Chinese Medical Journal 2013;126(23):4568-4574:10.3760/cma.j.issn.0366-6999.20131127
Antiviral therapy for “difficult-to-treat” hepatitis C virus-infected patients

Tatsuo Kanda, Osamu Yokosuka and Masao Omata

Keywords
advanced cirrhosis; direct antiviral agents; elderly; hepatocellular carcinoma; hepatitis C virus; interferon-free treatment; liver transplant
Abstract
Objective To review the updated research on direct antiviral agents (DAAs)-including regimens for hepatitis C virus (HCV), and focus on “difficult-to-treat” HCV-infected patients.
Datasources The literature concerning DAAs and hepatitis C cited in this review was collected from PubMed and Google Scholar databases published in English up to July 2013.
Studyselection Data from published articles regarding HCV and DAAs in clinical trials and in clinical use were identified and reviewed.
Results It was recognized that some “difficult-to-treat” patients would still exist, even though stronger treatments using such as DAAs, including telaprevir and boceprevir, which lead to higher sustained virological response rates, are available. Such patients include those with advanced fibrosis/cirrhosis, elderly persons, children, HCV-human immunodeficiency virus co-infected patients, HCV-infected recipients, and so on.
Conclusions Certain “difficult-to-treat” patients would still exist, even though stronger treatment is available. Although evidence from clinical trials is still lacking, interferon-sparing regimens could have stronger effects for eradicating HCV in such cases.
Hepatitis C virus (HCV) infection is one of the major causes of chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation.1-3Thus it is important to eradicate HCV as early as possible to prevent advanced liver disease from becoming established. Since 2011, the HCV NS3/4A protease inhibitors telaprevir and/or boceprevir have been available for the treatment of HCV genotype 1-infected patients in the US, other western countries and Japan.4-10Before the appearance of these drugs, the standard of care (SOC) treatment for HCV genotype 1-infected patients consisted of the combination of peginterferon and ribavirin for 48 weeks, leading to onlyabout 50% sustained virological response (SVR) rates in treatment-naive patients.11,12Then, adding direct antiviral agents (DAAs) such as telaprevir or boceprevir to the combination of peginterferon-ribavirin treatment for 24 weeks could lead toabout 70% SVR rates in treatment-naive HCV genotype 1-infected patients.4-10However, it is also recognized that some “difficult-to-treat” patients would still exist.13In this review, we focused on these “difficult-to-treat” patients, despite the availability of stronger treatment with combinations with DAAs, discussing their current and future treatments.
NEW SOC TREATMENT WITH TELAPREVIR OR BOCEPREVIR FOR CHRONIC HEPATITIS C
The HCV genome is a positive-strand ~9.6-kb RNA, and has a 5’ nontranslated region (5’NTR), a long open reading frame, and a 3’NTR. A single precursor polyprotein is processed by host signal peptidases and HCV proteases, resulting in structural (core, envelopes E1 and E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins that are encoded by the HCV genome.11-13DAAs against HCV target these specific proteins and their functions. Two HCV NS3/4A protease inhibitors, telaprevir and boceprevir, are now available as first-generation protease inhibitors for the treatment of HCV infection.13Telaprevir is a linear peptidomimetic HCV NS3/4A serine protease inhibitor that improves the chance of SVR when used in combination with peginterferon plus ribavirin.4,5Telaprevir with peginterferon plus ribavirin was associated with significantly higher SVR rates (69%–75%) in HCV genotype 1-treatment-naive patients, compared with SOC alone (44%) (Figure 1A).5Further, the addition of telaprevir to peginterferon plus ribavirin was associated with significantly higher SVR rates (51%–52%) in HCV genotype 1-treatment-experienced patients, compared with SOC alone (14%) (Figure 1B),4which means that a telaprevir-including regimen leads to better SVR rates especially in relapsers to previous treatment.4
Boceprevir is a peptidomimetic ketoamide protease inhibitor binding reversibly to the HCV NS3 active site.8,9Boceprevir plus the combination of peginterferon and ribavirin for treatment-naive HCV genotype 1 patients led to 63%–66% SVR rates, higher than 38% with SOC treatment, although SVR rates differed between non-black and black cohorts (Figure 2A).8The addition of boceprevir to peginterferon plus ribavirin resulted in significantly higher SVR rates (59%–66%) in treatment-experienced HCV genotype 1 patients, as compared with SOC alone (21%) (Figure 2B).9SVR was achieved after boceprevir was added to SOC, in 33%–34% of the patients with a poor response to interferon, defined as a decrease in the HCV RNA level to less than 1 log10 IU/ml at week 4, as compared with 0% in patients retreated with SOC alone.9
