A Local Performance Site of the New England AETC

A Local Performance Site of the New England AETC
Hepatitis C in 2014 Lisa M. Chirch, M.D. Assistant Professor of Medicine University of Connecticut Health Center A Local Performance Site of the New England AETC

Disclosures None

Objectives Describe epidemiology, transmission, and clinical presentation of Hepatitis C infection Understand and implement new testing and screening recommendations Apply relevant data from recent publications regarding treatment of chronic hepatitis C infection

Hepatitis C - Chapter 3 - 2012 Yellow Book | Travelers' Health | CDC
Most common indication for liver transplantation in the U.S. Hepatitis C - Chapter Yellow Book | Travelers' Health | CDC wwwnc.cdc.gov

Magnitude of the Problem
Nearly 4 million persons in United States infected Approximately 35,000 new cases yearly Acute infections on the rise since 2010 <10% chronically infected patients are treated Leading cause of Chronic liver disease Cirrhosis Liver cancer Liver transplantation Nearly 4 million persons in the United States are infected with hepatitis C virus (HCV). Approximately 35,000 new cases are diagnosed each year. A major issue is that most cases—approximately 85%—become chronic resulting in hepatitis C accounting for the leading cause of chronic liver disease, cirrhosis, and liver cancer in the United States, as well as the number one indication for liver transplantation (EACH COSTING ABOUT 600,000$)

Incidence is a measure of disease that allows us to determine a person's probability of being diagnosed with a disease during a given period of time Incidence is the number of newly diagnosed cases of a disease. An incidence rate is the number of new cases of a disease divided by the number of persons at risk for the disease. Prevalence is a measure of disease that allows us to determine a person's likelihood of having a disease. Therefore, the number of prevalent cases is the total number of cases of disease existing in a population. A prevalence rate is the total number of cases of a disease existing in a population divided by the total population.

“Silent Epidemic” NHANES survey: estimated unidentified HCV infections – 43% May 2011: U.S. Viral Hepatitis Action Plan Federal platform Educate providers and communities Increase awareness, testing and linkage to care USPSTF has aligned with CDC on testing recommendations – Grade B B = The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. NHANES = National Health and Nutrition Examination Survey Ronald Valdiserri – DHHS Deputy Assistant Secretary; The Liver Meeting 2013

Hepatitis C, a Silent Killer, Meets Its Match
November 4, 2013

Sources of Infection with HCV

Indications for HCV screening?
HIV IDU History of chronic HD, transfusion, blood product or organ transplant prior to 1992 Unexplained persistent elevation in ALT (?RNA) and….

Hepatitis C: Screening guidelines
CDC 2012: Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965 Recommendations and Reports, August 17, 2012 …one-time testing without prior ascertainment of HCV risk for persons born during , a population with a disproportionately high prevalence of HCV infection and related disease. Those born in this time period are 5 times more likely to have hep C

2013: Update of Guidance for Clinicians and Laboratories
MMWR May 2013 Availability of rapid test for HCV antibody (OraQuick) Fingerstick or venipuncture CLIA waiver by FDA in 2011 Discontinuation of the RIBA HCV Recommended testing sequence:

MMWR May10, 2013 * For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered. † To differentiate past, resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

Question A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her? A) 0% B) 15% C) 50% D) 75% E) 99%

Answer A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her? A) 0% B) 15% C) 50% D) 75% E) 99%

Hepatitis C Virus Infection Natural History
Acute HCV Resolved 15% (15%) Chronic HCV 85% (85%) Stable 80% (68%) Cirrhosis 20% (17%) Slowly progressive 75% (13%) HCC Liver failure 25% (4%) HCC, hepatocellular carcinoma

Hepatitis C Virus Genotypes in the USA
17% Type 3 There are 3 major types of HCV in the United States. The most common is genotype 1, which represents approximately 72% of HCV-infected patients in the United States. The prevalence of genotypes 2 and 3 is fairly equally split and represents the majority of the remaining approximate 25%. In this large study published in 2004, genotype 2 represented 17% and genotype 3 represented 10% of HCV-infected patients in the United States. There are other HCV genotypes, including genotypes 4, 5, and 6, which are almost exclusively found in individuals originating from areas of the world where these particular genotypes are endemic. For example, genotype 4 is almost completely restricted to individuals who immigrate to the United States from Egypt and the Middle East, genotype 5 is predominantly from South Africa, and genotype 6 is generally from Southeast Asia. 10% Type 1 72% All others 1% McHutchinson JG, et al. N Engl J Med. 1998;339:

Management of Chronic HCV
Disease Severity Response to Therapy AST/ALT Bilirubin Albumin Pro-time (INR) Platelet count Liver histology Transient Elastography ALT HCV RNA HCV genotype

IL28B IL28B:gene coding for IFN-λ3, associated with IFN sensitivity
–C/C genotype (vs C/T or T/T) associated with favorable response to HCV treatment in pts treated with PEG/ribavirin Chromosome 19; encodes Type III interferon family of cytokines Clark PJ, Am J Gastroenterol Oct 2010

