May 17, 2013

Hepatitis C in the United States Perspective (screening/care)

Provided by NATAP

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Scott D. Holmberg, M.D., M.P.H., Philip R. Spradling, M.D., Anne C. Moorman, M.P.H., and Maxine M. Denniston, M.S.P.H. From the Epidemiology and Surveillance Branch, Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta.

N Engl J Med May 16 2013

Care for hepatitis C is evolving rapidly, with increasingly effective and better-tolerated antiviral therapies being evaluated and approved for use. It's clear, however, that not everyone who would qualify for therapy has been tested and identified, referred for appropriate care, and offered or given the best therapy available. Furthermore, currently used antiviral drugs - pegylated interferon and ribavirin "base" plus either telaprevir or boceprevir - can cost more than $70,000 for a full course of therapy. It is expected that the new oral antiviral agents will be just as expensive, at least in the short term. All these factors affect personal, medical, public health, and national policy decisions. One fundamental problem in making such decisions is that it's difficult to estimate the number of people with chronic hepatitis C virus (HCV) infection in the United States who have been identified and have received appropriate care.

Over the past 4 years, members of the Division of Viral Hepatitis at the Centers for Disease Control and Prevention (CDC) have executed and analyzed two large studies of hepatitis C in the United States. Researchers conducting the Chronic Hepatitis Cohort Study (CHeCS) are currently examining records from more than 13,000 patients with hepatitis C (and more than 3500 with hepatitis B) who have been seen at four health care organizations in the United States (in Detroit, Michigan; Danville, Pennsylvania; Portland, Oregon; and Honolulu, Hawaii) since 2006. These patients are drawn from a population of about 1.6 million adults who have received care at these four sites during the approximately 6 years for which retrospective and prospective analysis has been under way.1,2 The National Health and Nutrition Examination Survey (NHANES) takes a different approach: random sampling of approximately 5000 noninstitutionalized U.S. civilians per year, using standardized household interviews, physical examinations, and testing of serum samples.3 Details and results of these two studies give a consistent picture of the status of HCV infection in the United States (see flow chart).

An examination of the prevalence of chronic HCV infection in the United States during the period 1999 through 2002, based on NHANES data and factoring in persons who were institutionalized, incarcerated, or homeless, suggested that there were about 3.5 million HCV-infected U.S. residents.4 According to an as-yet-unpublished study by Denniston et al., a more recent prevalence estimate based on NHANES data from 2003 through 2010 reveals the effect of increasing mortality on this population. These analyses indicate that a reasonable estimate of the current number of infected people in the United States is about 3.2 million.

The CHeCS investigators examined 1.2 million people who used the four integrated medical care systems during 2006 through 2008, and 57% of the number estimated to have HCV infection had actually been tested and identified as infected. In the broader population from which the 30,140 NHANES participants were drawn, 50% of persons who had tested positive for antibodies to HCV and provided information during in-depth telephone interviews were aware of their HCV-infection status before being notified of that infection by the NHANES.3 The CHeCS researchers are currently examining reasons why the people who were found to be infected in their study had or had not been tested previously. In the population on which the CHeCS draws, less than half of people who had had two or more abnormal alanine aminotransferase results were subsequently tested for HCV infection.2

As an indication of access to care, of the first 8810 CHeCS patients - who are receiving care at integrated health care organizations - 62% had private insurance, 35% had public insurance (Medicare or Medicaid), and 3% had none.1 In the NHANES, 128 of 170 HCV-infected people who responded to follow-up surveys (75%) said they had health insurance,3 but the type of insurance was not included in the analysis.

As for follow-up care, of 9086 adults in the population from which the CHeCS cohort was drawn who had a positive HCV-antibody test during 2006 through 2008, a total of 3428 (38%) had no follow-up HCV RNA testing documented in the electronic database1; but since there was laboratory evidence of HCV RNA testing for 63% (though results of tests performed outside the participating health care networks could not be obtained), this percentage should be viewed as the minimum proportion who received at least some follow-up care. In the NHANES, 77% of respondents indicated that they had seen a clinician after their first HCV test result; these included 71 of 82 persons who knew they were infected before they were tested in the NHANES (87%) and 59 of 85 persons who discovered their infection because of their participation (69%). From these data it seems reasonable to deduce that 63 to 77% of people who have tested positive for HCV antibodies - 32 to 38% of all HCV-infected people in the United States - received follow-up hepatitis care.

Among those receiving care, such as the 8810 who were initially examined in the CHeCS, 5540 (63%) had had at least one HCV RNA measurement between 2001 and 2010. Of the HCV-infected people in the CHeCS - people who are more likely than average to be receiving specialist care for HCV - 3380 (38%) had undergone a liver biopsy between 2001 and 2010.1 In the NHANES, of 66 persons who said they received care for their HCV infection, 31 (47%) said they had undergone a biopsy. These proportions translate to about 12 to 18% of the total HCV-infected population.

In the CHeCS, 36% of people who knew they were infected - about 18% of the estimated total infected population who had been identified as infected - had evidence in their electronic or hard-copy chart of any treatment for HCV.1 In the NHANES, 22 of the 170 HCV-infected persons who answered follow-up surveys (13%) said they had received treatment for HCV infection.3

It is more difficult to determine whether treatment has been successful, but in the CHeCS the most recent test results indicated that HCV RNA was "undetectable" in 21% of patients, and 80% of patients with such results had documentation of having received antiviral therapy1 - that is, about 17% of the total CHeCS cohort, or about 5 to 6% of all HCV-infected people.

