Wednesday, January 4, 2012

Treatment of patients with genotype 3 chronic hepatitis C- current and future therapies

Treatment of patients with genotype 3 chronic hepatitis C- current and future therapies

  1. Shiv K. Sarin,
  2. Chandan K. N. Kumar

Article first published online: 29 DEC 2011

DOI: 10.1111/j.1478-3231.2011.02715.x

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Liver International

Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C

Volume 32, Issue Supplement s1, pages 141–145, February 2012


Genotype 3 is a common type of HCV infection, and standard therapy using pegylated interferon (PEG-IFN) and ribavirin (RBV) is quite effective in these patients. While a short course of 16 weeks may result in comparable end of therapy responses, relapse rates are often high. A 24-week course is therefore preferable, and is expected to result in sustained virological response (SVR) rates of more than 70%. The 24-week course is especially recommended in the presence of steatosis (often associated with Genotype 3 infection), fibrosis stage two or more, high BMI and high viral load. In patients who do not achieve a rapid viral response (RVR) with combination therapy, an extended course up to 48 weeks should be considered. While not as definite as for genotype 1 patients, the presence of the CC variant of IL28b could help in the initial prognosis and the need for additional treatment, if an RVR is not achieved. The role of directly acting antiviral agents (DAA) has not been fully evaluated in treatment naïve, non-responders and relapsers in genotype 3 patients. Initial results with the cyclophilin inhibitor Debio-025 are quite encouraging. There is an urgent need for large clinical trials using DAA and host modulators in patients with G3 infection.

According to WHO, around 130–170 million people are chronically infected with the hepatitis C virus (HCV) worldwide, reflecting the magnitude of this global health burden [1]. The estimated prevalence is around 2%. Epidemiological surveys have also shown a geographical variation in the prevalence and distribution of hepatitis C genotypes worldwide. Although HCV genotype 1 predominates in the Western countries, genotype 3 accounts for 35–80% of chronic HCV infections in regions such as the Indian subcontinent [2], Southeast Asia and Australia [3].

The standard of care (SOC) therapy for patients with chronic HCV infection has been the combination of peginterferon (PEG-IFN) and ribavirin (RBV). These drugs are administered for either 48 weeks (HCV genotypes 1, 4, 5 and 6) or 24 weeks (HCV genotypes 2 and 3), inducing sustained virological response (SVR) rates of 40–50% in those with genotype 1, and of 80% or more in those with genotypes 2 and 3 infections [4]. However, the rates of SVR in patients infected with genotype 3 are lower than those with genotype 2 [5]. Second, compared with other genotypes, genotype 3 is associated with a higher incidence of hepatic steatosis and the rapid progression of liver fibrosis [6]. We have previously shown that the median rate of the progression of fibrosis per year is 0.25 (0.0–1.5) fibrosis units in patients with genotype 3 in India and higher in patients who acquire infection after 30 years of age. The median time for progression to cirrhosis was 16 years [7]. According to a recent meta-analysis, the odds ratio for the association of genotype 3 infection and accelerated progression of liver fibrosis was 1.52 in single biopsy studies suggesting faster fibrosis progression compared with other genotypes [8].

In a retrospective study of 353 patients, Nkontchou et al. [9] showed that hepatitis C genotype 3 was associated with a higher incidence of hepatocellular carcinoma (HCC) in patients with ongoing cirrhosis. The risk factors for an increased risk of HCC were male gender, older age, higher body mass index, low platelet count and genotype 3. Probably because of the rapid progression to fibrosis, genotype 3 could predispose to HCC along with other defined risk factors. The HCV genotype 3 core protein causes steatosis [10, 11, 12] that can lead to oxidative stress and reactive oxygen species predisposing to carcinogenesis [13, 14]. Thus, better treatment must be found for this dreadful yet curable infection.

Present treatment for hepatitis C genotype 3

According to the recent AASLD guidelines [15], PEG-IFN [alpha]-2b (1.5 μg/kg/week) plus RBV (800–1400 mg/day) or PEG-IFN [alpha]-2a (180 μg/week) plus RBV (800 mg/day) for 24 weeks are the established SOC regimens for patients with chronic hepatitis C genotype 2 or 3. However, optimal administration of PEG-IFN/RBV, in particular, the duration and the dosage have still not been clearly established in relation to outcome in rapid and slow responders. Based on the concept of ‘response guided treatment,’a recent meta-analysis evaluated the issue of decreasing the duration of treatment to improve tolerance and cost effectiveness, and most importantly to decrease viral resistance to the standard bitherapy [16]. Treatment with PEG-IFN and weight-based RBV for 16 weeks in patients a with rapid virological response (RVR) resulted in an SVR of 76.3% and 86.4% with 24 weeks of treatment, unlike genotype 2 which was 83.8% and 89.3% respectively. This was because of increased relapse rates in patients with genotype 3. Manns et al. [17] showed that the relapse rate was 26% after 16 weeks of treatment and 18% after 24 weeks in genotype 3 patients. The increased relapse rates could be because of steatosis, and as already mentioned, the increased rate of fibrosis in thes patients. In a cohort of 932 treatment-naïve patients, investigators of the ACHIEVE-2/3 trial [18] showed that hepatic steatosis significantly increases the risk of relapse independent of HCV RNA levels in patients with genotype 3 who achieve an RVR with IFN-based regimens. This may be because of altered IFN-[alpha] signalling, increased intrahepatic RNA levels or increased quasispecies diversity. Other known risk factors for relapse are male gender, black race, age over > 40, increased viral load, presence of fibrosis, body weight > 85 kgs and presence of diabetes mellitus.

