This blog is all about current FDA approved drugs to treat the hepatitis C virus (HCV) with a focus on treating HCV according to genotype, using information extracted from peer-reviewed journals, liver meetings/conferences, and interactive learning activities.
Risk Of Developing Liver Cancer After HCV Treatment
This journal is intended to be a resource for physicians and other health care practitioners who are actively involved in the care of patients with HIV or other viral infections
Cases From the Field
Barriers to Treatment Access for Chronic Hepatitis C Virus Infection: A Case Series
Alexander J. Millman, MD; Boatemaa Ntiri-Reid, JD, MPH; Risha Irvin, MD, MPH; Maggie H. Kaufmann, MA, MPH; Andrew Aronsohn, MD; Jeffrey S. Duchin, MD; John D. Scott, MD, MSc; Claudia Vellozzi, MD, MPH
Abstract
Restrictive policies on access to new, curative hepatitis C treatments represent a substantial barrier to treating patients infected with hepatitis C. This case series demonstrates challenges experienced by patients and practitioners in accessing these treatments and highlights several strategies for navigating the treatment preauthorization process. Full Article - Download PDF Download the entire issue, or select individual articles below.
This week’s topics include treating resistant hepatitis C infection, a new regimen for breast cancer, evolution of non-small cell lung cancer, and minocycline for MS.
A translational study published in the latest issue of the American Journal of Gastroenterology investigates resistance emergence using sequential direct-acting antiviral agents for Hepatitis C using ultra-deep sequencing.
Direct-acting antiviral agents against hepatitis C virus (HCV) have recently been developed and are ultimately hoped to replace interferon-based therapy.
However, direct-acting antiviral agents monotherapy results in rapid emergence of resistant strains and direct-acting antiviral agents must be used in combinations that present a high genetic barrier to resistance, although viral kinetics of multidrug-resistant strains remain poorly characterized.
Dr Kazuaki Chayama and colleagues from Japan studied the emergence and fitness of resistance using combinations of telaprevir and NS5A or NS5B inhibitors with genotype 1b clones.
HCV-infected chimeric mice were treated with direct-acting antiviral agents, and resistance was monitored using direct and ultra-deep sequencing.
Combination therapy with telaprevir and BMS-788329 (NS5A inhibitor) reduced serum HCV RNA to undetectable levels.
The team noted that presence of an NS3-V36A telaprevir resistance mutation resulted in poor response to telaprevir monotherapy but showed significant HCV reduction when telaprevir was combined with BMS-788329.
However, a BMS-788329-resistant strain emerged at low frequency.
The team noted that infection with a BMS-788329-resistant NS5A-L31V mutation rapidly resulted in gain of an additional NS5A-Y93A mutation that conferred telaprevir resistance during combination therapy.
The research team found that infection with dual NS5AL31V/NS5AY93H mutations resulted in poor response to combination therapy and development of telaprevir resistance.
Although HCV RNA became undetectable soon after the beginning of combination therapy with BMS-788329 and BMS-821095 (NS5B inhibitor), rebound with emergence of resistance against all 3 drugs occurred.
Triple resistance also occurred following infection with the NS3V36A/NS5AL31V/NS5AY93H triple mutation.
Dr Chayama's team concludes, "Resistant strains easily develop from cloned virus strains."
"Sequential use of direct-acting antiviral agents should be avoided to prevent emergence of multidrug-resistant strains."
Five CME activies on hepatitis C were released in June/July online at IAS–USA; four of these courses are in an easy to watch webcast format.
The IAS–USA programs – such as conferences, Web-based CME publications, and practice guidelines – are offered as part of a nationwide effort to inform health care practitioners about the evolving challenges of caring for patients with viral infections.
Hepatitis C patients taking part in these open CME programs will acquire new knowledge about either HCV drugs undergoing clinical trials or those currently in clinical practice.
CME Webcast
Beyond Telaprevir and Boceprevir: Resistance and New Agents for HCV Infection Presenter(s): David L Wyles MD
Airdate:July 27, 2012
Topics Discusses resistance and new agents for HCV Infection including interferon free regimens Instructions
1-Watch the Webcast
2-Scroll to the bottom of the page to confirm you have read and understand the instructions.
A Practical Approach to the Management of Adverse Effects and Complications in the Treatment of HCV Infection: A Case-Based Discussion
Presenter(s): Kenneth E Sherman MD, PhD
Airdate: June 07, 2012
Instructions
1-Watch the Webcast
2-Scroll to the bottom of the page to confirm you have read and understand the instructions.
HCV Drug Interactions: Trials, Tribulations, and Downright Confusion: A Case-Based Discussion
Presenter(s): Charles W Flexner MD
Airdate: June 07, 2012
Instructions 1-Watch the Webcast
2-Scroll to the bottom of the page to confirm you have read and understand the instructions.
Managing End-Stage Liver Disease in HCV Patients: The Minimum You Need to Know: A Case-Based Panel Discussion
Presenter(s): Marion G Peters MD
Airdate: June 07, 2012
Instructions 1-Watch the Webcast 2-Scroll to the bottom of the page to confirm you have read and understand the instructions.
CME
Management of Chronic Hepatitis C Virus Infection in Advanced Liver
Disease
Kenneth E. Sherman, MD, PhD, and Syed Hussain, MD
Release Date: July 27, 2012
Instructions
1-Click Here To Begin
2-Scroll to the bottom of the page to confirm you have read and understand the instructions.
3-Click Begin Activity
Graham R. Foster, FRCP, PhD, provides expert opinion on how to avoid the development of HCV resistance with new direct-acting antiviral regimens through a review of 4 patient cases.
The CME discusses appropriate stopping rules, missed doses, managing null responders and the risks and benefits of deferring current HCV therapy.
Click here to view the presentation
*Free registration required
Jean-Michel Pawlotsky, MD, PhD, emphasizes the importance of optimal drug exposure and adherence levels to avoid the development of resistant hepatitis C virus variants, along with strategies to optimize adherence rates.
