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
Health-related quality of Life in patients with chronic hepatitis C receiving Sofosbuvir-based treatment, with and without Interferon: a prospective observational study in Egypt
Naglaa F. A. Youssef, Mohamed El Kassas, Amany Farag and Ashley Shepherd
Email author
1)Assess the PROs (i.e. health-related quality of life, mental health and perceived social support) of HCV patients receiving direct acting antivirals (DAAs) therapy prior, during and at the end of therapy.
2)Evaluate PROs of Interferon-free (dual) users versus Interferon-containing (triple) users prior, during and at the end of treatment.
3)Identify the predictors of HRQoL of DAAs therapy users prior, during and at the end of therapy.
Abstract Background The Egyptian government introduced the first directly acting antivirals (DAAs) into Egypt through the government funded National Treatment Program. As yet, there has been no investigation into the effects of these new DAAs therapies on patient reported outcomes (PROs). This study aimed to (1) assess the PROs (health-related quality of life (HRQoL), mental health and perceived social support) of HCV patients receiving DAAs therapy prior, during and at the end of therapy; (2) evaluate PROs of Interferon-free (dual) users versus Interferon-containing (triple) users cross the three different time periods; and (3) identify the predictors of HRQoL of DAAs therapy users cross the three different time periods.
Methods A prospective observational design was used. Patients with chronic HCV undergoing treatment following the Egyptian National Guidelines at one of the national treatment centers were approached. Data collection occurred in the period from February to October 2015. Data was collected at three time points: (1) baseline (time 0: T0), before initiating therapy); (2) 5/6 weeks after initiation of therapy (time 1 of therapy: T1) and at the end of the therapy (Time 2: T2). Four PROs questionnaires were utilized for data collection: (1) Multidimensional Scale of Perceived Social Support (MSPSS), (2) The Depression Anxiety Stress Scales (DASS-21), (3) the Liver Disease Symptom Index-2.0 (LDSI-2.0) for testing disease specific HRQoL and (4) the Center for Adherence Support Evaluation (CASE) Index, alongside the background data sheet.
Results Sixty-two patients participated. There was a change in HRQoL, symptom experience and mental health across the three different time periods. HRQoL was impaired more after starting the course of therapy (T1) than at baseline (T0) and end of therapy (T2), z ≥ -2.04, p ≤ .04. Also, symptom experience deteriorated more during the treatment period than at the baseline, Z ≥ -1.97, p ≤ .04. Anxiety and stress were significantly higher during the treatment period than at the end of treatment. Perceived social support was significantly higher during the treatment period than at baseline and end of therapy, Z ≥ -2.27, p ≤ .023. During the course of therapy, triple users were more likely to report poorer HRQoL and anxiety than dual users (p ≤ .04). By the end of therapy, the two arms of therapy had no significant differences in any of the PROs.
At baseline, the predictor model significantly (p = .000) explained 37.5% of the variation in the HRQoL prior to therapy. Depression was the main variable that contributed to (41.3%) predicting change in HRQoL prior to therapy. During therapy, the model significantly (p = .000) explained 76% of the variation in the HRQoL-T1. Stress-T1, body mass index (BMI)-T1 and HRQoL-T0 significantly and respectively predicted 44.4, 46.5 and 31.1% of the variation in HRQoL-T1. At the end of therapy, the model significantly (p = .000) predicted 80.5% of the variation in the HRQoL-T2. HRQoL-T1 and anxiety-T2 significantly predicted 72.3 and 61.6% of the variation in HRQoL-T2.
Conclusions Baseline HRQoL, depression and BMI should be systematically assessed before starting the antiviral therapy for early detection and the improvement of the impairment before the initiation of therapy. Anxiety should be frequently assessed and followed up through the course of antiviral therapy. The triple group required more nursing and practitioner attention due to increased anxiety levels and impaired HRQoL during the treatment therapy.
Abstract Background and Objectives
Multiple treatment options with direct-acting antivirals are now available for hepatitis C virus (HCV). Study aims were to understand (1) the informational topics patients want to have to make informed treatment decisions; (2) the importance patients place on each topic; and (3) the topics patients prioritize as most important. Methods
We used a mixed-methods study of two samples recruited from an academic liver center. Participants were not currently on treatment. Sample I (n = 45) free listed all informational topics deemed important to decision making. Raw responses were coded into several broad and subcategories. Sample II (n = 38) rated the importance of the subcategories from Sample I and ranked their highest priorities on two surveys, one containing topics for which sufficient research existed to inform patients (‘static’), and the other containing topics that would require additional research. Results
The topics listed by Sample I fell into six broad categories with 17 total subcategories. The most oft-cited informational topics were harms of treatment (100%), treatment benefits (62%), and treatment regimen details (84%). Sample II rated 16 of 17 subcategories as “pretty important’ or “extremely important”. Sample II prioritized (1) viral cure, (2) long-term survival, and (3) side effects on the survey of topics requiring additional research, and (1) liver disease, (2) lifestyle changes, and (3) medication details on the second survey of the most important static topics patients needed. Conclusions
Patients weighed several informational topics to make an informed decision about HCV treatment. These findings lay the groundwork for future patient-centered outcomes research in HCV and patient-provider communication to enhance patients’ informed decision making regarding direct-acting antiviral treatment options.
Key Points for Decision Makers
Patients contemplating hepatitis C virus treatment want a great deal of information to make informed treatment decisions.
The most commonly cited informational topics included treatment harms such as side effects, treatment benefits such as viral cure, details of the treatment regimen, details about the virus, liver disease, and the risks of not receiving treatment.
The most important topics that require additional investigation were information about viral cure, long-term survival, and treatment side effects. The most important topics for which we have sufficient information that can be shared with patients include liver disease, lifestyle changes needed for treatment, and details about the medications and treatment protocol.
I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about the treatment and management of hepatitis C.
Three anti-HCV regimens “highly effective” in achieving SVR
A comparison of three different anti-HCV regimens concluded that all of them appeared highly effective in achieving sustained virologic response (SVR).
A study at the University of Southern California compared the SVR rates achieved 12 weeks post-treatment in 11,464 patients treated with three such agents by the Veterans Health Administration.
Without controlling for other risk factors, a SVR at least 12 weeks post treatment was achieved in 92% of ledipasvir/ sofosbuvir, 86% of ombitasvir/paritaprevir/ritonavir/dasabuvir, and 83% of simeprevir/sofosbuvir patients.