Predictors of response

IL28b polymorphism

There is recent evidence suggesting that polymorphisms near the IL28b gene, which codes for interferon (IFN)-λ3, predict response to PEG-IFN-[alpha] and RBV treatment in HCV genotype 1 infected patients. However, several studies have shown that this pathway is also applicable to genotype 3 patients and can help predict those who can achieve RVR. The single nucleotide polymorphism (SNP) rs12979860 (CC/CT/TT) is located 3 kb upstream of the IL28B gene on chromosome 19, which codes for IFN- λ3, and rs8099917 (TT/TG/GG) SNP is located 8 kb downstream of the IL28B gene and 6 kb upstream of the IL28A gene, which codes for IFN- λ2. Moghaddam et al. [19] found that factors that predicted RVR were IL 28B SNPs rs12979860 (CC allele), rs8099917 (TT allele), age < 40 years old and viral load (< 4 × 10^5 IU/ml). This was not associated with an SVR because of the increased rate of relapse with the CC allele along with higher pretreatment viral loads and ALT levels. Thus, the ‘host responder genotypes’, namely the rs12979860 CC allele and the rs8099917 TT allele were more likely to relapse after an early response. This is in contrast to the genotype 1 response in which host–responder genotypes are associated with a RVR and SVR as well as a decreased rate of relapse. Lindh et al. [20] studied the association between the IL28B gene variation at rs 12979860 and viral kinetics observed during treatment of chronic hepatitis C in a cohort of 345 treatment-naïve chronic hepatitis C patients (241 patients with genotype C). Viral response kinetics were assessed using viral RNA levels at days 0, 3, 7 and 29. The first phase of viral decline was a change in RNA levels from baseline to day 3. The decline rate for the second phase i.e. the slope, was calculated using HCV RNA values from days 3 and 7 in patients who were HCV RNA negative on day 29, and values from days 3, 7 and 29 for the remaining patients. This study found that the IL28b CC allele was strongly associated with a rapid early phase viral decline by a median of 5.68 log10 IU/ml compared with 4.82 and 4.62 log10 IU/ml in patients with CT or TT at rs12979860 respectively. Thus, the patients with a CC allele had a better chance of achieving an RVR (67%) than those with the CT (60%) or TT alleles (47%). In patients who received 24 weeks of antiviral treatment, the probability of achieving an SVR in those who did not achieve an RVR, was higher in those with the CC allele (74%) than with the CT (59%) or TT alleles (29%). Mangia et al. [21] reported that IL28B influenced treatment outcome in patients who did not achieve an RVR, with SVR rates of 29%, 67% and 87% in patients carrying the TT, CT or CC alleles at rs12979860 respectively. Another important conclusion of the study by Lindh et al. was that even though the IL28B CC allele was associated with a rapid early viral decline, it was not associated with an SVR when patients received a short course of 12 weeks of treatment. This was because of the high baseline viral load that is frequently observed in these patients. However, in a group with a baseline HCV RNA of 5.6 log10 IU/ml, 33/38 patients (87%) treated for 12 weeks achieved an SVR if they carried the CC or CT SNP rs12979860 genotypes. As part of the lead-in phase of the HALT-C trial, Freedman et al. [22] showed fascinating evidence that the consumption of three or more cups of coffee per day was an independent predictor of response to standard bitherapy in chronic HCV patients. After adjustment for other predictors of response such as age, ethnicity, alcohol, cirrhosis, IL28b polymorphism rs12979860, the odds ratio for coffee drinkers vs non-drinkers was 2.0 for a response at week 12, 2.1 for a response at week 20, 2.4 for a response at the end of treatment and 1.8 for SVR.

Other predictors of response

In a recent retrospective study by Amanzada et al. [23], a subgroup of patients with genotype 3, who were under the age of 40, who had an ‘ultrarapid’ virological response within 2 weeks (HCV RNA undetectable at week 2 of treatment), low ƴ-GT/ALT ratios and an absence of steatosis on liver biopsy, were found to achieve an SVR with IFN-[alpha]2A monotherapy 3–6 Million Units (MU) either daily or three times a week. Neither IL28b SNPs rs12979860 or rs8099917 genotypes, nor the duration therapy (24 weeks vs. 48 weeks) were related to treatment outcome. Moreover, this treatment was better tolerated because of the absence of the adverse effects of RBV. However, further randomized controlled trials are needed to validate these findings. A summary of the other predictors of response to standard treatment in chronic hepatitis C genotype 3 are given below (Table 1).