One limitation of both the CHeCS and the NHANES results is that because estimates are unavoidably based on progressively smaller numbers of patients, they have wide confidence intervals. Both studies were biased toward following (in the CHeCS) or recruiting for interview (in the NHANES) persons who were more likely to have health insurance and to be receiving health care; thus, the resulting estimates may actually be high. Still, these data and estimates derive from two large U.S. studies using different methods and sampling sources, one a managed-care population (CHeCS) with the largest cohort of HCV-infected patients in the United States and the other the noninstitutionalized civilian U.S. population (NHANES). Despite the different methods and unavoidable selection biases, the results appear to be consistent and credible.

This big picture suggests that there are many points of intervention - or opportunities - to improve the identification and care of patients with HCV and to mitigate the increase in hospitalizations and deaths resulting from HCV infection. For example, the CDC recently recommended a one-time test for everyone born between 1945 and 19655 to help identify the many infected people who would not be targeted for testing as the result of established risk-based testing strategies. Clearly, there is also a need to do a better job of getting HCV-infected persons who know their HCV status into care, evaluated, and, as appropriate, treated. It is past time to address more vigorously what Assistant Secretary for Health Howard Koh has called the silent epidemic of viral hepatitis.

The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Source

Provided by NATAP

Download the PDF here

Download the PDF here

"robust health care infrastructure will be needed.....infrastructure in the current U.S. health care system is woefully inadequate....Successful treatment of HCV infection has undeniable long-term benefits with respect to reducing morbidity and mortality......most challenging issue is not whether there will be medical tools to effectively manage and treat HCV infection, but whether the economic resources and societal commitment will be adequate to embark on an ambitious agenda to eliminate this global public health problem."

T. Jake Liang, M.D., and Marc G. Ghany, M.D., M.H.Sc.
From the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
N Engl J Med May 16 2013

"Conclusions: If the past is a harbinger of the future, therapy for HCV infection will probably continue to advance at a brisk pace. Many additional potent agents are in the clinical pipeline, and interferon-free regimens are likely to dominate the HCV therapeutic landscape within the next 5 years. If a simple treatment regimen becomes a reality, a robust health care infrastructure will be needed to identify, triage, and treat the millions of HCV-infected patients who are unaware of their status. The infrastructure in the current U.S. health care system is woefully inadequate. The rate of death from HCV infection has already outpaced the rate of death from HIV infection in the United States.71 Successful treatment of HCV infection has undeniable long-term benefits with respect to reducing morbidity and mortality.26-29Perhaps the most challenging issue is not whether there will be medical tools to effectively manage and treat HCV infection, but rather whether the economic resources and societal commitment will be adequate to embark on an ambitious agenda to eliminate this global public health problem."

Only 20 years after the discovery of the hepatitis C virus (HCV), a cure is now likely for most people affected by this chronic infection, which carries a substantial disease burden, not only in the United States but also worldwide.1 The recent approval of two direct-acting antiviral agents that specifically inhibit viral replication has dramatically increased the viral clearance rate, from less than 10% with the initial regimen of interferon monotherapy to more than 70% with current therapy. Moreover, many other drugs targeting viral or host factors are in development, and some will almost certainly be approved in the coming years. The questions of who should be treated and with what regimen will be increasingly complex to address and will require careful consideration. As therapy improves, systemwide identification and care of patients who need treatment will be the next challenge. Because most infected persons are unaware of their diagnosis, the Centers for Disease Control and Prevention recently recommended screening for HCV all persons born between 1945 and 1965. 2,3 It is anticipated that in the course of such a screening process, a large number of persons will be found to be infected with the virus; whether it will be possible to treat all these people is unclear. This article reviews the current therapy for HCV infection and the landscape of drug development.

Mechanism of Action of Therapy for HCV Infection

Basic research aimed at understanding the molecular pathways of the life cycle of the virus has been the engine that has driven the development of therapies for HCV infection over the past 20 years. HCV is a positive-strand RNA virus encoding a polyprotein that undergoes proteolytic cleavage to 10 polypeptides, each with distinct functions (Figure 1). The structural proteins consist of two envelope glycoproteins, both of which are targets of host antibody response, and the core protein, which interacts with progeny viral genomes for assembly of the virus.8 The nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B form a complex with viral RNA to initiate viral replication in a cytoplasmic membranous structure.8 Assembly of HCV requires close interactions with lipid droplets and lipoprotein metabolism.9 Mature virus is released from cells as lipoviral particles.10 HCV infects predominantly hepatocytes and has an uncanny ability to evade the host immune response in multiple ways.11

Interferon alfa is a potent inhibitor of HCV replication that acts by inducing interferon-stimulated host genes that have antiviral functions. Its pegylated form remains a mainstay of HCV therapy. By virtue of its diverse actions on HCV, interferon alfa is not associated with viral resistance. A lack of clinical response to interferon alfa is the result of chronic HCV infection that confers resistance to exogenous interferon alfa in the liver by interfering with host interferon response and interferon-stimulated gene expression.12 Ribavirin, a key component of the therapeutic regimen, acts synergistically with and is used in combination with interferon alfa in the treatment of HCV infection; it probably has multiple mechanisms of action.13

Recent efforts to develop antiviral agents for the treatment of HCV infection have focused on small-molecule inhibitors of HCV infection (Figure 1), which can be categorized on the basis of the target of action. Some antiviral agents act directly on viral targets, whereas others target host proteins that are vital to HCV replication. The initial effort focused on two viral-encoded enzymes, the NS3/4A serine protease, which cleaves the HCV polyprotein, and the NS5B RNA-dependent RNA polymerase. The first two direct-acting antiviral agents that were approved, telaprevir and boceprevir, are inhibitors of the NS3/4A protease.14Another target, the NS5A viral protein, has gained traction recently because of its importance in the assembly of the cytoplasmic membrane-bound replication complex and the high potency of its inhibitors as indicated by in vitro studies and studies involving humans.15 Additional viral proteins, such as core protein (which has a role in assembly of the virus), p7 (which forms ion channels involved in assembly of the virus), and NS4B (which has a role in the formation of the replication complex), are being explored as drug targets (Figure 1).16-19