Learning Objectives
Upon completion of this activity, participants should be able to:
Evaluate the importance of optimal drug exposure for treatment success rates in HCV-infected patients receiving triple therapy
Explain to colleagues and patients the importance of avoiding protease inhibitor monotherapy for HCV-infected patients
Apply strategies to maximize adherence rates in patients receiving triple therapy for HCV infection
Importance of Pharmacokinetics and Adherence to Avoid Emergence of Resistant HCV Variants
Source: Clinical Implications of HCV Resistance: Laying the Foundation for Optimal Treatment Today and in the Future
Introduction
Hepatitis C virus (HCV) resistance to a direct-acting antiviral (DAA) agent corresponds to the selection during treatment of viral variants that bear amino acid substitutions that alter the drug target; therefore, they are less susceptible to the inhibitory activity of the drug. These drug-resistant variants preexist as minor populations within the patient’s HCV quasispecies. Drug exposure profoundly inhibits replication of the dominant “wild-type” drug-sensitive viral population, and the resistant variants gradually occupy the vacant replication space. Moreover, viruses with low-level or partial resistance that can continue to replicate in the presence of drug, often favored by suboptimal drug exposure, may accumulate further mutations, leading to stepwise decreases in drug susceptibility, albeit often at a cost of reduced replicative capacity. If insufficient antiviral activity is provided because of suboptimal dosing or adherence, inadequate virologic suppression and the selection of resistance is inevitable. Therefore, to reduce the development of resistance, it is essential to achieve optimal drug concentrations through proper dosing and maximal adherence.
Resistance to antiviral drugs is classically prevented by combining several drugs with potent antiviral activity and no cross-resistance. Indeed, HCV resistance to DAAs is observed significantly less frequently when one of these drugs is administered in combination with peginterferon and ribavirin.[3,4] Therefore, the triple combination of peginterferon, ribavirin, and a PI—telaprevir or boceprevir—has become the new standard-of-care therapy for both treatment-naive and treatment-experienced patients with genotype 1 HCV infection.[5-8] For the reasons defined above, it is crucial that optimal exposure to all 3 drugs in the regimen be achieved for these patients...
Jean-Michel Pawlotsky⇑
National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est,
51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; INSERM U955, Créteil, France
Barriers exist to protect. The first images of World War II show the invaders breaking a barrier at the border of Poland, signifying the end of a peaceful world and the beginning of chaos… This is analogous to viral resistance to antiviral drugs. The invader is the drug-resistant virus; this virus preexists as poorly fit, minority viral populations. The “barrier to resistance” of a drug or a drug combination prevents their outgrowth in the presence of the drug(s), thus preventing virological breakthrough, disease progression, and eventually severe complications. If the barrier to resistance is high enough, resistant viral variants are not selected and do not grow; if it is not, they rapidly fill in the replication space and become the dominant (or exclusive) viral population associated with high-level replication.
The main components of the barrier to resistance in vivo are: (i) the “genetic barrier to resistance”, defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question. If a single substitution is sufficient to confer high-level resistance, then the drug is considered to have a low genetic barrier to resistance, while the need for three or more substitutions represents a high genetic barrier; (ii) the “in vivo fitness” of the resistant viral variant population, defined as its ability to survive and grow in the replicative environment; (iii) drug exposure, defined as the drug concentration achieved in vivo relative to the 50% and 90% inhibitory concentrations (IC) and efficient concentrations (EC) [1].
A number of direct acting antiviral (DAA) drugs are in development for the treatment of chronic hepatitis C virus (HCV) infection. Two NS3/4A protease inhibitors, telaprevir and boceprevir, have been recently approved in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of genotype 1 chronic hepatitis C [2], [3], [4], [5]. Other DAAs are at various stages of preclinical to late clinical development. They can be schematically classified into two groups, according to their barrier to resistance. Drugs with a low barrier to resistance include first-generation NS3/4A protease inhibitors (e.g. telaprevir and boceprevir and numerous other molecules in development), NS5A inhibitors, and non-nucleoside inhibitors (NNI) of HCV RNA-dependent RNA polymerase (RdRp) [6]. Their administration as monotherapies has been reported to be associated with early virological breakthroughs due to the selection and subsequent outgrowth of fit resistant viral populations carrying one or several substitutions that confer resistance to the drug [7], [8], [9]. Drugs with a high barrier to resistance include nucleoside/nucleotide analogue inhibitors of HCV RdRp, cyclophylin inhibitors (drugs that target a host cell protein involved in viral replication), and potential second-generation NS3/4A protease inhibitors. They can be administered alone for weeks without any virological breakthrough due to resistance in the majority of cases [10], [11].
Prevention of resistance, particularly when drugs with a low barrier to resistance are used, is based on the combination of several molecules that are potent and have no cross-resistance. No cross-resistance means that each member of the combination is fully active on viruses that are resistant to the others. This concept was the basis for combining NS3/4A protease inhibitors (or other DAAs with a low barrier to resistance) with pegylated IFN-α and ribavirin. Unfortunately, in patients who do not respond adequately to IFN-α and ribavirin, treatment fails and as a result DAA-resistant variant populations grow [1]. In order to cure infection without selecting for resistance, it is also possible to combine potent DAAs without cross-resistance, with the double goal of achieving better antiviral efficacy and substantially increasing the barrier to resistance. Attempts with combinations of drugs with low barriers to resistance, such as an NS3/4A protease inhibitor with an NS5A inhibitor, or an NS3/4A protease inhibitor with an NNI, have been disappointing [12], [13]. Although cure was achieved in a few patients receiving the former combination [14], the rates of failure due to selection of viral variants bearing substitutions at both drug target sites were frequent in these studies, suggesting that the barrier to resistance of a combination of two HCV drugs with low barriers to resistance is not dramatically greater than that of each drug alone.
There are four distinct groups of NNI inhibitors of HCV RdRp in development. Each targets a different allosteric site at the surface of the enzyme, and they have been reported to have different resistance profiles in vitro, without cross-resistance. Thus, although targeting the same viral enzyme, NNIs from different classes could theoretically be combined together. In this issue of the Journal of Hepatology, Delang et al. report their assessment of the antiviral potencies and resistance selection profiles of members of three of the four NNI groups [15]. These compounds were tested alone and in double or triple combination in replicon-harboring Huh7 cell lines, the usual model for this type of experiments. The authors confirmed the low barrier to resistance of each NNI alone and the lack of cross-resistance between them. They also showed that these drugs have additive antiviral effects in vitro.
When a stepwise, long-term procedure was used, the authors were able to select variants resistant to each pair-wise combination, which carried amino acid substitutions conferring high-level resistance to both tested NNIs on the same strain. Triple resistant replicons were also generated, starting from a replicon that was already resistant to two NNIs and was subsequently exposed to the third one. The triple-resistant replicons harbored substitutions conferring resistance to the three drugs tested. It was also cross-resistant with the fourth class of NNIs, not used in the experiments [15]. Whether such triple resistant variants naturally preexist in infected patients remains unknown. Short-term replication models, such as replicons in Huh7 cell lines, could underestimate the extent of HCV variability encountered in patients who have been infected for decades. Indeed, it has been recently suggested, based on mathematical modeling, that in HCV-infected patients, all possible single and double mutants are generated multiple times each day, all viable single and double mutants that confer drug resistance preexist and may compete with the wild-type virus during therapy, and triple mutants can be selected by sequential mutations when single or double mutants replicate [16]. It is therefore highly likely that HCV variants that are resistant to three drugs preexist at baseline in a substantial proportion of patients, or that they can be generated through replication of double-resistant viruses.
