Report Hepatitis Management: State of the Art

Transcription

1 Introduction The first annual conference, Hepatitis Management: State of the Art, provided an overview of the burdens associated with hepatitis infections, a review of current treatment issues in the management of hepatitis B virus infection, and an in depth exploration of the virology and clinical management of hepatitis C virus (HCV) disease. Given the increasing prevalence of its complications and complex biology, HCV held the center stage of the conference. The group of 16 renowned faculty members offered their insights through in depth presentations on hepatitis research, clinical management, and case studies; they also addressed a range of attendees questions regarding specific patient situations. At the end of this report is a faculty recommended list of journal articles and other resources on the topics presented during the course. 1

2 The Burden of Viral Hepatitis In his presentation, The Burden of Viral Hepatitis, David L. Thomas, MD, MPH, sketched the context into which all the issues discussed by other faculty members would fit. Although acute hepatitis causes some morbidity and mortality, by far the greatest impacts on individual and public health are due to chronic infection with either hepatitis B virus (HBV) or hepatitis C virus (HCV). Along with the medical complications of cirrhosis and hepatocellular carcinoma (plus vasculitis and dermatologic and central nervous system complications), chronic hepatitis infection has significant economic, personal (reduced quality of life, stigma), and societal implications. Economics of Hepatitis Dr. Thomas offered sobering numbers illustrating the very large economic burden of chronic hepatitis and its implications in the United States: $5.46 billion HCV related costs in 1997 o Chronic HCV: 92% o Hepatocellular carcinoma (HCC): 8% Cirrhosis and liver disease related costs (2004) o Direct costs: $2.5 billion o Indirect costs: approximately $10.6 billion All cause costs paid by managed care plans ( ) o HCV positive patients: $20,961 (HCV related: $6,864 per person annually) o HCV negative patients: $5,451 Prevalence World Health Organization (WHO) estimates have placed the numbers of chronic hepatitis infections at: HBV 350 million individuals HCV 170 million individuals These figures are several years old, and new ones are expected to become available in In addition, the global distribution of these epidemics is far from even: HBV infection o < 1% to 2% of persons born in Scandinavia have chronic HBV o 10% of persons born in some regions of Asia HCV infection o 1% to 2% of persons in the United States and Europe o 15% of persons > 30 years of age in Egypt US epidemics. Prevalence estimates for the United States are: HBV 1 to 2 million persons HCV 3 to 5 million persons Lack of surveillance funding and the demographics of the affected populations account for the imprecision of these estimates: 2

3 Increasingly, immigrants from HBV endemic regions comprise a large proportion of the chronic HBV epidemic e.g., Asian Pacific Islanders comprise < 5% of the US population but > 50% of chronic HBV cases. Disproportionate numbers of HBV infections occur among injection drug users (IDUs), men who have sex with men (MSM), persons with other sexually transmitted diseases, and hemodialysis patients. HCV infection occurs primarily among IDUs, with some infections related to noninjection drug use and outbreaks among MSM. Mortality The WHO estimates that globally chronic hepatitis has one of the highest impacts of all infectious diseases: HCC is the third leading cause of cancer related mortality and one of the few types of cancer with increasing incidence. Together, HBV and HCV account for > 50% of the global burden of cirrhosis (30% and 27%, respectively) and > 75% of HCC cases (53% and 25%, respectively). Using 2002 worldwide mortality estimates, these percentages represent 929,000 deaths due to chronic HBV and HCV infections (446,000 cirrhosis and 483,000 HCC deaths). In the United States, chronic HCV infection is the principal cause of hepatitis related mortality and the leading cause of liver transplantation. The age adjusted The age-adjusted incidence of HCC in the United States tripled from 1975 to 2005, with approximately 50% attributable to HCV. incidence of HCC in the United States tripled from 1975 to 2005, with approximately 50% attributable to HCV. Current projections anticipate a doubling of the public health impact of chronic HCV infection in the next decade. During the period 1999 to 2007, as HIV related mortality declined, chronic HCV related mortality was increasing and now exceeds HIV related mortality. Controlling the Burdens Despite such sobering statistics, Dr. Thomas expressed confidence that the burdens of chronic hepatitis infection can be reduced and controlled. In fact, in some sectors, considerable success has already been achieved: Post transplantation hepatitis infections decreased dramatically with the introduction of screening procedures for HBV in the 1970s and for HCV in the 1990s. Introduction of an HBV vaccination program in Taiwan was associated with a reduction in childhood HCC from 0.52 per 100,000 population during 1974 to 1984 to 0.13 per 100,000 population during 1984 to Besides prevention efforts, treatment also represents an important strategy in controlling the burden of hepatitis. Several studies have demonstrated that patients who achieve sustained virologic response (SVR) with HCV treatment experience significantly less morbidity (e.g., HCC and end stage liver disease) and mortality. Despite such successes, further improvements will require more comprehensive efforts to identify and treat patients infected with HCV. Even the most efficacious treatments, Dr. Thomas stressed, will not help if patients are not identified and linked to care. Whereas an estimated 80% of HIV infected persons in the United States are aware of their HIV status, < 50% of chronic HBV and HCV infections have been 3

4 diagnosed. With 65.6% of HCV infected persons born during the 1945 to 1965 period, routine screening of individuals in this birth cohort may represent one approach to achieving greater diagnosis and successful treatment, and a recent study has reported that such screening can be cost effective. Dr. Thomas cited the success of the President s Emergency Plan for AIDS Relief (PEPFAR) in reducing HIVrelated mortality as an example of the success that can be attained when significant funding and other resources are committed to combating a chronic infectious disease. He concluded by citing data demonstrating the dramatically lower amounts of funding allocated to HBV and HCV research, prevention, and care vs. those allocated to HIV. Hepatitis B Management After Dr. Thomas s overview of the burdens of chronic hepatitis, with her presentation, Hepatitis B Management, Marion G. Peters, MD, discussed issues of testing, diagnosis, treatment, and patient outcomes in hepatitis B virus (HBV) infected patients. She began by stressing that chronic HBV infection is a lifelong, dynamic condition requiring careful monitoring: Increased risk of end stage liver disease and hepatocellular carcinoma (HCC) in adults who have ongoing inflammation and viremia Fibrosis potentially reversible Decreased fibrosis progression possible with medications HBV controllable but not curable Reactivation possible even in patients who have lost hepatitis B surface antigen (HBsAg) Testing Recommendations The fact that HBV prevalence in the United States is greater than previously thought especially among Asian/Pacific Islanders underlines the importance of testing and diagnosis. The US Centers for Disease Control and Prevention (CDC) recommends that members of these populations should be tested for HBV infection: Blood and organ donors Hemodialysis patients 4

