therapies are developed without PEG-IFN.

Sofosbuvir and ribavirin is the first all-oral therapy regimen that has been approved in the US by the FDA for use in Genotype 2 and 3 patients, while it is also a consideration in select genotype 1 patients.[99] However, these regimens have not yet been approved outside of the US. Thus, globally, as it stands now, pegylated interferon and RBV continue to be the mainstay of therapy. With the rapid development of additional DAA strategies, through combination of multiple drugs such as a pangenotypic NS5A inhibitor and nucleotide NS5B inhibitor, along with other combinations, it may be reasonable to wait for these in those with relatively mild disease severity. Patients with more advanced fibrosis and cirrhosis have an urgent need and for those who are treatment naïve, either pegylated interferon and ribavirin for a variable duration (Figure 2), or sofosbuvir and RBV for 24 weeks are good options; in prior-pegylated interferon and ribavirin failures, sofosbuvir and ribavirin for 24 weeks is the only treatment option. Although studied in small cohorts,[86-88] pegylated interferon, ribavirin and sofosbuvir for 12 weeks, primarily for reasons of cost, is a viable consideration as well.

Authorship

Guarantor of article: K. Rajender Reddy.

Author contributions: Javier Ampuero, Manuel Romero-Gómez and K. Rajender Reddy wrote the paper and contributed to the design of the review. All authors approved the final version of the manuscript.

Acknowledgement

Declaration of personal interests: MRG: Advisory Board: Roche, MSD, Janssen, BMS, Gilead, Madaus Ratiopharm, GSK, Abbvie; Speaker: Roche, Janssen, Merz, MSD, Gilead, Alpha-Wasserman. KRR: Advisory Board: Merck, Genentech-Roche, Gilead, Abbvie, Vertex, Janssen, BMS, Idenix. Research support: Merck, Genentech-Roche, Vertex, Janssen, Gilead, BMS, Abbvie.

Declaration of funding interests: None.

References

Source

Hepatitis C virus: Here comes all-oral treatment

doi: 10.3949/ccjm.81a.13155 Cleveland Clinic Journal of Medicine March 2014 vol. 81 3 159-172

EDUCATIONAL OBJECTIVE: Readers will assimilate direct-acting antiviral drugs into the treatment of patients with chronic hepatitis C virus infection

MOHANNAD DUGUM, MD

ROBERT O’SHEA, MD⇑

+ Author Affiliations

ADDRESS: Robert O’Shea, MD, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue/A30, Cleveland, OH 44195; e-mail: oshear@ccf.org

Abstract

Treatment for chronic hepatitis C virus (HCV) infection is evolving rapidly. The approval in 2013 of two new direct-acting antivirals—sofosbuvir (a polymerase inhibitor) and simeprevir (a second-generation protease inhibitor)—opens the door for an all-oral regimen, potentially avoiding interferon and its harsh side effects. Other direct-acting antivirals are under development.

Key points

In clinical trials of treatment for chronic HCV infection, regimens that included a direct-acting antiviral agent were more effective than ones that did not.

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3, and in combination with ribavirin and interferon in patients infected with HCV genotype 1 or 4. It is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation.

Simeprevir is approved in an oral dose of 150 mg once daily in combination with ribavirin and interferon for patients with HCV genotype 1.

The new drugs are expensive, a potential barrier for many patients. As more direct-acting antiviral agents become available, their cost will likely decrease.

Combinations of direct-acting antiviral agents of different classes may prove even more effective and could eliminate the need for interferon entirely.

In late 2013, the US Food and Drug Administration (FDA) approved sofosbuvir and simeprevir, the newest direct-acting antiviral agents for treating chronic hepatitis C virus (HCV) infection. Multiple clinical trials have demonstrated dramatically improved treatment outcomes with these agents, opening the door to all-oral regimens or interferon-free regimens as the future standard of care for HCV.

See related editorial, page 173

In this article, we discuss the results of the trials that established the efficacy and safety of sofosbuvir and simeprevir and led to their FDA approval. We also summarize the importance of these agents and evaluate other direct-acting antivirals currently in the pipeline for HCV treatment.

HCV IS A RISING PROBLEM

Chronic HCV infection is a major clinical and public health problem, with the estimated number of people infected exceeding 170 million worldwide, including 3.2 million in the United States.¹ It is a leading cause of cirrhosis, and its complications include hepatocellular carcinoma and liver failure. Cirrhosis due to HCV remains the leading indication for liver transplantation in the United States, accounting for nearly 40% of liver transplants in adults.²

The clinical impact of HCV will only continue to escalate, and in parallel, so will the cost to society. Models suggest that HCV-related deaths will double between 2010 and 2019, and considering only direct medical costs, the projected financial burden of treating HCV-related disease during this interval is estimated at between $6.5 and $13.6 billion.³

Drugs mentioned in this paper

• boceprevir (Victrelis)
• interferon
• ribavirin (Rebetol, Copegus)
• simeprevir (Olysio)
• sofosbuvir (Sovaldi)
• telaprevir (Incivek)

RNA VIRUS WITH SIX GENOTYPES

HCV, first identified in 1989, is an enveloped, single-stranded RNA flavivirus of the Hepacivirus genus measuring 50 to 60 nm in diameter.⁴ There are six viral genotypes, with genotype 1 being the most common in the United States and traditionally the most difficult to treat.

Once inside the host cell, the virus releases its RNA strand, which is translated into a single polyprotein of about 3,000 amino acids. This large molecule is then cleaved by proteases into several domains: three structural proteins (C, E1, and E2), a small protein called p7, and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (FIGURE 1).⁵ These nonstructural proteins enable the virus to replicate.

FIGURE 1

GOAL OF TREATING HCV: A SUSTAINED VIROLOGIC RESPONSE

The aim of HCV treatment is to achieve a sustained virologic response, defined as having no detectable viral RNA after completion of antiviral therapy. This is associated with substantially better clinical outcomes, lower rates of liver-related morbidity and all-cause mortality, and stabilization of or even improvement in liver histology.^6,7 This end point has traditionally been assessed at 6 months after the end of therapy, but recent data suggest the rates at 12 weeks are essentially equivalent.

Interferon plus ribavirin: The standard of care for many years

HCV treatment has evolved over the past 20 years. Before 2011, the standard of care was a combination of interferon alfa-polyethylene glycol (peg-interferon), given as a weekly injection, and oral ribavirin. Neither drug has specific antiviral activity, and when they are used together they result in a sustained virologic response in fewer than 50% of patients with HCV genotype 1 and, at best, in 70% to 80% of patients with other genotypes.⁸

Nearly all patients receiving interferon experience side effects, which can be serious. Fatigue and flu-like symptoms are common, and the drug can also cause psychiatric symptoms (including depression or psychosis), weight loss, seizures, peripheral neuropathy, and bone marrow suppression. Ribavirin causes hemolysis and skin complications and is teratogenic.⁹

An important bit of information to know when using interferon is the patient’s IL28B genotype. This refers to a single-nucleotide polymorphism (C or T) on chromosome 19q13 (rs12979860) upstream of the IL28B gene encoding for interferon lambda-3. It is strongly associated with responsiveness to interferon: patients with the IL28B CC genotype have a much better chance of a sustained virologic response with interferon than do patients with CT or TT.