Resistance to DAAs is often feared as the main cause of treatment failure with new HCV therapies. This is not the case with the triple combination of a DAA with pegylated IFN-α and ribavirin, during which treatment failure results of an inadequate response to IFN-α that favors the outgrowth of resistant viral variants selected by the DAA [1], [2], [3], [4], [5]. In contrast, control of resistance will be key during the era of all-oral, IFN-free regimens. Indeed, antiviral potency and a high barrier to resistance are required to ensure that inhibition of HCV production is sustained for a sufficient amount of time in order for every infected cell to clear the remaining viruses. If any viral population is not controlled by the drug combination, it replicates, is produced, infects new cells and leads to treatment failure. Intuitively, the best way to prevent such failure is to include at least one drug with a high barrier to resistance, such as a nucleoside/nucleotide analogue or a cyclophylin inhibitor, in any combination of HCV DAAs. However, these drugs have not yet reached the market and the results of long-term combination studies including one or two nucleoside/nucleotide analogue(s) are awaited.
What will be the role of NNIs in this context? Recent results with the two most advanced in development NNIs, tegobuvir and filibuvir, have been disappointing: no difference was observed between the triple combination of different doses of the NNI with pegylated IFN-α and ribavirin vs. pegylated IFN-α and ribavirin alone [17], [18]. Nevertheless, this failure appears to be principally related to the lack of antiviral potency of these compounds rather than to their barrier to resistance, which is not fundamentally different from that of telaprevir or boceprevir. It is therefore possible that more potent NNIs could prove to be useful in combination with pegylated IFN-α and ribavirin.
What the study by Delang et al. teaches us is that combinations of NNIs are unlikely to be helpful, even if the molecules belong to different classes, have different target sites and no cross-resistance. In vitro results in the replicon system have proven to be accurate in predicting resistance in vivo; thus, single, double, and triple-resistant variants are likely to be selected early by NNI combinations in infected patients. How will we use NNIs in IFN-free regimens in the future? Ideally, in combinations including at least one drug with a high barrier to resistance (e.g. a nucleoside/nucleotide analogue, a cyclophylin inhibitor, or a second-generation NS3/4A protease inhibitor with an improved resistance profile compared to first-generation ones). Nevertheless, if these drugs are potent enough, they should, at least theoretically, be able to block virus production without resistance emergence for long enough for the virus to be cleared by host cells without the need for other drugs. If this is the case, drugs with a narrow genotype coverage and a low barrier to resistance, such as NNIs, may not be absolutely required in the HCV drug armamentarium. This question will be solved by ongoing and future clinical trials.
Overall, trial designers and clinicians should remember that, if resistance is not a major threat in patients treated with the triple combination of a DAA with pegylated IFN-α and ribavirin, since the final outcome depends mainly on the IFN response, its prevention will be key in the design of all-oral treatment strategies based on DAA combinations. Only combinations with a high enough barrier to resistance should be envisaged, as they are the only ones that can ensure sustained inhibition of viral production for the time needed for host cells to get rid of the virus. As in any war, the final victory depends on the allies you chose. Our mission is now to find the best alliance to keep the invaders out. This is the price to pay for a peaceful world, i.e. a world without hepatitis C.
Conflict of interest
The author has received research grants from Gilead and Roche. He has served as an advisor for Abbott, Anadys, Biotica, Boehringer-Ingelheim, Bristol-Myers Squibb, DebioPharm, Gilead, Glaxo-SmithKline, Idenix, Janssen-Cilag, Madaus-Rottapharm, Schering-Plough/Merck, Novartis, Pfizer, Pharmasset, Roche, Vertex and Virco.
References
Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology. 2011;53:1742–1751
Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al.Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–1217
Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al.Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416
Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al.Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–1206
Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al.Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–2428
Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology. 2007;132:1979–1998
Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M, et al.Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767–1777
Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, et al.Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96–100
Mori J, Hammond JL, Srinivasan S, Jagannatha S, van der Ryst E. Genotypic characterisation of filibuvir (PF-00868554) resistance in patients receiving four weeks co-administration of filibuvir with pegIFN/RBV (12-week analysis). J Hepatol. 2010;52:S15
Le Pogam S, Seshaadri A, Ewing A, Kang H, Kosaka A, Yan JM, et al.RG7128 alone or in combination with pegylated interferon-alpha2a and ribavirin prevents hepatitis C virus (HCV) replication and selection of resistant variants in HCV-infected patients. J Infect Dis. 2010;202:1510–1519
Coelmont L, Gallay P, Bobardt M, Kaptein S, Paeshuyse J, Vliegen I, et al.Particular in vitro anti-HCV activities and resistance profile of the cyclophylin inhibitor DEBIO-025. J Hepatol. 2009;50:S36
Zeuzem S, Buggisch P, Agarwal K, Manns MP, Marcellin P, Foster GR, et al.Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment-naïve, genotype 1 HCV subjects. Hepatology. 2010;52:400A
Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib RH, et al.Combination therapy with BMS-790052 and BMS-650032 alone or with PegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders. Hepatology. 2010;52:877A
Lok A, Gardiner D, Lawitz E, Martorell C, Everson G, Ghalib R, et al.Quadruple therapy with BMS-790052, BMS-650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders. J Hepatol. 2011;54:S536
Delang L, Vliegen I, Leyssen P, Neyts J. In vitro selection and characterization of HCV replicons resistant to multiple non-nucleoside polymerase inhibitors. J Hepatol. 2011;
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Jacobson I, Pockros PJ, Lalezari J, Lawitz E, Rodriguez-Torres M, DeJesus E, et al.Virologic response rates following 4 weeks of filibuvir in combination with pegylated interferon alfa-2a and ribavirin in chronically-infected HCV genotype 1 patients. J Hepatol. 2010;52:S465
Lawitz E, Jacobson I, Godofsky E, Foster GR, Flisiak R, Bennett M, et al.A phase 2B trial comparing 24 to 48 weeks treatment with tegobuvir (GS-9190)/PEG/RBV to 48 weeks treatment with PEG/RBV for chronic genotype 1 HCV infection. J Hepatol. 2011;54:S181
Research into range of mutations provides clues to improve treatment
A team of international researchers, led by Matthias Götte from McGill’s Department of Microbiology and Immunology, believes it has found a key factor in understanding why certain drug-resistant strains of the hepatitis C virus are seen so frequently, while others are rarely detected.