Promising host targets include cyclophilin A and miR122. Cyclophilin A is a crucial component of the viral replication complex.8 Cyclosporin A, a cyclophilin A inhibitor, is a potent inhibitor of HCV replication in cell culture. Its derivatives, such as alisporivir, NIM811, and SCY-635, which lack immunosuppressive properties, are being tested in clinical trials.20 MiR122 is a microRNA that is expressed abundantly in the liver and binds to viral RNA to facilitate replication.21 A nucleic acid inhibitor of miR122 (miravirsen) potently inhibits HCV replication in the chimpanzee model and in humans.22,23 Entry factors are other potential host targets; inhibitors of these factors block the access of HCV into cells (Figure 1).4 Inhibitors of viral entry may be particularly important for the treatment of patients undergoing liver transplantation, because patients with HCV infection are invariably reinfected after transplantation, and post-transplantation hepatitis C remains a major challenge to manage and treat.24

Therapy for HCV Infection, Genotype 1
Current Standard of Care

The goal of therapy for chronic hepatitis C is eradication of the virus, which should limit or prevent the development of complications. The end point of successful therapy is a sustained virologic response, defined as undetectable HCV RNA in serum 24 weeks after treatment has been stopped.25 This end point is predictive of long-term eradication of the virus and correlates with a reduction in symptoms and in the rate of negative clinical outcomes. 26-29 The combination of peginterferon and ribavirin has been the standard of care for patients with chronic hepatitis C, regardless of the strain of the virus (genotype 1, 2, 3, 4, 5, or 6).25 This regimen results in rates of sustained virologic response of 70 to 80% among patients with HCV genotype 2 or 3 infection and rates of 45 to 70% among patients with any of the other genotypes.25

The approval of boceprevir and telaprevir has led to triple therapy for HCV genotype 1 infection - one of these two protease inhibitors in combination with peginterferon and ribavirin.30-33 These two triple-therapy regimens result in similar response rates but differ greatly with respect to the timing of administration (both when they should be administered and for how long) (Figure 2).30-34 Neither boceprevir nor telaprevir should be used alone, nor should the dose of either drug be reduced, because drug-resistant variants can emerge rapidly.35,36 Similarly, one agent should not be substituted for the other because they have very different treatment schedules and similar drug-resistant mutations. They are not approved for use in patients who have HCV infection with genotypes other than genotype 1. Either peginterferon-alfa-2a or peginterferon-alfa-2b may be used in the regimen.37

Challenges of Triple-Therapy Regimens

Although the approved triple-therapy regimens are more efficacious than a regimen of peginterferon and ribavirin without a protease inhibitor, they have additional side effects and are quite complex to adhere to because patients must take an increased number of pills and the schedule requires pills to be taken every 8 hours. The most common side effects with boceprevir are anemia, neutropenia, and dysgeusia (altered taste sensation),30,31 and the most common side effects with telaprevir are anemia, rash, and anorectal discomfort.32,33 Anemia (a hemoglobin level of <10 g per deciliter) occurs in 36 to 50% of cases and is the most challenging complication to manage. 30,32

Erythrocyte-stimulating agents have been used with some success to manage the anemia, but these agents have serious side effects, are costly, and are not approved for routine use in patients with chronic hepatitis C.30,38 Studies have shown that a reduction in the dose of ribavirin, even as early as week 2 and to a level as low as 600 mg per day, is an effective strategy for managing anemia and is the recommended first approach.38,39

DrugÐdrug interactions constitute another concern. Boceprevir is metabolized by the aldo-ketoÐreductase and Cyp3A4/5 pathways and telaprevir by the Cyp3A pathway.40,41 Both molecules are inhibitors of Cyp3A4 and P-glycoprotein transporter.42 Cyp3A enzymes are abundant in the liver and are involved in the metabolism of many drugs. The activities of these enzymes can also be reduced in advanced liver disease. Therefore, when these agents are administered, one should consider not only the effects of coadministered drugs on boceprevir and telaprevir levels but also the effects of boceprevir and telaprevir on the levels of other drugs. A number of medications, such as certain statins, antidepressants, anticonvulsants, analgesics, and sedatives, are contraindicated with these agents.41,43 All prescribers of boceprevir and telaprevir are strongly advised to check for the effects of drugÐdrug interactions before administering these agents. Important information can be obtained from a number of useful websites, from the prescribing information disseminated with the drugs, and from review articles.41-43

Antiviral resistance is another major concern and may develop as early as 4 days after initiation of the drug when these agents are used as monotherapy.35,36 The various drugs in the class of protease inhibitors have a similar pattern of drug-resistant mutations, which means that if resistance-associated variants emerge when one agent is used, another agent in the same class would not be effective. Therefore, patients who no longer have a response to one of the approved regimens should not be treated with the other. Once the drug is stopped, resistance-associated variants disappear over time, probably because they do not replicate as efficiently as does the wild-type virus. Certain mutations may persist in the viral population in a given patient for 3 years or longer after discontinuation of therapy.44,45 Adherence to the prescribed regimen and dietary considerations (to maximize absorption of the drug) should be reinforced with patients to limit the development of antiviral resistance. There are scant data on the efficacy of these approved regimens in difficult-to-treat populations that traditionally have lower response rates to peginterferon and ribavirin, such as patients with cirrhosis or human immunodeficiency virus (HIV) coinfection and patients who have undergone liver transplantation. In phase 3 trials of boceprevir and telaprevir, patients with cirrhosis, accounting for only approximately 10% of the populations studied, had lower rates of sustained virologic response than did patients without cirrhosis. Although the numbers of patients with cirrhosis were small, there was a trend toward lower response rates with response-guided regimens, and patients with cirrhosis should therefore receive 48 weeks of therapy.30-33 In preliminary studies, the response rate among patients with HIV coinfection was similar to that among patients without HIV coinfection, but the approved regimens are problematic in patients who have undergone liver transplantation because of drugÐdrug interactions and serious side effects.46-48