SOC TREATMENT FOR CHRONIC HEPATITIS C
It has been well-known that the administration of standard interferon or peginterferon appeared effective against HCV infection. HCV could be eradicated with interferon-including regimens, resulting in a decrease in the progression of fibrosis as well as the occurrence of HCC,14-17although there are opposing opinions in the case of advanced liver disease.18-21In HCV genotype 1-infected individuals, standard interferon alfa for 24 weeks and peginterferon alfa monotherapy for 48 weeks were associated with very limited SVR rates, in ranges ofabout 10% and 20%, respectively.22The synthetic guanosine analog ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) has shownin vitroanti-viral action against a range of DNA and RNA viruses and is available in oral form.23-34The combination of peginterferon and ribavirin against HCV genotype 1 for 48 weeks and HCV genotype 2/3 for 24 weeks, respectively, led toabout 50% and 80% SVR rates of treatment-naive patients, respectively.11,12,35
“DIFFICULT-TO-TREAT” HEPATITIS C PATIENTS AGAINST ANTIVIRAL THERAPY
At present, those who are ruled out as candidates for boceprevir- or telaprevir-based therapy are as follows: patients with advanced fibrosis/cirrhosis, elderly patients, children, patients coinfected with HIV, patients with liver transplant and patients with certain other problems:(1) intolerance of interferon, autoimmune diseases, severe heart diseases, severe pulmonary diseases, severe psychiatric disorders, or severe anemia;(2) drug-drug interaction; and(3) DAA nonresponders, including DAA drug-resistant virus. Of course, patients with contra-indications for peginterferon plus ribavirin treatment also are not candidates. Some of them are participants in clinical trials with these HCV NS3/4A protease inhibitors. But most of the patients will be candidates for new DAAs or other future treatment options.13,36
Patients with HCV infection and advanced
fibrosis/cirrhosis
HCV genotype 1/4 patients with cirrhosis treated with SOC for 48 weeks had 13%–33% SVR rates.37-39HCV genotype 2/3 patients with cirrhosis treated with SOC for 24 weeks had 31%–60% SVR rates,37,38and those treated with SOC for 48 weeks had 75% SVR rates.39,40These cirrhotic patients were classified into Child-Pugh class A.37-39Although liver biopsy remains the gold standard for evaluating the grade of hepatic fibrosis, transient elastography41and platelet counts42are also useful for estimating the hepatic fibrosis grade noninvasively. In treatment-naive patients, the SVR rate of a pretreatment platelet count <130000/mcl group (37.0%) was significantly
lower than that of a count>130 000/mcl group (62.0%).43
Although first-generation protease inhibitors with peginterferon plus ribavirin seem to represent a new step forward, as the SVR rate of telaprevir or boceprevir with peginterferon plus ribavirin improved by 10%–30% compared to SOC in HCV genotype 1 patients with severe fibrosis or cirrhosis,44,45an interferon-sparing regimen of DAA combinations will provide a higher SVR in patients with not only compensed cirrhosis but also decompensed cirrhosis.45-47
Elderly patients
Japanese HCV-infected patients tend to be older than those in other countries, with their older age favoring the onset of HCC, which continues to rise in Japan.48As a result, we have to treat advanced-age patients infected with HCV. Both age and gender may be associated with the SVR rates of SOC in HCV genotype 1-infected individuals. We also reported SVR rates of patients aged<65 and >65 years of 50.9%and 44.0%, respectively, and those of males and females of 56.5% and 39.0%. The SVR rate of SOC against HCV genotype 1-infected females aged >65 years was only 19.0%.49SVR was attained independently of adherence 80/80/80.49,50Telaprevir and boceprevir could cause severe adverse events such as rash and severe anemia, and they possess drug-drug interaction potential.10,51Many elderly patients take other drugs for other diseases and this requires particular attention in daily clinical practice. Further, the safe use of HCV NS3/4A protease inhibitors for children has not yet been established. Further assessments will be needed for the use of HCV NS3/4A protease inhibitors for children and the elderly.