Boceprevir and telaprevir: First-generation protease inhibitors

In May 2011, the FDA approved the NS3/4A protease inhibitors boceprevir and telaprevir for treating HCV genotype 1, marking the beginning of the era of direct-acting antiviral agents.¹⁰ When these drugs are used in combination with peg-interferon alfa and ribavirin, up to 75% of patients with HCV genotype 1 who have had no previous treatment achieve a sustained virologic response.

But despite greatly improving the response rate, these first-generation protease inhibitors have substantial limitations. Twenty-five percent of patients with HCV genotype 1 who have received no previous treatment and 71% of patients who did not respond to previous treatment will not achieve a sustained virologic response with these agents.¹¹ Further, they are effective only against HCV genotype 1, being highly specific for the amino acid target sequence of the NS3 region.

Also, they must be used in combination with interferon alfa and ribavirin because the virus needs to mutate only a little—a few amino-acid substitutions—to gain resistance to them.¹² Therefore, patients are still exposed to interferon and ribavirin, with their toxicity. In addition, dysgeusia is seen with boceprevir, rash with telaprevir, and anemia with both.^13,14

Finally, serious drug-drug interactions prompted the FDA to impose warnings for the use of these agents with other medications that interact with CYP3A4, the principal enzyme responsible for their metabolism. Thus, these significant adverse effects dampen the enthusiasm of patients contemplating a long course of treatment with these agents.

The need to improve the rate of sustained virologic response, shorten the duration of treatment, avoid serious side effects, improve efficacy in treating patients infected with genotypes other than 1, and, importantly, eliminate the need for interferon alfa and its serious adverse effects have driven the development of new direct-acting antiviral agents, including the two newly FDA-approved drugs, sofosbuvir and simeprevir.

SOFOSBUVIR: A POLYMERASE INHIBITOR

Sofosbuvir is a uridine nucleotide analogue that selectively inhibits the HCV NS5B RNA-dependent RNA polymerase (FIGURE 1). It targets the highly conserved nucleotide-binding pocket of this enzyme and functions as a chain terminator.¹⁵ While the protease inhibitors are genotype-dependent, inhibition of the highly conserved viral polymerase has an impact that spans genotypes.

Early clinical trials of sofosbuvir

Sofosbuvir has been tested in combination with interferon alfa and ribavirin, as well as in interferon-free regimens (TABLE 2).^16–20

Rodriguez-Torres et al,¹⁵ in an early double-blind clinical trial, randomized 64 previously untreated patients with HCV genotype 1 to receive one of three doses of oral sofosbuvir (100, 200, or 400 mg) plus interferon and ribavirin or placebo plus interferon and ribavirin for 4 weeks, followed by 44 weeks of interferon and ribavirin alone. The rates of sustained virologic response were:

• 56% with sofosbuvir 100 mg, peg-interferon, and ribavirin

• 83% with sofosbuvir 200 mg, peg-interferon, and ribavirin

• 80% with sofosbuvir 400 mg, peg-interferon, and ribavirin

• 43% with peg-interferon and ribavirin alone.

The ATOMIC trial¹⁶ tested the efficacy and safety of sofosbuvir in combination with peg-interferon and ribavirin in patients with HCV genotype 1, 4, or 6, without cirrhosis, who had not received any previous treatment. Patients with HCV genotype 1 were randomized to three treatments:

• Sofosbuvir 400 mg orally once daily plus peg-interferon and ribavirin for 12 weeks

• The same regimen, but for 24 weeks

• Sofosbuvir plus peg-interferon and ribavirin for 12 weeks, followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin.

The rates of sustained virologic response were very high and were not significantly different among the three groups: 89%, 89%, and 87%, respectively. Patients who were able to complete a full course of therapy achieved even higher rates of sustained virologic response, ranging from 96% to 98%. The likelihood of response was not adversely affected by the usual markers of a poorer prognosis, such as a high viral load (≥ 800,000 IU/mL) or a non-CC IL28B genotype. Although patients with cirrhosis (another predictor of no response) were excluded from this study, the presence of bridging fibrosis did not seem to affect the rate of sustained virologic response. The results in patients with genotypes other than 1 were very encouraging, but the small number of patients enrolled precluded drawing firm conclusions in this group.

Important implications of the ATOMIC trial include the following:

There is no benefit in prolonging treatment with sofosbuvir beyond 12 weeks, since adverse events increased without any improvement in the rate of sustained virologic response.

There is a very low likelihood of developing viral resistance or mutation when using sofosbuvir.

There is no role for response-guided therapy, a concept used with protease inhibitor-based regimens in which patients who have complete clearance of the virus within the first 4 weeks of treatment (a rapid virologic response) and remain clear through 12 weeks of treatment (an extended rapid viral response) can be treated for a shorter duration without decreasing the likelihood of a sustained virologic response.

Lawitz et al¹⁷ conducted a randomized double-blind phase 2 trial to evaluate the effect of sofosbuvir dosing on response in noncirrhotic, previously untreated patients with HCV genotype 1, 2, or 3. Patients with HCV genotype 1 were randomized to one of three treatment groups in a 2:2:1 ratio: sofosbuvir 200 mg orally once daily, sofosbuvir 400 mg orally once daily, or placebo, all for 12 weeks in combination with peg-interferon (180 μg weekly) and ribavirin in a dosage based on weight. Depending on the viral response, patients continued peg-interferon and ribavirin for an additional 12 weeks if they achieved an extended rapid viral response, or 36 weeks if they did not achieve an extended rapid virologic response, and in all patients who received placebo. Patients with HCV genotype 2 or 3 were given sofosbuvir 400 mg once daily in combination with interferon and ribavirin for 12 weeks.

As in the ATOMIC trial, all patients treated with sofosbuvir had a very rapid reduction in viral load: 98% of patients with genotype 1 developed a rapid virologic response, and therefore almost all were eligible for the shorter treatment course of 24 weeks.¹⁷ The latter finding again suggested that response-guided treatment is not relevant with sofosbuvir-based regimens.