After adjusting for patient characteristics, simeprevir/sofosbuvir (93.3%) and ledipasvir/sofosbuvir (96.2%) patients were statistically more likely than ombitasvir/paritaprevir/ritonavir/dasabuvir (91.8%) patients to demonstrate a SVR.
HIV, HBV, diabetes, obesity, previous treatment history and augmentation therapy using ribavirin did not impact the SVR rates. Sustained SVR rates were lower for patients under age 65, with cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, indications of fibrosis or a non-genotype 1 infection. Women and Caucasian patients were more likely to achieve a SVR.
One of the most interesting questions attending the remarkable pace of new therapies for patients with chronic hepatitis C is to what extent IL28B genotype plays a role in management—both now and in the future.
IL28B: Still Important With PI Therapy How do I currently use IL28B genotype in my practice? In the era of peginterferon/ribavirin plus protease inhibitor therapy, IL28B can be used to provide an increment of additional data that may assist with decision making. For the patient who needs to be treated (advanced fibrosis) or who really wants to be treated, I will not be deterred from starting therapy, so the test has limited value. On the other hand, for the patient with more limited disease in whom we could justifiably defer therapy, the finding of a CC genotype may persuade the patient toward giving treatment a try, particularly given the high likelihood of being able to abbreviate treatment to 24 weeks. If it’s clear that the patient has no inclination to consider interferon-containing therapy, then again the test has little value.
IL28B With Investigational Therapies Given the postulated mechanisms of direct-acting agents (DAAs)—offering a stranglehold on virus replication by means of blocking enzymes or proteins that contribute to the replication machinery—the use of DAAs should “level the playing field” by halting replication until it’s extinguished. Under this scenario, we might then expect the contribution of IL28B genotype to be rendered either irrelevant or minimally relevant, given that it was discovered due to its relationship with interferon responsiveness. However, in recent phase II DAA studies, IL28B status still mattered in predicting outcome in genotype 1 patients being treated with interferon-free regimens. I found this to be somewhat unexpected but quite revealing about the role of this polymorphism in dictating outcome.
Contribution of HCV Subtype How might IL28B be contributing to success under these circumstances? Let’s drill down somewhat deeper. In SOUND-C2, a study of the combination of a protease inhibitor plus nonnucleoside polymerase inhibitor with or without ribavirin, it appeared that in subtype 1b patients, responsiveness was excellent across the board, regardless IL28B status. By contrast, those subtype 1a patients with non-CC IL28B genotypes did poorly compared with those with the CC genotype who performed as well as the 1b subjects. This suggests to me that genotype 1 may need to be cleaved further into 1a/1b subtype distinctions for future clinical trials, and I can envision that DAA regimens may even be tailored to HCV subtype. In current practice, we routinely obtain subtype information with our genotype assays, so no additional information generally needs to be requested. However, subtype has less bearing presently on the decision to treat with current regimens, since overall SVR rates with these regimens are not terrifically different between subtypes.
The findings also suggest that HCV subtype 1a is an inherently more difficult-to-treat virus and that the right innate immune “equipment”—in this case, represented by IL28B genotype—is essential to maximize response for this group of patients. These data further imply to me that IL28B status does matter even in the absence of exogenous interferon. In the case of a virus with a low barrier to resistance development, such as HCV subtype 1a, the strength of the innate response coupled with antiviral therapy becomes critical. This might be reflected in an enhanced ability to respond to locally produced interferon and to minimize breakthrough of resistant viral variants. By contrast, in the case of HCV subtype 1b, where there is a generally higher barrier to virally encoded resistance, the DAA regimen alone may suffice, given the lower hurdle presented to the regimen.
Of course, these hypotheses are nothing more than that until we understand more precisely how IL28B genotype functionally produces its phenotype. Until then, we are left stratifying for subtype and IL28B in upcoming trials. Of course, the development of regimens that present ever higher barriers to resistance, including those that contain nucleotide polymerase inhibitors, may overcome these concerns at the end of the day.
Your Thoughts How about you? Are IL28B testing and HCV subtyping an important part of your practice workup when making decisions about HCV therapy? Do you see this changing in the future?
Raymond T. Chung, MD, is Director of Hepatology, Vice Chief of Gastroenterology, Massachusetts General Hospital and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts.
Dr. Chung has disclosed that he has received funds for research support from Gilead Sciences, Mass Biological, Pfizer, and Romark.
Editorial -Hepatitis C Virus Therapeutics: At the End of the Beginning
Robert T. Schooley, MD
Those of us who have been engaged in HIV therapeutics for the past 2 decades remember all too well the excitement of the 24-month period from 1994 to 1996 that witnessed the treatment paradigm shift from sequential failing regimens of nucleoside analogue reverse transcriptase inhibitors (nRTIs) to stable, “fully” suppressive combination regimens. AIDS as we knew it during the first 15 years of our awareness of the illness has shifted in the most recent 15 years from an inexorably progressive disease to one that can be arrested for a prolonged period of time.1 The speed of this paradigm shift was the result of a well-integrated research effort that included basic, translational, and clinical components that were able to take advantage of a robust pipeline of antiretroviral drugs. Many have argued that the transformation in the prognosis of HIV infection was one of the most impressive demonstrations in recent history of the value of investments in biomedical research.
Although it has received less comment, the equally rapid application of research findings to clinical practice in the United States and Europe was also unprecedented. The translation of research findings to clinical practice was even more impressive in view of the complexity of initial combination treatment regimens and the need for physicians to incorporate rapidly evolving laboratory management tools such as plasma HIV-1 RNA assays and genotypic and phenotypic resistance tests.
The impact of the research findings would never have been realized in the absence of a talented and dedicated HIV treatment community that has continued to bring advances in therapy from clinical trials to the clinic in short order. By the efficient introduction of research findings into medical practice, it is estimated that more than 2.8 million quality-adjusted life-years were saved in the United States between 1989 and 2003.
The HIV treatment community that emerged during the first phase of the epidemic included physicians from a number of different disciplines, including internal medicine, infectious diseases, oncology, dermatology, general medicine, and others.
Despite the broad spectrum of professional training experiences, the HIV treatment community was relatively cohesive, interactive, and well defined. Because of the complexity of HIV management, it quickly became apparent that the best (and most contemporary) care came from those who devoted most of their professional time to HIV care and worked in multidisciplinary teams that included specialists with HIV-specific knowledge in their own subspecialties.