Indications for Triple Therapy

The indications for the approved triple therapy remain the same as those for peginterferon and ribavirin. The patient must have documented viremia, no contraindications to therapy, and no serious coexisting illness.25 It is particularly important to consider initiating treatment promptly in patients with an advanced stage of fibrosis (Ishak fibrosis score of 4, 5, or 6 on liver biopsy [with scores ranging from 0 to 6 and higher scores indicating greater degrees of fibrosis]) (see the Supplementary Appendix, available with the full text of this article at NEJM.org) because these patients are at the greatest risk for disease progression.49 The benefits of a sustained virologic response - lower rates of hepatic decompensation, amelioration of symptoms, and a reduction in the risk of liver-related death - particularly among patients with advanced liver disease, have been firmly established.26-29 The availability of boceprevir and telaprevir has not significantly changed the riskÐbenefit ratio of therapy for a number of reasons. First, the side effects of triple therapy are worse than those of peginterferon and ribavirin. Second, response rates among the patients who stand to benefit the most from treatment - those with cirrhosis - remain relatively low. Third, antiviral resistance develops in most patients who have not had a response to treatment.30,32 Better, and presumably safer, interferon-free regimens will probably be available in the not-too-distant future.

Which patients with HCV genotype 1 infection should be considered for therapy with the currently approved regimens? Previously untreated patients without cirrhosis and patients with an initial response to treatment who subsequently had a relapse after stopping therapy - the two populations in which high rates of response have been reported - are good candidates for therapy (Figure 3).30-33 However, patients with mild disease who have not received prior treatment can probably defer therapy and wait for more effective and safer regimens to become available. Patients with cirrhosis and those who have not had a response to prior therapy stand to benefit the most from triple therapy but have the lowest response rates.30-33 An individualized approach is recommended for all patients, once the benefits of therapy, the likelihood of a response, and the potential side effects of treatment have been discussed. The efficacy of the two approved triple regimens is similar, although they have not been directly compared. Factors such as the patient's preference, the duration of protease-inhibitor administration, the side-effect profile, and the cost should be considered in selecting a regimen.

Therapy for HCV Infection, Genotypes 2 through 6

The combination of peginterferon and ribavirin remains the recommended therapy for HCV genotypes 2, 3, 4, 5, and 6 infection (Figure 3).25 Preliminary results of a study of a polymerase inhibitor (sofosbuvir) in combination with ribavirin, administered for 12 weeks, showed a 100% rate of sustained virologic response among patients with HCV genotype 2 or 3 infection.53 As reported in this issue of the Journal, two phase 3 trials of the same oral combination showed similar response rates among patients with genotype 2 infection (93% and 97% in the two studies) but much lower response rates among patients with genotype 3 infection (56% and 61% in the two studies),51,52 indicating that better oral regimens are still needed for patients with genotype 3 infection. Activities of various direct-acting antiviral agents against other genotypes are also being investigated.

Therapies in Clinical Development
Direct-Acting Antiviral Agents

The major drawback of boceprevir and telaprevir is their limited antiviral efficacy in patients with HCV infections other than genotype 1 and their low genetic barrier to resistance (Table 1). There are about a dozen second-generation protease inhibitors in phase 2Ð3 development that are better than the first-generation agents.54 Two classes of NS5B polymerase inhibitors - nucleoside and nonnucleoside analogue inhibitors - are being developed. The nucleoside inhibitors target the conserved nucleotide-binding pocket of the enzyme and function as chain terminators. The nonnucleoside inhibitors bind to other regions of NS5B and act as allosteric inhibitors. There are about eight NS5A inhibitors and more than a dozen NS5B inhibitors in phase 2Ð3 studies. The properties of these newer agents are summarized in Table 1. All the above agents are being tested in clinical trials in various combinations, with or without ribavirin or peginterferon. NS4B and p7 viral proteins are also being explored as alternative targets of direct-acting antiviral agents (Table 1). In general, the drugs targeting NS4B and p7 are not as potent as those that target NS3/4A, NS5A, and NS5B and have a relatively narrow genotypic coverage.18,55

Host-Targeting Antiviral Agents

Inhibitors of cyclophilin A and of miR122 are promising host-targeting antiviral agents that have advanced to phase 2 or 3 clinical trials (Figure 1 and Table 1). Alisporivir, an inhibitor of cyclophilin A with broad genotypic coverage, has shown reasonable potency in a 14-day monotherapy trial (approximately a 3 log10 reduction in HCV levels).56 Related compounds such as SCY-635 and NIM811 are being tested in clinical trials.57,58 Mutations conferring viral resistance to this class of compounds can emerge in the NS5A protein but occur less frequently than with direct-acting antiviral agents.56 A combination of alisporivir with peginterferon and ribavirin has shown improved efficacy over peginterferon and ribavirin alone, both in patients who have received prior treatment and in those who have not.20 The drug is currently on hold at the Food and Drug Administration because of several cases of severe pancreatitis that may have been associated with it. In a phase 2a trial, miravirsen, a drug that targets miR122 and is administered subcutaneously once a week, has led to a modest reduction in HCV levels (<3 logs10) after 5 weeks of monotherapy.23 The effects appear to last for several weeks after the last dose, and no resistant mutations have been identified.