Very high rates of sustained virologic response were seen: 90% in patients with genotype 1 treated with sofosbuvir 200 mg, 91% in those with genotype 1 treated with 400 mg, and 92% in those with genotype 2 or 3. Although 6% of patients in the 200-mg group had virologic breakthrough after completing sofosbuvir treatment, no virologic breakthrough was observed in the 400-mg group, suggesting that the 400-mg dose might suppress the virus more effectively.¹⁷

The ELECTRON trial¹⁸ was a phase 2 study designed to evaluate the efficacy and safety of sofosbuvir and ribavirin in interferon-sparing and interferon-free regimens in patients with HCV genotype 1, 2, or 3 infection. Sofosbuvir was tested with peg-interferon and ribavirin, with ribavirin alone, and as monotherapy in previously untreated patients with genotype 2 or 3. A small number of patients with genotype 1 who were previously untreated and who were previously nonresponders were also treated with sofosbuvir and ribavirin.

All patients had a rapid virologic response, and viral suppression was sustained through the end of treatment. All patients with genotype 2 or 3 treated with double therapy (sofosbuvir and ribavirin) or triple therapy (sofosbuvir, peg-interferon, and ribavirin) achieved a sustained virologic response, compared with only 60% of patients treated with sofosbuvir monotherapy. The monotherapy group had an equal number of relapsers among those with genotype 2 or 3. Of the genotype 1 patients treated with sofosbuvir and ribavirin, 84% of those previously untreated developed a sustained virologic response, whereas only 10% of the previous nonresponders did.

Phase 3 clinical trials of sofosbuvir

The NEUTRINO trial¹⁹ studied the efficacy and safety of sofosbuvir in previously untreated patients with HCV genotype 1, 4, 5, or 6. In this phase 3 open-label study, all patients received sofosbuvir plus peg-interferon and weight-based ribavirin therapy for 12 weeks. Of the patients enrolled, 89% had genotype 1, while 9% had genotype 4 and 2% had genotype 5 or 6. Overall, 17% of the patients had cirrhosis.

The viral load rapidly decreased in all patients treated with sofosbuvir irrespective of the HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Ninety-nine percent of patients with genotype 1, 4, 5, or 6 achieved a rapid virologic response, and 90% achieved a sustained virologic response at 12 weeks after completion of treatment with sofosbuvir and ribavirin. Patients with cirrhosis had a slightly lower rate of sustained virologic response (80%, compared with 92% in patients without cirrhosis). Also, patients with non-CC IL28B genotypes had a lower rate of sustained virologic response (87% in non-CC allele vs 98% in patients with the favorable CC allele).

The FISSION trial¹⁹ recruited previously untreated patients with genotype 2 or 3 and randomized them to therapy with either sofosbuvir plus ribavirin in a weight-based dose for 12 weeks, or 24 weeks of interferon and ribavirin. In this study, 20% of patients in each treatment group had cirrhosis.

As in the NEUTRINO trial, the viral load rapidly decreased in all patients treated with sofosbuvir irrespective of HCV genotype, IL28B status, race, or the presence or absence of cirrhosis. Here, 100% of patients with genotype 2 or 3 who were treated with sofosbuvir and ribavirin achieved a rapid virologic response. Differences in outcome emerged based on genotype: 97% of those with genotype 2 and 56% of those with genotype 3 achieved a sustained virologic response. The overall rate was 67%, which was not different from patients treated with peg-interferon and ribavirin. In the subgroup of patients with cirrhosis, 47% of those treated with sofosbuvir and ribavirin achieved a sustained virologic response, vs 38% of those who received peg-interferon plus ribavirin.

In both the NEUTRINO and FISSION trials, few patients discontinued treatment, with higher rates of most adverse events occurring in patients treated with peg-interferon and ribavirin.

POSITRON,²⁰ a phase 3 clinical trial, tested sofosbuvir in patients with HCV genotype 2 or 3 who were ineligible for peg-interferon, unwilling to take peg-interferon, or unable to tolerate peg-interferon (mainly because of clinically significant psychiatric disorders). Patients were randomized to two treatment groups for 12 weeks: sofosbuvir plus ribavirin, or placebo. About 50% of patients had HCV genotype 3, and 16% had cirrhosis.

The overall rate of sustained virologic response at 12 weeks after treatment was 78% in the sofosbuvir-and-ribavirin group (93% in genotype 2 patients and 61% in genotype 3 patients). Again, cirrhosis was associated with a lower rate of sustained virologic response (61% of patients with cirrhosis achieved a sustained virologic response vs 81% of patients without cirrhosis). None of the sofosbuvir-treated patients had virologic failure while on treatment.

FUSION,²⁰ another phase 3 trial, evaluated sofosbuvir in patients infected with HCV genotype 2 or 3 for whom interferon-based treatment had failed. They were randomized to either 12 weeks or 16 weeks of sofosbuvir and weight-based ribavirin treatment. About 60% of patients had HCV genotype 3, and 34% had cirrhosis.

The overall sustained virologic response rate was 50% in the patients treated for 12 weeks and 73% in those treated for 16 weeks: specifically, 86% of patients with genotype 2 achieved a sustained virologic response at 12 weeks and 94% at 16 weeks, whereas in those with genotype 3 the rates were 30% at 12 weeks and 62% at 16 weeks.

Cirrhosis was again a predictor of lack of response to sofosbuvir. In the group treated for 12 weeks, 31% of those with cirrhosis achieved a sustained virologic response compared with 61% in those without cirrhosis. In the group treated for 16 weeks, 61% of those with cirrhosis achieved a sustained virologic response compared with 76% in those without cirrhosis.

In both the POSITRON and FUSION trials, relapse accounted for all treatment failures, and no virologic resistance was detected in patients who did not have a sustained virologic response. The investigators concluded that 12 weeks of treatment with sofosbuvir and ribavirin can be effective for HCV genotype 2 infection, but extending the treatment to 16 weeks may be beneficial for genotype 3. This may be especially important in patients with cirrhosis or those who did not have a response to peg-interferon-based treatment.

VALENCE,²¹ an ongoing phase 3 trial in Europe, is assessing the safety and efficacy of sofosbuvir 400 mg once daily and weight-based ribavirin in patients with HCV genotype 2 or 3. Eighty-five percent of the trial participants have received previous treatment, and 21% have cirrhosis. Patients were originally randomized in a 4:1 ratio to receive sofosbuvir plus ribavirin for 12 weeks or matching placebo, but as a result of emerging data suggesting that patients with genotype 3 would benefit from more than 12 weeks of treatment, the study was subsequently amended to extend treatment to 24 weeks for patients with genotype 3.

Overall rates of sustained virologic response were 93% in patients with genotype 2 and 85% in patients with genotype 3. In previously treated patients with genotype 2 who were treated for 12 weeks, the rates of sustained virologic response were 91% in those without cirrhosis vs 88% in those with cirrhosis. In previously treated patients with genotype 3, the rates in those treated for 24 weeks were 87% in patients without cirrhosis vs 60% with cirrhosis. The safety profile was consistent with that of ribavirin.

