January 5, 2012

New “virtual liver” technology helps detect liver tumours

PASSPORT_project

Published on Thursday, 5, January, 2012 at 17:44

Scientists and surgeons from France, Germany, United Kingdom and Switzerland have developed a “virtual liver,” using EU research funding, which will help surgeons better plan and carry out tumour operations and ensure quicker patient recovery.

The PASSPORT project (Patient-Specific Simulation and Pre-Operative Realistic Training) makes a uniquely accurate “virtual liver” available to physicians based on medical images sent by the radiologist to a PASSPORT online service, which helps surgeons decide whether they should or not operate. Surgeons can now see more precisely where a tumour is and where they will have to operate to safely remove it.

European Commission Vice President Neelie Kroes said, “Liver cancer claims hundreds of thousands of lives in Europe and the world. The technology developed in the EU-funded PASSPORT project is a breakthrough that will improve diagnosis and surgery, and help to save lives.”

The liver performs more than 100 vital functions in the human body. Liver diseases, including cancer and sclerosis of the liver, kill thousands of people every year. Liver transplants are only an option for a very small proportion of patients with liver disease. Another option is to remove the infected part of the organ and allow the liver to regenerate. To do so, surgeons need to know the tumour’s precise location, the volume of the functional liver which would remain, and the patient’s overall health in order to accurately assess the chance of a successful intervention. Under current practices, less than 50% of patients undergo surgery. PASSPORT’s virtual liver could considerably increase this percentage.

The virtual software being used in the project is based on open source technology available online making it easier for surgeons to collaborate and share their analysis.

Using EU-research funding to help improve citizens’ lives, medical knowledge, and enable high-tech industries are among the goals of the Digital Agenda for Europe.

First results of the project clearly demonstrate the cost effectiveness and benefits of patient-specific surgical planning. The next step is making the software commercially available. This commercialisation will be a first step towards the routine clinical use of PASSPORT results. In practice, this means that a surgeon based anywhere in the world will be able to use this model, adjust it to the needs of each patient and considerably lower the cost of each patient’s operation.

The PASSPORT project started in June 2008 and ended in December 2011. The total cost was €5,457,174 of which €3,635,049 came from EU funding. PASSPORT is part of the “Virtual Physiological Human” Network of Excellence (VPH NoE). The VPH NoE is a project which aims to help support and advance European research in biomedical modelling and simulation of the human body. It allows the surgeon to zoom in from the body to the organ, from the organ to the tissue, from the tissue to the cell. It thus allows a “multi-layered” approach so specialists can track the disease and see the way in which the disease propagates through the different levels of the body.

PASSPORT Project co-ordinator: IRCAD (France)

Partners:

Eidgenössische Technische Hochschule • Zürich (Switzerland)

Technische Universität München (Germany)

Imperial College of Science, Technology and Medicine (UK)

Institut National de Recherche en Informatique et en Automatique (France)

Universität Leipzig (Germany)

University College London (UK)

Université de Strasbourg (France)

KARL STORZ GmbH & CO. KG (Germany)

Institut National de la Santé et de la Recherche Médicale (France)

Source

Provided by NATAP

Download the PDf here

Clinical Infectious Diseases Advance Access published December 14, 2011

David L. Thomas,1 John G. Bartlett,1 Marion G. Peters,2 Kenneth E. Sherman,3 Mark S. Sulkowski,1 and Paul A. Pham1
1Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; 2Department of Medicine, University of California, San Francisco

School of Medicine; and 3Department of Medicine, University of Cincinnati School of Medicine, Ohio

Data reported at conferences in 2011:

AASLD: Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: A 24-Week Treatment Interim Analysis - (11/08/11)

IDSA: Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients - (10/25/11)

HepDart: Sustained Virologic Response in Prior Null Responders to Peginterferon/Ribavirin (PR) After Retreatment With Boceprevir + PR: The PROVIDE Study (12/07/11)

AASLD: In Null Responders 4 Week Peg/Rbv Lead-In Predicts SVR' - Different Likelihood of Achieving SVR on a Telaprevir-containing Regimen Among Null Responders, Partial Responders and Relapsers Irrespective of Similar Responses after a Peginterferon/Ribavirin 4-week Lead-in Phase: REALIZE Study Subanalysis - (11/09/11)

CROI: Pharmacokinetic Interactions Between Antiretroviral Agents and the Investigational HCV Protease Inhibitor Telaprevir in Healthy Volunteers - (03/2/11)

CROI: Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions - (03/2/11)

Provisional Guidance on the Use of Hepatitis C Virus Protease Inhibitors for Treatment of Hepatitis C in HIV-Infected Persons
Abstract

In May 2011, hepatitis C virus (HCV) protease inhibitors (PIs) were approved by the US Food and Drug Administration to treat persons with genotype 1 chronic hepatitis C virus (HCV) infection, but not those dually infected with human immunodeficiency virus (HIV). Although critical safety and efficacy data are lacking, the availability of the drugs and substantial medical need justify the off-label use of HCV PIs in select HIV/HCV-coinfected persons. Pending results of ongoing investigations, this article represents provisional guidance on the use of HCV PIs in HIV-infected persons.

On 13 May 2011 and 23 May 2011, boceprevir (BOC) and telaprevir (TVR), respectively, were approved by the US Food and Drug Administration to be used with peginterferon and ribavirin for treatment of genotype 1 chronic hepatitis C virus (HCV) infection. Use of these NS3/4A serine protease inhibitors (PIs) with peginterferon and ribavirin improves sustained virologic response by 25%-31% in human immunodeficiency virus (HIV)-uninfected persons [1, 2]. These efficacy data and drug availability raise the question of whether HCV PIs should be used in HIV/HCV-coinfected persons pending final results of ongoing phase 2 and subsequent phase 3 clinical trials of both BOC and TVR. Lacking the relevant data on HIV/HCV-coinfected persons, clinical and policy decisions must be made largely on data from HIV-uninfected persons. The following opinions were provided to the Maryland AIDS Assistance Program and may be useful to others.