HCV-HIV co-infected patients
Due to shared modes of transmission, 20%–30% of HIV-infected patients in the US are co-infected with HCV,52but little is known about the effects of HCV on the progression of HIV-associated disease. Individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV, but recently individual therapy has become widely available. This highlights the importance of the HCV treatment forco-infected patients.53In such patients, the SVR rate achieved by SOC is even lower, atabout 20% with genotype 1 andabout 60% with genotype 2/3 infection.54-59
Use of telaprevir or boceprevir with peginterferon plus ribavirin improves SVR in HIV-uninfected person, and it could increase EVR by 30%–50% and the end-of-treatment response by 20%–40% in HIV/HCV co-infected persons.52,60Telaprevir and boceprevir are both substrates and inhibitors of cytochrome P450 3A4.61When co-administering boceprevir with the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (a CYP3A inhibitor), the minimum concentration (Cmin) level of boceprevir decreased by 44%.61,62Telaprevir also should not be combined with efavirenz, lopinavir/ritonavir, fosamprenavir/ritonavir, darunavir/ritonavir or atazanavir/ritonavir due to antiviral treatment failure.61
HCV-infected patients associated with liver
transplantation
HCV infection is one of the major causes of end-stage liver diseases and liver transplantation in most countries.63Recurrent HCV disease is the most common cause of graft loss and potential mortality in HCV-infected post-liver transplant recipients.64Spontaneous clearance of HCV post-transplantation is a rare event. Most patients have recurrent HCV viremia within days after transplantation.64,65HCV treatment is performed to prevent liver-related complications and graft loss. There are two basic approaches for the treatment against HCV in liver transplantation: (1) pre-transplant antiviral therapy given with the intent of preventing HCV infection post-transplantation, and (2) post-transplant antiviral therapy.64SVR before transplantation eliminates the risk of HCV infection after transplantation.65With the achievement of undetectable HCV RNA before transplantation, the risk of HCV re-infection after transplantation is reduced byabout 40% after transplantation.65In liver-transplant patients infected with HCV who were cirrhotics and wait-listed, the SVR rate achieved by SOC is even lower, at 7%–30% in genotype 1/4 and 32%–50% in genotype 2/3 infections.66-71Although telaprevir and boceprevir improve the SVR rates when combined with peginterferon and ribavirin in HCV genotype 1 patients, both are substrates and inhibitors of CYP3A4, resulting in severe drug-drug interactions when co-administered with immunosuppressants such as cyclosporine, tacrolimus, or sirolimus.61A preliminary report62has indicated that the combination of sofosbuvir (formerly known as GS-7977), an oral nucleoside analogue inhibitor of HCV polymerase activity, and daclatasvir, an HCV NS5A inhibitor, was useful for the treatment of severe recurrent cholestatic hepatitis C in a liver transplant recipient infected with HCV genotype 1.63The excellent safety and adverse event profiles of these drugs make this interferon-sparing regimen an attractive treatment for liver transplant recipients with recurrent HCV infection.63Interferon-sparing regimens may also be useful for HCV patients with unfavorable IL28B genotypes.72-78
Combination treatment with DAAs for the treatment of HCV-infected patients with HCC
HCV-related HCC usually occurs in cirrhotic liver.79,80Inflammation in the background non-cancerous cirrhotic portion of the liver would promote malignant progression in HCC development from HCV-associated cirrhosis.81Some cirrhotic patients have thrombocytopenia, anemia, neutropenia, and bleeding tendency, and it is difficult to use SOC and to achieve SVR in the treatment of HCV. Interferon therapy after tumor ablation improves prognosis in HCV-HCC.82HCC development and HCC recurrence were significantly reduced in SVR-achieved patients.83,84So, interferon-sparing regimens, which have less adverse events, could lead to more SVR and might be useful for the prevention of HCC development and recurrence after curative treatment for HCC as one of the future treatment options.