Side effects of sofosbuvir

In clinical trials, side effects occurred most often when sofosbuvir was combined with interferon and ribavirin and were consistent with the known side effects of the latter two agents. The most frequently reported side effects included fatigue, insomnia, nausea, rash, anemia, headache, and arthralgia, with most of these adverse events rated by treating clinicians as being mild in severity.^15,20

In the ATOMIC trial, the most common events leading to drug discontinuation were anemia and neutropenia, both associated with interferon and ribavirin. Patients receiving sofosbuvir monotherapy after 12 weeks of triple therapy showed rapid improvement in hemoglobin levels and neutrophil counts, indicating that hematologic abnormalities attributed solely to sofosbuvir are minimal. In the FISSION trial, the incidence of adverse events was consistently lower in those receiving sofosbuvir-ribavirin than in patients receiving interferon-ribavirin without sofosbuvir.¹⁹

In the POSITRON trial, discontinuation of sofosbuvir because of adverse events was uncommon, and there were no differences in the incidence of adverse events and laboratory abnormalities between patients with and without cirrhosis when they received sofosbuvir and ribavirin.²⁰

Sofosbuvir dosage and indications

Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3 and in combination with ribavirin and interferon alfa in patients infected with HCV genotype 1 or 4 (TABLE 3). It could be considered for HCV genotype 1 in combination with ribavirin alone for 24 weeks in patients who are ineligible for interferon.

Sofosbuvir is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation, for up to 48 weeks or until they receive a transplant, to prevent posttransplant reinfection with HCV.

Sofosbuvir is expensive

A course of therapy is expected to cost about $84,000, which is significantly more than the cost of previous triple therapy (peg-interferon, ribavirin, and either boceprevir or telaprevir).²² This high cost will undoubtedly lead to less widespread use in developing countries, and potentially even in the United States. As newer direct-acting antiviral agents become available, the price will likely come down, enhancing access to these drugs.

SIMEPREVIR: A SECOND-GENERATION PROTEASE INHIBITOR

Telaprevir and boceprevir are NS3/A4 protease inhibitors that belong to the alfa-ketoamid derivative class. Simeprevir belongs to the macrocyclic class and has a different way of binding to the target enzyme.²³ Like sofosbuvir, simeprevir was recently approved by the FDA for the treatment of HCV genotype 1.

The therapeutic efficacy of simeprevir has been tested in several clinical trials (TABLE 4), including QUEST-1²⁴ and QUEST-2²⁵ (in previously untreated patients), PROMISE²⁶ (in prior relapsers), and ASPIRE²⁷ (in prior partial and null responders). Results from these trials showed high overall rates of sustained virologic response with triple therapy (ie, simeprevir combined with peg-interferon and ribavirin). It was generally well tolerated, and most adverse events reported during 12 weeks of treatment were of mild to moderate severity.

In QUEST-1 and QUEST-2, both double-blind phase 3 clinical trials, previously untreated patients infected with HCV genotype 1 were randomized in a 2:1 ratio to receive either simeprevir 150 mg daily or placebo for 12 weeks; both groups also received peg-interferon and ribavirin. Patients then received peg-interferon and ribavirin alone for 12 or 36 weeks in the simeprevir group (based on response) and for 36 weeks in the placebo group.

The overall rate of sustained virologic response at 12 weeks was 80% in the simeprevir group (75% in those with genotype 1a and 85% in those with genotype 1b) vs 50% in the placebo group (receiving peg-interferon and ribavirin alone).^24,25

PROMISE,²⁶ another double-blind randomized phase 3 clinical trial, evaluated simeprevir in patients with HCV genotype 1 who relapsed after previous interferon-based therapy. It had a similar design to QUEST-1 and QUEST-2, and 15% of all patients had cirrhosis.

The overall sustained virologic response rate at 12 weeks after treatment was 79% in the simeprevir group (70% in patients with genotype 1a and 86% in those with genotype 1b) vs 37% in the placebo group. Rates were similar in patients with absent to moderate fibrosis (82%), advanced fibrosis (73%), or cirrhosis (74%).

ASPIRE.²⁷ Simeprevir efficacy in patients with HCV genotype 1 for whom previous therapy with peg-interferon and ribavirin had failed was tested in ASPIRE, a double-blind randomized phase 2 clinical trial. Patients were randomized to receive simeprevir (either 100 mg or 150 mg daily) for 12, 24, or 48 weeks in combination with 48 weeks of peg-interferon and ribavirin, or placebo plus peg-interferon and ribavirin for 48 weeks.

The primary end point was the rate of sustained virologic response at 24 weeks. Overall, rates were 61% to 80% for the simeprevir treatment groups compared with 23% with placebo, regardless of prior response to peg-interferon and ribavirin. By subgroup, rates were:

• 77% to 89% with simeprevir vs 37% with placebo in prior relapsers

• 48% to 86% with simeprevir vs 9% with placebo in prior partial responders

• 38% to 59% with placebo vs 19% for prior nonresponders.

The best rates of sustained viral response at 24 weeks were in the groups that received simeprevir 150 mg daily: 85% in prior relapsers, 75% in prior partial responders, and 51% in prior nonresponders.

Simeprevir vs other direct-acting antiviral drugs

Advantages of simeprevir over the earlier protease inhibitors include once-daily dosing, a lower rate of adverse events (the most common being fatigue, headache, rash, photosensitivity, and pruritus), a lower likelihood of discontinuation because of adverse events, and fewer drug-drug interactions (since it is a weak inhibitor of the CYP3A4 enzyme).

Unlike sofosbuvir, simeprevir was FDA-approved only for HCV genotype 1 and in combination with interferon alfa and ribavirin. Compared with sofosbuvir, the treatment duration with simeprevir regimens is longer overall (interferon alfa and ribavirin are given for 12 weeks in sofosbuvir-based regimens vs 24 to 48 weeks with simeprevir). As with sofosbuvir, the estimated cost of simeprevir is high, about $66,000 for a 12-week course.

Simeprevir dosage and indications

Simeprevir was approved at an oral dose of 150 mg once daily in combination with ribavirin and interferon alfa in patients with HCV genotype 1 (TABLE 5).

The approved regimens for simeprevir are fixed in total duration based on the patient’s treatment history. Specifically, all patients receive the drug in combination with peg-interferon and ribavirin for 12 weeks. Then, previously untreated patients and prior relapsers continue to receive peg-interferon and ribavirin alone for another 12 weeks, and those with a partial or null response continue with these drugs for another 36 weeks.

Patients infected with HCV genotype 1a should be screened for the NS3 Q80K polymorphism at baseline, as it has been associated with substantially reduced response to simeprevir.