The vast majority of those who stepped forward to do this were those who had been caring for patients with the illness during the “palliative era.” It was a natural step for those who had become comfortable with the disease and its patient population to follow therapeutic developments into the modern treatment era.
We have now entered an era in hepatitis C virus (HCV) therapeutics that promises to be analogous to the “wonder years” of 1994 to 1996 in HIV therapeutics. The first 2 direct- acting antivirals (DAAs) for HCV infection were approved less than a year ago, and more than 30 additional drugs are in clinical trials. When either of the 2 new HCV protease inhibitors is combined with peginterferon alfa and ribavirin,treatment success rates for previously untreated HCV genotype 1–infected patients have increased from approximately 45% to the 60% to 70% range.3,4
As with the case of HIV antiretroviral treatment, it is quite clear that combination treatment will be required for most (or all) patients with HCV infection. It is also clear that as more DAAs emerge from clinical trials and enter clinical practice, management decisions will be complex and will require substantial expertise in many of the same skill sets that characterize contemporary HIV management.
Since the introduction of interferon alfa monotherapy in the early 1990s, HCV therapeutics has been characterized by gradually improving treatment success rates but only incremental increases in the number of people seeking therapy.
Most of those treated received therapy because progression of their liver disease forced the issue. Because accurate assessment of liver disease usually required a liver biopsy, most treatment candidates ended up in the hands of hepatologists before therapy was contemplated. Treatment for HCV was usually undertaken by hepatologists and their nurses, and patients were either cured and returned to the primary care system, or experienced treatment failure and returned to the primary care system for general medical care, with intermittent returns to the hepatologist for complications of liver disease.
In the setting of a fairly steady number of new patients who entered the treatment population as treatment-initiation decisions were made on a one-by-one basis, the number of people actively treated for HCV has remained relatively stable over time (see Box).
Box. HIV and Hepatitis C Virus (HCV) Care Paradigms
Click Image To Enlarge
In contrast, HIV-infected persons are generally referred to HIV specialists and even if treatment succeeds (as is the case for many), these patients then remain in care for life. Thus, the number of people in HIV care has continued to rise steadily, and HIV treatment capacity has expanded correspondingly. As in other areas of medicine, there are geographic disparities, but the overall capacity of the HIV care system has managed so far to keep up with demand.
Current indications are that over the next 18 months to 24 months, we will witness the end of the “interferon alfa” eraof HCV management.5 As this happens, the dialogue about whether to initiate HCV therapy will shift from “Are you telling me that my liver disease is so bad that I really can’t wait any longer?” to “I’m ready for my virectomy; what are we waiting for?”. If treatment success can be achieved in 12 weeks to 24weeks with well-tolerated, all-oral regimens, and if treatment success rates rise to the 90% to 95% range (which seems quite feasible), it is quite likely that there will be a very large influx of HCV-infected persons into the treatment queue.
The roll-out of HCV awareness and screening campaigns will further stimulate treatment demand. Although treatment will be greatly simplified for the patient, it is assumed that for the near future, it will remain complicated for the practitioner. Treatment-initiation decisions will be easier, but treatment management may become more complex before it gets easier. In the peginterferon/ribavirin era, once treatment began, management mainly consisted of following HCV RNA levels for futility and managing well-defined toxicities with dose modification.
Most management decisions were relatively simple, and most patients could be followed primarily by nurse practitioners and physician assistants The field of HCV therapeutics is moving rapidly and much remains to be learned; thus, firm predictions are inherently risky. It is likely, however, that for the foreseeable future, management decisions will require much more thought than they did in the “easy” days of interferon alfa–based regimens.
Considerations in crafting combination regimens will likely include HCV genotype, treatment history, and drug-drug interactions as well as patient-centered considerations such as patient genetics, regimen complexity, toxic effect profile, and adherence challenges.
Management of therapy will be guided by plasma HCV RNA kinetics, and decisions about drug discontinuation and substitution will require detailed knowledge of adverse-effect profiles; resistance-barriers, magnitude and pathways; and future treatment options.
Therefore, at the same time that we can expect a large increase in the number of people seeking therapy, we should also expect that more complex treatment paradigms will require much more ongoing active management.
It is unlikely that the gastroenterology community alone can respond adequately to the challenges posed by dramatically increased numbers of HCV-infected patients seeking much more complex treatment regimens.
Most HCV care is currently provided by the minority within the hepatology community who are interested in viral hepatitis. It is also highly unlikely that gastroenterologists or hepatologists not currently primarily engaged in viral hepatitis therapeutics will be motivated by rapidly changing treatment paradigms to close their procedure rooms to manage a large influx of “E and M” (evaluation and management) patients. Second, as treatment decisions become less amenable to algorithm-guided management by nonphysicians, it seems likely that some of the current HCV treatment community will exit the field. This leads us to ask from where the next generation of HCV treaters might be recruited.
Given the complexity of treatment decisions (at least over the short- to mid-term), HCV care will likely not migrate from the subset of presently engaged hepatogists to the primary care community. It will instead require the development of a new community of treaters with an interest in complex treatment decisions guided by an appreciation of disease pathogenesis. These physicians will need to be comfortable dealing with psychosocial issues, close laboratory monitoring, response-guided therapy, drug-drug interactions, and a host of other issues.
Having worked through all of these issues in the management of HIV disease, the community of HIV-treating physicians seems uniquely situated to step to the forefront and assume responsibility for managing a disease that is shifting from a liver disease to a viral disease in the coming all oral treatment era. It will, of course, be essential to maintain strong relationships with the hepatology community because expert management of liver disease will continue to be a required element of multidisciplinary HCV care.
The evolution of a care system in which hepatologists are called upon primarily to manage liver disease collaboratively could actually increase the number of hepatologists engaged in HCV care, because virtually the entire hepatology community would be comfortable managing liver disease, though only a subset will remain comfortable managing complex antiviral regimens.
Much research remains to be done as we work through the host of promising HCV therapeutics in the pipeline, but itseems likely that the current 24-month period following the approval of the first 2 DAAs will be viewed as the end of the beginning in HCV therapeutics. It is essential that we now thoughtfully plan for the coming treatment era if we are to bring research advances to the clinic as rapidly as we did in HIV therapeutics 15 years ago.
Mortality from viral hepatitis has recently surpassed that of HIV.6 We are armed with a rapidly evolving understanding of disease pathogenesis and an exciting array of new therapeutic agents, so prospects for dramatic advances in HCV therapy have never been better. The HIV treatment community can and should play a pivotal role in bringing these advances to the clinic.