DAAs for HCV non-genotype 1 patients
Some patients infected with HCV non-genotype 1 will still be treatment-refractory.85-87Telaprevir monotherapy is also effective for HCV genotype 2 patients but not for HCV genotype 3 patients.88The addition of telaprevir to SOC could lead to the improvement of SVR rates in HCV genotype 2 patients. Sofosbuvir and ribavirin is a safe and effective treatment as an interferon-sparing regimen for the treatment of patients with HCV genotype 1, 2, or 3 infection.89-93DAAs also seemed useful for the eradication of HCV non-genotype 1 infection. Taken together, there might be an urgent need for large clinical trials using DAAs and host modulations in patients infected with HCV non-genotype 1.94,95
Patients with DAA drug-resistant virus
Susser et al96performed a clonal sequence analysis of the HCV NS3 gene at long-term follow-up in HCV genotype 1-infected patients who recieved telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end of treatment. HCV RNA was still detected in 28 of 82 patients after a median follow-up of 4.2 years. Resistance variants were detected in 2 of 14 teraprevir- and in 4 of 14 boceprevir-treated patients. V36M, V36A and A156T resistance mutations and V36A, T54A/S, V55A and T54S+R155K resistance mutations were detected in telaprevir- and voceprevir-treated patients, respectively. Some patients with these variants before these treatment also seems not to achieve SVR.97Cross-resistance to resistance of first-generation HCV NS3/4A protease inhibitors such as telaprevir or boceprevir exists extensively among the different compounds of second-generation HCV NS3/4A protease inhibitors.98The barrier to this resistance is lower in HCV subgenotype 1a than HCV subgenotype 1b strains, resulting in higher breakthrough rates in the HCV subgenotype 1a-infected patients.99The R155K and D168 mutations have shown particular cross-resistance to faldaprevir, simeprevir, asunaprevir, GS9451 and ABT-450.100It maybe that combinations of DAAs other than HCV NS3/4A protease inhibitors (plus ribavirin) with or without peginterferon could treat these patients successfully.
CONCLUSION
Although there are still a lot of “difficult-to-treat” patients infected with HCV, new DAAs possess stronger antiviral activity against HCV. Clinicians also need to be aware of “drug-drug interaction” as well as other adverse events with the use of most DAAs. Although evidence from clinical trials is still lacking, interferon-sparing regimens could provide more and stronger effects for eradicating HCV in “difficult-to-treat” patients because of the effects of interferon-sparing regimen independent of IL28B genotypes. Further studies are warranted.
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(Received April 26, 2013)
Edited by CUI Yi

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Figure 1.Sustained virological response (SVR) rates in telaprevir-based triple therapy in HCV genotype-1 patients. A:SVR rates in treatment-naïve patients (reported by Jacobson et al5). B: SVR rates in treatment-experienced patients (reported by McHutchison et al4).
Figure 2. Sustained virological response (SVR) rates in boceprevir-based triple therapy in HCV genotype-1 patients. A:SVR rates in treatment-naïve patients (reported by Poordad et al8). White columns, non-black cohort; gray columns, black cohort. B: SVR rates in treatment-experienced patients (reported by Bacon et al9).