HCV RNA and Liver Histology Fibrosis
Serum HCV RNA does not correlate with level of fibrosis 8 Genotype 6 1 Log HCV RNA (copies/mL) 2 4 This figure looks at levels of HCV in individuals with variable degrees of liver fibrosis. You can see that the level of HCV RNA is very constant across the spectrum of liver disease severity. 3 2 4 No Fibrosis Portal Fibrosis Bridging Fibrosis Cirrhosis Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

How to Stage . So what is new in staging
. Traditionally staging has been done by liver biopsy. But now we have noninvasive tests such as blood markers and Fibroscan. I will talk about these tests briefly . While it is important obatining HCV RNA levels and GT tests, they don’t help in staging of the disease. . Although US/CT and MRI can show cirrhosis they are pretty much insensitive and frequently miss advanced liver disease; so cannot be used for staging

Hepatitis C Virus Infection Liver Biopsy
Only test that can accurately assess Severity of inflammation Degree of fibrosis Determines Risk for developing cirrhosis in future Need for therapy Need for ongoing therapy when initial treatment has failed The final way to assess liver disease severity in hepatitis C is with liver biopsy. This is the only test able to accurately assess severity of inflammation and degree of fibrosis. The baseline degree of inflammation and fibrosis are able to determine risk of cirrhosis development in the future, the need for therapy, and the need for ongoing therapy if initial treatment has failed. For example, an individual who failed interferon therapy and has mild liver disease and no apparent cirrhosis based on liver biopsy, has little urgency to undergo retreatment with new or more aggressive therapies. In contrast, an individual with more scarring and bridging fibrosis on biopsy may request such treatments. The biopsy is very useful for managing patients in these scenarios.

Staging of liver fibrosis in hepatitis C virus infection according to Ishak (6 stages) [22]. Trichrome stain of 4 liver biopsies showing different stages; fibrous tissue is stained blue and hepatocytes pink. A, No fibrosis, Ishak stage 0 of 6. B, Periportal fibrosis, Ishak stage 2 of 6. C, Advanced bridging fibrosis, Ishak stage 4 of 6. D, Complete cirrhosis, Ishak stage 6 of 6. METAVIR: F0-4 – measure of fibrosis, A0-3 – measure of necrosis

Sampling error of liver biopsy
There may be variability in the degree of fibrosis that may be reported from the same patient depending where you insert the needle into the liver. You may 65% fibrosis area if you insert z needle in the first area but if you happen to put the needle just next to that in z pink healthy liver tissue you will just get 15% fibrosis area

Serum Markers of Liver Fibrosis
So that leads us to the blood markers which are noninvasive. There are different tests in the market. Fibrotest also known as Fibrosure is a little bit complicated and uses all these blood markers including age and sex in the final calculation. But you already have one of the tests whether you know it or not. It is the APRI score and is calculated as AST/upper limit of AST to Platelet divided by There are online calculator readily available to calculate these noninvasive tests. Value >1 has about 72% sensitivity for cirrhosis

Fibroscan As I said before liver biopsy is invasive and an imperfect way of evaluating for liver fibrosis. Now we have a noninvasive test in It is called transient elastography, also known as Fibroscan. Usonic sound waves are put into the liver using the probe and the stiffness of the liver will change the transduction of the sounds waves. And that stiffness is determined mainly by the degree of fibrosis. And it has been approved for use in the US in 2013 having been used in Europe for many years

Validity of Fibroscan Versus Biopsy
The Area under the Receiver Operating Characteristic is a common summary statistic for the goodness of a predictor in a binary classification task. It is equal to the probability that a predictor will rank a randomly chosen positive instance higher than a randomly chosen negative one Fibroscan has it own limitation as well. It is quite good in picking up high level of liver fibrosis- F4 as compared with F2. As you can see in the bottom, in coinfected patients Fibroscan is not quite good in picking up the low grades of liver fibrosis. Nonetheless it is a good test. Disadvant include; it does not work well in obese patients and not every institution has this machine. It was mentioned in the workshop that it costs in the range of $120,000. But it is completely noninvasive test

HCV Fibrosis Progression Effect of Alcohol
4.0 3.0 Alcohol intake Fibrosis Score 2.0 > 50 g/day* < 50 g/day 1.0 Another factor that affects fibrosis progression is alcohol use; individuals with hepatitis C who drink alcohol on a regular basis have a higher mean fibrosis score according to time of infection compared with individuals who do not drink alcohol. The impact of consuming alcohol continues to increase stepwise over the decades. < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years) *50 g is equal to approximately 3.5 drinks Poynard T, et al. Lancet. 1997;349:

Fibrosis Progression in HCV Effect of Steatosis
Cumulative Probability of Fibrosis According to Level of Steatosis 100 80 60 Cumulative Probability of Fibrosis Progression (%) Year 4 Year 6 Another factor that can affect fibrosis progression in HCV-infected patients is degree of steatosis. Individuals with more fat on liver biopsy tend to have more fibrosis and, as a result, develop cirrhosis at a faster rate. Individuals with lower degrees of fat have less fibrosis on liver biopsy. One of the important things you can do for your hepatitis C patients who do not want therapy is encourage weight loss. The more the patient weighs, the higher the likelihood that the patient will have fatty liver. That fat is going to contribute to more severe hepatitis C. 40 33% 30% 20 18% 18% 6% 7% 2% 4% < 5% 5%-10% 11%-30% > 30% Percentage of Steatosis at Initial Biopsy Fartoux L, et al. Hepatology. 2005;41:82-87.