It has been estimated that 170 million people around the world are infected with the hepatitis C virus (HCV). Close to 300,000 of them live in Canada. Chronic infection with the virus is associated with severe liver disease, including cirrhosis and cancer. Unlike hepatitis A and B, there is currently no vaccine to prevent people from catching the disease. Although new medications show great promise in curing HCV infection, the virus is able to develop resistance to each class of antiviral drugs. And as a result, treatment may fail.
It was already known that humans are not infected by a single species of virus, but rather by billions of different, mutant viruses that sometimes differ from one another only by a single nucleotide, i.e. the basic building blocks of viral RNA. The researchers have now demonstrated that the viral polymerase, the enzyme responsible for copying sequences from RNA, is inaccurate in the way it replicates these sequences and as a result generates mutations when connecting one nucleotide after the other. “The surprising finding we had is that some mutations are much more easily made than others,” says Götte.
They next submitted HCV RNA samples taken from infected patients to sequence analyses and were able to distinguish between rare and common types of mutations. Together, the data suggest that the bar for the development of drug resistance is much higher if rare mutations are involved. This study has therefore important implications for the development of potent drug combinations that are less likely to result in the emergence of resistance.
The research was funded by: Cancer Research Society, Canadian Institutes of Health Research
Career awards and stipends were provided by: Fonds de Recherche en santé du Québec, Canadian Institutes of Health Research, and the National Canadian Research Training Program in Hepatitis C.
The paper describing the research was published by the Proceedings of the National Academy of Sciences (PNAS).
Adherence for targeted therapies is even more essential now than it ever has been. This case case studies of services offered at a specialty pharmacy illustrates the impact of hepatitis C patients.
As the delivery of pharmaceutical agents evolves, patients will appreciate an increase in autonomy regarding medication administration. Historically, many medications required administration in an infusion suite. However, more and more medications are being formulated or reformulated for oral administration at home. There are even opportunities to increase dosing intervals from daily to weekly.
Targeted therapies allow for improved medication side effect profiles, affording patients the opportunity to receive once-debilitating treatment regimens for a reduced duration. With this autonomy, however, comes a greater need for patients to maintain medication adherence. In the case of hepatitis C (HCV), adherence is more essential now than it has ever been.
In May 2011, 2 specialty agents within a new class of medications for hepatitis C (HCV) were approved and quickly adopted as the current standard of care when used in combination with pegylated interferon and ribavirin. This new regimen allows for a shortened course of therapy for patients with HCV genotype 1. Patients expecting 48 weeks of therapy now have an option to be treated for 24 or 28 weeks.
Despite the allure of the shorter treatment duration, these protease inhibitors are particularly prone to HCV viral resistance when not taken as directed. As little as a single missed dose of the 3-times-daily protease inhibitors can lead to viral resistance and ultimate regimen futility. This is in significant contrast to previous therapies for HCV that have proven reliance on adherence for positive outcomes, as reported in several studies which have shown an improvement in cure rates when patients take more than 80% of their doses for at least 80% of the prescribed duration.
Preventing Barriers While patients are realizing more autonomy with medication administration, providers must focus on preventing barriers to medication adherence. These barriers are present for most, if not all, self-administered medication regimens. The potential influence of acute and chronic side effects on therapeutic outcomes establishes a need for patient education before and during therapy with specialty medications.
These side effects can be debilitating, ranging from flu-like symptoms to kidney failure. Most specialty medications will carry black-box warnings related to their toxicities and they require frequent laboratory visits and trips to provider offices to monitor the unwanted physical and mental effects of some treatments. The effects on a patient’s quality of life are significant with specialty medications as well. Many patients may alter their work schedule due to fatigue and insomnia, become self-conscious due to hair loss, or seek assisting devices to cope with muscle weakness and bone pain.
In addition to medication side effect profiles, cost ranks as a significant barrier to adherence. The financial impact on a patient’s life as they initiate a specialty medication regimen can be quite significant. For this reason, many patients will delay treatment until they are financially able to maintain the prescribed duration of therapy. Medicare Part D and private insurances include most specialty pharmaceuticals in their formularies; however, prior authorizations tend to slow medication delivery and the resulting copayments may still prove to be a financial burden. Finally, although patients appreciate the option for autonomy when it comes to medication administration, this task can be both challenging and complex for those with physical and emotional barriers, as well as those with deficiencies in health literacy that may interfere with medication administration.
Hepatitis C Case Study At Prosperity Specialty Pharmacy, a Community Specialty Pharmacy Network (CSPN) member located in Fairfax, Virginia, services include medication therapy management, drug–drug interaction checks, a refill reminder program, injection trainings, and providing patients access to disease-specific financial assistance. These services have translated into cost-saving outcomes for patients, providers, and the pharmacy.
With the help of a clinical pharmacy specialist, a pharmacy resident, student pharmacists, and clinically trained pharmacy technicians, the services at Prosperity Specialty Pharmacy have increased adherence rates for many patients. In an observational study conducted by the pharmacy’s community practice resident, entitled “Impact of a Specialty Pharmacy Refill Reminder Program on Hepatitis C Patient Adherence and Incidence of Early Virologic Response,” the impact of the pharmacy’s refill reminder program on rates of HCV patient adherence was assessed.
The study also aimed to determine the impact of adherence on early virologic response (EVR), an HCV viral load measure predictive of treatment success assessed at the end of the first 12 weeks of therapy with pegylated interferon and ribavirin. The study reported an 81% adherence rate to pegylated interferon and ribavirin over the initial 12 weeks of therapy. This outcome was compared with data from a study by Vincent et al (2009), which concluded that EVR was most common among patients with adherence rates to HCV therapy greater than or equal to 85%. Despite a less than optimal overall adherence rate for patients enrolled in the Prosperity Specialty Pharmacy study, 40% of study participants achieved EVR, while 29% of study participants in the Vincent et al study achieved EVR with an adherence rate of less than 85%. 1 Additional studies at Prosperity Specialty Pharmacy are underway and aim to further examine adherence rates and incidence of EVR and sustained viral load among the HCV patient population in hopes of defining the influence that specialty pharmacy can have on therapeutic outcomes.