Table 1. Factors that predict response to treatment in hepatitis C genotype3
Age < 40 years
Female gender
White race
Body weight < 85 kgs
Absence of diabetes mellitus
Absence of steatosis on liver biopsy
Fibrosis on liver biopsy ≤ 2
IL 28B polymorphisms
rs12979860 (CC allele)
rs8099917 (TT allele)
Viral load < 4 × 10^5 IU/ml
Consumption of coffee (> 3 cups per day)

Future treatment options for patients with genotype 3

HCV is a 9.6-kb positive-sense, single-stranded RNA virus. It encodes a large single open reading frame corresponding to a poly-protein precursor of about 3000 amino acids, which is proteolytically processed by cellular signal peptidases and HCV-encoded proteases into at least 10 individual proteins, in the order of C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. Newer antivirals, more commonly known as directly acting antivirals (DAA), have mainly focused on two viral proteins, the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase, both of which have enzymatic activities essential for viral replication [24]. The peptidomimetic inhibitors of the NS3/4A serine proteases, telaprevir (VX-950) and boceprevir (SCH-503034) have created a revolution in the treatment of genotype 1 and have recently been recommended in combination with the standard bitherapy PEG-IFN/RBV for the treatment of patients with chronic hepatitis C genotype 1 [4]. However, these drugs have not shown to be of great benefit in the treatment of patients with genotype 3.

An alternative strategy is to target host factors that are also required for viral replication. Cyclophilins are a family of cellular peptidyl-prolyl isomerases required for HCV replication [25]. In an in vitro study by Mathy et al., combinations of a host factor (cyclophilin) inhibitor, NIM811, were studied with the three main classes of virus specific inhibitors: BILN2061 (ciluprevir), first NS3-4A protease inhibitor, a non-nucleoside NS5B polymerase inhibitor thiophene-2-carboxylic acid, and NM107, the active moiety of NM283 (valopicitabine), the first nucleoside NS5B inhibitor. Based on mathematical modelling, the effect of these combinations was shown to be synergistic for NIM811 with a nucleoside or a non-nucleoside viral polymerase inhibitor and additive for NIM811 with a viral protease inhibitor. The key advantages of targeting host factors are long lasting antiviral response and a greater genetic barrier to the emergence of viral escape mutants. The use of the oral cyclophilin B inhibitor Debio-025 was first investigated in a randomized double blind, placebo controlled trial of 19 patients co-infected with HIV and HCV [26]. Of the 19 co-infected patients, those treated with Debio-025 1200 mg twice daily for 15 days (n = 16) experienced a significantly greater maximum reduction of log10 HCV RNA copies/ml (only in genotypes 1, 3 and 4) than placebo treated (n = 3) patients. The least squares mean of the maximum reduction of log10 HCV RNA copies/ml for the Debio-025 group was −3.63 compared with −0.73 in the placebo group. The greatest response was observed in patients with genotype 3 who achieved a least squares mean maximum reduction of log10 HCV RNA copies/ml of −4.46 log10. None of the patients developed a viral breakthrough in the treatment arm, and time to relapse varied after the end of treatment. This was the first study to show the antiviral effects of oral cyclophilin inhibitors in a clinical study; however, larger studies are needed before this regimen can be clinically recommended. Another group of host factors was studied by Lupberger et al. [27]. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that regulates a number of key processes, including cell proliferation, survival and differentiation during development, tissue homeostasis and tumorigenesis.

Ephrin receptor A2 (EphA2) mediates cell positioning, cell morphology, polarity and motility. HCV entry is a multistep process involving viral envelope glycoproteins and host cell factors. Attachment of the virus to the target cell is mediated through binding of HCV envelope glycoproteins to glycosaminoglycans. HCV is internalized in a clathrin-dependent endocytic process requiring CD81, scavenger receptor type B class I (SR-BI), claudin-1 (CLDN1) and occludin (OCLN). Inhibition of EGFR or EphA2 activity reduced CD81-CLDN1 association, hence hampering the cell entry process of HCV. The in vitro results showed that EGFR or EphA2 inhibition was associated with decreased cell entry, fusion, cell-to-cell transmission and subsequently decreased viral spread. This was extrapolated in in vivo studies conducted using an erlotinib (EGFR inhibitor) chimeric urokinase plasminogen activator–severe combined immunodeficiency (uPA-SCID) mouse model. Its treatment decreased steady-state HCV RNA levels by more than 90%. However, viral load increased, once the treatment was discontinued. Treatment was well-tolerated and did not induce any marked changes in safety parameters such as serum concentrations of alanine transaminase, albumin or body weight. These fascinating results provide a glimmer of hope, although there is a long way to go before they can be recommended in patients with chronic hepatitis C. There are many drugs in the pipeline, some of which are being studied in phase III trials (Table 2).

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