Chronic Hepatitis C Virus Extrahepatic Manifestations
Nonspecific antibodies Essential mixed cryoglobulinemia Glomerulonephritis Porphyria cutanea tarda Leukocytoclastic vasculitis Mooren’s corneal ulcer Non-Hodgkin’s lymphoma Autoimmune thyroiditis Diabetes mellitus Sjögren’s syndrome Hepatitis C is associated with many extrahepatic manifestations, including nonspecific antibody production, essential mixed cryoglobulinemia, glomerular nephritis, porphyria cutanea tarda (PCT), leukocytoclastic vasculitis, non-Hodgkin’s lymphoma, autoimmune thyroiditis, diabetes, and Sjögren’s syndrome. The key to preventing these is treating the HCV. Likely related to hyperproliferation of B cells and resulting hypergammaglobulinemia

HCV Treatment Goals Goals of treatment for chronic HCV
Viral eradication (undetectable viral load) Delay progression of fibrosis Prevent decompensation, HCC, and death Best indicator of successful treatment is sustained virologic response (SVR)

Sustained virologic response
SVR: serum HCV RNA is undetectable based on a quantitative HCV RNA assay with lower limit of detection of 50 IU/mL or less at 24 weeks after treatment ends SVR 12: …12 weeks after treatment ends RVR EVR

Interferons discovered in 1957 as mediators of viral interference; known to have complex antiviral and immunomodulating actions (ifn alpha, beta) – produced by nearly all cells in response to viral infection, IL-1, IL-2, TNF

Treatment of Chronic HCV Peginterferon and Ribavirin
100 80 60 Sustained Virologic Response (%) PegIFN-2a/RBV 40 PegIFN-2b/RBV The 2 studies shown in this slide illustrate the effectiveness of the 2 peginterferons approved for treatment of hepatitis C—peginterferon alfa-2a and peginterferon alfa-2b. Approximately 80% of individuals with genotype 2 or 3 HCV achieve a sustained virologic response with peginterferon combined with ribavirin, meaning 80% are cured of hepatitis C. Unfortunately, genotype 1 is more resistant to treatment, yet 40% to 45% of patients with genotype 1 achieve a sustained virologic response after treatment with peginterferon and ribavirin. 20 1 2-3 Genotype Fried MW, et al. N Eng J Med. 2002;347: Manns MP, et al. Lancet 2001;358:

Interferon Flu-like symptoms: fatigue, headache, myalgias
Dose-related myelosuppression Reversible with dose reduction (cost?) Use of G-CSF and erythropoietin Depression: risk assessment prior to therapy initiation 35-40% Management with SSRIs and TCAs

Time Course of Treatment-Associated Psychiatric Adverse Effects
100 80 Depression 60 Incidence/Severity 40 Fatigue 20 Influenza-like symptoms 1 2 3 4 Months Dan A, et al. J Hepatol. 2006;44: Constant A, et al. J Clin Psychiatry. 2005;66:

Ribavirin Nucleoside analog Teratogenic
Inhibits inosine monophosphate dehydrogenase Potentiates purine analogs, ie didanosine Immune modulator, shift from Th2 to Th1 response Teratogenic both men and women must use contraception during and for 6 months after treatment Dose-dependent hemolytic anemia Increased risk for lactic acidosis

Hepatitis C classification—this is a Flaviviridae virus
Hepatitis C classification—this is a Flaviviridae virus. It is a single-stranded RNA. One of the important characteristics about this virus is its rapid rate of viral production. It is estimated that a trillion virions are produced per day from an infected person. In addition, the RNA-dependent RNA polymerase is error-prone. What that means is there are frequent mutations. So, hepatitis C exists as a family of mutant or related viruses. This heterogeneity is found in a couple of different ways that are clinically important. The first is genotype. Hepatitis C exists as 6 major genotypes that I will review a bit later. These are related, but different viruses. In fact, they are less than 60% identical. And then, when an individual human being is infected, hepatitis C exists as multiple variants, known as quasispecies. These are related viruses that have all changed over time.