HIV/HCV PHASE 2 DATA

Telaprevir

In the only data available in the public domain, HIV/HCV-coinfected individuals taking no antiretroviral therapy (ART) with well-controlled HIV infection (n = 13) or taking tenofovir/emtricitabine with either efavirenz (n = 24) or ritonavir-boosted atazanavir (n = 22) were randomized to peginterferon and ribavirin for 48 weeks or TVR plus peginterferon and ribavirin for the first 12 weeks, followed by the continuation of peginterferon and ribavirin for 36 additional weeks [3]. Notably, shortened durations of treatment with response-guided therapy to TVR are not currently being evaluated in HIV/HCV-coinfected patients. Baseline HCV RNA was >800 000 IU/mL for 83%; 69% of patients were white, and only 2 had cirrhosis. Telaprevir was given 750 mg every 7-9 hours with food with ≥20 g of fat (or 1125 mg every 7-9 hours if also taking efavirenz). The proportion of persons with undetectable HCV RNA at week 4 (26 of 37 [70%]) was substantially greater in the TVR arms than with placebo (1 of 22 [5%]). Likewise, at the planned week 12 evaluation, virologic responses were superior in the TVR arm (Figure 1). There were no unexpected adverse events reported through week 12. There were no instances of HIV breakthrough, but 2 patients experienced HCV breakthrough that is typically associated with resistance. In the TVR group, there were more skin and gastrointestinal complaints and 2 patients discontinued due to adverse events (jaundice and anemia). Complete safety and efficacy data to register TVR with peginterferon and ribavirin for use in HIV/HCV-coinfected individuals are not anticipated before 2013.

Boceprevir

A phase 2 trial of BOC in combination with peginterferon and ribavirin in HIV/HCV-coinfected persons is ongoing. In this study, 99 HIV/HCV-coinfected patients with stable HIV disease are being treated with an initial 4 weeks of peginterferon plus weight-based ribavirin (lead-in), then randomized 2:1 to the addition of BOC 800 mg every 7-9 hours or placebo to peginterferon alfa and ribavirin for an additional 44 weeks (total therapy, 48 weeks). Subjects were excluded if they were on zidovudine, didanosine, stavudine, efavirenz, etravirine, or nevirapine. Raltegravir and ritonavir-boosted PIs were permitted. An interim analysis was presented for 98 patients (34 placebo and 64 boceprevir) [4]. Baseline HCV RNA was >800 000 IU/mL for 88%; 82% were white; and 5% had cirrhosis. The proportion of persons for whom HCV RNA was undetectable at treatment week 8 (4 weeks of boceprevir vs placebo) was higher in those taking BOC (24 of 64 [37.5%]) than in those taking placebo (5 of 34 [14.7%]) (Figure 2). Likewise, at treatment week 24, HCV was undetectable in 43 of 61 patients (70.5%) in the BOC arm compared with 11 of 32 (34.4%) in the placebo arm. Treatment was discontinued due to an adverse event in 3 (9%) and 9 (14%) of the patients in the placebo and BOC arms, respectively. Complete safety and efficacy data to register BOC with peginterferon and ribavirin for use in HIV/HCV-coinfected individuals are not anticipated before 2013.

PROVISIONAL RECOMMENDATIONS

Pending more conclusive data and regulatory approval, decisions to use or withhold HCV PIs in HIV/HCV-coinfected persons must take into account multiple related factors. On the one hand, liver fibrosis progression is more rapid and peginterferon and ribavirin treatment is less effective in HIV/HCV-coinfected persons than in those without HIV, and liver transplantation is neither widely available nor highly successful in HIV/HCV-coinfected persons [5]. On the other hand, the safety and efficacy of HCV PIs are largely unproven in HIV/HCV-coinfected persons, data regarding drug-drug interactions are limited, additional anti-HCV medications are being developed, and the price of HCV PIs may add to the cost of the peginterferon and ribavirin treatment regimen. At current cost levels used by the Maryland AIDS Administration and dosing used in phase 2 studies, a full course of BOC would add $51 116, while a full course of TVR would add $51 957 or $77 936 (for the additional pill required for coadministration with efavirenz [EFV]). The collective cost of HCV medications could detract from funds available for other medications, and the cost-effectiveness of treatments for HCV has not been rigorously compared with treatments already being supported for HIV.

Until additional data or alternative treatments are available, some experts believe that HCV PIs should be used in combination with peginterferon and ribavirin in certain HIV/HCV-coinfected persons. Since AIDS drug assistance programs will need to consider the provision of HCV PIs alongside other competing priorities, the following interim information was provided by an expert panel in June 2011 to the Maryland AIDS Drug Assistance Program regarding the use of HCV PIs in HIV/HCV-coinfected persons:

1. Peginterferon and ribavirin remain the standard of care for treatment of HCV infection in patients with HCV genotype 2, 3, or 4 HCV infection or in patients for whom pharmacokinetic interactions between these HCV PIs and other necessary medications, including ART, cannot be confidently eliminated or managed (see Pharmacokinetics below) or in patients for whom HCV PIs are not available.

2. For some coinfected patients with chronic genotype 1 HCV infection, HCV PIs should be used with peginterferon and ribavirin. Use of HCV PIs alone (or with peginterferon but not ribavirin) is contraindicated because HCV PI-resistant viruses are rapidly selected if the medications are used without both peginterferon and ribavirin. Accordingly, persons with contraindications for peginterferon and ribavirin (eg, pregnancy, didanosine use, or severe, uncontrolled psychiatric or medical disease) also have contraindications for HCV PI-inclusive therapy. HCV PIs and/or peginterferon and ribavirin treatment should not be used for persons with liver failure (decompensated cirrhosis) because there is evidence that peginterferon and ribavirin may exacerbate liver disease in such patients [6]. The benefits of HCV PIs plus peginterferon and ribavirin treatment are most likely to outweigh the risks for individuals with significant liver fibrosis (often defined as greater than METAVIR fibrosis stage 0-1 or the equivalent). Although HIV/HCV-coinfected persons have more rapid progression of liver disease than HIV-uninfected persons and HCV treatment is more efficacious at a lower disease stage, some experts believe that it is safer to monitor patients with little or no fibrosis for evidence of progression while awaiting additional safety and efficacy data in HIV/HCV-coinfected persons, as well as additional new antiviral agents.

3. When possible, HIV infection should be controlled before treatment with HCV PIs and peginterferon/ribavirin. HIV control is often defined in persons off ART as CD4 cell count >500/mm3 and HIV RNA <20 000 copies/ml or in those on ART as HIV RNA <50 copies/mL. Importantly, HCV PIs should not be used with some medications that have proven or suspected pharmacologic interactions, while dosing adjustments may be required with other combinations (Table 1).

4. Before use in any patient, package inserts for the specific HCV PI should be consulted for a list of contraindicated drug combinations and details of multiple other drug-drug interactions.