Interferon-Free Regimens

For a number of reasons, an interferon-free regimen would be advantageous for the treatment of chronic hepatitis C. Considerable progress has been made in this regard with the use of various combinations of direct-acting antiviral agents with or without ribavirin. Combining drugs that have different targets of action should result in an additive or synergistic antiviral effect while lessening the chance of antiviral resistance. The challenge is to identify the right combination of drugs with the highest potency and barrier to resistance and the best side-effect profile. What the final regimen will be remains to be determined. Currently, many combinations of protease, NS5A, and polymerase inhibitors, with or without ribavirin, are being evaluated. In a proof-of-concept study, patients with chronic hepatitis C, both those who had received prior treatment and those who had not, were treated with an interferon-free and ribavirin-free regimen consisting of the polymerase inhibitor RG7128 (a nucleoside inhibitor) and the protease inhibitor danoprevir, administered for 13 days, followed by peginterferon and ribavirin.59 A substantial proportion of patients who received the highest doses had undetectable HCV RNA levels after only 13 days, indicating that viral clearance could be achieved without the use of interferon or ribavirin.59 Several trials of other combinations of direct-acting antiviral agents have resulted in viral clearance in patients undergoing therapy.60,61 A study of the protease inhibitor asunaprevir in combination with the NS5A inhibitor daclatasvir, administered for 24 weeks in patients with genotype 1a or 1b infection who had not had a response to previous therapy, showed eradication of the virus in 4 of 11 patients (36%).62 Another study, which used the same regimen but only in patients with genotype 1b infection who had not had a response to previous therapy, showed a 90% rate of sustained virologic response.63 These latter studies highlight the effect of HCV subtype on the response to a regimen that consists entirely of direct-acting antiviral agents. The combination of a direct-acting antiviral agent with a host-targeting antiviral agent may circumvent the issue of the difference in response according to genotype. Two recent studies also showed high rates of sustained virologic response (80 to 90%) with other oral combinations among patients with HCV genotype 1 infection.53,64 For a discussion of other therapeutic approaches, see the Supplementary Appendix.

Precision Medicine in HCV Therapy

Advances in biomarker and genomic medicine have provided a unique opportunity to personalize the approach to treatment for patients with hepatitis C. Various clinical traits (e.g., the presence of cirrhosis) and virologic traits (e.g., genotype 1 vs. genotype 2 or 3) have already been incorporated into current regimens as the standard of care. In addition, monitoring the virologic response during treatment often determines the duration of therapy (response-guided therapy) (Figure 2). Demographic and other factors that have previously been found to correlate with a response to peginterferon and ribavirin are also important determinants of a response to the approved direct-acting antiviral regimens; these factors include younger age (<45 years), non-black race, lower body-mass index, no history of diabetes, absence of cirrhosis on liver biopsy, low baseline viral load (<800,000 IU per milliliter), and HCV subtype 1b.30-33 New biomarkers (e.g., serum IP10 levels) and genetic tests (e.g., to determine polymorphisms in the IL28B gene) appear to have strong predictive value with respect to interferon-based therapy.64 Polymorphisms in the inosine triphosphatase gene were recently identified as pharmacogenomic markers of ribavirin-induced anemia65,66; however, the polymorphisms conferring protection are rare in the general population, and screening for those polymorphisms is therefore not useful. Recent costÐbenefit analyses of data from a study in which a treatment regimen was chosen on the basis of the IL28B genotype suggest that patients with a favorable IL28B genotype, a subgroup in which the rate of a sustained virologic response approaches 80%, could receive peginterferon and ribavirin first, with the approved direct-acting antiviral regimen provided subsequently if the initial treatment failed.67 Although testing for the IL28B genotype has not been formally approved as a standard of care, such testing may be helpful if the patient or provider desires additional information on the probability of a response to treatment (Figure 3).14 However, since more potent anti-HCV drugs and interferon-free regimens are being developed, these markers may no longer be relevant.

Studies of the natural history of chronic HCV infection have shown that the majority of HCV-infected persons have an indolent course of liver disease that rarely progresses to life-threatening complications.68 Another personalized approach to treating patients with HCV infection may be to treat only those in whom severe disease is likely to develop. However, the clinical and genetic markers that have been identified in such patients do not have strong predictive power, and better predictive markers need to be identified.69,70

Conclusions

If the past is a harbinger of the future, therapy for HCV infection will probably continue to advance at a brisk pace. Many additional potent agents are in the clinical pipeline, and interferon-free regimens are likely to dominate the HCV therapeutic landscape within the next 5 years. If a simple treatment regimen becomes a reality, a robust health care infrastructure will be needed to identify, triage, and treat the millions of HCV-infected patients who are unaware of their status. The infrastructure in the current U.S. health care system is woefully inadequate. The rate of death from HCV infection has already outpaced the rate of death from HIV infection in the United States.71 Successful treatment of HCV infection has undeniable long-term benefits with respect to reducing morbidity and mortality.26-29Perhaps the most challenging issue is not whether there will be medical tools to effectively manage and treat HCV infection, but rather whether the economic resources and societal commitment will be adequate to embark on an ambitious agenda to eliminate this global public health problem.

Source

Hepatitis Testing Day

May 17, 2013 • By Ronald Valdiserri, M.D., M.P.H., Deputy Assistant Secretary for Health, Infectious Diseases, and Director, Office of HIV/AIDS and Infectious Disease Policy, U.S. Department of Health and Human Services

Dr. Ronald Valdiserri

This week, we mark the second annual observance of Hepatitis Testing Day. Establishment of this national health awareness day on May 19 was called for in the Action Plan for the Prevention, Care and Treatment of Viral Hepatitis as part of efforts to decrease health disparities by raising greater public and health care provider awareness, particularly among those populations most affected by hepatitis B and C infections. To achieve the goals of the Action Plan, we must address the fact that millions of Americans have chronic hepatitis, but most of them do not know they are infected.

Unfortunately, too many Americans at risk for or living with hepatitis B or hepatitis C infections remain uninformed about various facets of viral hepatitis, including the need for testing and care, associated adverse health effects, and the availability of treatment. By raising the profile of these infections and the importance of testing, we hope to generate greater awareness and encourage more people to learn about their risk and discuss hepatitis testing with their health care providers.