5 Pregnant women Infants of HBsAg positive mothers Behavioral contacts o Family and household members o HIV positive patients o Men who have sex with men (MSM) o Injection drug users (IDUs) Individuals from countries where HBV prevalence is 2% Patients receiving immunosuppressive therapy Patients with abnormal alanine aminotransferase (ALT) of unknown cause Treatment After screening but before deciding whether treatment is indicated, clinicians must ascertain the status of a patient s HBV infection. Even patients who lose serum HBsAg and acquire hepatitis B surface antibodies (HBsAb) can experience reactivation under potent immune suppression because they may have covalently closed circular DNA (cccdna) in hepatocyte nuclei. Currently no successful therapy is available for patients in the immune tolerant phase and with inactive chronic hepatitis B. The following are the characteristics indicating HBV control: Inflammatory normal serum ALT and biopsy Virologic decreased HBV DNA Immunologic seroconversion o HBeAg to HBeAb o HBsAg to HBsAb Patients with active viral replication that is causing liver inflammation and fibrosis are candidates for antiviral therapy an approach agreed upon by guidelines from the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and expert panels. However, specific details of these guidelines vary such as levels of serum ALT and HBV DNA indicating need for therapy. 5

6 HBeAg positive patients with HBV DNA > 20,000 IU/mL with persistently elevated ALT for 3 to 6 months should be treated. For HBeAg negative patients, a lower level of HBV DNA, > 2000 IU/mL, is utilized. Because HBV DNA and ALT levels may wax and wane in HBeAg negative patients, their levels should be monitored for 3 to 12 months to determine the need for therapy. Although not required before treatment, liver biopsy can help determine the severity of fibrosis, especially in HBeAg negative patients and in those who have mildly elevated ALT or lower HBV DNA levels than those the guidelines recommend for therapy. Certain additional patients who may not meet criteria recommended in the guidelines could benefit from therapy: Patients with cirrhosis and detectable serum HBV DNA Patients with decompensated cirrhosis or organ transplantation Some patients with acute hepatitis B or during pregnancy Patients with HCV, hepatitis D virus (HDV), or HIV coinfection Patients with chronic renal failure Patients undergoing chemotherapy or treatment with biologic response modifiers Patients with HBV should also be screened for coinfection with HCV, HIV, and HDV. Medications Currently licensed agents for treatment of HBV infection include: Adefovir Entecavir Interferon alfa 2b Lamivudine Pegylated interferon alfa 2a Telbivudine Tenofovir First line therapy should employ one of the potent oral antiviral agents (eg, entecavir or tenofovir) or pegylated alfa interferon. These therapies have shown the highest response rates with respect to: Loss of HBeAg (only in HBeAg positive patients) Loss of serum HBV DNA Loss of HBsAg, in a minority of patients Pegylated interferon is given as weekly injections for 12 months. Treatment with oral antivirals should continue in patients who are HBeAg positive for 12 months after loss of HBeAg and acquisition of HBeAb. Durability of response is nearly 80%. HBeAg negative patients, however, may need to continue to receive therapy for life. In patients with lamivudine resistant HBV and in pregnancy, tenofovir is the preferred treatment. Potential tenofovir associated renal abnormalities and bone loss require patient monitoring. Tenofovir toxicity. Signs of tenofovir toxicity include: Fanconi syndrome Acute tubular necrosis 6

7 Nephrogenic diabetes insipidus (rare) Pregnancy Considerations Many women with chronic HBV infection are immune tolerant during pregnancy. Treatment during pregnancy e.g., lamivudine for 1 month has been associated with decreased risk of transmitting HBV to the newborn. Pregnant women with chronic active HBV disease should receive standard treatment according to the guidelines. Children born to HBsAg positive mothers should receive hepatitis B immunoglobulin and the first dose of HBV vaccine within 24 hours of birth, with subsequent vaccine doses at 1 and at 3 to 6 months of age. HBV Reactivation High rates of HBV reactivation occur in immunosuppressed patients who have been infected with HBV, so that routine screening for hepatitis markers is appropriate in: Patients receiving chemotherapy HIV positive individuals, following immune reconstitution Post transplantation organ recipients Patients receiving steroids or biologic response modifiers e.g., rituximab, TNF inhibitors Hepatitis C Management In his presentation on Hepatitis C Management, Ira M. Jacobson, MD, provided detailed information regarding how the 2011 approval of the first hepatitis C virus (HCV) protease inhibitors (PIs) has altered the landscape of HCV therapy. The last 10 years have brought refinements in the use of pegylated interferon plus ribavirin (PR) for the treatment of HCV infection: The importance of viral kinetics in predicting treatment failure and success, resulting in possibly shorter therapy or improved chance of sustained virologic response (SVR) in some patients The importance of weight based ribavirin in patients with HCV genotype 1 infection Identification of patient populations in whom therapeutic response is suboptimal or limited by safety considerations or both: o African Americans o HCV/HIV coinfected persons o Decompensated cirrhotics o Renal failure patients and liver transplant recipients SNPs. The discovery of a group of single nucleotide polymorphisms (SNPs) in the region of the IL28B gene represented a key development in PR therapy. These SNPs serve as the most powerful known baseline predictor of response to PR therapy, especially in genotype 1 patients. Approximately 70% of patients with the CC genotype vs 25% to 35% of those with the CT or TT genotype attain SVR when treated, and determination of IL28B genotype is now considered when making decisions regarding treatment. 7

8 Protease Inhibitors A major leap forward occurred with approval of the PIs telaprevir and boceprevir for use in patients with HCV genotype 1. Results of the registrational phase 3 trials demonstrated the superior efficacy of PIbased therapy over PR alone and laid the foundation for response guided therapy (RGT), by which total duration of therapy is shortened in patients who meet specific rapid response criteria. Dr. Jacobson then provided detailed overviews of the registrational trials for both telaprevir and boceprevir. ADVANCE and ILLUMINATE Studies Telaprevir therapy (750 mg 3 times daily) was initiated in treatment naive genotype 1 patients simultaneously with PR in a 12 week regimen (T12PR), followed by PR alone for either 12 weeks (for patients achieving undetectable HCV RNA at 4 weeks and maintaining it at 12 weeks i.e., extended rapid virologic response [ervr]) or 36 weeks (for patients having detectable HCV RNA at either 4 or 12 weeks). The ADVANCE trial demonstrated a marked increase in SVR in African American patients from 25% with PR to 62% with T12PR. However, those rates remained lower vs those in non African American patients (75%), indicating that host factors associated with impaired interferon response can be substantially overcome with potent direct acting antivirals (DAAs) coadministered with PR. In addition, patients with advanced fibrosis experienced an increase in SVR to 62% in the ADVANCE T12PR arm vs. 33% on PR alone, although SVR rates remained lower vs. patients with no or mild fibrosis, in whom the SVR rate was 78%. Virologic failure during the first 12 weeks (3%) was associated with high level telaprevir resistance, but subsequent failure was associated with increased wild type virus or lower level telaprevir resistance. However, clinicians considering discontinuation of telaprevir at 8 weeks due to adverse effects should be aware that there is only a slightly lower probability of attaining SVR. Adverse events associated with use of telaprevir included: Pruritus Rash (predominantly eczematous) Anemia Nausea Diarrhea Anorectal symptoms The primary laboratory abnormality observed was an incremental hemoglobin decline of a mean of slightly more than 1 g/dl. In the pooled telaprevir groups, 38% had a decline in hemoglobin to < 10 g/dl vs 14% of controls; 9% of the telaprevir patients vs. 2% of controls had decline in hemoglobin to < 8.5 g/dl. Use of erythropoiesis stimulating agents (ESAs) was excluded from the trials. The results of the ADVANCE trial strongly suggested that 24 weeks of total therapy were sufficient for patients who achieved ervr. ILLUMINATE, a supportive phase 3 trial, randomized patients attaining ervr on a T12PR regimen to 24 vs. 48 weeks of therapy (T12PR24 and T12PR48, respectively). Patients who had failed to attain ervr received T12PR48. ILLUMINATE established the noninferiority of T12PR24, with a 92% SVR rate vs. 88% 8