Telaprevir option:

a. Telaprevir plus peginterferon/ribavirin for 12 weeks followed by peginterferon and ribavirin for an additional 36 weeks (total therapy, 48 weeks) plus:

i. No ART with controlled HIV disease.

ii. Ritonavir-boosted atazanavir (ATV/r) 300/100 mg once daily plus tenofovir/emtricitabine 1 tab once daily with TVR 750 mg every 7-9 hours with food with ≥20 g of fat.

iii. Although there are no clinical data with TVR plus raltegravir, coadministration does not appear to affect TVR pharmacokinetics, and the 31% increase in raltegravir is not considered significant enough to affect dosing [7]. Thus, some experts endorse the use of raltegravir 400 mg orally twice daily, tenofovir/emtricitabine 1 tab once daily, and TVR 750 mg every 7-9 hours with food (with ≥20 g of fat) in patients unable to take ATV/r, or to prevent the added cost and pill burden of using a higher TVR dose with EFV (see below).

iv. EFV 600 mg daily at bedtime plus tenofovir/emtricitabine 1 tab once daily with increased TVR dose to 1125 mg every 7-9 hours with food (with ≥20 g of fat).

v. To minimize the risk of selecting for TVR resistance, patient adherence should be high. TVR should be stopped if there is HCV rebound (>1 log increase in HCV RNA). Treatment with peginterferon, ribavirin, and TVR should be stopped if HCV RNA is not suppressed <1000 IU/mL at treatment weeks 4 and 12. Individuals who meet these week 4 and 12 milestones but have detectable HCV RNA at treatment week 24 should also discontinue peginterferon/ribavirin.

Boceprevir option:

b. Peginterferon/ribavirin for 4 weeks, followed by BOC plus peginterferon/ribavirin for 44 weeks (total therapy, 48 weeks) plus:

i. No ART with controlled HIV disease.

ii. A ritonavir-boosted PI or raltegravir plus tenofovir/emtricitabine 1 tab once daily with BOC 800 mg every 7-9 hours with food.

iii. Until research demonstrates safety, BOC should NOT be used with efavirenz, etravirine, or nevirapine.

iv. To minimize the risk of selecting for BOC resistance, patient adherence should be high. BOC should be stopped if there is HCV rebound (>1 log increase in HCV RNA). Treatment with peginterferon, ribavirin, and BOC should be stopped if HCV RNA is > 100 IU/mL at treatment week 12. Individuals who meet the week 12 milestone but have detectable HCV RNA at treatment week 24 should also discontinue peginterferon/ribavirin.

5. To ensure that the benefits of treatment are sustained and outweigh the risks, persons should be judged to have a limited risk of reinfection.

6. Peginterferon, ribavirin, and HCV PI therapy is expected to be less efficacious in persons who did not clear HCV RNA with prior peginterferon and ribavirin treatment (so-called partial responders or nonresponders) and/or those with cirrhosis, unfavorable IL28B genotype, or African ancestry. Data regarding use of these agents in HCV treatment-experienced patients are lacking. However, triple therapy response is higher in re-treated patients than in patients treated with peginterferon and ribavirin alone, and guidelines for use similar to that in treatment-naive patients should be applied pending availability of additional data.

7. Since data are needed to answer many remaining questions, when available, clinical trials should be considered for HIV/HCV coinfected persons considering treatment.

PHARMACOKINETICS

Telaprevir is a P-glycoprotein and CYP3A4 substrate and inhibitor [8]. Blood concentrations are reduced by ritonavir-boosted fosamprenavir, darunavir, lopinavir, and, to a lesser extent, atazanavir (Table 1) [9]. Efavirenz also reduces blood concentrations of TVR, an effect that can, in part, be offset by using a higher TVR dose (1125 every 8 hours). TVR use significantly reduces the concentrations of darunavir and fosamprenavir. Boceprevir is primarily metabolized by aldo-keto reductases, and to a lesser extent, may undergo oxidative metabolism via CYP3A4/5 [10]. Boceprevir trough concentrations are decreased 44% with EFV coadministration, and BOC concentrations are also decreased by 19% with low-dose ritonavir at steady state (100 mg twice daily) [11]. Similar to TVR, BOC is an inhibitor of CYP3A4 that increases concentration of substrates such as midazolam, tacrolimus, and atorvastatin.

SUMMARY

Approvals of boceprevir and telaprevir for treatment of HCV infection are major advances for the care of persons with chronic genotype 1 HCV infection. Although the medications are not approved by the US Food and Drug Administration for treatment of HIV/HCV-coinfected persons, the benefits of including these medications will outweigh the risks for some individuals. In the future, HIV/HCV-coinfected persons should be included at earlier stages in drug development so that practice guidelines can be based more on data and less on expert opinion.

Source

nihhhsnews

FOR IMMEDIATE RELEASE
Wednesday, Jan. 4, 2012

MEDIA AVAILABILITY

Study Reveals Factors Associated with Prevention, Control of HIV Infection

WHAT:
New vaccine research in monkeys suggests that scientists are homing in on the critical ingredients of a protective HIV vaccine and identifies new HIV vaccine candidates to test in human clinical trials. The research, which appears online in Nature on Jan. 4, was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

In the study, scientists report that several Simian Immunodeficiency Virus (SIV) prime-boost vaccine regimens have demonstrated partial protection against acquisition of infection by a virulent, tough-to-neutralize SIV strain that is different from the strain used to make the vaccine—a scenario analogous to what people might encounter if an HIV vaccine were available. The experimental vaccine regimens reduced the monkeys’ likelihood of becoming infected per exposure to SIV by 80 to 83 percent compared to a placebo vaccine regimen. Further, in those monkeys that did become infected, the experimental vaccine regimens substantially reduced the amount of virus in the blood compared to controls. Now plans are underway for early-stage clinical trials of a human-adapted version of one of the study’s prime-boost vaccine combinations.

The best predictor of protection from SIV in the vaccinated monkeys was the presence of antibodies that latched onto the virus surface protein. This finding reinforces what scientists have learned so far about why the first modestly effective HIV vaccine worked in humans and indicates that the HIV surface protein Env is a critical vaccine ingredient. The new research also provides strong evidence that the immune system’s mechanism for preventing infection is significantly different from its mechanism for controlling viral replication.

The research was led by first author Dan Barouch, M.D., Ph.D., of Beth Israel Deaconess Medical Center at Harvard Medical School and the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard. The senior authors of the new paper are Nelson Michael, M.D., Ph.D., of the U.S. Military HIV Research Program (MHRP), and Jaap Goudsmit, M.D., Ph.D., of Crucell Holland BV. NIAID intramural investigators Vanessa Hirsch, S.D., D.V.M., and Ilnour Ourmanov, Ph.D., collaborated on the research. MHRP and the Ragon Institute co-funded the studies with NIAID.