Financial Disclosure: Dr Schooley has served as a consultant to 3-V Biologicals, Gilead Sciences, Inc, Inhibitex, Inc, Johnson & Johnson Services, Inc, Laboratory Corporation of America, Merck & Co, Inc, Santaris Pharma, and Tobira Therapeutics. He has stock options for Achillion Pharmaceuticals, Inc.
References
1. Palella FJ, Jr., Delaney KM, Moorman AC, et al. Declining morbidity
and mortality among patients with advanced human immunodeficiency
virus infection. HIV Outpatient Study Investigators. N Engl J
Med. 1998;338:853-860.
2. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of
AIDS treatment in the United States. J Infect Dis. 2006;194:11-19.
3. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously
untreated chronic hepatitis C virus infection. N Engl J Med.
2011;364:2405-2416.
4. Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated
chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-
1206.
5. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral
agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216-
An exciting new journal called "Clinical Liver Disease"-(CLD) has recently been launched, you can view the February issue here. This journal is an official digital educational resource from the American Association for the Study of Liver Diseases.
This March articles from the journal have been released for open access. The article topics are listed below. Visitors are able to view videos, full data, and download files in either HTML or PDF formats.
The first article has been posted on the blog below
Introduction To The New Journal Watch the video presentation of this article
It is with great enthusiasm that I welcome you to an exciting new educational product. It is called Clinical Liver Disease, and it is an official digital educational resource from the American Association for the Study of Liver Diseases.
Clinical Liver Disease is an online educational journal that takes advantage of new technology to provide online information on the rapidly changing field of hepatology. This topic-focused resource selects a clinically relevant area within hepatology with new and emerging knowledge and presents it to you in written, audio, and video formats. All contributions to Clinical Liver Disease will be commissioned from thought leaders in hepatology. We will offer continuing medical education and board exam style questions and answers.
More than anything else, our goal is to provide you with cutting-edge information related to the care of the patient with liver disease—whenever you want it and in whatever format you prefer. With Clinical Liver Disease, you can learn from some of the leading authorities in hepatology. Anytime. Anywhere.
Whether you are a doctor, advanced practice nurse, student, fellow, resident, or any other health care professional interested in advances in liver disease, Clinical Liver Disease is designed for you. We are pleased that we can make Clinical Liver Disease free to the user because of financial support provided to the publication in the form of educational grants.
So, let me be the first to welcome you to Clinical Liver Disease. We want to hear from you about the content and format and about topics and authors of interest to you. We invite you to comment on controversies and challenging new information. Most of all, with Clinical Liver Disease, we hope to provide you the opportunity to never stop learning.
Watch the interview with the authors Watch the video presentation of this article
It is currently estimated that 3 to 4 million individuals in the United States and up to 170 million individuals worldwide are chronically infected with hepatitis C virus (HCV).1–3 HCV remains the most common chronic blood-borne infection in the United States and accounts for up to two-thirds of newly diagnosed cases of chronic liver disease.3, 4 Because HCV is primarily transmitted through parenteral routes, populations known to have a particularly increased risk of exposure to HCV include recipients of blood transfusions before 1992 or coagulation factors before 1987, hemophiliacs, hemodialysis patients, individuals infected with human immunodeficiency virus (HIV), and injection drug users.5 Consequently, these groups are included in the current recommendations for identifying individuals who would benefit from screening5, 6 (Table 1). Although these recommendations have been in place for more than a decade, it remains questionable whether this strategy has been effective in identifying individuals with chronic HCV infections, most of whom were born between 1945 and 1964.3 An additional consideration is that certain populations with the greatest prevalence of HCV, such as injection drug users, incarcerated individuals, and the homeless, may not have access to health care or may not be included in population-based surveillance programs; as a result, the true prevalence of HCV may be underestimated.1 Injection drug use remains the most frequent means of HCV transmission in the United States; the seroprevalence of the antibody to HCV may rise to more than 70% with 3 to 5 years of habitual exposure7, 8 (Fig. 1). Efforts to implement prevention and treatment strategies in this population may become increasingly important for controlling new HCV infections.
Figure 1. Risk factors for exposure occurring within 6 months of the presentation of an acute HCV infection (identified in 2075 individuals included in a national surveillance program conducted by the Centers for Disease Control and Prevention from 1994 to 2006).
*The HCV-positive sex partner category includes both known and suspected HCV positivity.
**The aggregate risk category indicates circumstances in which the individual acknowledged an exposure risk but would not specify the category.
Adapted with permission from Archives of Internal Medicine.7
Table 1. At-Risk Individuals Currently Recommended for HCV Screening
Injection drug users or individuals with a history of injection drug use
Individuals infected with HIV
Individuals with hemophilia
Recipients of clotting factors or other blood products before 1987
Hemodialysis patients
Individuals with elevated liver enzyme levels
Recipients of solid organ transplants before 1992
Recipients of blood transfusions before 1992
Children born to HCV- positive mothers
Individuals with any known potential exposure via HCV-positive blood donors, organ donors, or occupational exposures
Sexual partners of HCV-infected individuals
This table was adapted with permission from Hepatology
5 and MMWR Recommendations and Reports.6
HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
The importance of effective screening strategies is highlighted by the recent availability of increasingly effective antiviral therapy.9, 10 The achievement of long-term viral clearance after a course of antiviral therapy, which is defined as a sustained virological response, is durable and demonstrates that the eradication of HCV is possible with successful treatment.11, 12 In addition, the successful treatment of an HCV infection can have a major impact on the natural history of HCV-associated chronic liver disease because the achievement of a sustained virological response may result in a substantial decrease in the risk of hepatocellular carcinoma (HCC) and liver-related mortality.13–17 Although an important step in minimizing the overall burden associated with HCV infections is the identification of individuals with chronic HCV who may be candidates for antiviral therapy, emerging data suggest that the majority of individuals with chronic HCV have not been diagnosed and remain untreated (Fig. 2). As many as 75% of those with chronic HCV in the United States are unaware that they are infected.18 In addition, only a small proportion of those diagnosed with chronic HCV undergo antiviral therapy.19–22 Barriers to treatment may include a failure to identify the infection, a lack of awareness of the seriousness of the infection, limited access to adequate health care or insurance, a fear of treatment side effects, and misperceptions about the effectiveness of treatment.23 Outlining a national strategy for the prevention and control of HCV, a recent report by the Institute of Medicine emphasized these findings and stressed the importance of increased awareness, recognition, and management of chronic HCV.18
Figure 2. Estimated proportions of individuals with chronic HCV in the United States who have been diagnosed with HCV and have then undergone antiviral therapy.18–22
Up to 85% of adults acutely exposed to HCV progress to a chronic infection; at least 20% of these individuals may progress to advanced liver disease over a 20- to 30-year period.24 Factors associated with an increased risk of disease progression include the duration of the HCV infection, heavy alcohol intake, advanced age, obesity, fatty liver disease, male sex, and HIV coinfection with low CD4 cell counts.25 Chronic liver disease associated with HCV is a major health care burden in the United States and globally and results in significant morbidity and mortality. Currently, more than 12,000 deaths occur annually in the United States as a result of HCV-related liver disease,26 and the number of deaths attributable to HCV may be greater than 360,000 per year on a global scale.27 As individuals with HCV continue to age and their duration of chronic infection increases, the prevalence of advanced hepatic fibrosis, end-stage liver disease, and HCC is also increasing. Indeed, the prevalence of cirrhosis and decompensation has doubled over the last decade, and the prevalence of HCC has increased 20-fold.28 Although HCV remains the leading indication for liver transplantation in the United States, the proportion of cases attributable to HCV appears to have plateaued, perhaps because of the aging of these individuals. However, the proportion of transplants related to HCC is rapidly increasing, and most of these cases are due to HCV29–31 (Fig. 3).