Sofosbuvir and simeprevir in combination

The COSMOS trial.²⁸ Given their differences in mechanism of action, sofosbuvir and simeprevir are being tested in combination. The COSMOS trial is an ongoing phase 2 randomized open-label study investigating the efficacy and safety of simeprevir and sofosbuvir in combination with and without ribavirin in patients with HCV genotype 1, including nonresponders and those with cirrhosis. Early results are promising, with very high rates of sustained virologic response with the sofosbuvir-simeprevir combination (93% to 100%) and indicate that the addition of ribavirin might not be needed to achieve sustained virologic response in this patient population.

THE FUTURE

The emergence of all-oral regimens for HCV treatment with increasingly sophisticated agents such as sofosbuvir and simeprevir will dramatically alter the management of HCV patients. In view of the improvement in sustained virologic response rates with these treatments, and since most HCV-infected persons have no symptoms, the US Centers for Disease Control and Prevention²⁹ recently recommended one-time testing of the cohort in which the prevalence of HCV infection is highest: all persons born between 1945 and 1965. This undoubtedly will increase the detection of this infection—and the number of new patients expecting treatment.

Future drugs promise further improvements (TABLE 6).^30–35 Advances in knowledge of the HCV molecular structure have led to the development of numerous direct-acting antiviral agents with very specific viral targets. A second wave of protease inhibitors and of nucleoside and nonnucleoside polymerase inhibitors will soon be available. Inhibitors of NS5A (a protein important in the assembly of the viral replication complex) such as daclatasvir and ledipasvir, are currently in phase 3 clinical trials. Other viral proteins involved in assembly of the virus, including the core protein and p7, are being explored as drug targets. In addition, inhibiting host targets such as cyclophilin A and miR122 has gained traction recently, with specific agents currently in phase 2 and 3 clinical trials.

Factors that previously were major determinants of response to treatment, such as IL28B genotype, viral load, race, age, extent of fibrosis, and genotype 1 subtypes, will become much less important with the introduction of highly potent direct-acting antiviral agents.

Many all-oral combinations are being evaluated in clinical trials. For example, the open-label, phase 2 LONESTAR trial tested the utility of combining sofosbuvir and ledipasvir (an NS5A inhibitor) with and without ribavirin for 8 or 12 weeks in previously untreated patients with HCV genotype 1, and for 12 weeks in patients with HCV genotype 1 who did not achieve a sustained virologic response after receiving a protease inhibitor-based regimen (half of whom had compensated cirrhosis).³⁶ Sustained virologic response rates were very high (95% to 100%) in both previously treated and previously untreated patients, including those with cirrhosis. Similar rates were achieved by the 8-week and 12-week groups in noncirrhotic patients who had not been previously treated for HCV. The typical hematologic abnormalities associated with interferon were not observed except for mild anemia in patients who received ribavirin. These results suggest that the combination of sofosbuvir and ledipasvir could offer a very effective, short, all-oral treatment for patients with HCV genotype 1, including those with cirrhosis, who up to now have been difficult to treat.

Challenges remaining

The success of sofosbuvir and simeprevir paves the way for interferon-free regimens.³⁷ For a long time, the treatment of HCV infection required close monitoring of patients while managing the side effects of interferon, but the current and emerging direct-acting antiviral agents will soon change this practice. Given the synergistic effects of combination therapy—targeting the virus at multiple locations, decreasing the likelihood of drug resistance, and improving efficacy—combination regimens seem to be the optimal solution to the HCV epidemic. Lower risk of side effects and shorter treatment duration will definitely improve the acceptance of any new regimen. New agents that act against conserved viral targets, thereby yielding activity across multiple genotypes, will be advantageous as well. TABLE 7 compares the rates of sustained virologic response of the different currently approved HCV treatment regimens.

Clinical challenges remain, including the management of special patient populations for whom data are still limited. These include patients with cirrhosis, chronic kidney disease, renal failure, and concurrent infection with human immunodeficiency virus, and patients who have undergone solid organ transplantation. Clinical trials are under way to evaluate the treatment options for these patients, who will likely need to wait for the emergence of additional agents before dramatic improvement in sustained virologic response rates may be expected.³⁸

As the treatment of HCV becomes simpler, safer, and more effective, primary care physicians will increasingly be expected to manage it. Difficult-to-treat patients, including the special populations above, will require specialist management and individualized treatment regimens, at least until better therapies are available. The high projected cost of the new agents may limit access, at least initially. However, the dramatic improvement in sustained virologic response rates and all that that implies in terms of decreased risk of advanced liver disease and its complications will undoubtedly make these therapies cost-effective.³⁹

• Copyright© 2014 The Cleveland Clinic Foundation

REFERENCES

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The Cost of Treatment Failure

Journal of Viral Hepatitis

Resource Use and Costs Incurred by Hepatitis C Virus Genotype 1-Infected Patients Who Do or Do Not Achieve Sustained Virological Response to Therapy

M. Backx, A. Lewszuk, J. R. White, J. Cole, A. Sreedharan, S. van Sanden, J. Diels, A. Lawson, K. R. Neal, M. J. Wiselka, T. Ito, W. L. Irving

J Viral Hepat. 2014;21(3):208-215

Abstract and Introduction

Abstract

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost-effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium-term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS 'Payment by Results' database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non-SVR) with mean follow-up of 3.5 (SVR) and 4.9 (non-SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non-SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5-year post-treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13-fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56-fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real-life data for future cost-effectiveness analyses related to the treatment for chronic HCV infection.

Introduction

An estimated 130–170 million people worldwide are chronically infected with hepatitis C virus (HCV), with around 216 000 living in the United Kingdom (UK).^[1] Chronic infection may result in progressive liver damage, leading to cirrhosis and its sequelae in at least 20–30% of individuals.^[2] Both hospital admissions and deaths related to chronic HCV infection are rising in the UK,^[1] and end-stage liver disease resulting from chronic HCV infection is now a leading indication for liver transplantation.^[3] It is estimated that by 2020, nearly 16 000 individuals will be living with HCV-related cirrhosis or hepatocellular carcinoma in England if left untreated.^[4] Estimates of direct medical expenses related to HCV infection in the USA predict a rise in total expenditure to over $10 billion in the next decade.^[5] The management of chronic HCV infection thus places a significant health and economic burden on national health services worldwide.