ARTICLE:
D Barouch et al., Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature DOI: 10.1038/nature10766 (2012).

Source

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 74–78, February 2012

Review Article

Donald M. Jensen1,*, Stanislas Pol2

Article first published online: 29 DEC 2011

DOI: 10.1111/j.1478-3231.2011.02712.x

© 2012 John Wiley & Sons A/S

Abstract

An association between variations at the IL28B gene locus and HCV clearance (spontaneous recovery or sustained virological response under pegylated interferon (PEG-IFN) and ribavirin (RBV) has been extensively described. In genotype 1-infected patients, the new direct antiviral agents (DAA) including the two approved protease inhibitors boceprevir and telaprevir, in association with the PEG-IFN/RBV combination is the new standard of care making it necessary to redefine the interest of the IL28B genotype in the decision to treat and how to treat genotype 1-infected patients. In treatment-naïve patients, IL28B status can certainly identify those with a high probability of achieving SVR with response guided therapy and probably in whom the duration of treatment can be markedly reduced. In experienced patients, the impact of IL28B genotypes is limited and cancelled by early viral kinetics. However, the decision to initiate or withhold therapy remains a clinical one. In summary, although it was a major milestone in the treatment of patients with PEG-IFN/RBV,IL28B polymorphism testing entered the clinical arena almost 10 years too late.

Well established on treatment and baseline predictors of sustained virological response (SVR) to pegylated interferon and ribavirin (PEG-IFN/RBV) in patients with chronic hepatitis C virus (HCV) genotype 1 infection include rapid virological response (RVR; undetectable HCV RNA at week 4), low baseline viral load (<600 000 IU/ml), non-Black race, and absence of severe fibrosis or insulin resistance [1]. For some years, low serum levels of the 10 kDa interferon gamma-induced protein (IP-10) have also been associated with a better PEG-IFN/RBV response [2, 3].

Genetic variations have long been sought to explain the differences in host antiviral responses, and it is now well established that host genetics plays a role in the response to IFN-based therapy in HCV infection. Genome Wide Association Studies (GWAS) have described single nucleotide polymorphisms (SNPs) on chromosome 19 in the region of the IL28B gene that were highly predictive of spontaneous resolution of acute hepatitis C infection [4], response to PEG-IFN α/RBV therapy in the general population [5, 6, 7, 8, 9] as well as in human immunodeficiency virus (HIV) co-infected individuals [10] and liver transplant recipients in whom both donor and recipient IL28B haplotypes contribute to the probability of treatment response [11].

Although an association between outcomes of treatment response in HCV infection and variations in the IL28B gene locus were observed, a causal variant responsible for these effects remains unknown: the specific immunological mechanisms involved in HCV clearance associated with IL28B genotype remains elusive and a functional link between IL28B genotype and liver cytokine expression has not been established (12). It is however known that type III interferons, including IFN-λ3, are encoded by IL28B (13, 14). These type III interferons activate the Jak-STAT pathway which leads to induction of several IFN stimulated genes (ISGs) which are responsible for their antiviral activity (15). Thus, it is involved in the T-cell adaptive immune response [12]and IL28B has been associated with increased CD8+ cytotoxic T cell responses [16]. Interestingly, it has been demonstrated that in non-responders, some interferon-stimulated genes were upregulated before treatment [17, 18].

In addition, minor alleles of IL28B polymorphisms (i.e. rs8099917 G and rs12979860 T) have been associated with reduced IL28B expression in peripheral blood mononuclear cells [19]. Thus, IL28B genotypes may play a role in viral containment, and recent results suggest that IL28B polymorphisms associated with poor HCV clearance may actually be protective against hepatic necroinflammation and fibrosis progression, particularly in patients with HCV genotypes other than one [20]. The aim of this controversy is to re-define at the time of triple therapy the interest of the IL28B genotype in the decision to treat and how to treat genotype 1-infected patients.

IL28B and the pegylated interferon ribavirin combination

In clinical trials investigating responses to PEG-IFN/RBV (not including DAA), the association of IL28B genotype with SVR seemed to be similar to that of the viral genotype. In CC homozygous patients of Caucasian origin (around 30% of patients) without severe fibrosis, the probability of achieving SVR is estimated at 86%, vs. 36% and 43% for TT and CT respectively. An RVR was obtained in 30% of CC patients vs. 5% of CT or TT patients but in cases of RVR, the SVR rates were greater than 90% irrespective of the IL28B genotype. This suggests that RVR is a stronger predictor of SVR than IL28B CC genotype. However, there are no data yet assessing the efficacy of 24 weeks of therapy in CC patients with RVR. In the absence of RVR, SVR was achieved in 60% of CC patients. It is noteworthy that the odds ratios (OR) that describe the strength of association between IL28B genotype and virological response to PEG-IFN/RBV therapy vary according to the study taken into consideration. Tanaka et al. reported an OR for the association of the rs12980275 and rs8099917 polymorphisms with ‘null virological response’ of 17.7 and 27.1 with highly significant P values of 2.84 × 10−27 and 2.68 × 10−32 respectively. [9] Ge et al. determined a combined SVR OR of 3.1 for rs12979860[6] and Suppiah et al. found a combined SVR OR of 1.98 for rs809917. [8] It is challenging to ascertain the predictive value of a particular IL28B allele in the first two studies cited; however, Suppiah and colleagues were careful to note that ‘according to a model of dominant inheritance, the rs8099917 G allele predicts non-response with 57% sensitivity and 63% specificity’. They went on to report a negative predictive value (NPV; indicating correct prediction of treatment failure) of only 64%. Polymorphisms in the region of IL28B gene have been associated with PEG-IFN/RBV treatment response mainly in genotype 1 HCV infections. Recently, in genotype four patients with chronic hepatitis C, a better treatment response rate was associated with IL28B gene SNP rs12979860. The response rates were 81.8%, 46.5% and 29.4% for genotype CC, CT and TT respectively [21].