9 for those receiving T12PR48, among patients who attained ervr. A subanalysis showed that, among cirrhotics with ervr, 67% of those on T12PR24 had SVR, vs. 92% on T12PR48. REALIZE Study The REALIZE study evaluated the efficacy of 2 telaprevir regimens in PR experienced relapsers, partial responders ( 2 log decline in HCV RNA at week 12 of prior therapy), and null responders (< 2 log decline in HCV RNA at week 12 of prior therapy). There were 3 study arms for each group: Telaprevir plus PR from the outset for 12 weeks 4 week PR lead in followed by 12 weeks of triple therapy PR control arm for 12 weeks Response guided therapy (RGT) evaluation was not performed. Response rates were: Relapsers: 86% Partial responders: 57% Null responders: 31% Although there were no significant SVR differences between the lead in and non lead in arms, these rates demonstrated significant superiority vs. those receiving PR alone. SVR rates in patients with advanced fibrosis or cirrhosis were substantially lower. SPRINT 2 Study The phase 3 SPRINT 2 study evaluated boceprevir 800 mg 3 times daily in treatment naive genotype 1 patients, employing a lead in PR phase in all boceprevir arms; the study also evaluated RGT: Control arm: peginterferon alfa 2b 1.5 μg/kg/week plus ribavirin 600 to 1400 mg/day for 48 weeks 4 week PR lead in followed by addition of boceprevir for 48 weeks RGT guided arm: 4 week PR lead in followed by the addition of boceprevir o If HCV RNA was undetectable at week 8 through week 24, all therapy discontinued at week 28 o If HCV RNA was detectable at week 8 but undetectable by week 24, triple therapy continued until week 28, followed by PR for another 20 weeks for a total treatment of 48 weeks The trial was divided into: Cohort 1 (non African Americans) o Control arm SVR rates: 40% (relapse: 23%) o 48 weeks of treatment SVR rates: 68% (relapse: 8%) o RGT arm SVR rates: 67% (relapse: 9%) Cohort 2 (African Americans) o Control arm SVR rates: 23% (relapse: 14%) o 48 weeks of treatment rates: 53% (relapse: 17%) o RGT arm SVR rates: 42% (relapse: 12%) Adverse events. The main adverse events observed were anemia and dysgeusia. Use of erythropoiesisstimulating agents was permitted, and ribavirin dose reduction was more common with boceprevir than without it. Clinicians may consider use of ESAs for individual patients, recognizing the potential adverse 9

10 effects and the fact that they are not licensed for use in HCV management. However, in most patients the first approach to address treatment induced anemia should be ribavirin dose reduction. RESPOND 2 Study The RESPOND 2 study evaluated the efficacy of boceprevir 800 mg 3 times daily in relapsers and partial responders, but not in null responders: Control arm: 4 week PR lead in followed by PR plus placebo through week 48 (SVR = 21%) 48 week treatment arm: 4 week PR lead in followed by PR plus boceprevir through week 48 (SVR = 66%) RGT arm: 4 week PR lead in followed by the addition of boceprevir (SVR = 59%): o If HCV RNA undetectable at week 8, all therapy discontinued at week 36 o If HCV RNA undetectable at week 8 but detectable at week 12, triple therapy for 32 more weeks, followed by a 12 week PR tail for a total treatment of 48 weeks Most of the disparity in SVR between the RGT and 48 week groups was due to the cirrhotic patients; the prescribing information now recommends that cirrhotics, whether treatment naive or experienced, be considered ineligible for RGT. Resistance Telaprevir and boceprevir have generally similar resistance profiles, with the resistance barrier for HCV genotype 1a being lower vs. genotype 1b. Therefore, genotype 1b patients experienced slightly higher SVR rates vs. genotype 1a patients. Most patients who experience virologic failure with PI therapy will retain resistant variants, which, if they persist, could make them less suitable to receive future regimens that include these or other PIs having similar resistance profiles. However, currently available data indicate a steady decline in the prevalence of the resistant variants over time. Whether this decline represents reconstitution of the patient s same viral population as before treatment is unclear; it is also unclear what degree of reconstitution is necessary to restore the patient to being eligible for repeat PI therapy. For now, clinicians should mention but not overemphasize the issue of resistance and the uncertainties surrounding it. No patients for whom PI therapy is approved should be categorically denied access to PIs, but some, such as null responders, should be informed that their risk of resistance is higher than other groups. Drug drug Interactions Both boceprevir and telaprevir are strong inhibitors of CYP3A4, which is involved in the metabolism of numerous drugs, thereby creating the potential for significant elevations of the levels of other drugs that are substrates of CYP3A4. On the other hand, drugs that induce CYP3A4 could result in lower PI exposures, with the potential risk for treatment failure. Therefore, the package inserts for both PIs contain lists of contraindicated drugs and longer lists of drugs that must be used with caution. Clinicians must have ready access to this information during patient visits and carefully review each patient s medication list for potential interactions. (For more information about drug drug interactions, please see the section in this report, Pharmacokinetics and Drug Interactions. ) 10

11 Stopping Rules and RGT The package inserts for telaprevir and boceprevir provide lists of the stopping (futility) rules, as well as algorithms for RGT for each drug. Some of these differ from the phase 3 trial procedures and were based on re analyses of the data around the time of the FDA approval and labeling processes. (For more information about stopping rules and RGT, please see the sections in this report, Adverse Events Management and Preparing the Patient for DAA Therapy, respectively.) The 10 Commandments Dr. Jacobson concluded his presentation with the 10 Commandments of PI Therapy : I. You shall not use PIs as monotherapy, nor with ribavirin in the absence of interferon. II. You shall not try to replace ribavirin with a PI, nor shall you use 2 PIs together. III. You shall emphasize the importance of adherence to your patients. IV. You shall understand how and when to apply response guided therapy, and know which patients are not eligible for it (cirrhotics, PR nonresponders). V. You shall be aware of the futility rules and apply them consistently. VI. You shall explain the principles of viral resistance to patients at an appropriate level. VII. You shall understand the differences in outcomes between genotypes 1a and 1b. VIII. You shall be aware of drug drug interactions and be constantly mindful of what medications your patients are taking. IX. You shall be aware of, and know how to manage, the toxicities of PIs that you use. 11 The 10 Commandments I. You shall not use PIs as monotherapy, nor with ribavirin in the absence of interferon. II. You shall not try to replace ribavirin with a PI, nor shall you use 2 PIs together. III. You shall emphasize the importance of adherence to your patients. IV. You shall understand how and when to apply response-guided therapy, and know which patients are not eligible for it (cirrhotics, PR nonresponders). V. You shall be aware of the futility rules and apply them consistently. VI. You shall explain the principles of viral resistance to patients at an appropriate level. VII. You shall understand the differences in outcomes between genotypes 1a and 1b. VIII. You shall be aware of drug-drug interactions and be constantly mindful of what medications your patients are taking. IX. You shall be aware of, and know how to manage, the toxicities of PIs that you use. X. You shall be aware of ongoing developments to optimize your ability to help your patients make informed decisions.