Until recently, the standard of care (SoC) for chronic HCV infection involved combination therapy with pegylated interferon and ribavirin. For genotype 1 disease, this resulted in a sustained viral response (SVR) in approximately 40–50% of patients,^[6] which in turn results in lower rates of liver-related morbidity and mortality.^[7] Recent advances in the understanding of HCV biology have led to the development of directly acting antiviral (DAA) agents. Two of these therapies, telaprevir and boceprevir, act on the viral NS3/4a protease and, in combination with pegylated interferon and ribavirin, have been shown to significantly improve SVR both in treatment-naïve and in treatment-experienced patients with genotype 1 disease. In the USA, triple therapy is now considered the new standard of care for patients with genotype 1 infection.^[8] In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has recommended the use of telaprevir or boceprevir, each in combination with pegylated interferon and ribavirin, as treatment options for genotype 1 chronic HCV infection in adults with compensated liver disease for both treatment-naïve and treatment-experienced patients.^[9,10]

As treatment options for genotype 1 chronic HCV infection expand, it will be important to understand the cost reductions associated with achievement of an SVR, in addition to the obvious clinical benefits to an individual patient. Previous cost-effectiveness analyses of antiviral therapy have made assumptions that achieving an SVR reduces costs.^[11–13] Prior to this study, no previous paper has contrasted the resource use and costs of genotype 1 patients with and without SVR to assess the relative value of successful antiviral treatment in terms of offsetting morbidity costs.

This study aimed to compare disease progression, use of health services and costs to the UK National Health Service (NHS) between patients with genotype 1 infection who achieved an SVR following pegylated interferon and ribavirin therapy vs those who did not, using real-world data representative of routine NHS practice in the UK.

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Computed tomography findings in liver fibrosis and cirrhosis

19 February 2014, doi:10.4414/smw.2014.13923
Cite this as: Swiss Med Wkly. 2014;144:w13923

Huber Adrian^a, Ebner Lukas^a, Montani Matteo^b, Semmo Nasser^c, Roy Choudhury Kingshuk^d, Heverhagen Johannes^a, Christe Andreas^a

^a Institute of Radiology, University Hospital Inselspital, Bern, Switzerland
^b Institute of Pathology, University of Bern, Switzerland
^c Institute of Hepatology, University Hospital Inselspital, Bern, Switzerland
^d Statistics Department, University College Cork, Ireland

Summary

PRINCIPLES: Computed tomography (CT) is inferior to the fibroscan and laboratory testing in the noninvasive diagnosis of liver fibrosis. On the other hand, CT is a frequently used diagnostic tool in modern medicine. The auxiliary finding of clinically occult liver fibrosis in CT scans could result in an earlier diagnosis. The aim of this study was to analyse quantifiable direct signs of liver remodelling in CT scans to depict liver fibrosis in a precirrhotic stage.

METHODS: Retrospective review of 148 abdominal CT scans (80 liver cirrhosis, 35 precirrhotic fibrosis and 33 control patients). Fibrosis and cirrhosis were histologically proven. The diameters of the three main hepatic veins were measured 1–2 cm before their aperture into the inferior caval vein. The width of the caudate and the right hepatic lobe were divided, and measured horizontally at the level of the first bifurcation of the right portal vein in axial planes (caudate-right-lobe ratio). A combination of both (sum of liver vein diameters divided by the caudate-right lobe ratio) was defined as the ld/crl ratio. These metrics were analysed for the detection of liver fibrosis and cirrhosis.

RESULTS: An ld/crl-r <24 showed a sensitivity of 83% and a specificity of 76% for precirrhotic liver fibrosis. Liver cirrhosis could be detected with a sensitivity of 88% and a specificity of 82% if ld/crl-r <20.

CONCLUSION: An ld/crl-r <24 justifies laboratory testing and a fibroscan. This could bring forward the diagnosis and patients would profit from early treatment in a potentially reversible stage of disease.

Key words: liver fibrosis and cirrhosis; abdominal computed tomography; hepatic vein diameter; caudate right lobe ratio

Introduction

Liver cirrhosis is the final consequence of all chronic liver diseases [1]. Most common causes are alcoholic fatty liver disease (AFLD), nonalcoholic fatty liver disease (NAFLD) and viral hepatitis [2, 3]. Chronic inflammation leads to potentially reversible liver fibrosis and ends in irreversible cirrhosis with cross-linked collagen and regenerative nodules [4]. Early diagnosis improves the benefit of therapeutic strategies before the development of irreversible and potentially lethal complications such as loss of liver function, oesophageal variceal bleeding, hepatic encephalopathy and hepatocellular carcinoma [5, 6].

The noninvasive diagnosis of liver fibrosis and cirrhosis is built on laboratory testing and the well-established fibroscan [7]. Recently, new sensitive methods using magnetic resonance imaging (MRI) have been described, such as MR-elastography [8], double contrast-enhanced MRI [9] and diffusion weighted MRI [10]). Computed tomography (CT) is useful for imaging liver cirrhosis complications, such as portosystemic collaterals with bleeding or hepatocellular carcinoma (HCC). However, this is not an appropriate method for the primary diagnosis of liver fibrosis, because of the radiation dose and inferior accuracy compared to the fibroscan. On the other hand, clinically occult liver fibrosis as an auxiliary finding in routine abdominal CT scans is underdiagnosed. Even liver cirrhosis has a mediocre sensitivity (77.1%–84.3%) and specificity (52.9%–67.6%) in CT [11]. However, since CT is an important and frequently used diagnostic tool in modern medicine, an accurate method to detect liver fibrosis in CT scans could bring forward the diagnosis and enable treatment in an early stage of fibrosis before its clinical appearance.

We hypothesise that indirect findings of liver remodelling occur rather late when chronic portal hypertension has already been established (e.g. splenomegaly, gastrointestinal wall thickening, portosystemic collaterals, recanalisation of the umbilical vein and ascites [12–14]).

Qualitative direct signs of liver remodelling (atrophy of the right liver lobe with a notch between right and caudate lobe, heterogeneity of liver parenchyma, nodular surface, blunt liver edge and enlarged gall bladder fossa [12–14]) are limited parameters as a result of subjective reader impression and experience.

Thus, we propose the use of quantifiable direct signs of hepatic remodelling which are assessable in axial planes without the need for time-consuming image reconstructions.

There are two interesting metrics for direct liver remodelling: the caudate-right lobe ratio (crl-r) [18], which describes the width of the caudate lobe in proportion to the width of the right hepatic lobe, and measurement of the hepatic vein diameters [19]. We hypothesise that these metrics correlate with early liver fibrosis in a precirrhotic stage and can be used as quantifiable markers to depict liver fibrosis in abdominal CT scans. An analysis of these metrics alone and in combination for the detection of liver fibrosis was performed, as was a comparison with other qualitative and quantitative imaging findings.

Patients and methods

Patient population:

A total of 148 patients (108 male/40 female) were retrospectively included between January 2009 and March 2012 at our hospital, including 80 patients with histologically proven liver cirrhosis (fibrosis stage 4), 35 with histologically proven precirrhotic liver fibrosis stage 1–3 and a control group of 33 trauma patients without known liver pathology. The mean age of all selected patients was 57.3 years (range: 32–75 years). Informed consent was not required owing to the retrospective nature of this study.