IL28B and direct acting antiviral agents (DAA)

The IL28B genotype status is the most important pretreatment predictor to PEG-IFNα/RBV therapy and it is increasingly evident that after the development of chronic infection, the response to triple therapy is also partially governed by polymorphisms at the IL28B locus [22]. IL28B status and outcome to therapy has been evaluated in several phase 3 clinical trials of telaprevir and boceprevir when used in conjunction with PEG-IFNα/RBV. SPRINT-2 and RESPOND-2 are randomized, double-blind, placebo-controlled studies of boceprevir, PEG-IFN-α/RBV. SPRINT-2 registered treatment-naïve genotype 1 hepatitis C patients [23] whereas the RESPOND-2 trial enrolled genotype 1 patients who had failed prior therapy with PEG-IFNα/RBV (relapsers and partial responders) [24]. Poordad et al. presented data pointing to IL28B status as the most important pretreatment predictor of response in patients receiving triple therapy [25]. In both trials, the IL28B CC genotype was significantly predictive of a favourable response to therapy as defined by SVR in all arms. In addition, IL28B CC genotype can also be used as a predictor of eligibility for shortened therapy as it was significantly associated with undetectable HCV RNA after 8 weeks of therapy in both SPRINT-2 (89% for CC vs. 52% for CT and TT combined, respectively) and RESPOND-2 (89% and 82% ,respectively for the CC genotype vs. 52% and 51% for the CT and TT genotypes). In the SPRINT-2 study, IL28B genotype was an independent predictive factor for SVR (OR = 4.5; P < 0.001). SVR rates in the combined boceprevir-based treatment arms were 81% in CC patients, 68% in CT patients and 57% in TT patients. Since responses with PEG-IFN/RBV therapy alone were also high in CC patients, the difference in SVR rate for boceprevir treated patients compared with PR48 was smaller in CC vs. CT or TT patients (3% vs. 40% or 30%, respectively). However, in the RESPOND-2 study, IL28B polymorphisms did not have a significant effect on SVR which rates were 78% in CC patients, 67% in CT patients and 66% in TT patients treated with boceprevir-based therapy. This was consistently higher than those obtained with PEG-IFN/RBV alone: 46%, 17% and 50% in CC, CT or TT patients respectively.

The ADVANCE study, a randomized, double-blind, placebo-controlled phase III trial examined the safety and efficacy of PEG-IFN-α, RBV, and telaprevir in treatment-naïve patients with genotype 1 hepatitis C virus [26]. A stepwise decrease in overall SVR rates occurred with increasing stage of fibrosis (81% in F0-F1, 75% in F2 and 62% in F3-F4) [27]. Only Caucasian patients were analysed for IL28B status (evaluated in 42% (454/1088) of the patient population) and demonstrated an increased SVR across all IL28B genotypes, but patients with the favourable CC genotype still had the best outcome as determined by SVR in all arms of the study taken into consideration. In addition, patients with the CC genotype were most likely to attain RVR and to have shortened durations of therapy [26]. In summary, although the results of the multivariate analysis have not yet been presented, the IL28B genotype had some impact on treatment outcome with 90% of CC, 71% of CT and 73% of TT patients achieving a SVR. Although the SVR rate was higher with triple therapy vs. PEG-IFN/RBV alone whatever the IL28B genotype, the difference between treatment arms was more striking in CT and TT patients than in CC patients (SVR difference in T12/PR arm vs. PR48: 47% for CT and TT genotypes combined vs. 26% for CC).

The REALIZE study has demonstrated that treatment with telaprevir in combination with PEG-IFN/RBV significantly increases SVR rates in prior relapsers and non-responders, including prior partial and null responders, compared with PEG-IFN/RBV-only control. The subanalysis of IL28B genotypes (SNP rs12979860) did not show differences in SVR rates across the genotypes and according to prior response [28]. Although there was a trend for increased eRVR (undetectable HCV RNA at week 4 and week 12 of therapy) and decreased relapse rates in prior partial or null responder patients with the CC vs. CT or TT genotypes, it is difficult to draw firm conclusions owing to the small number of patients in some groups. Thus, IL28B genotype may have limited value as a prognostic marker in patients with prior PEG-IFN/RBV treatment failure who are being evaluated for retreatment with a boceprevir- or telaprevir-based regimen.

Finally, as more potent DAA combinations are developed, some of which will not require an IFN backbone, it will be important to note how valuable these pretreatment predictors will be. There is also increasing evidence that more potent DAA regimens reduce the importance of IL28B genotype status as a determinant of the likelihood of response. In patients enrolled in PILLAR, a phase IIb study of TMC435, a second generation NS3-4A protease inhibitor in combination with PEG-IFNα/IFN for treatment-naïve genotype 1 patients, high rates of viral response were achieved in all patients regardless of IL28B genotype or pretreatment IP-10 levels.

IL28B and clinical decision-making

So how does IL28B genotype knowledge really affect clinical decisions? This is the fundamental question. Does it impact decision-making? Although it is comforting to know that IL28B status relates to antiviral response, will knowledge of IL28B status impact the doctor-patient decision to initiate treatment? Or to chose one treatment over another?

Pro

For treatment-naïve patients, IL28B status certainly can identify those who would have a high likelihood of SVR with response guided therapy. This is valuable not only for the patient (information on the chance of recovery and of reduction of treatment duration which affects safety and tolerability) but also for health authorities (cost of therapies). Other than for counselling, knowledge of IL28B genotype will be useful if this information is used to avoid treatment; an additional predictor for a decision that more rightfully should be based upon disease severity characteristics.

The other potential reason to consider IL28B testing in treatment-naïve subjects would be to avoid protease inhibitor therapy entirely: one might also argue that an individual with a CC genotype could be spared the expense and adverse events associated with boceprevir or telaprevir therapy, and would achieve similarly excellent results with PEG-IFN/RBV alone, in those patients with RVR since SVR is not different between dual and triple therapy.

In future, IL28B genotype could be used to propose a shorter duration of triple therapy: a retrospective analysis of the French patients of the Prove2 study reports a 100% SVR rate in the CC patients treated by the short arm of 12 weeks of triple therapy with telaprevir, PEG-IFN/RBV compared to 40% in the CT and 20% in TT patients (work in progress).

Con

Although the IL28B genotype has a clear impact on SVR in naïve (and to a lesser extent treatment-experienced) patients treated with PEG-IFN/RBV as well as triple therapy, the on-treatment virologic responses provide equally compelling prognostic data. Given the advantage of triple therapy over dual therapy across all IL28B genotypes, the question is mainly a clinical one: treatment or no treatment. In particular, will patients benefit from treatment now or should they wait until further therapeutic improvements? Decisions should be based upon disease severity, cost, tolerability, potential for medication adherence, and not necessarily upon who will have the greatest SVR, although this is an important factor. If considered in this light, knowledge of IL28B status has somewhat less relevance. Would we not offer treatment to an IL28B TT prior partial responder with cirrhosis? Of course we would.