HCV Life Cycle and DAA Targets
Receptor binding and endocytosis Transport and release Fusion and uncoating Translation and polyprotein processing ER lumen (+) RNA Virion assembly LD LD NS3/4 protease inhibitors LD DAAs, direct-acting antivirals; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain. Now, one of the advantages of direct-antivirals for hepatitis C virus is that, unlike some of other virus, like HBV, for example, hepatitis C has a number of potential targets for drug development, and this has led to multiple classes of direct-acting antivirals being developed. So, if we look at this schematic of the HCV life cycle, you can see that after the virus enters the cell, the viral RNA is translated to lead to the viral proteins and then these are chopped up by the virally encoded protease. And of course, the first direct-acting antivirals were inhibitors of the NS3/4A protease. Subsequently, the viral RNA is replicated, and again, the HCV NS5B polymerase has been a target for inhibition, with both nucleotide polymerase inhibitors and nonnucleotide or nonnucleoside polymerase inhibitors, which act by a different mechanism of action but target the same enzyme. In addition, after viral replication occurs, the virus must be assembled and part of the replication complex involved in assembly is the nonstructural 5A protein—or NS5A—and a number of direct-acting antivirals target the NS5A protein. So, at least to date, the DAAs that have gone through clinical development include protease inhibitors, nucleotide and nonnucleotide polymerase inhibitors, and NS5A inhibitors. As we consider the HCV life cycle and direct-acting antiviral targets, we should consider in fact that there are multiple steps in the life cycle and multiple steps at which inhibitors can be targeted. So following receptor binding and endocytosis of the virus in the hepatocyte through membrane receptors and coreceptors, there is a fusion of the viral genome and uncoating of that genome into the cytoplasm, whereupon it is translated into a long viral polyprotein, which is processed by both host and virally encoded proteases, including the NS3-4A protease, into mature peptides that carry out the business of replication of the virus. And that replication occurs on a replication complex found on a structure known as the membranous web, and here the NS5B polymerase is the business-end of replication in which the RNA strand is replicated into a complementary negative-strand RNA, and which in turn serves as a template for new plus-strand genomic RNA synthesis. And this is catalyzed by the NS5B RNA-dependent RNA polymerase, to which 2 classes of agents, both nucleoside and nucleotide polymerase inhibitors and nonnucleoside polymerase inhibitors which cause allosteric conformational changes of the polymerase to block access of the growing viral RNA chain, can lead to inhibition of viral replication through polymerase inhibition. Then virus assembly occurs, again, in the membranous web, through the endoplasmic reticulum, aided and abetted by the so-called lipid droplet, which carried viral proteins in opposition to other viral proteins. Once the assembly of the virus has occurred, then transport and release occur. The NS5A class inhibitors block both replication complex formation as well as assembly, and potentially it is an attractive class because it acts at multiple steps in the viral life cycle. Membranous web NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside RNA replication ER lumen *Block replication complex formation, assembly NS5A* inhibitors Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:

What Are the Key Elements of an Ideal HCV Regimen?
Easy Dosing Once daily, low pill burden Highly Effective High efficacy in traditionally challenging populations (ie, poor IFN sensitivity, cirrhosis) All Oral PegIFN/RBV replaced with alternate backbone with low chance of resistance IFN, interferon; pegIFN, peginterferon; RBV, ribavirin. So what are the key elements of an ideal HCV regimen? First it should be of course highly effective, with high efficacy in traditionally challenging populations, including those patients with limited interferon sensitivity and those patients with advanced liver disease, such as cirrhotics. It should be easily administered: Once daily, with a low pill burden, would be ideal. An all-oral regimen, in which peginterferon/ribavirin have been replaced by an oral backbone with a minimal development of resistance. Pan-genotypic regimens, one that can be used not across not just genotype 1, 2 and 3, but even other genotypes such as 4, 5, and 6. It should be simple: short duration, with simple and straightforward stopping rules. And it should be of course safe and tolerable, with few or easily manageable adverse events. Simple Regimen Short duration, simple, straightforward stopping rules Pan-Genotypic Regimen can be used across all genotypes Safe and Tolerable Few or easily manageable adverse effects