12 X. You shall be aware of ongoing developments to optimize your ability to help your patients make informed decisions. Audience Questions Should pregnant women be screened for HCV antibodies? Dr. Jacobson replied that the CDC does not recommend such testing, primarily on the ground that there is no proven method for prevention of mother to child transmission of HCV infection. In addition, the drugs used in HCV treatment are teratogenic. He further explained that the recommendation for agecohort HCV screening which would include many women of child bearing age is the most effective way to identify infected individuals. In a cirrhotic HCV infected patient who has achieved SVR, how often should screening for HCC be performed? Dr. Jacobson said that this requires a good news, bad news answer for such patients, the risk for HCC decreases dramatically, but it never completely disappears. He advised that imaging be performed for these patients every 6 months indefinitely. He added that clinicians who do not regularly screen patients like this will eventually lose a patient. How should a clinician deal with the case of a healthcare worker who has experienced a large bore needle stick injury while treating an HCV infected patient with high viral load? Dr. Jacobson replied that although the risk of HCV transmission in such settings is 2% to 3%, the worker should be tested immediately. He also advised the early performance of a PCR screening and, if treatment is warranted, the worker should receive pegylated interferon/ribavirin. There may also be a role for checking the worker s IL28B genotype, as persons with the CC genotype are more likely to clear HCV spontaneously. In the era of DAAs for treatment of HCV infection, what should the role of liver biopsy be? According to Dr. Jacobson, biopsy is the most useful tool in not just deciding whether to initiate HCV treatment but also in making intra treatment or post treatment decisions, as there will be baseline biopsy data against which to compare any future findings. 12

13 HCV Virology Introduced as the dean of hepatitis C research, Charles M. Rice, PhD, discussed HCV Virology, with the aims of shedding light on how the hepatitis C virus (HCV) is studied in the laboratory, what the steps in its lifecycle are, and which viral and host factors could be targets for therapeutic intervention. Since the discovery of HCV in 1989, the clinical goals of research have been straightforward, although the virus itself certainly is not: To prevent HCV infection by: o Assuring the safety of the blood supply a goal that has been achieved o Developing education efforts and potentially a vaccine for members of groups at high risk for infection Providing successful treatment for HCV infected persons by: o Identifying infected individuals o Improving currently available treatments Eradicating the virus from infected individuals Two primary challenges have slowed progress to achieving these goals through HCV research: HCV replicates poorly in cell cultures. Until recently, there had been no small animal model in which productive infection can be introduced. Chimpanzees can be infected, but ethical concerns have increasingly called use of that model into question. Investigative Tools HCV, a hepatotropic pathogen and a member of the flavivirus family, replicates in human hepatocytes; it is a cytoplasmic virus i.e., it does not incorporate its genome into the host cell s nucleus. In 1993, its genome was shown to be of the positive strand RNA type, consisting of a long polyprotein that is cleaved prior to replication by a combination of viral and cellular proteases into 10 segments. By 1997, researchers developed the first HCV infectious clone, using an HCV strain obtained from a patient experiencing acute non A, non B hepatitis. This allowed the transcription of full length HCV RNA, which was then introduced to both a chimpanzee and cell culture. Although HCV replication and spread occurred in the chimpanzee, neither process occurred in the culture. The development of the RNA replicon technology in the late 1990s became a workhorse of many approaches to HCV virologic investigation, although researchers still lacked key elements of a model that would allow assembly and release of virus particles. Finally, the development of the Japanese fulminant hepatitis (JFH)1 derived complete virus replication system (reported in 2005) made available a cell culture that enabled the production of significant amounts of infectious virus particles. Perhaps most importantly, the human xenograft (i.e., humanized) mouse models, along with genetically modified mice, are able to support the entire HCV life cycle, thereby providing an alternative to experimentally infecting chimpanzees. These 2 developments have led to major advances in the knowledge of the HCV life cycle. The HCV particle consists of 2 viral glycoproteins a basic capsid protein and a positive sense genome RNA of 9.6 kilobases. In addition, HCV particles are often associated with cellular lipoproteins, such as low density lipoprotein (LDL) and very low density lipoprotein (VLDL); the importance of this association is an area of ongoing research. 13

14 Viral Entry and Spread The factors involved in HCV entry have been an area of intense research during the last few years, and much remains to be clarified about this process. The complex process of virus entry into the host hepatocyte involves a number of cellular factors, more and more of which continue to be discovered. These include membrane proteins localized on the hepatocyte s basolateral surface and in its tight junction components. Uptake of the virus is mediated by endocytosis, and fusion of the virus envelope to the host cell membrane requires an acidic environment. Dr. Rice explained that viral entry and spread are being closely explored as potential therapeutic targets because the combination of entry inhibitors and direct acting antivirals (DAAs) may offer protection to uninfected cells and delay the spread of drug resistant variants. In addition, the development of entry inhibitors could help solve the problem of allograft reinfection, which occurs in virtually all liver transplant patients with HCV infection. Replication Within the host cell, translation of the virus s genome RNA is mediated by an internal ribosome entry site (IRES) and leads to the production of a polyprotein that is cleaved into 10 proteins by 2 cellular and 2 viral proteases. One of the 2 viral proteases, the NS3 4A serine protease, is now the target of the 2 licensed DAAs, the protease inhibitors telaprevir and boceprevir. Other key viral proteins involved in the replication of its RNA include the NS5A phosphoprotein and the NS5B RNA dependent RNA polymerase; these are currently also leading candidate targets for the development of new anti HCV drugs. HCV replicates its RNA on intracellular membranes by synthesizing a complementary negative strand intermediate, which then serves as a template for the production of the HCV genome s positive strand RNA. The process of HCV RNA replication is prone to the production of a high number of errors, resulting in the emergence of a multitude of viral variants both within an HCV infected individual and among worldwide HCV populations. Virus particles are assembled in association with lipid droplets, and assembly appears to be closely associated with the biosynthesis and secretion of lipoproteins. Besides the cellular receptors and coreceptors required for HCV to enter host cells, several other cellular factors have been found to be required for efficient replication of new viral particles, including: The microrna mir 122 The peptidylprolyl isomerase cyclophilin A The phosphatidylinositol 4 phosphate (PI4P) producing kinase PI4Kllla In addition to the HCV proteins that are required for each step in the viral life cycle, researchers are evaluating these and other cellular factors as possible targets for the development of antiviral agents. Target Pros and Cons After his review of the structure of HCV, the infectious process, and the related host factors, Dr. Rice listed the advantages and disadvantages of targeting either viral or cellular factors for therapeutic intervention: Viral o Advantages 14