Figure 3. Number of liver transplants performed in the United States for chronic HCV and HCC on a yearly basis from 1992 to 2010 (based on data from the Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients).32
It has been projected that the overall prevalence of HCV in the United States will decline over the next 2 decades; however, the health care and social burden associated with advancing HCV-related liver disease will continue to rise.33, 34 Predictive modeling has estimated that by 2030, the proportion of individuals with chronic HCV who have cirrhosis will approach 50% (Fig. 4). Likewise, the prevalence of clinical decompensation and HCV-associated HCC is expected to increase during this time period. In addition, the annual number of liver-related deaths attributed to chronic HCV could more than double in the years leading up to 2030.33 Ultimately, this trend will have an economic impact as well. The estimated economic burden of HCV in the United States in 1997 was $5.5 billion.35 This amount is expected to nearly double to just under $10 billion per year over the next decade.36
Figure 4. Projected prevalence of cirrhosis in individuals with chronic HCV in the United States through 2030 (based on predictive modeling data).33
Antiviral therapy should decrease the prevalence of cirrhosis and liver-related deaths associated with HCV. The impact of therapy should become more pronounced as the efficacy of treatment improves. The treatment of half of HCV-infected persons today could result in overall decreases of 30% to 40% in liver failure, HCC, and liver-related mortality over the next decade.33 These findings highlight the importance of the early detection and selection of treatment candidates. An improved understanding of the demographics of HCV infection may lead to more effective screening strategies, which could possibly include both a targeted approach and the casting of a wider net based on age groups at the greatest risk for past exposure.37 Ultimately, the control of new HCV infections will require continued efforts to educate and increase awareness in populations at the greatest risk, including those exposed to injection drug use.
References
1
Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int2011;31:1090–1101.
Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, (1999 through 2002). Ann Intern Med2006;144:705–714.
Bell BP, Manos MM, Zaman A, Terrault N, Thomas A, Navarro VJ, et al. The epidemiology of newly diagnosed chronic liver disease in gastroenterology practices in the United States: results from population-based surveillance. Am J Gastroenterol2008;103:2727–2736.
Direct Link:
5
Ghany MG, Strader DB, Thomas DL, Seeff LB; for American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology2009;49:1335–1374.
Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep1998;47:1–39.
7
Williams IT, Bell BP, Kuhnert W, Alter MJ. Incidence and transmission patterns of acute hepatitis C in the United States, 1982–2006. Arch Intern Med2011;171:242–248.
Tseng FC, O'Brien TR, Zhang M, Kral AH, Ortiz-Conde BA, Lorvick J, et al. Seroprevalence of hepatitis C virus and hepatitis B virus among San Francisco injection drug users, (1998 to 2000). Hepatology2007;46:666–671.
Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al.; for ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med2011;364:2405–2416.
Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al.; for SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med2011;364:1195–1206.
Maylin S, Martinot-Peignoux M, Moucari R, Boyer N, Ripault MP, Cazals-Hatem D, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology2008;135:821–829.
Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med1997;127:875–881.
Singal AK, Singh A, Jaganmohan S, Guturu P, Mummadi R, Kuo YF, et al. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol2010;8:192–199.
Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnù L, Mazzella G, et al.; for Italian Association of the Study of the Liver Disease (AISF). Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology2007;45:579–587.
Mallet V, Gilgenkrantz H, Serpaggi J, Verkarre V, Vallet-Pichard A, Fontaine H, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med2008;149:399–403.
Bruno S, Zuin M, Crosignani A, Rossi S, Zadra F, Roffi L, et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a long-term prospective study. Am J Gastroenterol2009;104:1147–1158.
Iacobellis A, Siciliano M, Perri F, Annicchiarico BE, Leandro G, Caruso N, et al. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study. J Hepatol2007;46:206–212.
Colvin HM, Mitchell AE, eds. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC: National Academies Press; 2010.
19
Volk ML, Tocco R, Saini S, Lok AS. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology2009;50:1750–1755.
Rocca LG, Yawn BP, Wollan P, Kim WR. Management of patients with hepatitis C in a community population: diagnosis, discussions, and decisions to treat. Ann Fam Med2004;2:116–124.
Shehab TM, Orrego M, Chunduri R, Lok AS. Identification and management of hepatitis C patients in primary care clinics. Am J Gastroenterol2003;98:639–644.
Direct Link:
24
Seeff LB. Natural history of chronic hepatitis C. Hepatology2002;36(suppl 1):S35-S46.
Massard J, Ratziu V, Thabut D, Moussalli J, Lebray P, Benhamou Y, et al. Natural history and predictors of disease severity in chronic hepatitis C. J Hepatol2006;44(suppl):S19-S24.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol2006;45:529–538.
Kanwal F, Hoang T, Kramer JR, Asch SM, Goetz MB, Zeringue A, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology2011;140:1182–1188.
Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from (1975 to 2005). J Clin Oncol2009;27:1485–1491.
Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology2010;138:513–521.
Kershenobich D, Razavi HA, Cooper CL, Alberti A, Dusheiko GM, Pol S, et al. Applying a system approach to forecast the total hepatitis C virus-infected population size: model validation using US data. Liver Int2011;31(suppl 2):4–17.
Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health2000;90:1562–1569.
Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med2012;156:263–270.
Careful Patient Selection, Education Is Key for Success
by Christina Frangou
San Francisco—Soon after the FDA approved two direct-acting antiviral agents (DAAs) last spring for treating infection with hepatitis C virus (HCV), a 57-year-old black man came to see gastroenterologist Andrew Muir, MD.
The man had been diagnosed with hepatitis C in 2001. A liver biopsy one year later revealed he had stage II fibrosis. At the time, the patient declined treatment, saying the duration was too long and offered too few benefits.
But recently, he came back to Dr. Muir wanting to try a new protease inhibitor. Based on his reading, the man believed he could avoid interferon (IFN) and ribavirin (RBV), take a protease inhibitor as monotherapy for 24 weeks and expect a 75% chance of achieving a sustained virologic response (SVR).
Unfortunately, the patient’s expectations were unrealistic on all counts. The new protease inhibitor can only be given in conjunction with IFN and RBV, and the treatment duration varies. For blacks, therapy usually lasts a full 48 weeks, and in clinical trials, only 30% of black patients achieved an SVR with 28 weeks of therapy. Moreover, among black patients in the Phase III trials, SVR rates fell short of the 75% that the patient expected, and in treatment-naive blacks, only 62% receiving telaprevir and 53% on boceprevir achieved an SVR.
Educate To Encourage Adherence
Unrealistic expectations are common among patients with HCV infection who, after years of waiting for better therapies, are eager to try treatment with the new DAAs, said Dr. Muir. The DAAs on the market today are complex, with varied stoppage rules, monitoring points and some serious adverse events and drug–drug interactions.
“This is a real problem for clinicians. There’s tremendous excitement about these new therapies, but oftentimes, patients’ expectations are not in line with what these drugs can deliver,” said Dr. Muir, clinical director of hepatology at Duke University Medical Center, Durham, N.C.
In a presentation at The Liver Meeting 2011, Dr. Muir stressed that clinicians need to take time to carefully prepare patients for DAA therapy. Physicians must have clear, detailed discussions with their patients before and throughout treatment to optimize the benefits of DAA therapy, he said.
“The major challenges are preparing patients for the rigors of therapy, checking in frequently to make decisions about the duration of treatment and managing any issues as the patient goes along,” said Dr. Muir.
When patients come into the office considering treatment with DAAs, the first step is to clarify their expectations, said Dr. Muir. Patients need to learn the reality about DAAs if they want treatment to succeed.
Dr. Muir outlines for patients the complex prescribing rules, the contraindications, the lifestyle changes and duration of treatment with DAAs. The lifestyle changes can be significant, he cautions patients. Both telaprevir and boceprevir must be taken three times a day, or once every eight hours, and always with a meal. Dr. Muir then asks if the patient still wants treatment when these things are taken into account.
“That’s no small feat. Patients must adhere to that regimen because lapses in the concentration of telaprevir and boceprevir have historically been the risk period for breakthrough variants on therapy,” said Raymond Chung, MD, chief of hepatology and vice-chief of gastroenterology at Massachusetts General Hospital, Boston. Many of Dr. Chung’s patients limit or reschedule their work hours while on DAA therapy to help with adherence.
The key to getting patients through DAA treatment successfully is to select patients carefully and prepare them assiduously, said Gary L. Davis, MD, director of general and transplant hepatology at Baylor University Medical Center, Dallas. “This means that any issues that might impact compliance, tolerance and drug access should be dealt with before treatment starts. Educating the patient is essential. Patients and their support person need to clearly understand the importance of dosing compliance, lab monitoring and treatment stopping rules/end points.”
The treatment care team then needs to remain in close contact with the patient throughout treatment to reinforce adherence and offer feedback on their process, he added. At Dr. Chung’s office at Massachusetts General Hospital, one nurse practitioner has been assigned full-time to managing patients on DAAs. She works with them on everything from managing possible reactions like rash and anemia to helping them set up a daily schedule for taking the medications.
“We have 50 to 100 patients in varying stages of DAA treatment,” said Dr. Chung. “Every one of these patients is coming in for frequent visits—weekly in the beginning—and they are very much in need of monitoring, not just for adverse events like rash but also for fatigue and their ability to carry out work.”
Begin With a Thorough History
Before patients start the new therapies, gastroenterologists and hepatologists should consider getting a liver biopsy to help guide treatment, said Dr. Muir. Physicians also should confirm a patient’s history of treatment for HCV. If patients were previously on antiviral therapies, physicians need to find out as much as they can about that experience.
“You must ask whether we can improve upon previous treatment,” said Dr. Muir. “Were there adverse events with treatments? Were there dose reductions? If so, were they appropriate? How was patient adherence to medications? Did they use alcohol?”
Based on that information, physicians should outline the likelihood of each individual patient achieving an SVR, he said. The key predictors of SVR are whether patients are treatment-naive or treatment-experienced, whether they have cirrhosis and their race. Another important issue for patients is treatment duration. Duration will vary depending on each patient’s characteristics. “It’s important to speak with every patient about their likelihood of a shorter duration of treatment,” said Dr. Muir.
The American Association for the Study of Liver Diseases recommends 48 weeks of treatment for all patients with cirrhosis, as fewer patients with cirrhosis were included in the clinical trials that led to approval of the new drugs. Among those included, virologic response levels were lower than for patients without cirrhosis. For treatment-naive patients, 46% of non-black and 29% of black patients in the boceprevir SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial achieved undetectable levels of HCV by 28 weeks, making them eligible for the shortened course of treatment (Poordad F et al. N Engl J Med 2011;364:1195-1206). In the telaprevir trial, 58% of patients had an early rapid virologic response (Jacobson IM et al. N Engl J Med 2011;364:2405-2416).
Patients’ interleukin-28B (IL28B) genotype also affects the expected duration of treatment. For both boceprevir and telaprevir, patients with the IL28B CC genotype are most likely to attain an early virologic response, more likely to receive a shortened course of therapy and more likely to have an SVR, according to studies presented at last year’s annual meeting of the European Association for the Study of the Liver.