The 80 patients (59 male/21 female) with liver cirrhosis (29 Child A, 31 Child B, 30 Child C) and the 35 patients with precirrhotic stage of liver fibrosis (6 fibrosis grade 1, 10 fibrosis grade 2 and 19 fibrosis grade 3) were included if they had undergone a CT scan with portal venous phase in the radiological information system (Centricity RISi 4.1, GE Healthcare) of our hospital. Liver fibrosis and cirrhosis was histologically proven by intercostal percutaneous biopsy from the right liver lobe with the “Menghini-technique” with pre- and post-procedural sonographic checks. Patients who had undergone an earlier partial liver resection or liver transplantation or those who had a transjugular portosystemic shunt (TIPS) were excluded.

Reasons for the abdominal CT scans were as follows (cirrhosis group/precirrhotic fibrosis group): HCC (40/18), tumour other than HCC (9/6), portal vein thrombosis (8/0), abscess (6/4), bleeding (7/0), acute abdomen (4/2), pancreatitis (3/3), trauma (2/1), abdominal hernia (1/0) and portal vein thrombosis (0/1).

The control group consisted of 33 consecutively selected trauma patients (23 male/10 female) with a mean age of 58.4 years (range: 51–70 years) who were examined with a portal venous phase abdominal CT scan. Patients with liver laceration, known liver fibrosis or cancer, and patients receiving potentially hepatotoxic medication were excluded. A summary of the patient population is shown in figure 1.

Figure 1 Patient population. Abdominal computed tomography scans of 148 patients were retrospectively analysed. Included were 80 patients with liver cirrhosis, 35 patients with earlier liver fibrosis and 33 control patients without known liver disease.

The clinical records of all patients in the fibrosis/cirrhosis group were surveyed. The aetiology of fibrosis was as follows: AFLD in 42 patients (37%), viral hepatitis in 45 patients (39%), NAFLD in 11 patients (10%), haemochromatosis in 5 patients (4%) and alpha-1–antitrypsin deficiency (A1AD) in 2 patients (2%). Aetiology of the fibrosis was unknown in 10 patients (9%).

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APASL 2014 CEVHAP Symposium summary

Friday March 14, 2014

Source CEVHAP

Hepatitis C Infection Tied to Higher Risk of Death From Non-liver Cancers

Reuters Health Information

By Bridgett Novak
February 26, 2014

NEW YORK (Reuters Health) - In addition to their increased risk of death from hepatocellular carcinoma, chronic hepatitis C virus (HCV)-infected patients also have a higher mortality rate from non-Hodgkin lymphoma and pancreatic, rectal, and oral and pharyngeal cancers, according to a new study.

The findings were presented February 20 at the annual meeting of the American College of Preventive Medicine in New Orleans, Louisiana.

Cancer-related mortality was analyzed for 12,126 chronic HCV-infected patients in the Centers for Disease Control and Prevention's (CDC) Chronic Hepatitis Cohort Study and compared to Multiple Cause-of-Death mortality data for 2006 to 2010 from the National Center for Health Statistics after age adjustment.

Twelve percent (1496) of the HCV patients died during the five-year period, 25% (372) of them from cancer. Compared to the general population, the HCV group was more likely to die from non-Hodgkin lymphoma (RR, 2.27) and rectal (RR, 2.60), pancreatic (RR, 1.63), and oral cavity or pharyngeal cancers (RR, 5.22).

As expected, the risk of dying from liver cancer was elevated among HCV-infected patients - nearly 30 times higher than among non-infected individuals.

Study author Dr. Robert D. Allison from Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, said it is important to point out that "chronic hepatitis C infection is a known risk factor for developing non-Hodgkin lymphoma (NHL). But to our knowledge, this is the first U.S. study to investigate and show that persons with chronic hepatitis C have a higher risk of death from NHL."

He said there are multiple possible explanations for the other cancers. "The HCV group had a higher rate of smoking and alcohol use than the general population. So, it's hard to say for sure if the increased risk of death from the three smoking-related cancers (oral, pancreatic, and rectal) was related to HCV infection. However, NHL is not associated with either smoking or alcohol use."

Dr. Allison told Reuters in an email, "We also analyzed the average age of death. We found that persons with chronic hepatitis C died an average of 12 years earlier than the general population from 12 different cancers - i.e., bladder, breast, colon, esophagus, leukemia, liver, lung, non-Hodgkin lymphoma, oral, pancreatic, prostate, and rectal cancers. This was an unexpected and concerning finding that may have HCV treatment and cancer screening implications."

Dr. T. Jake Liang, chief of liver diseases and deputy director for translational research at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, was not involved in the new research. He told Reuters Health, "These findings are significant in the sense that chronic HCV infection may predispose an infected person to cancer of organ systems other than the liver, where the virus infects."

Dr. Allison added, "Baby boomers make up 70% of the hepatitis C infected population in the U.S. (77% in our study). The CDC and the U.S. Preventive Services Task Force recommend that all these individuals - i.e., persons born between 1945 and 1965 - get tested."

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Image analysis of liver biopsy samples measures fibrosis and predicts clinical outcome

Journal of Hepatology

Article in Press

Yi Huang, W. Bastiaan de Boer, Leon A. Adams, Gerry MacQuillan, Max K. Bulsara, Gary P. Jeffrey 

Received 19 September 2013; received in revised form 20 January 2014; accepted 22 February 2014. published online 07 March 2014.
Accepted Manuscript

Abstract

Background & Aims

Histopathological scoring of liver fibrosis mainly measures architectural abnormalities and requires a minimum biopsy size (greater than or equal to 10mm). Liver collagen quantification may allow use of small size biopsies and improve the prediction of clinical outcomes. This study evaluated the ability of the collagen proportional area (CPA) measurement to predict clinical outcomes.

Methods

Clinical outcomes were determined using population based data-linkage for chronic hepatitis C (CHC) patients from 1992-2012. Quantitative digital image analysis of liver biopsies was used for CPA measurement.

Results

533 patients with a biopsy size greater than or equal to 5 mm were included. Median follow up was 10.5 years. 26 developed hepatocellular carcinoma (HCC), 39 developed liver decompensation and 33 had liver related death. 453 had Metavir F0-F2 and 80 had F3-F4. CPA ranged from 1.3%-44.6%. CPA and Metavir stage were independently associated with liver related death. Metavir stage, CPA stage and age were independently associated with HCC. CPA stage (C1: 0%-5%, C2: 5%-10%, C3: 10%-20%, C4: >20%) stratified risk and a significant difference in outcomes was present between all CPA stages for HCC and between C2-C3 and C3-C4 for decompensation and liver related death. The 15 year composite endpoint-free survival was 97% for C1, 89% for C2, 60% for C3, 7% for C4. C4 had significantly worse survival than ⩽C3 (p<0.001) in cirrhotic patients.