It is true that knowledge of a CC IL28B genotype might be used to consider dual therapy with PEG-IFN/RBV and the advantages of concomitant protease inhibitor therapy might be offset by the concern that stopping at 24 weeks might be associated with relapse in those subjects with any negative predictors. But the real advantage would be if PEG-IFN/RBV could also be shortened to 24 weeks. The high SVR results reported by Ge and colleagues in the IDEAL trial [2] in Caucasians with the CC genotype only included those who completed a 48 weeks course of therapy and at least 12 weeks of follow-up. The results in real life may not be comparable because the confounding effects of age, cirrhosis, obesity and insulin resistance need to be considered and may further diminish response to PEG-IFN/RBV. The ability to shorten PEG-IFN/RBV therapy to 24 weeks is restricted to rare patients with an on treatment RVR (‘super responders’, largely Caucasians) with low baseline viral loads (< 600 000 IU/ml) and thus is not equivalent to the response guided therapy using telaprevir or boceprevir in which baseline negative predictors (viral load, insulin resistance…) have less impact.

In summary, although it was a major milestone in the treatment of patients with PEG-IFN/RBV, IL28B polymorphism testing entered the clinical arena almost 10 years too late. Predictive medicine is still difficult and IL28B genotypes will probably help in the decision to treat or not to treat with PEG-IFN/RBV in countries with limited resources and in rare patients with intermediate fibrosis where there may be either a hesitation between using triple therapy or waiting for future combinations. Although the interest of testing for IL28B polymorphism in the era of DAA will probably be to reduce triple therapy from 24 to 12 weeks or from 48 to 24 weeks, depending on other baseline predictors including fibrosis, this must still be clearly established. As HCV therapy and the field moves away from IFN-based regimens, and as more and more potent antiviral agents are approved, IL28B will probably become a footnote in the history of hepatitis. What a pity!

Conflicts of interest

Dr Jensen has received honoraria from the following entities: Advisory Boards for scientific input towards clinical trial design and interpretation: Abbott, Boehringer-Ingelheim, BMS,Genentech, Merck, Pharmasset, Roche Global, Tibotec/J&J, Vertex. Research Funding for clinical trials and/or investigator-initiated studies: Abbott, Boehringer-Ingelheim, Genentech/Roche, Pharmasset. Dr. Pol declares the following: consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Vertex, Janssen/Tibotec, Novartis, Gilead, Roche, Schering-Plough/Merck, Abbott, Sanofi and GlaxoSmithKline, and grants from Bristol-Myers Squibb, Gilead, Roche and Merck/Schering Plough.

References

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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 32–38, February 2012

Review Article

Christophe Hézode1,2,*

Article first published online: 29 DEC 2011

DOI: 10.1111/j.1478-3231.2011.02707.x

© 2012 John Wiley & Sons A/S

Abstract

Effective management of adverse events (AEs) is important to prevent treatment discontinuation and optimize hepatitis C virus infection eradication rates. The addition of direct-acting antiviral agents, telaprevir (TVR) or boceprevir to pegylated interferon (PEG-IFN) and ribavirin (RBV) represents a new era of therapy associated with an improvement in treatment response rates and an impairment of the safety profile compared to PEG-IFN/RBV. An increase in the frequency and severity of anaemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the TVR-based regimen. These AEs are generally manageable and do not lead to early discontinuation. The management of anaemia has not been clearly established, and the impact of RBV dose reductions and erythropoietin alpha use on treatment efficacy and safety must be clarified. The management of rashes, which were mild and moderate in more than 90% of the cases, is well planned, does not require TVR discontinuation and can be treated using emollients and topical corticosteroids. However, approximately 5% of rashes were severe, and a few cases were classified as severe cutaneous adverse reactions leading to treatment discontinuation.

Because of the consequences of treatment failure in patients with chronic hepatitis C virus (HCV) infection, optimizing treatment efficacy and safety is essential to prevent the development of morbidities and increase survival rates [1, 2, 3]. Managing adverse events (AEs) during antiviral treatment plays an important role in improving adherence and reducing premature treatment discontinuation. In addition, interactions among different drugs in the regimen may affect the efficacy and/or safety of therapy and must be managed appropriately in each patient. While AEs and drug–drug interactions are generally well established for standard peginterferon (PEG-IFN)/ribavirin (RBV) therapy [4, 5, 6], the addition of direct-acting antiviral agents (DAAs) to PEG-IFN/RBV as part of a triple therapy regimen will change the factors to be taken into account in patient management. The oral DAA, telaprevir (TVR) and boceprevir (BOC), in combination with PEG-IFN/RBV, have led to a significant improvement in sustained virologic response (SVR) in HCV genotype 1 patients, but have been associated with an increase in several AEs compared with PEG-IFN/RBV alone. In clinical practice, the effective management of safety and drug–drug interactions will be essential to optimize the benefits provided by these agents for patients infected with HCV genotype 1.

Managing safety and tolerance to triple combination therapy

In placebo-controlled phase II/III studies, the most common AEs that occurred more frequently with TVR than with placebo (>5% difference) included pruritus, rash, anaemia and gastrointestinal disorders (anorectal symptoms, nausea and diarrhoea), which were generally manageable and did not lead to premature discontinuation [7, 8, 9]. In both BOC phase III studies, the main AEs were an increase in the occurrence of fatigue, anaemia, nausea, diarrhoea, dysgeusia (taste alteration) and neutropenia [10, 11, 12].