HCV Therapy: Past, Present and Future
Frequent curability of diverse populations without IFN IFN-free DAA combinations (GT1) Ribavirin Suppression of HCV with DAA combination (PI + NI) Potential approval of other DAAs with IFN Proof of concept for DAA (PI) Telaprevir and boceprevir Interferon DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; IFN, interferon; NI, nucleotide polymerase inhibitor; P/R, peginterferon + ribavirin; RBV, ribavirin; SOF, sofosbuvir. Some of you will recall that interferon was first approved for hepatitis C at a thrice-weekly dose of 3 million units in about 1991, and we soon learned that the results, in terms of SVR, were quite meager, particularly in genotype 1 patients. The next major advance occurred in 1998 with the introduction of ribavirin, a relatively weak antiviral when given by itself, but it did augment considerably the SVR rate when added to interferon. The next advance was a modification rather than a quantum leap but was an important one nevertheless and consisted of the introduction of pegylated interferons, such that either peginterferon alfa-2b or -2a could be administered parenterally once a week, instead of 3 times a week, with somewhat better results and greater convenience for the patients, though still similar safety profiles. Some of you may recall the excitement that attended the presentation, at AASLD in 2002, of the first proof of concept for the ability to profoundly suppress HCV replication, specifically in genotype 1, with the first protease inhibitor studied clinically. It was called BILN-2061, and it was administered for only a few days, showing profound suppression, but unfortunately, its development was halted because of cardiotoxicity in a monkey model. Intense activity ensued for most of the next decade in the development of a variety of other direct-acting antivirals, both of the protease inhibitor class and other classes. And an exciting study was presented in 2009, showing the capacity to profoundly suppress HCV replication with a combination of a protease inhibitor called danoprevir and a nucleotide polymerase inhibitor called mericitabine. These drugs were given for 2 weeks, again with profound viral suppression, without the emergence of resistance, although it was not a study that was conducted for a sufficient duration of time to test the hypothesis of ability to attain SVR. Two major events in the evolution of HCV therapy occurred in 2011, with the introduction of the 2 protease inhibitors, telaprevir and boceprevir, after many years of work, culminating in completed phase III trials. But historically, I think 2011 will also go down, equally importantly, for the demonstration, finally, of proof of concept that you could cure hepatitis C infection without interferon—a concept which had been much debated amongst clinicians and scientists for years. There followed in the next year and a half the demonstration that not only could HCV be cured without interferon, but that it could be cured at an astonishingly high rate of SVR in diverse populations, without interferon. And we’ve now witnessed the very recent approval of another landmark development or set of developments, namely, the approval of the protease inhibitor simeprevir, a once-daily protease inhibitor, and sofosbuvir, a once-daily nucleotide polymerase inhibitor, each studied in phase III trials with interferon and ribavirin for patients with genotype 1 infection. Also of historical magnitude, we’ve witnessed the recent approval of the first ever oral interferon-free therapy—specifically, sofosbuvir and ribavirin—for patients with genotypes 2 and 3. We can expect the possible introduction of additional direct-acting antivirals in the next few months, perhaps, particularly, faldaprevir, another HCV protease inhibitor that’s completed its phase III trials. And we’re very excited about what seems to be the overwhelming likelihood of the holy grail of hepatitis C materializing—as shown in this diagram—in late 2014 or early 2015, namely, the introduction of highly effective interferon-free directing-acting antiviral combinations for patients with the highly prevalent genotype 1 that we see so much of in the United States, Europe, Japan, and other parts of the world. Curability of HCV without interferon Approval of simeprevir and sofosbuvir with IFN First approved IFN-free therapy: SOF + RBV for GT2/3 Pegylated interferons

Telaprevir - PROVE 100 80 60 Patients (%) 40 20 Wk 4 Wk 12 Wk 24 Wk 48
12-wk TVR + pegIFN/RBV (n = 17) 100 12-wk TVR + 24-wk pegIFN/RBV (n = 79) 81* 81* 12-wk TVR + 48-wk pegIFN/RBV (n = 79) 80 80 Control (n = 75) 71 71 67‡ 68 65 61† 60 59* 57 57 Patients (%) 47 45 41 40 35 33 TVR a novel investigational inhibitor of HCV NS3-4A protease Coadministration with pegIFN/RBV hypothesized to reduce risk of emergence of resistance mutations while enhancing antiviral potency of standard of care therapy Current study assessed efficacy and safety of combining TVR with pegIFN/RBV in treatment-naive genotype 1 HCV patients[2] Ability of combination to shorten duration of therapy also assessed 23 20 11 6 N/A N/A N/A 2 Wk 4 Wk 12 Wk 24 Wk 48 SVR Relapse Undetectable HCV RNA N/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control. McHutchison JG, et al. N Engl J Med. 2009;360:

Summary of Key Conclusions
12-week course of TVR with 24 or 48 weeks of pegIFN/RBV increased SVR rates in treatment-naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV TVR increased rate of treatment discontinuation due to adverse effects, predominantly anemia, rash, rectal symptoms (FIARRHEA) Small subset experienced virologic breakthrough with protease resistance mutations McHutchison JG, et al. N Engl J Med. 2009;360:

Treatment is more effective but much more difficult
No Free Lunch Treatment is more effective but much more difficult And unfortunately with these new agents, although they have improved efficacy, they have come with a host of other side effects, predominantly anemia. We’ve seen problems with rash. And of course, interferon is still required, so all of the interferon-associated side effects that we were already familiar with. So, clearly treatment’s more effective, but it’s certainly more difficult with the first-generation protease inhibitors. Jordan Feld, MD, MPH. Toronto Western Hospital Liver Centre

Other Issues With PI-Based Therapy
Pill burden Food requirement Resistance BOC, boceprevir; PI, protease inhibitor; RBV, ribavirin; TVR, telaprevir. And they have a number of other issues, including a high pill burden, a food requirement, significant number of drug interactions, and this looming concern about the development or emergence of antiviral resistance with these agents. BOC = 12/day RBV = 4-7/day TVR = 6/day RBV = 4-7/day CYP3A4 PI metabolites Drug-drug interactions