Conclusions

CPA stage gave additional information regarding risk stratification for adverse clinical outcomes independent of Metavir stage.

Abbreviations: CPA, collagen proportional area, CHC, chronic hepatitis C, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, AUROC, area under receiver operating characteristic curves, HR, hazard ratio

Keywords: Collagen proportional area, Chronic hepatitis C, Histological stage, Liver complication, Liver related death

No full text is available. To read the body of this article, please view the PDF online.

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Prospective evaluation of Fibrotest®, Fibrometer® and Hepascore® for staging liver fibrosis in chronic hepatitis B: Comparison with hepatitis C

Journal of Hepatology

Article in Press

Vincent Leroy, Nathalie Sturm, Patrice Faure, Candice Trocme,  Alice Marl, Marie-Noëlle Hilleret, Françoise MorelJean-Pierre Zarski

Received 8 November 2013; received in revised form 24 January 2014; accepted 22 February 2014. published online 12 March 2014.
Accepted Manuscript

Abstract

Background & aims

Fibrosis blood tests have been validated in chronic hepatitis C. Their diagnostic accuracy is less documented in hepatitis B. The aim of this study was to describe the diagnostic performance of Fibrotest®, Fibrometer® and Hepascore® for liver fibrosis in hepatitis B compared to hepatitis C.

Methods

510 patients mono-infected with hepatitis B or C and matched on fibrosis stage were included. Blood tests were performed the day of the liver biopsy. Histological lesions were staged according to METAVIR.

Results

Fibrosis stages were distributed as followed: F0 n=76, F1 n=192, F2 n=132, F3 n=54, F4 n=56. Overall diagnostic performance of blood tests were similar between hepatitis B and C with AUROC ranging from 0.75 to 0.84 for significant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to 0.87 for cirrhosis. Optimal cut-offs were consistently lower in hepatitis B compared to hepatitis C, especially for the diagnosis of extensive fibrosis and cirrhosis, with decreased sensitivity and negative predictive values. More hepatitis B than C patients with F greater than or equal to 3 were underestimated: Fibrotest®: 47% versus 26%, Fibrometer®: 24% versus 6%, Hepascore®: 41% versus 24%, p<0.01. Multivariate analysis showed that hepatitis B (0R 3.4, CI95% 1.2-19.2, p<0.02) and low γGT (OR 7.3, CI95% 2.0-27.0, p<0.003) were associated with fibrosis underestimation.

Conclusion

Overall the diagnostic performance of blood tests is similar in hepatitis B and C. The risk of underestimating significant fibrosis and cirrhosis is however greater in hepatitis B and cannot be entirely corrected by the use of more stringent cut-offs.

Abbreviations: CHC, chronic hepatitis C, CHB, chronic hepatitis B, TE, Transient elastography, FT, Fibrotest, AUROC, Area under the receiver operator characteristic, FM, Fibrometer, HS, Hepascore, HBV, Hepatitis B virus, HCV, Hepatitis C virus, PPV, Positive predictive value, NPV, Negative predictive value

Keywords: Blood tests, Fibrosis, Cirrhosis, Non-invasive diagnosis, Diagnostic performance

No full text is available. To read the body of this article, please view the PDF online.

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Hepatitis C treatments: Australia urged to subsidise 'revolutionary' new drugs

By Deborah Cornwall
Posted Sat 15 Mar 2014, 3:11pm AEDT

Professor Geoff McCaughan says the new hepatitis C treatments have limited side effects.
Giulio Saggin, file photo: ABC News

Public health experts say effective new drugs to treat hepatitis C should be subsidised in Australia to avert a looming strain on the national health system.

Australians who contracted hepatitis C decades ago are only now starting to develop terminal liver disease at an alarming rate.

More than half of Australia's 250,000 hepatitis C sufferers are baby boomers who contracted the virus back in the 1960s and 1970s, when experimental drug taking was rampant.

Most of these patients have, until now, remained in good health, but after 30 or more years living with the virus, the number getting liver cancer or waiting for liver transplants is now dramatically on the rise - leaping from 10 per cent to 40 per cent in the past five years.

It is a trend which could put pressure on healthcare resources.

Until recently, treatments have had such a low success rates and brutal side effects, even doctors have advised patients to wait for a better treatment to come along, hopefully before liver failure claims them first.

Audio: Listen to Deborah Cornwall's report (AM)

Public health researcher Jack Wallace is one of those with hepatitis C who has not treated the disease, hoping they are not among the one in three who will die of liver failure.

"I've been putting off treatment for the last 20 years because the current treatments, the side effects of them are too hard for me to contemplate actually doing treatment," he said.

However, one of Australia's leading hepatologists, Professor Geoff McCaughan, says a new "revolutionary" treatment is being rolled out in the United States and Europe.

"We are talking about 95 per cent cure rates with one or two tablets a day, essentially without any side effect," he said.

The drugs have arrived at a time when the first generation of hepatitis C sufferers in Australia - the baby boomers - are starting to succumb to liver failure.

"Liver cancer associated with hepatitis C is the most rapidly growing cancer in the Western world," Professor McCaughan said.

"So 40 to 50 per cent of liver cancer is hepatitis C; 40 to 50 per cent of adults requiring liver transplant, hepatitis C."

New hepatitis C treatment comes at a high price

Professor McCaughan and his colleagues are lobbying hard to have the new therapy subsidised in Australia, starting with the most vulnerable patients.

"If you walk in the door with chronic hepatitis C infection, academically and medically you should be able to get these medications at some stage within the next one to three to five years," he said.

"The problem at the moment is the cost of these drugs in Europe and the United States is extraordinarily high - you know, $90,000 to $100,000 or even more."

“The problem at the moment is the cost of these drugs in Europe and the United States is extraordinarily high - you know, $90,000 to $100,000 or even more.”

Professor Geoff McCaughan

Hepatitis C is also such a stigmatised disease there are no high-profile lobby groups and sufferers themselves tend to keep their condition a secret.

Mr Wallace says such is the lack of understanding of the disease, few Australians even realise most people with the virus are middle class citizens.

"Once you disclose you've got hepatitis C, you are publicly disclosing the fact that you've injected drugs, and injecting drugs in Australia is a shameful thing to admit," he said.

"It's really interesting - it's been 30 years since I last injected drugs, and most of the people that I interact with on a daily basis would have absolutely no idea of my history."

Professor McCaughham said hepatitis sufferers come from all walks of life.

"They're lawyers, some of them are doctors, some of them are bankers, musicians, tradesmen - you know, the late 60s and 70s was a pretty wild time," he said.

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