Case Study: Step by Step The refill reminder program at Prosperity Specialty Pharmacy is just one of the services provided to patients to ensure optimal treatment outcomes. The following case highlights many of the services available at Prosperity Specialty Pharmacy and other specialty pharmacies like it. Day 1: Receipt of Order Patient name: John Smith Date of birth: 10/19/1954 Diagnosis: Hepatitis C HCV genotype: 1a HCV viral load: 5,123,345 IU/mL Rx 1. pegylated interferon alpha-2a 180 mcg SQ QW 2. ribavirin 600 mg PO BID 3. telaprevir 750 mg PO every 7-9 hours with food
Upon order receipt, the pharmacy technician sends a fax to the prescribing physician’s office indicating that a prescription for Mr. Smith was received by the pharmacy. The pharmacy technician enters the prescription information into the pharmacy’s computer system, attempting to adjudicate a claim using the provided prescription insurance information. The claim is rejected by the patient’s insurance, with the request that a prior authorization be obtained. The pharmacy technician collects the necessary prior authorization forms from the third-party Web site and faxes them, along with a message to the prescribing physician requesting that the forms be completed and sent in to the third party for processing.
Day 2 The pharmacy technician resubmits the claim to see if it can be processed; the claim still can not be processed.
Day 3 The pharmacy technician resubmits the claim to see if it will be processed and the claim is paid. Mr. Smith is responsible for a $200 co-pay for a 1-month supply of medication. The pharmacy technician contacts the prescribing physician, letting her know that the claim was successfully processed and that a co-pay is due.
Next, the pharmacy technician calls Mr. Smith and explains the cost of the medication. Mr. Smith states that he will have a hard time paying $200 every month for his medication. The pharmacy technician informs him about assistance that may be available from the manufacturer and other charitable funding sources. The pharmacy technician is able to enroll Mr. Smith in an assistance program that will reduce his out-of-pocket expense to $50 a month. The pharmacy technician goes on to explain the pharmacy’s free medication delivery, refill reminder program, injection training services, and drug–drug interaction check service. Mr. Smith signs up for an injection training session and provides the pharmacy technician with a list of his medications so that the clinical pharmacist can review it.
The pharmacy technician fills the patient’s order and places it in a queue so that it can be verified by a pharmacist. The patient’s initial shipment includes his medications, a welcome packet with a description of the pharmacy’s services, and an HCV starter kit from the manufacturer of the pegylated interferon. The staff pharmacist verifies the prescription order, ensuring proper dose, duration, and directions. Mr. Smith’s medication order is then set aside in preparation for Mr. Smith’s injection training.
The pharmacy technician sends a fax to the prescribing physician’s office letting her know when Mr. Smith will receive his medication. The pharmacy technician also provides the clinical pharmacist with the list of medications that Mr. Smith is taking, so that a drug–drug interaction check can be performed. The following list of medications is collected from the patient: amlodipine, lisinopril, St. John’s wort, bupropion, aspirin, and ibuprofen.
The clinical pharmacist notices 2 drug–drug interactions, which she calls the patient to discuss: • Telaprevir amlodipine = increased concentrations of amlodipine • Telaprevir St. John’s wort = decreased concentrations of telaprevir
The clinical pharmacist explains the interactions to Mr. Smith and provides additional counseling for the new medications he will receive from the pharmacy. She reviews the importance of adherence, what side effects he may experience, what to do if he experiences side effects, what over-the-counter and herbal products to avoid, and what to do if he misses a dose of his medications. Finally, the clinical pharmacist informs Mr. Smith that he will receive a call in approximately 3 weeks so that his next medication shipment can be ordered. Noticing that Mr. Smith has signed up for an injection training session at the pharmacy, the clinical pharmacist proceeds to schedule the training and have Mr. Smith come into the pharmacy in 2 days. She explains that this will give her enough time to speak with the prescribing physician about the drug–drug interactions. After speaking with Mr. Smith, the clinical pharmacist drafts a fax to the prescribing physician to let her know about the drug–drug interactions present within Mr. Smith’s medication regimen.
Day 4 Upon receipt of the drug–drug interaction report, the prescribing physician calls the clinical pharmacist and thanks her for collecting the medication list from Mr. Smith. She admits that she was not aware that he was taking St. John’s wort or ibuprofen. She asks that the pharmacy reduce his dose of amlodipine to 5 mg. Mr. Smith arrives at the pharmacy to receive his injection training. During the training, the clinical pharmacist walks Mr. Smith step by step through the injection for pegylated interferon (PEgASyS). She also takes time to stress adherence and how important it is to report side effects. As the training session is about to end, the clinical pharmacist asks Mr. Smith if he has any additional questions. He replies “No, but thank you for taking so much time to help me.”
21 Days Later The pharmacy technician calls Mr. Smith to schedule his medication refill. During the call, the pharmacy technician asks Mr. Smith how everything is going. She makes sure to ask him if he has been seen by the prescribing physician since he started his medication and if he has been adherent with his laboratory visits. Mr. Smith mentions to the pharmacy technician that he has developed a rash since he started taking his medications. He also mentions some anorectal discomfort. Unable to address his concerns, the pharmacy technician proceeds in scheduling Mr. Smith’s refill and transfers the call to the clinical pharmacist, so that Mr. Smith’s concerns can be addressed. The clinical pharmacist assesses the patient for self care and recommends an over-the-counter steroid cream for the rash and a sitz bath for the anorectal discomfort. Finally, it is recommended that Mr. Smith discuss these side effects with his doctor at the next scheduled appointment.
7 Days Later It has been about a month since Mr. Smith started taking his medication. The clinical pharmacist calls him to check in with him and see how he is doing. She is particularly concerned about the side effects that he was experiencing since starting the medication. Mr. Smith states that he is doing well and that his side effects have subsided thanks to the advice he received from the clinical pharmacist about a week ago. He states that he has been in to see the prescribing physician since he started the medication and was told that he is responding well to therapy.
Opportunities for Pharmacy-Based Clinical Services
Opportunities to provide clinical services through a specialty pharmacy are numerous due to the “high-touch” nature of this niche. As prescription volumes begin to increase due to a growing specialty pipeline, and the concept of payment for pharmacy-based clinical services matures, demand will shift toward pharmacy services designed to address medication adherence. Determining where to integrate clinical services into the pharmacy work flow is the most challenging aspect of this endeavor. Specialty pharmacies might seek the talents of community pharmacists who have experience with clinical program development or those who have completed a community practice residency to address this demand. Training programs available through pharmacy associations may also assist in preparing pharmacists to provide specialty pharmacy–based clinical services. SPT Stephanie S. Holliday, PharmD, is the clinical pharmacy specialist for Prosperity Specialty Pharmacy, an independentlyowned specialty pharmacy focusing on the medication-related needs of patients with complicated disease states. Dr. Holliday creates and manages the pharmacy’s clinical initiatives, including a refill reminder program, injection trainings, immunization clinics, and MTM.