15 Specific to the virus itself Although recent years have brought much o Disadvantages greater understanding of the HCV lifecycle, Limited number of targets (10 proteins and revealed potential new therapeutic targets, 1 RNA) and stimulated the ongoing clinical Great genetic variability development of new therapies, every aspect of the HCV lifecycle has proven to Rapid emergence of resistance be complex, with many aspects still Cellular imperfectly understood. o Advantages Common requirements across viral genotypes Rare variation in targets Less chance for resistance to emerge Potential to use existing drugs o Disadvantages Lack of specificity, potentially resulting in adverse effects Host factor polymorphisms Dr. Rice concluded by saying that although recent years have brought much greater understanding of the HCV lifecycle, revealed potential new therapeutic targets, and stimulated the ongoing clinical development of new therapies, every aspect of the HCV lifecycle has proven to be complex, with many aspects still imperfectly understood. The Pipeline: Future Therapies for HCV Calling the approval in 2011 of the protease inhibitors (PIs) telaprevir and boceprevir a paradigm shift in the management of hepatitis C virus (HCV) infection, Raymond T. Chung, MD, in his presentation, The Pipeline: Future Therapies for HCV, surveyed the even more dramatic changes that are expected to reach the clinic in the relatively near future. Although highly effective when used in combination with pegylated interferon and ribavirin (PR), resistant viral variants emerge quickly during monotherapy with these PIs, and the necessity of relying on PR brings issues of tolerability due to its well known adverse events and certain PI specific toxicities. Building on these recent advances, the ultimate goal is the long desired availability of interferon sparing regimens. With so many novel anti HCV agents in various phases of development, Dr. Chung provided a top line overview of the clinical trials of the most promising ones. His presentation began with a table clarifying the principal characteristics of the main classes of direct acting antivirals (DAAs), providing a preview of which classes are likely to be most potent, have the highest and lowest resistance barriers, and so forth. 15

16 PILLAR The PILLAR study evaluated the efficacy of 2 different doses of the once daily PI TMC435 plus PR vs. PR plus placebo in 386 genotype 1 treatment naive patients. The investigators reported that the addition of TMC435 to PR was associated with significant improvements in sustained virologic response (SVR) rates, with SVR rates of 75% to 86%, vs. 65% in the control arm (the highest rate being in patients who received TMS mg plus PR throughout the 24 week trial). Participants with IL28B CC genotype experienced significantly higher SVR rates vs. those with the CT or TT genotypes. ATLAS In the ATLAS study, investigators evaluated 3 daily doses of the PI danoprevir plus PR vs. PR plus placebo in treatment naive genotype 1 patients for 24 weeks. The highest dose arm was discontinued due to adverse events; subjects in the other 2 arms experienced significantly higher rates of SVR vs. the control arm. Another study evaluating the effects of ritonavir boosting on danoprevir reported substantial enhancement of the PI s efficacy, and future studies of danoprevir will include ritonavir boosting. PROTON A novel nucleotide analog, PSI 7977, was evaluated in combination with PR in genotype 1 treatmentnaive patients in the PROTON study. Among DAA classes, the nucleo(s)tide NS5B polymerase inhibitors (NIs) feature an exceptionally high barrier to resistance, due to the high fitness cost exacted by mutations in the active site to which NIs bind. Although a single resistance mutation has been identified in tissue cultures, no in vivo selection of this mutation has been observed. Findings of the PROTON study, Dr. Chung said, had set a new baseline for treatment outcomes with a single agent add on to PR, with essentially 90% of treated patients achieving SVR in as little as 12 weeks. A Study A evaluated 2 dose levels of the NS5A inhibitor daclatasvir plus PR in treatment naive genotype 1 and a much smaller number of genotype 4 patients for 24 or 48 weeks. At 24 weeks, among patients who received triple therapy, 88% of those receiving daclatasvir 20 mg and 100% of 16

17 those receiving daclatasvir 60 mg had achieved SVR, improving on the complete early (12 week) virologic response rates of 78% and 75%, respectively. ZENITH Quadruple therapy incorporating 2 DAAs with PR have shown robust activity. One such study, ZENITH, which assessed the efficacy of the non nucleoside inhibitor (NNI) VX 222 plus telaprevir plus PR in 59 genotype 1 treatment naive patients, using response guided therapy (RGT), reported SVR rates in all groups ranging from 82% to 93% at week 12. Dr. Chung remarked that combinations such as this might serve as a type of salvage therapy for patients who have failed more conventional PR centered tripletherapy regimens or all oral DAA regimens. Interferon Free Regimens Achieving IFN free HCV regimens will mean taking into account the HCV polymerase s error prone nature and the frequency of preexisting DAA resistant variants by combining antivirals that: Have sufficient potency Are nonoverlapping in their resistance profiles Contain 1 class with a high barrier to virologic resistance Proof of concept studies have recently shown that the goal of IFN free regimens is achievable. INFORM 1 INFORM 1 evaluated the efficacy of the PI danoprevir plus the NI mericitabine for 14 days in 48 genotype 1 patients. The median change in HCV RNA from baseline to day 14 ranged from 3.7 log 10 IU/mL to 5.2 log 10 IU/mL. The greatest change in viral load and the highest rate of SVR were observed among patients with IL28B CC genotype vs those with non CC genotype. ELECTRON In another IFN free study, ELECTRON, 40 genotype 2 or genotype 3 patients received 12 weeks of GS 7977, a nucleotide polymerase inhibitor; 30 patients received concomitant PR for variable periods, and 10 received GS 7977 with ribavirin alone. Dr. Chung indicated that ELECTRON demonstrated 2 remarkable outcomes: All 40 patients experienced SVR. Of 10 patients who received GS 7977 alone, 6 achieved SVR and 4 had response followed by relapse. These findings demonstrate that a regimen including 1 potent NI having a high barrier to resistance, combined with RBV, is able to produce SVR. A similar study evaluated a regimen of GS 7977 plus ribavirin in 10 genotype 1 patients who had previous PR null response. All 10 patients experienced rapid virologic response (RVR). However, of the 9 patients with follow up data, 8 experienced relapse, all within 4 weeks of treatment discontinuation; 80% of these patients had unfavorable (i.e., non CC) IL28B genotypes. These findings support the idea that patients having favorable genotypes can achieve SVR with just 12 weeks of NI plus ribavirin. However, Dr. Chung cautioned, the high relapse rates among more difficult to treat patients points to 17

18 the important role of host factors such as innate immune responses even in patients receiving DAA regimens. Daclatasvir/asuneprevir Another study evaluated the potent NS5A inhibitor daclatasvir plus the PI asunaprevir in 11 patients with previous PR null response (< 2 log HCV RNA reduction after 12 weeks of therapy). Two of 2 genotype 1b patients and 2 of 9 genotype 1a patients experienced SVR after 24 weeks. Overall, 4 of 11 (36%) difficult to treat patients achieved cure with an all oral DAA regimen. This study also underscores the importance of genotype 1 subtype in the outcome of DAA regimens persons with genotype 1a consistently experience inferior response rates vs those with genotype 1b. SOUND C2 Another IFN free study, SOUND C2, evaluated the PI BI plus an NNI, BI , along with RBV, in 362 patients. After the end of treatment at 12 weeks, 43% and 69% of patients with genotype 1a and 1b, respectively, achieved SVR. Response rates in genotype 1a patients were affected by IL28B subtype (with SVR rates of 86% to 100% in non CC genotype patients), suggesting that at least with some DAA regimens, host pathways that are associated with enhanced innate antiviral immunity may help determine treatment outcomes. Other Investigational Agents MK 5172 A dose ranging study evaluated the efficacy of 7 days of treatment with MK 5172, a pangenotypic PI, in 48 genotype 1 and 30 genotype 3 patients. The investigators reported reductions in HCV RNA of as much as 5.39 log 10 IU/mL in genotype 1 participants and as much as 4.41 long 10 IU/mL in genotype 3 patients. INX INX 08189, a nucleotide polymerase inhibitor, was evaluated as monotherapy in a dose ranging study in 80 genotype 1 patients. Investigators reported the greatest reduction of HCV RNA ( 4.25 log 10 IU/mL) in patients receiving the highest dose, 200 mg. Host target Inhibitors The growing appreciation of the contribution made by host factors ( 100 of which have been identified) on HCV progression makes this a group of appealing targets for development of HCV therapies, particularly for DAA experienced patients who require further treatment. Although such targets could be numerous, with high barriers to resistance, they could also involve risks of toxicity to the host. Classes of host target inhibitors in development include: Cyclophilin antagonists mirna antagonists Inhibitors of cholesterol metabolism (HMG CoA reductase) VITAL 1 Alisporivir, an inhibitor of cyclophilin A, an essential host factor for HCV replication, is believed to be active across HCV genotypes, with a high barrier to resistance. VITAL 1, a dose ranging study, evaluated 18