As we approach Hepatitis Testing Day, I encourage you to learn more using the following resources:

  • Hepatitis Risk Assessment: Find out if you should be tested by taking a 5-minute online Hepatitis Risk Assessment. This CDC tool allows individuals to determine their risk for hepatitis B and hepatitis C by answering questions privately, either in their home or a health care setting. They can then print tailored recommendations based on CDC’s testing and vaccination guidelines for viral hepatitis to discuss with their doctor. Try the Hepatitis Risk Assessment out for yourself! We hope you’ll help us spread the word about the tool by sending out an online health e-card to your friends, colleagues and/or patients and by downloading free Hepatitis Risk Assessment web buttons and badges to feature on your website.
  • Baby Boomers at Higher Risk: According to the CDC, about 3 million adults in the U.S. are infected with the hepatitis C virus, and most of them are baby boomers. That’s why CDC recommends that all Americans born from 1945-1965 (the generation known as “baby boomers”) get tested for hepatitis C. People in this age group are five times more likely to have hepatitis C. Watch this brief new video Exit Disclaimer to learn more about why hepatitis C testing is important.
  • Hepatitis B Awareness for Asian Americans: Assistant Secretary for Health Dr. Howard Koh encourages Asian Americans to get tested for chronic hepatitis B in a free, downloadable poster that you can post and share with others. CDC also recently updated its page on Asian Americans and Hepatitis B.

Finally, in an important issue of CDC’s Vital Signs last week, we were reminded of the importance of confirmatory testing in the diagnosis of HCV infection. The issue discusses HCV testing among baby boomers and includes new findings from a CDC study indicating that only half of Americans with hepatitis C receive complete testing for the virus. A simple blood test, called a hepatitis C antibody test, can tell if you have been exposed to the hepatitis C virus, but cannot tell whether you are still infected. Only a different follow-up blood test – an RNA test – can determine if you are still infected. The data, based on reports sent to health departments in eight cities, show that only half of people with a positive hepatitis C antibody test had the follow-up test reported (diseases of public health significance, such as hepatitis C, are usually reported to local health departments when they are diagnosed to help identify disease trends and track outbreaks). The other half did not have a follow-up test reported (although some of them may have been tested but no report was done). Without the follow-up test, a person will not know if they still have hepatitis C and cannot get the medical care they need. As CDC notes, these findings suggest that HCV testing and reporting must improve if we are to meet the goal of the Action Plan to increase the proportion of persons who are aware of their infection.

We are pleased that many of the federal partners working to implement the Action Plan are joining in the observance of Hepatitis Testing Day, raising awareness of the observance among their staff, grantees, providers, and other stakeholders. We urge you to join us, too, by learning more and sharing what you learn with others. Together we can make this second annual Hepatitis Testing Day a great success by raising awareness of viral hepatitis and encouraging complete testing for those who may be chronically infected.

Related posts:

  1. Hepatitis Testing Saves Lives
  2. May 19 Is Hepatitis Testing Day
  3. CDC Invites Public Comment on Draft Recommendations for One-Time Hepatitis C Testing for Baby Boomers
  4. May Is Hepatitis Awareness Month
  5. CDC Launches Hepatitis Testing Day Event Page

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Hep C rising in baby boomers, but can they be treated?

By Rose Egge Published: May 17, 2013 at 10:56 AM PDT Last Updated: May 17, 2013 at 2:11 PM PDT

SEATTLE – If you’re a baby boomer, the United States Centers for Disease Control is recommending you get tested for Hepatitis C, regardless of whether or not you have any other risk factors. But, treatment may not be readily available for newly diagnosed patients, and the Affordable Care Act could make things even worse.

Hepatitis C can lead to liver cancer, liver failure and cirrhosis – irreversible and potentially fatal scarring of the liver. The virus kills about 600 people in Washington each year, and death rates have been steadily rising since 2005.

Of the 3.2 million people in the United States living with Hepatitis C, the CDC estimates 75 percent are baby boomers, and the majority don’t know they’re infected. Researchers don’t know why prevalence is so high among this group, but many blame blood transfusions before donations started being screened for Hepatitis C in 1990, as well as unsafe needle practices before HIV education.

If Hepatitis C is detected, treatments can effectively prevent serious symptoms and even cure the virus in 70 percent of patients, said Dr. John Scott, an infectious disease specialist with the University of Washington.

Still, treatment options are not widely available and can be cost prohibitive, discouraging some people from being tested at all.

“It doesn’t make sense to test people and put them through that mental trauma if we don’t have treatment for them,” Scott said.

Scott said it can be challenging for providers to keep up with emerging treatment options, especially for rural doctors who are more isolated and see fewer patients.

“It’s not fair that people get substandard care just because of where they live,” Scott said.

Patients can also be unaware of new, promising treatment options. Michael Ninburg, executive director of the Hepatitis Education Project in Seattle, said most don’t know about emerging therapies that could cure Hepatitis C without the drug interferon, a common, but toxic therapy that can cause depression, fever and hair loss.

“Those who test positive are not getting treated because of horror stories they hear [about interferon,]” Ninberg said.

Kathy Perkins, a disease intervention specialist with the Snohomish Health District, said many of her clients chose not to be screened for Hepatitis C because they don’t believe anything can be done if they are infected.

“I talk to people on a weekly basis who are Hepatitis C positive but don’t know it’s curable,” Perkins said.

But even those who find treatment options may still go untreated because of insurance and cost concerns.

According to Scott, 50 percent of Hepatitis C patients are uninsured. While some drug manufacturers offer free medications to Hepatitis C patients who don’t have insurance, this does not cover the cost of provider care.