Anaemia

Anaemia is a well-known RBV-related event which is exacerbated by the addition of TVR and BOC. The mechanism of anaemia with both DAA was not because of haemolysis but was thought to be the result of a bone-marrow suppressive effect. In clinical trials, triple therapy with TVR or BOC was associated with an increase in the incidence (approximately 20%) and severity of anaemia compared to PEG-IFN/RBV alone (Table 1). The frequency of anaemia, defined as haemoglobin levels below 10 g/dl, was about 50% for triple therapy with BOC and 40% with TVR. Haemoglobin values gradually improved after the end of TVR dosing at week 12 and were similar to those with PEG-IFN/RBV alone by week 20. The impact of anaemia on the SVR rate was different for the two drugs. Anaemia had no effect on efficacy outcomes in treatment-naïve patients [13] with TVR (Fig. 1). In contrast, for BOC, the SVR rate was more frequently achieved in patients with anaemia than in those without in treatment-naïve and -experienced patients [14] (Fig. 2). Premature discontinuation of antiviral treatment because of anaemia remained rare (Table 1). The management of anaemia in TVR and BOC clinical trials is summarized in Table 1. In BOC trials, 43% of patients received erythropoietin alpha (EPO) for the management of anaemia, de facto using a quadruple combination therapy [10, 11, 12]. This may be problematic in clinical practice, as BOC will have to be administered for 24 or 44 weeks. In phase II/III TVR trials, the use of EPO was generally prohibited, but EPO was used in 1% of patients only [9]. Blood transfusion was required in less than 5% of the patients for both drugs. A similar proportion of patients underwent RBV dose reductions to manage anaemia, approximately 22–26% (Table 1) [7, 8, 9, 10, 11, 12]. The retrospective analysis of phase III clinical trials with BOC and TVR showed that RBV dose reduction did not seem to have a negative impact on SVR (Figs 1 and 2) [13, 14]. In addition, the use of EPO did not seem to have a positive impact on SVR rate in BOC studies. These initial analyses must be discussed in relation to the results of large retrospective studies of patients treated with PEG-IFN/RBV. These studies have shown that a dose reduction of RBV only has a negative effect on the efficacy of outcomes when the cumulative dose is less than 60% of the initially planned dose. If the dose reduction of RBV occurs when HCV RNA is undetectable, the impact on SVR seems to be reduced [15]. When EPO is used, the full dose of RBV can often be maintained and the quality of life is improved [16]. In a post hoc analysis of a controlled study involving more than 3000 patients, it has been shown that patients who developed anaemia during a course of PEG-IFN/RBV had higher SVR rates than those who did not develop anaemia [17]. In this study, EPO increased the chance of eradicating HCV when it was administered in the first 8 weeks, probably when HCV RNA was still detectable. After the eighth week of treatment, EPO had no beneficial effect on the SVR rate. If these results are extrapolated to triple therapy, it may be necessary to maintain the full dose of RBV until HCV RNA becomes undetectable. Thus, EPO could be used according to the local regulations of each country. If anaemia occurs when HCV RNA is undetectable, the RBV dose could be reduced by stages of 200 mg daily. The value of administering EPO or reducing the dose of RBV in patients with haemoglobin levels below 10 g/dl is under investigation in a prospective clinical trial with BOC. The results of this important study will be available in 2012. The initial dose of protease inhibitors must be maintained in all cases. Finally, a few patients with cirrhosis were included in phase III clinical trials with BOC and TVR [7, 8, 10, 11]. The first safety report of the CUPIC cohort, related to the French early access programme and including a large number of treatment experienced patients with cirrhosis treated with triple therapy, showed a poor safety profile. BOC or TVR in combination with PEG-IFN/RBV was associated with high rates of serious AEs (40–57%) with a median treatment period of 84–89 days. EPO was used in 41–45% of patients, and blood transfusions were required in 4–17% of patients, suggesting that triple therapy must be administered cautiously with intensive safety monitoring, including anaemia, in patients with cirrhosis [18].

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Figure 1. Impact of anaemia and RBV reduction dose on SVR rate in treatment-naïve patients receiving triple therapy with TVR or PEG-IFN/RBV alone [13].

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Figure 2. Impact of anaemia and management of anaemia RBV on SVR rate in treatment-naïve and -experienced patients receiving triple therapy with BOC[14]

Table 1. (Click on Table to Enlarge) Incidence and management of anaemia with TVR and BOC in triple combination compared with PEG-IFN/RBV alone in controlled clinical trials [7, 8, 9, 10, 11, 12]

Table1

Dermatological adverse events

Dermatological reactions with PEG-IFN/RBV are well established and tend to be a uniform entity of dermatitis: generalized pruritus and skin xerosis, with eczematiform lesions accentuated by erythematous papules and microvesicles that are often excoriated, predominantly located on the extremities and on truncal skin sites exposed to friction [19]. These eruptions can be managed using the same approach as for chronic eczema (topical corticosteroids, gradually replaced by emollients), and there is usually no need to discontinue antiviral treatment [20]. The new treatment era with DAA is accompanied by additional patient management considerations for HCV-treating physicians. In particular, skin disorders are expected to be more frequent and more severe with triple combination regimens than with PEG-IFN/RBV alone.

In clinical trials, dermatological AEs have been reported at higher frequencies with TVR-based and sometimes with BOC-based therapy, compared with PEG-IFN/RBV alone [7, 8, 9, 10, 11, 12]. In placebo-controlled TVR phase II/III studies, in which 2012 patients received at least one dose of TVR and 764 patients received at least one dose of placebo, 55% of TVR-treated patients developed a rash compared with 33% of patients treated with PEG-IFN/RBV alone [9]. Although it was more extensive and severe, the typical rash in people who received a TVR-based regimen was virtually indistinguishable from the PEG-IFN/RBV rash visually and on histopathology. Rashes were primarily pruritic and eczematous, although some had an additional maculopapular component, which is not consistent with a typical hypersensivity. Histologically, the rash appeared to be a spongiform dermatitis, with predominantly lymphatic or eosinophilic perivascular infiltration. Most (>90%) rashes were mild or moderate (grade 1 and 2), involving less than 30% of the body surface area (BSA), and progression to more severe rash was infrequent (<10%) [9, 21]. Approximately 50% of rashes developed within the first 4 weeks of treatment, with the remaining 50% starting between 5 and 12 weeks and the median time to onset of rash (any grade) was 25 days (range 1–350) [21]. Therefore, skin eruptions can occur at any time during TVR treatment. Following the end of TVR treatment at week 12, all patients continued to receive PEG-IFN/RBV, and the incidence of rash was similar between TVR and placebo-treated patients.

Overall, the incidence of severe or grade 3 rash (primarily eczematous, pruritic and involving more than 50% of BSA) was 4.8 vs 0.4% with PEG-IFN/RBV alone [9]. Rash led to premature discontinuation of TVR alone in 5.8% of patients and of TVR combination therapy in 2.6% of patients compared with none of those receiving PEG-IFN/RBV. Following the end of TVR treatment or discontinuation, symptoms improved and usually resolved, although rashes may take several weeks to resolve.

A few cases of rash were classified as severe cutaneous adverse reactions (SCAR), which can be life-threatening if unrecognized or unmanaged, and require immediate discontinuation of antiviral treatment. In placebo-controlled phase II and III trials, 11 patients (0.4%) were recorded as having drug reactions with eosinophilia and systemic symptoms (DRESS) and three patients (<0.1%) had suspected Stevens–Johnson syndrome (SJS) [9, 21]. Among the 11 reported cases of DRESS, three were confirmed by a systematic retrospective assessment by expert dermatologists. One of these cases has been reported separately [22]. Among the three SJS cases, one occurred 11 weeks after TVR was discontinued and was not considered to be related to TVR. Of the two cases of suspected SJS that occurred during the TVR treatment phase, one was considered to be possible SJS by expert dermatologists and the other probable SJS. All of these severe reactions resolved when treatment was discontinued [9, 21]. Finally, the mechanism of TVR-related rash remains unknown and no predictors have been identified.