19 the efficacy of alisporivir in 328 treatment naive genotypes 2 and 3 patients, both as monotherapy and with or without either pegylated interferon or ribavirin. Investigators reported the following SVR rates in patients who remained on their assigned regimen for the full 24 weeks: 91% alisporivir 1000 mg monotherapy 91% alisporivir 600 mg plus ribavirin 94% alisporivir 800 mg plus ribavirin 86% alisporivir plus pegylated interferon 74% PR Miravirsen (mirna Inhibitor) MicroRNAs are small, noncoding RNAs that serve to regulate RNAs at the mrna level. Miravirsen, an injectable oligonucleotide targeting the mirna mir 122, was evaluated in 36 genotype 1 treatmentnaive patients in a dose ranging study. The highest dose, miravirsen 7 mg/kg was associated with a decrease in HCV RNA of 2.73 IU/mL. Dr. Chung concluded by reemphasizing the great promise of DAA based regimens to eventually replace IFN based regimens for the treatment of HCV infection, although ribavirin seems to be a critical component to achieve that goal, particularly in patients who are receiving less than optimally efficacious regimens. He added that genotype 1 subtype appears to be an important factor in determining patient outcome and that the performance of DAAs in cirrhotic patients requires further evaluation. Finally, he stated that in the future several different roads will lead to the cure of HCV, in part determined by host factors. In the future, several different roads will lead to the cure of HCV, in part determined by host factors. 19

20 Who Should Be Treated: Naives, Partials, Nulls Michael W. Fried, MD s, presentation, Who Should Be Treated: Naives, Partials, Nulls, focused on the complex challenges of determining which HCV infected patients should receive treatment with the recently licensed protease inhibitors (PIs) telaprevir and boceprevir. He began by listing the pros and cons of PI treatment: Pros Cons PIs substantially increase the probability of achieving sustained virologic response (SVR) in most patient groups. PIs shorten therapy duration in many patients. Successful treatment improves morbidity and mortality. The regimens are complicated, with challenging adverse events and drug drug interactions. Treatment failure is associated with the emergence of resistant variants, possibly limiting future treatment options. In several population groups (HIV/HCV coinfection, transplant recipients, decompensated cirrhotics), response rates are suboptimal or data are limited or nonexistent. Considerations for Treatment naive Patients Dr. Fried first provided an overview of the key findings from the clinical trials of telaprevir and boceprevir in treatment naive patients. (Please see the section of this report that includes details of these findings, Hepatitis C Management ) Treatment naive patients attain significantly higher rates of SVR with triple therapy vs dual therapy regimens. Treatment duration is 24 and 28 weeks with telaprevir and boceprevir, respectively, for patients who achieve and maintain a rapid virologic response (RVR). For all other patients and cirrhotic patients, the recommended treatment duration is 48 weeks. Several pretreatment factors that weigh the likelihood of response and of shortened therapy duration vs. the risk of adverse events may influence the decision of whether to initiate treatment in such patients. Factors favoring the chance of achieving SVR include IL28B CC genotype, mild severity of liver 20

21 disease, and non African American race. Nevertheless, all patient populations experience improved SVR with triple therapy regimens. Considerations for Retreatment with Triple Therapy Although boceprevir and telaprevir have similar mechanisms of action, they have distinct treatment regimens, management algorithms, and futility rules that optimize response rates. Both regimens employ response guided therapy (RGT) in certain patient groups, tailoring the duration of therapy based on virologic response milestones. Prior Response and Likelihood of Achieving SVR Dr. Fried provided the definitions of the different types of prior response: Partial response: HCV RNA decrease 2 log 10 IU/mL at week 12 but undetectability never reached Relapse: HCV RNA undetectable at end of treatment but detectable during follow up Null response: HCV RNA decrease < 2 log 10 IU/mL at week 12 of prior therapy The likelihood of achieving SVR with triple therapy in treatment experienced patients is directly related to their prior response with PR alone. Prior relapsers have the highest rates of SVR with triple therapy. This group, Dr. Fried said, arguably should be prioritized for retreatment because of their uniformly excellent outcome (75% to 86% SVR). In contrast, prior null responders achieve SVR at a rate of approximately 30%. Prior partial responders have intermediate responses. The lower SVR rates in null and partial responders suggest that decisions about retreatment should be individualized based on the patient s motivation and the severity of his/her liver disease. Clinicians should begin by considering: The type of response the patient had to previous therapy e.g., null vs. partial response, relapse, virologic breakthrough How well the patient tolerated the previous treatment The duration of the previous treatment The patient s ability and willingness to adhere to treatment Dr. Fried indicated that for patients who were nonresponders to previous treatment there are 2 options: Retreat with PI triple therapy Wait until newer agents become available Further considerations include: Viral factors: o HCV genotype o HCV RNA level Host factors: o IL28B genotype o Race o Presence of fibrosis or steatosis o Likelihood of disease progression i.e., presence of fibrosis or cirrhosis 21