20 grams of fat… Breakfast Ideas
2-egg omelet with 1 ounce shredded cheese; oatmeal with 1 ounce nuts and ½ tablespoon butter; toast with 2 tablespoons unsalted peanut butter and glass of 2% milk; bagel with 2 tablespoons cream cheese and glass of whole milk 1 egg and 1-3 sausage links (check sausage label, need 15 g fat) Lunch / Dinner 6 ounces salmon; ½ box prepared macaroni and cheese; 3 tablespoons of 2 cups of canned chili with meat; sandwich with 3 slices bologna; 1½ beef hot dogs; 1 chicken leg and thigh with skin; burrito with beans, cheese, and guacamole; 2 pork chops; french fries, medium order; quarter-pound hamburger or double cheeseburger

Drug–Drug Interactions a Clinical Challenge With Current Therapy
Several drugs contraindicated; many more require dose adjustment or caution Drug Class Contraindicated With BOC[1] Contraindicated With TVR[2] Alpha 1-adrenoreceptor antagonist Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin N/A Antimycobacterials Rifampin Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents Cisapride Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum HMG CoA reductase inhibitors Lovastatin, simvastatin Oral contraceptives Drospirenone Neuroleptic Pimozide PDE5 inhibitor Sildenafil or tadalafil when used for tx of pulmonary arterial hypertension Sedatives/hypnotics Triazolam; orally administered midazolam Orally administered midazolam, triazolam BOC, boceprevir; GI, gastrointestinal; N/A, not applicable; TVR, telaprevir; tx, treatment. Another issue besetting first-generation protease inhibitors are drug–drug interactions, which pose a real clinical challenge with the current regimens. As you can see here from this table, there are extensive drug–drug interactions as a result of the fact that boceprevir and telaprevir are extensively metabolized by CYP3A4. Moreover, not only are they substrates of 3A4, but they are also inhibitors of that 3A4 enzyme as well, so that, ultimately, there are contrary indications for the use of either boceprevir/telaprevir with a whole series of commonly administered agents, including alfa-1 adrenergic receptor antagonists; anticonvulsants; antimicrobacterials; ergot derivatives; GI motility agents like cisapride; herbal products, which we can’t forget, such as St John’s wort; HMG CoA reductase inhibitors such as lovastatin and simvastatin; oral contraceptives, for which boceprevir has been shown to actually lower drospirenone levels, making the efficacy of the contraceptives potentially at risk; neuroleptics; PDE5 inhibitors such as sildenafil or tadalafil, particularly when used for treatment of pulmonary hypertension; and sedatives and hypnotics such as benzodiazepines. So a careful inventory therefore of a patient’s medical regimen and concomitant medications is essential before embarking on a course of therapy. 1Boceprevir [package insert]. November Telaprevir [package insert]. October 2012.

Limited Efficacy With Telaprevir and Boceprevir in Some Patient Groups
100 75-83[1,2] 80 68-75[3,4] 42-62[3,4] 53-62[3,4] 60 40-59[1,2] SVR (%) 29-40[1,5] 40 20 SVR, sustained virologic response; TVR, telaprevir. On this slide, these are the pooled arms in phase III clinical trials of boceprevir and telaprevir, analysis was performed based on prior treatment response history, such that relapsers experienced excellent rates of response when subsequently retreated with peg, ribavirin, and telaprevir or boceprevir. Partial responders did less well, and null responders did least well. Null responders are defined as those patients who failed to experience a 2 log or greater HCV RNA decline with peginterferon- and ribavirin-based therapy. You will note that in subgroups that included cirrhotics—so when histology was considered, cirrhotic null responders had an even more poor response, namely, 14% in the REALIZE trial. So it’s fairly clear, then, that there is a descending order of efficacy based on the difficult-to-treat nature of the patients, whether it’s in regard to prior null response or advanced liver histology. 14[6]* Relapser Naive White/ Nonblack Naive Cirrhotic Naive Black Partial Responder Null Responder Cirrhotic Null Responder *Pooled TVR arms of REALIZE trial. 1. Zeuzem S, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Poordad F, et al. N Engl J Med. 2011;364: Bronowicki J, et al. EASL Abstract Zeuzem S, et al. EASL Abstract 5.

Question A) get a liver biopsy – this will help me decide
A 44 year old male with a history of prior heroin abuse (clean for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed? A) get a liver biopsy – this will help me decide B) He cannot receive therapy due to comorbidities C) Treat with just IFN/ribavirin, he will not likely tolerate a PI D) Treat with just telaprevir, he will not likely tolerate IFN E) wait for something better

Answer A) get a liver biopsy – this will help me decide
A 44 year old male with a history of prior heroin abuse (clean for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed? A) get a liver biopsy – this will help me decide B) He cannot receive therapy due to comorbidities C) Treat with just IFN/ribavirin, he will not likely tolerate a PI D) Treat with just telaprevir, he will not likely tolerate IFN E) wait for something better