Perkins said cost can keep many from being treated.

“People feel like ‘Great I’m Hepatitis C positive now how am I going to pay for treatment?’” she said.

Perkins does not believe healthcare reform will help Hepatitis C patients seeking treatment. While Medicaid covers treatment, she said finding a doctor who accepts state-funded insurance can be challenging.

In fact, Perkins said the Affordable Care Act is likely to lengthen the waiting lists among doctors who do treat Hepatitis C.

“I think it’s going to be a big problem with not enough providers offering treatment,” she said.

Already, doctors at rural clinics have backlogs of patients waiting for treatment. Dr. David Hachey, a pharmacist in Idaho said his family medicine clinic can only see Hepatitis patients one day every other week.

“We are at maximum capacity,” Hachey said. “We have a large subset of patients preparing for treatment or waiting for new medications to be approved.”

Some doctors are trying to combat lack of treatment options. The University of Washington’s Project ECHO (see slideshow for more information) connects clinics from Alaska, Idaho, Oregon, Montana and Washington with specialists who have more experience treating Hepatitis.

“I know how to treat Hepatitis C but we’re dealing with nasty drugs,” said Dr. Geoff Jones, a Newport, Wash., doctor who participates is Project ECHO. “It’s nice to have a bunch of people to discuss side effects with.”

But, until treatment becomes more readily available and affordable, Hepatitis C deaths, especially among baby boomers, could continue to rise.

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May is National Hepatitis Awareness Month

Thursday, 16 May 2013 13:40 Minnesota Department of Health

Health officials advise all people between the age of 48 and 68 to get a hepatitis C test
In observance of Hepatitis Awareness Month (May), health officials are calling for all U.S. baby boomers - the generation born from 1945 through 1965 - to get a one-time test for the hepatitis C virus. According to the Minnesota Department of Health, there are currently about 39,000 people living with hepatitis C in Minnesota.

Hepatitis C causes serious liver diseases, including liver cancer (the fastest-rising cause of cancer-related deaths) and is the leading cause of liver transplants in the United States. Hepatitis C is usually spread by blood, through sharing needles or other equipment to inject drugs. Before widespread screening of the blood supply began in 1992, hepatitis C was also unknowingly spread through blood transfusions and organ transplants. One in 30 baby boomers has been infected with hepatitis C and most don't know it.

"To identify undetected cases, the Centers for Disease Control and Prevention (CDC) are recommending a one-time blood test for hepatitis C for everyone between the ages of 48 and 68," said Dr. Edward Ehlinger, Minnesota Commissioner of Health. "Following the new recommendations can protect the health of an entire generation of Americans from liver disease and save thousands of lives."

More than 15,000 Americans, most of them baby boomers, die each year from hepatitis C-related illness, such as cirrhosis and liver cancer, and deaths have been increasing steadily for over a decade and are projected to grow significantly in coming years. More than 2 million U.S. baby boomers are infected with hepatitis C - accounting for more than 75 percent of all American adults living with the virus.

"Studies show that many individuals were infected with the virus decades ago, do not perceive themselves to be at risk, and have never been screened," said Ehlinger. "Getting tested and treated now can offset many of the long term consequences."

CDC estimates one-time hepatitis C testing of people between 48 and 68 years of age could identify more than 800,000 additional people with hepatitis C. With newly available therapies that can cure up to 75 percent of infections, expanded testing - along with linkage to appropriate care and treatment - would prevent the costly consequences of liver cancer and other chronic liver diseases and save more than 120,000 lives.

Health officials recommend baby boomers and others who may have had blood exposures talk with their health care provider about getting a test for hepatitis C. For additional information about hepatitis C testing recommendations, visit http://www.cdc.gov/knowmorehepatitis/index.htm.

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May 17, 2013 07:00 AM Eastern Daylight Time

DDW 2013

RALEIGH, N.C.--(BUSINESS WIRE)--Salix Pharmaceuticals, Ltd. (NASDAQ:SLXP) today announced that presentations related to the investigation of two of the Company’s products are scheduled to take place during Digestive Disease Week DDW®2013. DDW2013 is being held in Orlando, FL, Saturday, May 18 – Tuesday, May 21.

Rifaximin-Related Presentations

Poster #Su1298: Neff et al. “Improved Outcomes in Hepatic Encephalopathy Using Rifaximin Monotherapy Compared to Rifaximin and Lactulose Combination Therapy”

Poster #1300: Neff et al. “Efficacy and Tolerability of Rifaximin in Hepatitis C Patients with Recurrent Hepatic Encephalopathy”

Poster #1687: Hassanein et al. “Utility of the Hepatic Encephalopathy Scoring Algorithm (HESA) for Diagnosing Hepatic Encephalopathy in a Randomized, Controlled Trial of Rifaximin vs. Placebo”

Mesalamine-Related Presentation

Poster #Su1222: Lichtenstein et al. “Long-Term Safety and Tolerability of Once-Daily Mesalamine Extended-Release Capsules in Patients with Ulcerative Colitis”

About XIFAXAN® (rifaximin) 550 mg tablets

Indication for XIFAXAN® 550 mg

XIFAXAN 550 mg is a rifamycin antibacterial indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.

Important Safety Information for XIFAXAN® 550 mg

XIFAXAN (rifaximin) 550 mg tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores < 25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother.

The most common adverse reactions occurring in ≥ 10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%).

Xifaxan 550 mg is not available for sale outside the U.S.

Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc.

About APRISO® (mesalamine)

Indication for APRISO® (mesalamine)

APRISO® is a locally-acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in adults.

Important Safety Information for APRISO® (mesalamine)

APRISO® (mesalamine) extended-release capsules are contraindicated in patients with hypersensitivity to salicylates or aminosalicylates (sulfasalazine), or to any of the components of APRISO capsules.

It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease.

Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO.