22 He then provided an overview of the key findings from the clinical trials of telaprevir and boceprevir in patients with each of the different types of previous response. (Please see the section of this report that includes details of these findings, Hepatitis C Management ) Considerations for All Patients All patients being considered for triple therapy must be candidates for PR therapy the backbone of current triple therapy regimens. To help support patients adherence and to increase the probability of completing therapy, clinicians should discuss with patients the anticipated adverse effects that are specific to boceprevir and telaprevir and how such effects can be managed. To avoid drug drug interactions that can compromise the safety and efficacy of a variety of coadministered medications, clinicians should also carefully review patients concomitant medications. Futility Rules To minimize the selection of PI resistant virus and to decrease patients exposure to a demanding treatment regimen when a successful outcome is no longer possible, futility or stopping rules are available. These rules are applicable to both treatment naive and treatment experienced patients. Telaprevir futility rules: o HCV RNA > 1,000 IU/mL at week 4 or 12 discontinue all drug o Detectable HCV RNA at week 24 discontinue PR Boceprevir futility rules: o o HCV RNA at week 12 discontinue all drugs Detectable HCV RNA at week 24 discontinue all drugs Four Declarations Declaration 1 all prior relapsers should receive triple therapy. Declaration 2 null responders should wait for better treatments. Declaration 3 all partial responders should receive triple therapy. Declaration 4 all treatment-naive patients should receive triple therapy. Discontinuing treatment prematurely due to poor virologic response can be difficult for some patients to accept, particularly if HCV RNA levels have clearly decreased or remain just above the predetermined futility endpoints. To reduce disappointment if a patient fails to achieve virologic response milestones, clinicians should take care at the outset to establish expectations and explain the rationale underlying the potential need to discontinue therapy. International guidelines on the use of PI therapy from the American Association for the Study of Liver Diseases, the European Society for the Study of the Liver, and the United Kingdom offer somewhat varying recommendations regarding which patients should be offered treatment; clinicians should consult the appropriate guidelines for specific relevant recommendations. Four Declarations Dr. Fried concluded by condensing the key elements of current HCV treatment decision making into what he called a set of declarations: Declaration 1 all prior relapsers should receive triple therapy. Declaration 2 null responders should wait for better treatments. Declaration 3 all partial responders should receive triple therapy. Declaration 4 all treatment naive patients should receive triple therapy. 22

23 Preparing the Patient for DAA Therapy Mark S. Sulkowski, MD, began his presentation, Preparing the Patient for DAA Therapy, by sketching the presentation of a patient recently diagnosed with HCV infection. The remainder of his presentation provided a discussion of the type of educational information that clinicians should offer to such patients in considering the use of HCV direct acting antivirals (DAAs). This patient, a 42 year old married mother with hyperlipidemia and mild depression and anxiety, expressed these concerns: Is her HCV infection communicable? Can she occasionally have a glass of wine? Can she be cured? Treatment concerns: o Need to start treatment now? o Is a short treatment course possible? o What if the treatment fails? Patient Education = the Foundation The first step to prepare a newly diagnosed patient for possible treatment of chronic HCV infection with a regimen of one of the protease inhibitors (PIs) ie, telaprevir or boceprevir plus pegylated interferon/ribavirin (PR) is education. Clinicians should make their patients aware of the potential for HCV disease to progress to cirrhosis, liver failure, hepatocellular carcinoma, and, possibly, death. It is equally important to stress at the same time that HCV treatments have high efficacy rates, leading to cure in most patients who are able to initiate and complete therapy. With the availability of triple therapy (PI plus PR), the medical urgency to treat HCV disease, Dr. Sulkowski said, is generally based on fibrosis severity, which can be staged by liver biopsy (the gold standard), noninvasive serum markers, and/or transient elastography. The urgency to start treatment, of course, is greater in patients with more advanced fibrosis. 23

24 Viral Factors A patient s probability of achieving and maintaining sustained virologic response (SVR) is associated with HCV RNA level and HCV genotype. In using direct acting antivirals (DAAs), the genotype 1 subtype (a or b) may also play an important part patients with genotype 1a are more likely to experience virologic failure while receiving triple therapy vs. those with genotype 1b. Nevertheless, the inclusion of a PI substantially increases SVR in patients of either subtype. Patients whose HCV infection is determined to be non genotype 1 need to understand that they are not candidates for boceprevir or telaprevir treatment. Host Factors Clinicians should perform a careful assessment of a patient s medical and psychosocial conditions before recommending use of triple therapy, since comorbidities (e.g., depression or coinfections) may preclude its use or may require additional management before initiating therapy. Host IL28B genotype has now become an important consideration patients with the favorable IL28B haplotype (i.e., CC genotype) are more likely to experience spontaneous HCV clearance and to achieve SVR if receiving treatment. Moreover, adding boceprevir or telaprevir to PR for patients with genotype 1 and the unfavorable IL28B haplotype (CT or TT genotype) is associated with markedly higher SVR rates vs. patients receiving PR alone. In contrast, patients with IL28B CC genotype in clinical trials achieved high rates of SVR when receiving PR, with or without a PI. Also, more patients with the CC genotype (approximately 80% to 90%) qualified for shorter therapy based on higher rates of attaining rapid virologic response (RVR) vs. those with genotype CT or TT (approximately 50%). Since duration of treatment with either boceprevir or telaprevir plus PR can influence a patient s willingness to initiate therapy, clinicians should explain to patients that IL28B genotyping can be a significant factor in deciding if therapy is appropriate. On Treatment Assessment and Education Lead in phase Previously, many practitioners prescribed a lead in phase of PR treatment for 4 weeks before adding the PI, on the understanding that allowing the PR to reach pharmacologic steady state and suppress HCV RNA would lead to higher rates of SVR because there would be less virologic failure due to PI resistance. Subsequently, however, the SPRINT 1 and REALIZE trials evaluating lead in vs. no lead in failed to demonstrate higher rates of SVR in patients receiving PR first. But those trials did show that the magnitude of HCV RNA suppression at the end of 4 weeks of PR is highly predictive of the likelihood of achieving SVR after adding a PI. Patients who failed to achieve decreased HCV RNA level from the pretreatment level are significantly less likely to achieve SVR and more likely to experience emergence of PI resistant variants. In addition, in patients who achieved RVR at the end of the lead in, the addition of the PI was not associated with higher SVR rates vs. PR alone. Because of these findings, some clinicians prefer to evaluate HCV RNA response after 4 weeks of PR before adding a PI. In these situations, patients who achieve < 1 log 10 decrease after lead in may choose not to add the PI, as only approximately 35% of patients with poor response to PR go on to achieve SVR. On the other hand, patients with RVR after lead in may choose not to add the PI and continue PR. However, expert consensus on this approach is lacking since most patients appear to benefit by adding the PI due to the potential for higher SVR rates and/or shorter treatment duration. 24

25 Employing PR lead in may also allow clinicians to assess patients tolerance for and adherence to therapy before exposing a patient to a PI, which is both expensive and has the potential to select for resistant HCV variants. In particular, the observation of significant anemia after 4 weeks of PR could prompt clinicians to adjust ribavirin dose or add epoetin alfa in anticipation of even more anemia after adding a PI. On the whole, Dr. Sulkowski explained, PR lead in is a validated, though not required, tool that clinicians can choose to use in managing HCV infected patients. Response Guided Therapy (RGT) The concept that patients who achieve RVR require less treatment both is intuitive and has been validated in randomized controlled trials. For treatment naive and prior relapse patients, this approach is now the standard of care: Patients who attain undetectable HCV RNA after 4 weeks of telaprevir or boceprevir plus PR (week 4 of therapy with simultaneous start or week 8 of therapy with lead in) are potentially eligible for shorter therapy. Patients with detectable HCV RNA after 4 weeks of telaprevir or boceprevir plus PR who achieve undetectable HCV RNA by week 24 require longer therapy. The RGT approach has important implications for patient management: Clinicians should educate patients to understand that duration of therapy cannot be determined before treatment initiation and that shorter therapy cannot be guaranteed. Baseline measurement of HCV RNA and at the end of week 4 of triple therapy is critical. Clinicians should emphasize the need for this testing and inform the patient of the precise date when it needs to be performed. Whether shortened therapy is appropriate is more controversial in certain hard to treat patient populations e.g., HCV/HIV coinfected persons, prior partial or null responders to PR (< 1 log 10 decrease during lead in), African Americans, and cirrhotics. Some clinicians recommend longer duration of therapy for these patient groups. Clinicians should educate patients to For these reasons, clinicians must discuss with patients the understand that duration of therapy cannot rationale and limitations of RGT before starting therapy and be determined before treatment initiation and that shorter therapy cannot be should give high priority to the precise timing of HCV RNA guaranteed. testing during treatment. Adverse Events Management: Use of ESAs, Rash Management, and Shortening of Treatment In his presentation, Adverse Events Management, Paul Y. Kwo, MD, provided guidance in anticipating and managing the substantial array of adverse events and drug drug interactions commonly encountered during treatment with the hepatitis C virus (HCV) protease inhibitors (PIs) telaprevir and boceprevir. Although these PIs have ushered in a new treatment era for individuals infected with 25