Follow Through: Monitor for Response, Resistance, Reactions, Interactions
When the new HCV drugs were first approved, physicians’ offices reported some trouble getting approval from third-party payers for the full course of treatment, said Dr. Chung. His office had to provide documentation of successful early virologic response to get the go-ahead from payers to approve continuation of treatment with a protease inhibitor.
“You can imagine that if any gaps occur in the virologic tests or their reporting, this could lead to interruption of protease inhibitor therapy. It’s been a real challenge,” he said.
Experts recommend following patients very carefully over the course of treatment, monitoring any virologic breakthroughs or adverse reactions to the medications, particularly rash and anemia. Dr. Chung sees patients after the first, second and fourth week of therapy, and every four weeks thereafter if patients are having an uneventful course. Treatment monitoring is essential to prevent unwarranted continuation of treatment in patients when a breakthrough has occurred, he said.
“That would signal the emergence of resistant variants. Upon discovery, it would be paramount to discontinue the entire regimen to prevent selection of additional resistance mutations,” he said.
Equally important is the need to monitor patients closely for adverse reactions and drug–drug interactions. As IFN and RBV remain the backbone of this HCV regimen, the same contraindications exist as with standard dual therapy: decompensated cirrhosis, renal insufficiency, advanced cardiac/pulmonary disease, active depression, severe mental illness, anemia/neutropenia/thrombocytopenia and noncompliance.
Additionally, there are important drug–drug interactions with boceprevir and telaprevir. Both DAAs inhibit the CYP3A4/5 enzyme. Drugs metabolized by CYP3A4/5 may have increased effect in the presence of boceprevir or telaprevir. The DAAs themselves are metabolized by this cytochrome. As a result, other drugs that induce or inhibit CYP3A4/5 could affect HCV levels.
“Planning is key to deal with drug–drug interactions,” said Dr. Muir. It’s very important to do a risk–benefit analysis of treatment with boceprevir and telaprevir, taking into account patients’ comorbidities, he added.
It is important to review all drugs that the patient is taking, including over-the-counter and herbal medications. Check with the patient’s primary care provider, cardiologist and psychiatrist about medication use, Dr. Muir said. “It’s a good time to revisit the need for all medications. Ask if the antidepressant can be changed, the blood pressure medicines. Can the patient hold their statin for 12 weeks?” he said.
Women taking oral contraceptives should be advised to try other methods of contraception, such as an intrauterine device or barrier methods. Additionally, pregnant women should not take either drug, as both are considered pregnancy category X, meaning the risks “clearly outweigh potential benefits,” according to the FDA.
Anemia and rashes are the two most common adverse events associated with the new therapies. Experts suggest physicians be proactive about managing both.
Before a patient starts therapy, do a pretreatment evaluation for anemia and consider the impact on comorbidities, such as cardiac and pulmonary disorders. Weigh the benefits of reducing the dose versus increasing or starting erythropoietin.
For rashes, patients should be proactive by moisturizing twice a day, limiting sun exposure and wearing loose-fitting clothing. Dr. Chung recommends including a dermatologist on the treatment team.
Keep an Eye on the ‘Holy Grail of Therapy’
One other important element that needs to be taken into account when considering patients for DAA therapy is whether patients should wait for something else to be approved, said Dr. Chung. Recent results from Phase II studies of second-generation DAAs suggest that some combination of these could be approved in the next three years (see “New Polymerase Inhibitor Could Become Cornerstone of Interferon-free HCV Treatment Regimen,” by Christina Frangou. Gastroenterology & Endoscopy News 2012;63[2]:16 and “Second Study of New Hep C Drug Is Promising for Difficult-to-Treat HCV Genotype 1 Patients,” by Christina Frangou. Gastroenterology & Endoscopy News 2012;63[2]:17-19). These therapies omit IFN from the treatment regimen and can generally be taken orally once a day, with or without food.
“That’s something critical to consider. With all the complexities of therapy—the issues of tolerability, adherence, drug–drug interactions, quality of life—there’s another equally important set of events going on, and that’s the emerging data on all-oral, interferon-free treatments,” said Dr. Chung. “It’s clear that the promise of interferon-sparing therapy is very real. For all of us, that would be the holy grail of therapy.”
Dr. Chung currently recommends that all patients with HCV infection who have advanced-stage disease, regardless of whether they are treatment-naive or experienced, should be considered for boceprevir or telaprevir, provided the benefits outweigh the risks. Patients who can reasonably defer treatment because of early-stage disease or who cannot tolerate IFN may be able to wait for investigational therapies to be approved. These patients also may be eligible for investigational studies, which are ongoing.
Dr. Muir disclosed that he is on advisory committees or review panels for Merck & Co., and Vertex Pharmaceuticals; is a consultant for Inhibitex, Merck & Co., and Vertex Pharmaceuticals; and receives grant/research support from Abbott Laboratories, Anadys, Bristol-Myers Squibb, Gilead, Medtronic, Merck & Co., Pfizer, Roche, Santaris, Scynexis and Vertex Pharmaceuticals. Dr. Chung receives grant/research support from Gilead, Merck & Co., Pfizer and Romark. Dr. Davis is a consultant for Vertex Pharmaceuticals and receives grant/research support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Novartis, Pharmasset, Tibotec and Vertex Pharmaceuticals.
Benefits of hepatitis C treatment outweigh costs for patients with advanced disease
STANFORD, Calif. — A towering $60,000 bill, a year of fierce, flu-like symptoms and a running risk of depression are among the possible costs of two new hepatitis C treatments. But according to Stanford University health policy researchers, they might be worth it.
Using a computer model of hepatitis C disease — which accounts for different treatments, outcomes, disease stages and genetics — a research team led by Jeremy Goldhaber-Fiebert, PhD, found that new triple-therapies for genotype-1 hepatitis C are cost-effective for patients with advanced disease. Their results will be published Feb. 21 in the Annals of Internal Medicine.
"With so many simultaneous factors, it's very hard to know what to do," said Shan Liu, a graduate student in management science and engineering in the School of Engineering and lead author of the study. "I think building models is a very eloquent and abstract way to inform difficult policy decisions."
Nearly 4 million people in the United States are infected with genotype-1 hepatitis C — a virus that attacks the liver, causing swelling, scarring, cancers and the need for transplants. Many of those infected are age 50 or older, meaning they may have long-term infections and could face serious hepatitis C-related diseases. Unlike hepatitis B, there is no vaccine for hepatitis C. Until last summer, hepatitis C treatments were a gamble with many side effects, including anemia, vomiting, hair loss and depression.