Rosemary Kerwin, PharmD, is the director of clinical programs for Community Specialty Pharmacy Network (CSPN). She is also an independent clinical consultant for the pharmaceutical industry and practicing clinical pharmacist at Elwyn Pharmacy and Specialty Care in Glen Mills, Pennsylvania, where she focuses on disease management projects.
About CSPN Community Specialty Pharmacy Network (CSPN) is a company founded by a group of independent pharmacy owners who have specific expertise in the specialty pharmacy segment. Their purpose of organizing collective capabilities provides a viable solution for specialty pharmaceuticals. CSPN is the largest community specialty network in the country. CSPN will provide a comprehensive framework of accredited members and web-based software to uniformly collect and report data. We partner with healthcare payors, pharmaceutical manufacturers, wholesalers, GPO’s, physicians, and patients, to deliver cost-effective biopharmaceuticals and programs that provide optimal patient outcomes.
CSPN Mission Statement Our mission is to deliver a comprehensive care model that will have a positive impact on our patient’s lives. Our services are built on local trusted relationships with our patients, physicians, and healthcare providers. CSPN offers a unique costsavings alternative for managed care organizations and payors. We are currently composed of 185 credentialed specialty pharmacy operations in forty-two states and the District of Columbia and Puerto Rico.
These presentations were given at Digestive Disease Week 2011 in Chicago
In the session on liver and pancreatic diseases, Dr. Ira M. Jacobson, AGAF, of Weill Cornell Medical College discussed direct-acting antivirals for hepatitis C treatment. He emphasized that combination therapy must contain a drug with a high barrier to resistance, and he noted that the hope for sustained virologic response should be greater than 70%.
There are also genetic barriers to resistance, such as those seen in genotype 1 patients.Dr. Jacobson emphasized that gastroenterologists treating hepatitis C patients must understand the pros and cons of protease inhibitor therapy, and also said interferon and ribavirin will remain important treatments in the future.
Dr. Anna Mae Diehlof Duke University lectured on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis(NASH), as related to the obesity epidemic.
Dr. Diehl reported that NAFLD is 20 times more prevalent than chronic hepatitis C in the United States. Diagnostic advances involving serum-,biopsy- and DNA- based testing have been made. These diagnostic advances can help with prediction of the stage of fibrosis.
She also stressed that several effective therapeutic approaches have been identified,including vitamin E therapy, pioglitazone,and lifestyle modifications,and there is hope for individualized therapy involving evaluation of the host’s microbiome and liver repair responses.
Factors that influence the outcomes of NASH are being investigated.Dr. K. Rajender Reddy from the University of Pennsylvania discussed hepatic masses and how they can be treated most effectively.
Dr. Reddy outlined the differences between benign and malignant masses, and emphasized that biopsies usually are not needed. Hepatic adenomas have a less than 5% risk for malignant transformation. Factors that are associated with increased risk include size greater than 5 cm, having beta catenin biomarkers, and being symptomatic.Dr. Reddy also emphasized the use of serial imaging with dynamic CT or MRI for most lesions. Indeterminate lesions and those with symptoms require further investigation. Indeterminate masses should be biopsied, and laparoscopic unroofing is recommended for hepatic cysts.
Dr. Dhiraj Yadav from the University of Pittsburgh lectured on chronic pancreatitis and new risk factors for this disease.
Dr. Yadav reported data from an NIH funded study showing that smoking appears to be a dose-dependant risk factor for chronic pancreatitis; continued alcohol consumption and smoking are linked to progression from acute pancreatitis to chronic pancreatitis. Aggressive counseling can decrease the risk of acute pancreatitis recurrence and progression to chronic pancreatitis. He also emphasized that growing knowledge of genes andgene-environment interactions will soon provide a basis for new diagnostic and treatment approaches.
Dr. Suresh Chari from the Mayo Clinic lectured on autoimmune pancreatic disease and its overlap syndromes. Dr. Chari described two distinct forms of autoimmune pancreatitis (AIP) characterized by clinical, histological, and therapeutic features.Type 1 AIP is a multi-system disease that involves the pancreas. Type 2 AIP isa pancreas-specific disorder. He also explained the HISORt criteria (the mnemonic stands for histology, imaging, serology,other organ involvement, and response to therapy) and the IGG-associated systemic diseases afflicting some patients with autoimmune pancreatic disease.
He emphasized that long-term immunosuppressant therapy may be needed in some patients to maintain disease remission, and noted that rituximab has been used with some success based on anecdotal reports.Overall, the liver and pancreatic disease section was enlightening and very educational,providing clinicians with practical information to use in the diagnosis,treatment, and management of their patients with these diseases.
■DARWIN L. CONWELL, M.D., M.S., is Associate Director, Center for Pancreatic Disease, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, and Associate Professor of Medicine, Harvard Medical School,Boston
From CCO new data presented at the 2011AASLD
meeting " HCV Resistance "- Covers Boceprevir,Telaprevir
(TMC435) and BI 201335,MK-5172,
GS-7977 (formerly PSI-7977) Plus Ribavirin and Daclatasvir Plus Asunaprevir)
Hepatitis C virus resistance to protease inhibitors
Hepatitis C has always been extremely difficult to treat effectively because the virus evolves so quickly and develops resistance to drugs that are used to treat it. The new protease inhibitors can elicit resistance even in patients who follow dosing regimens. Today on the blog is data covering HCV resistance to protease inhibitors, which include abstracts, links to expert analysis from CCO, and a patient video on hepatitis C Drugs and Resistance. Also a summary of the AASLD guidelines for treating HCV published today in the October issue of Hepatology.
Those guidelines are available on this blog , or in this months issue of Hepatology and in a PDF format.
An easy to understand article was published in July by HCV Advocate. In the article "Resisting Resistance" written by Ms. Lucinda K. Porter, RN , viral resistance and the importance of taking the new protease inhibitors as directed is discussed.
The importance of stopping therapy in patients who do not experience SVR or a breakthrough has been stressed in the new guidelines. Patients with inadequate viral response are unlikely to achieve SVR, and may develop resistance.