Standard of Care of Chronic HCV Infection- October 2014
Genotype Regimen Duration Considerations 1 Sofosbuvir + Ledipasvir (FDC) 12 weeks (24 for experienced cirrhotics) FDA approved, not yet in guidance Sofosbuvir + IFN/RBV 12 weeks Minimal drug interactions Sofosbuvir + Simeprevir +/- RBV Off label to date For IFN ineligible 2 Sofosbuvir + RBV 3 24 weeks . So this table shows the standard of care that is anticipated in 2013 with the approval of newer agents,namely Sofosbuvir- NS5B inhibitor and Simeprevir- NS3/4A PI. . So in GT2 rather than using pefIFN and RBV, we are going to use Sofosbuvir and RBV.And it is going to be short course of Rx- 12 weeks compared with the current 24 weeks recommendation. . In GT3 Sofosbuvir might be less effective hence the duration of Rx is expected to be 16 weeks. . In GT1 infected pts, we are going to be using Sofosbuvir together w IFN and RBV or Simprevir together with IFN/RBV. The evidences for these agents use came from 4 large studies- FISSION and NEUTRINO studies for Sofosbuvir and Quest ½ studies for Simeprevir.. . Because of time constraints I will not go into the details of those studies

NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level
SVR12 According to Genotype SVR12 According to Fibrosis Level 100 100 96 100 92 89 80 80 80 60 60 SVR12 (%) SVR12 (%) David R. Nelson, MD: In a breakdown of the groups based on their genotype, patients with genotype 1 HCV had an SVR rate of 89%, and the small number of patients with genotype 4, 5 and 6 HCV had SVR rates between 96% and 100%. Overall, this sofosbuvir-based triple-therapy regimen resulted in very high SVR rates across all genotypes evaluated, with some of the highest SVR rates seen in an interferon-containing registration trial. Cirrhosis continues to be a significant factor affecting response rates in HCV therapy. In the NEUTRINO trial, there was a decrease in the overall response rates for patients with cirrhosis (SVR 80%) compared with noncirrhotics (SVR 92%). These data suggest that high cure rates are possible with short duration therapy in cirrhotics, who typically require 48 weeks of treatment with the current triple-therapy regimen, but also emphasize that cirrhosis still represents a negative host factor for response to these new therapies. Stefan Zeuzem, MD: I agree that cirrhosis is really the key problematic factor for HCV treatment, and although this 80% SVR rate is an impressive result, we still need to further improve treatment for this patient population, which will benefit the most from viral eradication. I would very much like to see future studies prolonging the duration of therapy since this was a short-duration regimen of only 12 weeks of therapy. Other studies are evaluating regimens containing additional DAAs to try to further improve the results for our patients with cirrhosis. Paul Y. Kwo, MD: Another important point from the NEUTRINO study is that nearly all patients achieved an end of treatment response. With sofosbuvir-based therapies, when treatment fails in either cirrhotic or treatment-naive patient populations, it is almost always due to virologic relapse and not, to date, resistance. Again, I want to echo that we do need to find ways to treat more difficult patient populations, such as those with cirrhosis. However, viral suppression with sofosbuvir-based therapies appears to occur in virtually all patients. 40 40 20 20 n/N = 261/292 27/28 7/7 252/273 43/54 GT 1 GT 4 GT 5,6 No Cirrhosis Cirrhosis Lawitz E, et al. EASL Abstract N Engl J Med 2013; 368:

COSMOS: SVR12 in Cohorts 1 and 2 by HCV Subgenotype and Baseline Q80K
GT1b GT1a without Q80K GT1a with Q80K Cohort 1 (F0-F2 Nulls)*[1] Cohort 2 (F3-F4 Naives/Nulls)*[2] 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 93 95 96 89 89 89 88 88 83 80 60 40 GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response. Q80K – naturally occurring polymorphism in NS3, rendering virus less susceptible to certain PIs 20 4/ 4 7/ 7 8/ 9 3/ 3 7/ 7 3/ 3 6/ 6 12/ 12 8/ 9 4/ 4 4/ 4 5/ 6 7/ 17 30/30 24/27 6/ 6 11/ 11 11/ 11 4/ 4 7/ 7 4/ 4 5/ 5 13/ 14 7/ 8 3/ 3 7/ 8 3/ 3 18/ 18 38/ 40 25/ 26 SMV/SOF + RBV SMV/SOF SMV/SOF+ RBV SMV/SOF SMV/SOF ± RBV SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOF SMV/SOF ± RBV 24 Wks 12 Wks Overall 24 Wks 12 Wks Overall *Excluding patients who discontinued for nonvirologic reasons. 1. Sulkowski M, et al. EASL Abstract O7. 2. Lawitz E, et al. EASL Abstract O165.