The second dermatological AE that was frequently reported with TVR was pruritus. This event was generally reported when rash was present, but could also be seen without it. Pruritus may be invalidating and cause rare treatment discontinuations.

Guidance for managing rashes

The goal of physicians should be to give patients the best chance of eradicating HCV, i.e. to continue antiviral therapy when possible in accordance with treatment and rash management protocols. However, to avoid exposing patients to the risk of severe drug-induced cutaneous reactions, physicians treating HCV should be able to easily distinguish between dermatitis and SCAR. The recommendations for grading and monitoring of dermatological reactions and for discontinuation of TVR, PEG-IFN and RBV because of such events are summarized in Table 2[9]. Figure 3 provides a guide to estimate BSA as an indicator of the severity of a dermatological reaction [23]. A number of clinical and biological criteria should help physicians to distinguish between TVR-related dermatitis and potential SCAR. If drug rash with eosinophilia and systemic symptoms (DRESS) alert criteria are present, including an onset between 5 and 10 weeks after the first dose of TVR that rapidly progresses to exanthema with a prolonged fever (>38.5°C) that is not related to the PEG-IFN injection and facial oedema, the following confirmation criteria should be assessed: enlarged lymph nodes (at least two sites), eosiniphilia (≥700/μl or ≥10%), atypical lymphocytes, internal organ involvement (liver and kidney) [21]. Patients presenting with rapidly progressing exanthema, skin pain, atypical or typical target lesions, mucosal involvement in at least two sites or with blisters or epidermal detachment should be suspected of having SJS and toxic epidermal necrolysis [21].

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Figure 3. Estimating body surface area [23].

Table 2. (Click on Table to Enlarge) Grading and recommendations for managing dermatological reactions with TVR-based triple combination therapy [9, 21]

Table2

In the case of grade 1 or 2 rash, patients can benefit from guidance on optimal skin care techniques that may limit symptoms and allow optimal antiviral therapy to be continued for as long as possible. Emollient cream, rather than lotions or ointments, may be effective in relieving eczematous reactions. Cream should be applied for at least 15 min, beginning with areas around the joints and progressing with broad strokes across the rest of the skin. This should be begun 15 min after showering or bathing and should be applied daily. Rashes can be primarily treated with topical corticosteroids. Permitted systemic antihistaminic drugs may also be used for the treatment of pruritus. Regular follow up is important, and the patient should be advised to limit exposure to sun/heat. Baking soda or oatmeal baths and loose-fitting clothes can be suggested. If grade 3 rash is present, TVR must be discontinued immediately and can be managed with topical corticosteroids without antiviral treatment (PEG-IFN/RBV) discontinuation. In case of SCAR, all antiviral treatment must be discontinued immediately, and the patient must be hospitalized in an appropriate department.

Anorectal disorders

In placebo-controlled TVR phase II/III trials, anorectal AEs occurred more frequently in TVR arms than in control arms: 26.2 vs 5.4% respectively [7, 8, 9]. Events usually developed within the first 2 weeks of treatment. Reported events included haemorrhoids, anal pruritus, anal discomfort or rectal burning. Most of these events were mild to moderate, very few led to treatment discontinuation, and they resolved after completion of TVR dosing. The mechanism is unknown and no evident association was found with either generalized pruritus or skin rash. An anal examination should be performed to exclude lesions that could explain the symptoms, especially haemorrhoids, fissure nor fistula. Generally, an anal examination shows non-specific erythema secondary to itching. Standard symptomatic care may be considered for managing anorectal disorders, including short-term use of non-specific topical ± including local anaesthetic in case of rectal burning. Topical corticosteroids and allowed systemic antihistaminic drugs may also be used for the treatment of pruritus.

Managing drug–drug interactions

Drug–drug interactions that lower antiviral or concomitant medication drug levels to below therapeutic ranges can result in a loss of efficacy, with suboptimal drug pressure potentially leading to drug resistance [24]. In contrast, drug–drug interactions that elevate drug levels and exposure can increase the risk of AEs [24]. Both of these effects may reduce the chances of treatment success, but with effective management they can be lessened.

The mechanisms of drug–drug interactions include absorption, gastrointestinal metabolism or transport, and hepatic metabolism or transport. For example, liver enzymes such as cytochrome P450 (CYP) 3A and transporters such as P-glycoprotein (P-gp) may affect plasma drug concentrations. Ultimately, whether an interaction takes place is dependent upon characteristics of both the drug and the patient.

Table 3 summarizes the key pharmacological characteristics of TVR and BOC that need to be accounted for when considering the risk of drug–drug interactions [9, 12].

Table 3. (Click on Table to Enlarge) Summary of key pharmacological characteristics of TVR and BOC[9, 12, 25, 26]

Table3

As a result of these characteristics, TVR and BOC are contraindicated with a number of drugs, in particular those that are highly dependent on CYP 3A (TVR) or CYP 3A4/5 (BOC) for clearance and for which elevated plasma concentrations are associated with serious of life-threatening events. Concomitant administration of TVR with active substances that strongly induce CYP 3A, and thus may lead to lower exposure and loss of efficacy of TVR, is also contraindicated (Table 4) [9, 12].

Table 4. (Click on Table to Enlarge) Contraindications to TVR and BOC[9, 12]

Table4

In summary, it is important to review all medications prior to initiation of triple combination therapy. Once this information has been collected, a key source of information and recommendations regarding co-administration with different compounds is the drug product label [9, 12]. As with HIV, online tools are now also becoming available to help healthcare professionals predict, avoid and manage drug interactions in HCV.

Conclusion

The addition of DAA (TVR or BOC) to PEG-IFN/RBV therapy will change the spectrum of elements to be taken into consideration for patient management compared to PEG-IFN/RBV alone [27]. The main AEs reported in clinical trials evaluating the efficacy and safety of TVR or BOC in combination with PEG-IFN/RBV were generally manageable and did not lead to premature discontinuation, although an increase in the frequency and severity of anaemia and skin disorders relative to PEG-IFN/RBV alone were noted. In clinical practice, monitoring and effective management of AEs and drug–drug interactions will be essential to optimize treatment with TVR and BOC and improve cure rates across different patient populations.

Conflicts of interest

Christophe Hézode is a speaker and adviser for BMS, Gilead, Merck, Roche and Janssen.

References

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