There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease.

Because dissolution of the coating of APRISO granules depends on pH, APRISO should not be co-administered with antacids. Caution should be taken to closely monitor blood cell counts during mesalamine therapy in patients ages 65 and older. Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 2.24 mg of phenylalanine per day.

The most common treatment-related adverse events occurring in at least 3% of adult patients taking APRISO and at a rate greater than placebo in clinical trials were headache (11%), diarrhea (8%), upper abdominal pain (5%), nausea (4%), nasopharyngitis (4%), influenza and influenza-like illness (4%), and sinusitis (3%).

About Salix

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription pharmaceutical products for the prevention and treatment of gastrointestinal diseases. Salix’s strategy is to in-license late-stage or marketed proprietary therapeutic products, complete any required development and regulatory submission of these products, and market them through the Company’s gastroenterology specialty sales and marketing team.

Salix markets XIFAXAN® (rifaximin) tablets 200 mg and 550 mg, MOVIPREP® (PEG 3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), OSMOPREP® (sodium phosphate monobasic monohydrate, USP and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO®(mesalamine) extended-release capsules 0.375 g, GIAZO™ (balsalazide disodium) tablets, COLAZAL® (balsalazide disodium) Capsules, METOZOLV® ODT (metoclopramide HCl), RELISTOR®(methylnaltrexone bromide) Subcutaneous Injection, FULYZAQ™ (crofelemer) delayed-release tablets, SOLESTA®, DEFLUX®, PEPCID® (famotidine) for Oral Suspension, DIURIL® (Chlorothiazide) Oral Suspension, AZASAN® (Azathioprine) Tablets, USP, 75/100 mg, ANUSOL-HC® 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC®25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT® Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT® Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg. Budesonide foam, RELISTOR® , LUMACAN and rifaximin for additional indications are under development.

For full prescribing information and important safety information on Salix products, including BOXED WARNINGS for OSMOPREP, AZASAN and METOZOLV, please visit www.salix.com where the Company promptly posts press releases, SEC filings and other important information or contact the Company at 919 862-1000 .

Salix trades on the NASDAQ Global Select Market under the ticker symbol “SLXP”.

For more information, please visit our Website at www.salix.com or contact the Company at 919-862-1000. Follow us on Twitter (@SalixPharma) and Facebook (www.facebook.com/SalixPharma). Information on our Twitter feed, Facebook page and web site is not incorporated in our SEC filings.

Please Note: The materials provided herein that are not historical facts are or might constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Although we believe the expectations reflected in such forward-looking statements are based on reasonable assumptions, our expectations might not be attained. Forward-looking statements involve known and unknown risks that could cause actual results to differ materially from expected results. Factors that could cause actual results to differ materially from our expectations expressed in the report include, among others: our dependence on our first seven pharmaceutical products, particularly Xifaxan, and the uncertainty of market acceptance of our products; the high cost and uncertainty of the research, clinical trials and other development activities involving pharmaceutical products; the unpredictability of the duration and results of regulatory review of New Drug Applications and Investigational New Drug Applications; intense competition, including from generics in an increasingly global market; the possible impairment of, or inability to obtain intellectual property rights and the costs of obtaining such rights from third parties in an increasingly global market; general economic conditions; our need to maintain profitability; the uncertainty of obtaining, and our dependence on, third parties to manufacture and sell our products; results of ongoing and any future litigation and investigations and other risk factors detailed from time to time in our other SEC filings.

Contacts

Salix Pharmaceuticals, Ltd.
Adam C. Derbyshire, 919-862-1000
Executive Vice President and Chief Financial Officer
or
G. Michael Freeman, 919-862-1000
Associate Vice President, Investor Relations and Corporate Communications

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Organ donor cards hard to implement in China, official says

BEIJING | Fri May 17, 2013 7:30am EDT

BEIJING (Reuters) - A system of donor cards indicating consent for organ transplants will not work in China as families will insist on having the final say, and many people see nothing wrong in using organs from executed prisoners, an official said on Friday.

Nearly 1.5 million people in China need transplants every year, but only 10,000 can get organs, according to the Health Ministry.

Many of those organs are taken from executed criminals and rights groups say it is often done without their consent - something the government denies, even as it tries to move away from obtaining organs from death-row inmates.

"China has an obvious family hierarchy," Huang Jiefu, who oversees transplants for the ministry, told a news conference when asked whether China could adopt an organ donor card system as practiced in countries like the United States and Britain.

"Every Chinese family has a core figure - be it the grandfather, father or grandmother - and this person has the final say," he said.

In traditional Chinese thought, the body is a sacrosanct gift from your parents not to be defiled, Huang said.

"That's why it won't work without family consent," he said.

However, Huang was optimistic that attitudes were changing, citing a ministry survey that found 70 percent of young people had no problem with organ donation.

China in 2007 banned organ transplants from living donors, except spouses, blood relatives and step or adopted family members, but launched a national system to coordinate donations after death in 2009. The organ shortage has driven a trade in illegal organ trafficking in the country.

Huang repeated that the goal was to reduce reliance on prisoners for organs by 2015, though he did not give any figures and China does not publish its death penalty numbers.

Still, many Chinese believe there is nothing wrong in using the organs of executed prisoners for transplants, he said.

"The legal philosophy of the death penalty is 'an eye for an eye' or 'a life for a life'. The public believes that saving a life is a worthy redemption of a dead prisoner.

"Every organ donation from executed prisoners has written consent from both the individual and the family," added Huang, who is an Australian-trained liver transplant surgeon.

But eventually, China will probably abolish the death penalty, so it will have to develop alternatives, he said.

"Depending on death row inmates for donations will lead China's organ transplants to a dead end."

(Reporting by Hui Li and Terril Yue Jones; Writing by Ben Blanchard; Editing by Robert Birsel)

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