Here is a summary of the recommendations
From the 2011 practice guideline by the American Association for the Study of Liver Diseases
View Full Guidelines HereRecommendations:
1. The optimal therapy for genotype 1, chronic HCV infection is the use of boceprevir or telaprevir in combination with peginterferon alfa and ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
2. Boceprevir and telaprevir should not be used without peginterferon alfa and weight-based ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective Level A Data derived from multiple randomized clinical trials or meta-analyses
For Treatment-Naïve Patients:
3. The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 24-44 weeks preceded by 4 weeks of lead-in treatment with peginterferon alfa and ribavirin alone (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
4. Patients without cirrhosis treated with boceprevir, peginterferon, and ribavirin, preceded by 4 weeks of lead-in peginterferon and ribavirin, whose HCV RNA level at weeks 8 and 24 is undetectable, may be considered for a shortened duration of treatment of 28 weeks in total (4 weeks lead-in with peginterferon and ribavirin followed by 24 weeks of triple therapy) (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studies
5. Treatment with all three drugs (boceprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is more then 100 IU/mL at treatment week 12 or detectable at treatment week 24 (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studies6. The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 12 weeks followed by an additional 12-36 weeks of peginterferon alfa and ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
7. Patients without cirrhosis treated with telaprevir, peginterferon, and ribavirin, whose HCV RNA level at weeks 4 and 12 is undetectable should be considered for a shortened duration of therapy of 24 weeks (Class 2a, Level A).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level A Data derived from multiple randomized clinical trials or meta-analyses
8. Patients with cirrhosis treated with either boceprevir or telaprevir in combination with peginterferon and ribavirin should receive therapy for a duration of 48 weeks (Class 2b, Level B).
Class 2b Usefulness/efficacy is less well established by evidence/opinion
Level B Data derived from a single randomized trial, or nonrandomized studies
9. Treatment with all three drugs (telaprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is more then 1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24 (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studiesFor treatment-experienced patients:
10. Re-treatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, can be recommended for patients who had virological relapse or were partial responders after a prior course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
11. Re-treatment with telaprevir, together with peginterferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of standard interferon alfa or peginterferon alfa and/or weight-based ribavirin (Class 2b, Level B.)
Class 2b Usefulness/efficacy is less well established by evidence/opinion
Level B Data derived from a single randomized trial, or nonrandomized studies
12. Response-guided therapy of treatment-experienced patients using either a boceprevir- or telaprevir-based regimen can be considered for relapsers (Class 2a, Level B for boceprevir; Class 2b, Level C for telaprevir), may be considered for partial responders (Class 2b, Level B for boceprevir; Class 3, Level C for telaprevir), but cannot be recommended for null responders (Class 3, Level C).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy Class 2b Usefulness/efficacy is less well established by evidence/opinion Class 3 Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful Level B Data derived from a single randomized trial, or nonrandomized studies Level C Only consensus opinion of experts, case studies, or standard-of-care
13. Patients re-treated with boceprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA more then 100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level B Data derived from a single randomized trial, or nonrandomized studies
14. Patients re-treated with telaprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 1,000 IU at weeks 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level B Data derived from a single randomized trial, or nonrandomized studiesViral Resistance and Monitoring
15. Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose (Class 2a, Level A).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level A Data derived from multiple randomized clinical trials or meta-analyses
16. Patients on protease inhibitor-based therapy should undergo close monitoring of HCV RNA levels and the protease inhibitors should be discontinued if virological breakthrough more then a 1 log increase in serum HCV RNA above nadir) is observed (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
17. Patients who fail to have a virological response, who experience virological breakthrough, or who relapse on one protease inhibitor should not be re-treated with the other protease inhibitor (Class 2a, Level C).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level C Only consensus opinion of experts, case studies, or standard-of-care
Role of IL28B Testing in Decision to Treat and Selection of Therapeutic Regimen
18. IL28B genotype is a robust pretreatment predictor of SVR to peginterferon alfa and ribavirin as well as to protease inhibitor triple therapy in patients with genotype 1 chronic hepatitis C virus infection. Testing may be considered when the patient or provider wish additional information on the probability of treatment response or on the probable treatment duration needed (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studies
From CCO Published Sept 2011
On-Treatment Management: Futility Rules and Prevention of Resistance Viral resistance with boceprevir and telaprevir occurs because of the selection of preexisting variants during the course of therapy, as a result of failure to eradicate infection on triple combination treatment.[54] In pooled analyses of subjects who had on-treatment failure or relapse during clinical trials with boceprevir or telaprevir, HCV variants emerged, which have been shown to carry several NS3 amino acid substitutions that reduce viral susceptibility to boceprevir and telaprevir (Table 10).[51,53] Extensive cross-resistance exists between the 2 drugs, one of several reasons why they should never be used together. Patterns of treatment-emergent amino acid substitutions were genotype 1 subtype specific.
Resistance was found to be more frequent among previous null responders and among those with subtype 1a HCV. The emergence of different substitutions among the subtypes can be explained by a different genetic barrier to resistance between subtype 1a and subtype 1b. For example, coding for R155K requires a single-nucleotide change in subtype 1a (AGG → AAG) but 2 nucleotide changes in subtype 1b (CGG → AAG). Thus, R155K is more likely to preexist in subtype 1a than in subtype 1b. The higher failure rates of boceprevir- or telaprevir-based therapy that are observed in treatment-experienced patients are owing to a poorer response to pegIFN/RBV than in treatment-naive patients, resulting in the subsequent outgrowth of resistant variants selected by boceprevir or telaprevir.
Table 10. Most Frequent Treatment-Emergent Substitutions During Boceprevir- or Telaprevir-Based Therapy
The clinical implications of treatment failure to boceprevir- or telaprevir-based therapy are unknown. In theory, the persistence of resistant variants could lead to patients being ineligible for, or unresponsive to, future regimens that incorporate PIs into novel regimens. Several lines of evidence and reasoning provide reassurance on this issue. First, HCV is not known to be capable of archiving its genome as do HIV or hepatitis B virus. Data suggest that after treatment withdrawal, treatment-emergent substitutions decline in relative abundance over time and that wild-type virus regains its predominance in the majority of cases.[55-57]
However, this may take 2-3 years, and subtype 1a tends to return to wild type more slowly. Moreover, the diversity of antiviral agents under development may overcome whatever adverse impact viral variants that are resistant to boceprevir or telaprevir might confer. Ultimately, trials in patients who have failed boceprevir or telaprevir therapy will be critical in addressing this question.
The panel underscored the importance of assessing the indications for treatment (particularly in null responders—weighing risk of treatment failure and resistance with need for therapy), adherence to stopping rules to minimize the risk of emergence of resistant variants, and any potential impact on future treatment options. For both drugs, the stopping rules put forth in the prescribing information have been harmonized for treatment-naive and treatment-experienced patients. Of note, the HCV RNA cutoffs used for boceprevir and telaprevir stopping rules differ.