TURQUOISE II: SVR12 With 3 DAAs + RBV in Cirrhotic Pts by HCV Subtype
GT1a 12 wks GT1b 93.3 100 100 100 92.9 92.2 92.9 24 wks 100 100 100 100 85.7 100 100 100 100 100 80.0 80 80 60 60 SVR12 (%) 40 40 DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response. Well tolerated: ALT elevation asymptomatic, transient, improved/resolved with continued dosing Bilirubin elevation transient, predominantly indirect, did not result in discontinuation Hemoglobin decrease managed with RBV dose reduction in 34 of 380 pts (8.9%) 20 20 59/64 52/56 14/15 13/ 13 11/11 10/10 40/50 39/42 22/22 18/18 25/25 20/20 6/7 3/3 14/14 10/10 Naive Relapse Partial Response Null Response Naive Relapse Partial Response Null Response Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders Poordad F, et al. EASL Abstract O163

Summary of Investigational HCV Agents
Class Drug Dosing NS3/4A protease inhibitor ABT-450/RTV 150/100 mg NS3 protease inhibitor Asunaprevir 200 mg BID Faldaprevir 120 mg or 240 mg QD GS-9451 200 mg QD MK-5172 100 mg QD Simeprevir* 150 mg QD NS5B nonnucleoside polymerase inhibitor ABT-333 400 mg BID BMS 75 mg or 150 mg BID Deleobuvir 600 mg BID GS-9669 500 mg QD NS5B nucleotide polymerase inhibitor Sofosbuvir* 400 mg QD NS5A inhibitor ABT-267 25 mg QD Daclatasvir 30 mg BID or 60 mg QD Ledipasvir** 90 mg QD MK-8742 20 or 50 mg QD PI-688 Daclatasvir approved in Europe, and part of the 2014 EASL guidelines *FDA approved December 2013; **October 2014

Approximate SVR in naïve/relapsers
Regimen Genotype Mechanism of Action Approximate SVR in naïve/relapsers Daclatasvir + Sofosbuvir +/- RBV 1,2,3 NS5A/NS5B polymerase 98/92/89% ION-1,2,3: Sofosbuvir + Ledipasvir (FDC) +/- RBV N Engl J Med Apr 11. 1, naïve and previously treated Polymerase / NS5A 97-99% Sof/LDV + RBV or GS 9669 1 Polymerase / NS5A inhibitor + non-nuc. 100/100% SAPPHIRE-I and –II: ABT-450/RTV + ombitasvir + Dasabuvir + RBV N Engl J Med 2014;370:17. Protease/NS5A/NS5B polymerase/ritonavir >95% TURQUOISE-II: N Engl J Med Apr 11. [Epub ahead of print] 1, cirrhosis 92-96% C-WORTHY: MK-5172/MK /- RBV 2nd gen protease, NS5A 90-100 HALLMARK-DUAL: Daclatasvir + asuneprevir 1b NS5A / 2nd gen protease 73-91% ION-3: SOF/LED +/- RBV 8 or 12 weeks – 93-95% naïve, no cirrhosis The Liver Meeting 2013, Washington, D.C.; EASL 2014, London, U.K.

Enter the Nonspecialist:
Will Evolving Hepatitis C Therapies Reduce the Need for Specialized Care? Graham R. Foster, FRCP, PhD - 10/8/2013 “A rapid expansion of patients and providers will mirror improving efficacies and gentler adverse event profiles…the introduction of a single-tablet regimen for HCV therapy—a development that will propel hepatitis C care to its future in nonspecialist providers offices. Information will be the key to overcoming preconceptions about adverse events and regimen complexities, finally allowing nonspecialists to take a central role in caring for HCV-infected patients”. Although the next wave of regimens for genotype 1 will continue to require interferon, before too long, I anticipate additional regimens that will remove the need for interferon. At some point thereafter, I expect ribavirin will go by the wayside, finally eliminating the last of the adverse events associated with the peginterferon/ribavirin-based regimens. Once this occurs, the numbers of patients initiating therapy will likely explode and the numbers and types of providers treating them will also increase significantly. This expansion of patients and providers will mirror improving efficacies and gentler adverse event profiles, but ongoing complexities of care probably will remain as a limiting factor for many nonspecialist providers. This is only likely to change with the introduction of a single-tablet regimen (STR) for HCV therapy—a development that will propel hepatitis C care to its future in nonspecialist providers offices. We must recognize that to take full advantage of these new agents, educating these providers and their patients must remain a priority. Information will be the key to overcoming preconceptions about adverse events and regimen complexities, finally allowing nonspecialists to take a central role in caring for HCV-infected patients. After the advent of the STR, what will be the place of the specialist? We will take a step back as nonspecialists gradually assume a larger role managing patients with few comorbidities and little or no liver disease. Graham Foster – hepatologist at St Marys University of London

Parting thoughts The last word…
“Back to the Future”…? The future is here. Liang and Ghany “The Costs of Success” Hoofnagle and Sherker Although this is likely to be the tip of the iceberg, we are living in an era when we are able to offer safe and effective therapy to people who previously had no good options: the “democratization” of hepatitis C therapy (Ira Jacobsen). This is an historical event with potential for huge public health successes. “The future is here”, but in order to globally apply these successes to those most in need we must address the COST problem. “The predicted costs of the new agents are as breathtaking as their effectiveness” – editorial April 2014 NEJM – Jay Hoofnagle, NIH

Connecticut Infectious Diseases Society Annual Meeting, New Haven, CT
Connecticut Infectious Diseases Society Annual Meeting, New Haven, CT. May 15, 2014

A Local Performance Site of the New England AETC

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