"These treatments are very uncomfortable and long — up to 48 weeks," said Goldhaber-Fiebert, assistant professor of medicine at the School of Medicine. "Many people likened the experience to cancer chemotherapy: hard to undergo if the chance of treatment success is not that high."
With an impending spike in illnesses among the hepatitis-C-infected population in the United States, researchers and physicians have been developing new tests and treatments. For instance, researchers recently identified a specific DNA sequence in the gene that codes an immune response regulator, called IL28b. Different IL28b sequences predict whether treatment will successfully clear the virus.
The latest in a series of improved therapies — and the focus of the study — are two new virus-targeting drugs called protease inhibitors, boceprevir (trade name Victrelis) and telaprevir (trade name Incivek).
The drugs, which came out in the summer of 2011, were designed to be taken in conjunction with the standard treatment, which itself is a combination of two drugs, an interferon and an antiviral called ribavirin. While the new triple therapies increase the chances of kicking the virus, they have more severe side effects — such as full body rash and rectal bleeding — and boost costs. Boceprevir adds $1,100 per week to the cost of treatment, and telaprevir adds $4,100 per week.
"At the outset, it was not at all clear to me that drugs as expensive as these, which are added onto the standard therapy, would result in sufficient benefits and reduced costs from averted liver cancers and transplants to make them cost-effective," said Goldhaber-Fiebert, who is also a faculty member of Stanford Health Policy at the university's Freeman Spogli Institute for International Studies.
Goldhaber-Fiebert, Liu and their colleagues wanted to know when or if doctors should prescribe the new treatments. Should doctors prescribe them to all hepatitis C patients? Or, should only patients with advanced disease be treated with the new drugs? With such high costs, the answers could have sweeping impacts on health-care budgets, particularly for public health systems such as the Department of Veterans Affairs hospitals where many hepatitis C patients receive care.
To find the answers, they used their model to compare the pros and cons of three treatment strategies: Giving all hepatitis C patients the standard treatment, giving all of them a triple therapy or giving triple therapy only to those patients less likely — based on their IL-28B gene — to respond to standard therapy. For each strategy, they examined both of the new triple therapies. They also considered patients with mild and advanced disease.
After intense statistical and simulation analysis, the model showed that the new triple therapies were indeed cost-effective for chronic hepatitis C patients with advanced liver disease. Despite the large price tag and side effects, the new treatments help these patients avoid costly cancers and liver transplants — as well as allowing them to live longer, higher-quality lives.
For those patients with mild disease, the model indicated that determining their IL-28B genotype is the best next step, before prescribing a treatment.
The closer the threat of severe disease, the more justified treatment costs and risks become, said Goldhaber-Fiebert. "That would be the bottom line."
Though these new drugs may offer relatively desirable options now, both Goldhaber-Fiebert and Liu noted that additional, and perhaps more effective, drugs are already in clinical trials.
"As more and better treatments become available, the decision will continue to evolve, requiring further analysis," Liu said. "Patients and health systems could also benefit from price competition with multiple treatment options available." But ultimately, she added, treatment decisions will remain a private conversation between a doctor and a patient.
Other co-authors include graduate student Lauren Cipriano; Mark Holodniy, MD, professor of medicine; and Douglas K. Owens, MD, professor of medicine and a senior investigator at the Veterans Affairs Palo Alto Health Care System.
The research was funded by a Stanford graduate fellowship, the Social Science and Humanities Research Council of Canada, the National Institutes of Health and the Department of Veterans Affairs.
Information about Stanford's Department of Medicine, which also supported the work, is available at http://medicine.stanford.edu.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
PRINT MEDIA CONTACT: Michelle Brandt at (650) 723-0272 (mbrandt@stanford.edu)
BROADCAST MEDIA CONTACT: M.A. Malone at (650) 723-6912 (mamalone@stanford.edu)
Pharmaceuticals
Enanta to develop new drug to treat hepatitis C virus
Enanta Pharmaceuticals Inc., a privately held drug research company in Watertown, said it is joining forces with Swiss pharmaceutical giant Novartis AG to speed development of a drug that targets the hepatitis C virus.
Novartis will pay $34 million to license EDP-239, a compound identified by Enanta that is believed to halt reproduction of the hepatitis C virus. Novartis, which operates a major research center in Cambridge, will fund research aimed at turning EDP-239 into an effective medication and bringing it to market.
Under the development agreement, Enanta could receive payments of up to $406 million if the drug meets a series of medical and regulatory benchmarks. The Watertown firm would also receive royalties on the sale of the drug, if it is approved by the US Food and Drug Administration, a process that typically takes several years. Novartis will also fund Enanta’s research into other compounds that may be effective against hepatitis C, Enanta officials said.
At least 170 million people worldwide have hepatitis C, including more than 3 million Americans. The disease is usually spread through infected blood during transfusions or drug abuse. It attacks the liver and causes permanent, often fatal damage. “It’s a huge global problem,’’ said Jay Luly, Enanta’s chief executive.
It’s also a huge business opportunity for drug makers. Last year, Vertex Pharmaceuticals Inc. of Cambridge won US government approval for Incivek, a hepatitis treatment that generated $456.8 million in sales in the fourth quarter of 2011.
Rival drug maker Merck & Co. brought out a hepatitis drug last year as well.
In November, California drug company Gilead Sciences Inc. agreed to pay $10.8 billion for Pharmasset Inc., a New Jersey firm working on a hepatitis cure, though shares of Gilead slumped last week when the Pharmasset drug delivered disappointing results in clinical tests.
In January, Bristol-Myers Squibb Co. agreed to pay $2.5 billion for Inhibitex Inc., another company working on a hepatitis drug.
Luly said the latest hepatitis treatments can cure the disease in about 70 percent of patients. Enanta and Novartis hope to equal or exceed the performance of existing hepatitis C drugs, while eliminating the need for interferon, an additional drug that current treatments require to be effective.
Interferon can have unpleasant side effects, such as nausea and vomiting. “Imagine a very bad case of the flu and having it every day for almost a year, ’’ said Luly.
In addition, he said, interferon must be injected, rather than taken as a pill.
“We’re in the hunt behind Vertex,’’ said Luly, “with a drug that’s safer, easier to use, and more efficacious, we believe.’’
Novartis officials could not be reached for comment yesterday Source Boston Globe