For all patients treated with boceprevir, the following futility rules should be employed:
If HCV RNA is ≥ 100 IU/mL at Week 12, all 3 medications should be discontinued.
If the patient has confirmed, detectable HCV RNA at Week 24, all 3 medications should be discontinued.
For all patients treated with telaprevir, the following futility rules should be employed:
If HCV RNA is more then 1000 IU/mL at treatment Week 4 or 12, all 3 medications should be discontinued.
If HCV RNA is detectable at Week 24, pegIFN/RBV should be discontinued.
Experts note that providers should be confident with strictly applying these stopping rules when making decisions about the continuation or discontinuation of boceprevir or telaprevir. If, for instance, a patient has an HCV RNA level slightly above the level recommended in the stopping rules, the experts suggest that clinicians adhere to the stopping rule and discontinue boceprevir or telaprevir, rather than continuing the patient on triple therapy to see if they will respond at a later time point. Some experts believe that pending further experience, continued pegIFN/RBV (in the absence of boceprevir or telaprevir) could be considered for treatment-naive patients with HCV RNA declines that are highly robust but fail to qualify for continuation by the new stopping rules together with frequent HCV RNA monitoring to ensure the HCV RNA continues to decline. In these cases, at a minimum, the usual stopping rules for pegIFN/RBV should be followed. In addition, some have suggested that, albeit not recommended in the label, Week 2 HCV RNA be measured to provide context to the Week 4 HCV RNA level (for example, to assess whether HCV RNA more then 1000 IU/mL at Week 4 of telaprevir represents a viral breakthrough). Publication of data demonstrating the negative predictive value of the new futility rules, along with additional experience with boceprevir and telaprevir, may shed further light on whether there is any role for continuing therapy if the thresholds of HCV RNA incorporated into the new futility rules are exceeded.
Both boceprevir and telaprevir must not be administered as monotherapy and must be administered together with both pegIFN and RBV. If pegIFN or RBV is discontinued for any reason, boceprevir or telaprevir must also be discontinued. Boceprevir and telaprevir must not be dose reduced. Boceprevir and telaprevir must not be stopped and then restarted. The importance of adherence should be emphasized to patients to ensure the greatest potential for treatment success and to minimize potential for treatment failure and subsequent resistance development.
Currently, there is no evidence to support switching from one PI to the other if treatment is not successful. The safety and efficacy of switching to the other PI because of a drug-specific adverse event also has not been established. Likewise, a patient for whom one PI was not successful should not be retreated with a regimen containing the other PI.
Panel Recommendations
Stopping rules for boceprevir- or telaprevir-based regimens should be strictly adhered to.
Fear of resistance should not be a reason to withhold telaprevir or boceprevir from a patient who is expected to benefit from therapy because resistance can be minimized as long as stopping rules are adhered to and it does not necessarily disqualify patients from future therapeutic options.
Please See The Featured Content Practical Guide for PI-Based HCV Therapy
Review guidance from experts on the optimal use of boceprevir and telaprevir for the treatment of HCV.
CCO does require free registration, however treatment updates including interactive virtual presentations by HCV experts is the best gateway to understanding the new drugs and the importance of adherence to Hepatitis C therapy. More @ CCO
Abstract
Background
Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance.
Objectives
Potential persistence of resistance mutations during long-term follow-up should be analyzed.
Study design
Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment.
Results
After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients.
For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4–9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1–10%) while in one patient additionally a combined variant (T54S + R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up.
Conclusions
In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.
Expert AnalysisFrom Podium to Practice: Clinical Impact of New Data From EASL 2011
Source: CCO Independent Conference Coverage of the 2011 Annual Meeting of the European Association for the Study of the Liver*
By: Graham R. Foster, FRCP, PhD, Paul Y. Kwo, MD, Stefan Zeuzem, MD
Analyses of Treatment-Emergent Telaprevir- or Boceprevir-Resistant HCV Variants
The key take-home message for the treating physician is: if the patient is not responding well, stop. treatment early and do not persist with ineffective therapy. Minimizing exposure to futile therapy may turn out to be very important to protect future treatment options.
***Free registration is required
Published online 31 March 2011 Nature doi:10.1038/news.2011.199
New drugs for hepatitis C on the horizon
Early studies showed that although a protease inhibitor given on its own was very effective initially, it often led to resistant strains of the virus in a matter of days, Gordon says. Even with interferon and ribavirin, resistance "remains a concern," he says. To keep it to a minimum, "clinicians must follow such patients very closely during therapy because if the viral level starts to rise after initially declining, then the protease inhibitor must be stopped to prevent the development of even more resistant strains."
Aug 8 2011
Hepatitis C-New Protease Inhibitor (NS3/4A) Drug Resistance Test
LabCorp and Monogram Biosciences are pleased to announce the launch of HCV GenoSure NS3/4A, a protease inhibitor drug resistance assay for the clinical management of patients with hepatitis c.
Aug 19 2011
In Case You Missed It Patient video;New hepatitis C Drugs and Resistance
Some new copies of HCV carry mutations, meaning they are slightly different from the original virus. Some mutated virus can keep multiplying even when you are taking anti-HCV medications. When this happens, the drug will stop working. This is called “developing resistance” to the drug. Resistance can develop quickly. It is very important to take antiviral medications according to instructions, on schedule, and not to skip or reduce doses. If your HCV viral load is too high after 4 weeks of treatment, your doctor might decide that you should stop taking telaprevir to avoid having your HCV develop resistance
A patient video about the new medications to treat hepatitis C
Some new copies of HCV carry mutations, meaning they are slightly different from the original virus. Some mutated virus can keep multiplying even when you are taking anti-HCV medications. When this happens, the drug will stop working. This is called “developing resistance” to the drug. Resistance can develop quickly. It is very important to take antiviral medications according to instructions, on schedule, and not to skip or reduce doses.
If your HCV viral load is too high after 4 weeks of treatment, your doctor might decide that you should stop taking telaprevir to avoid having your HCV develop resistance
LabCorp and Monogram Biosciences are pleased to announce the launch of HCV GenoSure NS3/4A, a protease inhibitor drug resistance assay for the clinical management of patients with hepatitis c.
HCV GenoSure NS3/4A provides a comprehensive sequence-based analysis of a patients hepatitis C virus to assess drug resistance (or susceptibility) to the NS3/4A protease inhibitors, boceprevir, and telaprevir. It also includes a detailed understanding of the viral population for the entire region of non-structural proteins NS3 and NS4A for hepatitis C virus genotype 1a or 1b.