26 genotype 1 HCV, Dr. Kwo stressed that clinicians should be prepared with an individualized adverse events management plan before initiating their use. Although these PIs have ushered in a new treatment era for individuals infected with genotype 1 HCV, clinicians should be prepared with an individualized adverse events management plan before initiating their use. To prepare the patient for both treatment and the management of treatment related adverse events, Dr. Kwo listed a set of data that should be gathered at the outset: HCV genotype and RNA level IL28B genotype (for treatment naives) Previous viral kinetics (for nonresponders) Complete blood count, cytidine monophosphate Fibrosis assessment Coadministered medications Identify dermatology consultant Regarding coadministered drugs, these PI pharmacology factors are key: Boceprevir: o Strong inhibitor of CYP3A4/5 o Partly metabolized by CYP3A4/5 o Potential inhibitor of and substrate for P glycoprotein Telaprevir o Substrate of CYP3A o Inhibitor of CYP3A o Substrate of P glycoprotein In addition, clinicians should be aware of this resource: druginteractions.org. 26

27 Telaprevir Adverse Events Management In phase 3 trials, adverse events reported more frequently than in PR control patients included: Rash (approximately 56% vs. 34% in controls) Anemia Gastrointestinal adverse effects (including nausea and diarrhea) Anorectal symptoms (including hemorrhoids, anorectal discomfort, and anal pruritus) Severe rash with possible prominent eczematous component was reported in 4% of individuals receiving telaprevir. Rarely (< 1 %), individuals develop Stevens Johnson syndrome or a serious skin reaction, including drug rash with eosinophilia and systemic symptoms (DRESS). Both Stevens Johnson syndrome and DRESS require immediate discontinuation of all therapy and urgent referral to a dermatologist. Mild to Moderate Rash Telaprevir associated rash can be categorized as mild (limited distribution with pruritus), moderate, or severe. For patients with mild rash, treatment includes antihistamines and avoidance of sun exposure, while continuing to receive PR plus telaprevir. Moderate rash which is diffuse with or without superficial skin peeling and pruritus must be monitored for development of systemic symptoms. Telaprevir may be continued, and antihistamines and topical steroids may provide relief; systemic steroids are not recommended. Both Stevens-Johnson syndrome and DRESS require immediate discontinuation of all therapy and urgent referral to a dermatologist. Severe Rash In patients who develop a severe rash, it is generalized or with vesicles or ulcerations. These patients should discontinue telaprevir immediately, but they may continue PR. If the rash fails to improve within 7 days after telaprevir discontinuation, the clinician should strongly consider interrupting the PR also. Topical corticosteroids and oral antihistamines may be beneficial, and avoidance of sun exposure may relieve some symptoms. Anemia Telaprevir associated anemia may be managed by reducing the ribavirin dose. Erythropoietin (EPO) analogs were not permitted in the phase 3 trials. Hemoglobin decreases during the first 4 weeks of telaprevir treatment, with the lowest value seen after the end of the 12 week telaprevir dosing, after which hemoglobin returns to levels typically observed during PR treatment. Clinicians should monitor patients hemoglobin level by at least week 2 of telaprevir therapy. However, Dr. Kwo recommended monitoring hemoglobin levels at week 1 after telaprevir initiation and at least every 4 weeks for the 12 weeks of treatment. For patients experiencing telaprevir associated anemia, ribavirin dose should be reduced directly to 600 mg, not the 200 mg reduction previously used for patients receiving triple therapy. Ribavirin dose reduction should begin when hemoglobin declines to 10 g/dl. If ribavirin must be discontinued to manage anemia, telaprevir must also be discontinued, because ribavirin discontinuation will markedly increase the risk of the emergence of resistance associated variants. 27

28 Anorectal Symptoms Approximately 29% of patients receiving telaprevir reported anorectal symptoms, although telaprevir discontinuation very rarely occurred. Short term topical corticosteroids and topical anesthetics can provide relief. Patients experiencing diarrhea may get relief by use of bulking agents such as fiber and loperamide during the 12 week treatment period; topical lidocaine also provides some relief. In addition, clinicians should advise patients receiving telaprevir to take the drug with 20 grams of fat to assist its absorption. Boceprevir Adverse Events Management Anemia is the primary adverse effect reported in patients receiving boceprevir. Other commonly reported events (all of which are also known to be interferon related) include: Fatigue Nausea Headache Dysgeusia In phase 3 trials, use of EPO to manage anemia was permitted in approximately 43% of patients receiving boceprevir. A post hoc analysis of the SPRINT 2 and RESPOND 2 studies suggested that patients attained comparable SVR rates regardless of which anemia management strategy was employed EPO only, ribavirin dose reduction only, or both. Therefore, clinicians should employ whichever strategy they currently use for managing ribavirin related anemia. A large trial comparing ribavirin dose reduction vs. use of EPO in boceprevir treated patients is underway. Futility Rules Clinicians may decide to discontinue therapy with either boceprevir or telaprevir for several reasons i.e., decide to apply the relevant futility rules, which are: Telaprevir: o HCV RNA level > 1000 IU/mL at weeks 4 or 12 or detectable HCV RNA at week 24 Boceprevir: o HCV RNA level > 100 IU/mL at week 12 or detectable HCV RNA at week 24 Clinicians should discontinue telaprevir therapy if severe rash develops, and all 3 drugs must be discontinued in the very rare event of Stevens Johnson syndrome or DRESS. With careful management by frequently monitoring complete blood count and using EPO with ribavirin dose reduction, treatment discontinuation for hematologic adverse effects is not common with either PI, so that most patients who have not reached futility can achieve SVR. Questions from the Audience Dr. Thomas began by asking Drs. Fried, Sulkowski, and Kwo to comment on how they handle treatment related anemia. Dr. Kwo advised that hemoglobin levels in patients receiving HCV therapy should be checked weekly to determine whether the ribavirin dose should be reduced. He added that if the hemoglobin reaches 10 28

29 g/dl, it is already too late. Furthermore, clinicians need to monitor hemoglobin in patients receiving telaprevir or boceprevir even more aggressively than in those receiving PR alone. He advised that clinicians managing patients who have physically demanding jobs should try to get those patients hemoglobin levels > 10 g/dl. Dr. Sulkowski added that in the HCV PI registrational trials, ribavirin concentrations were found to be too high, suggesting that the initial dose had been unnecessarily high and needed to be reduced in any case. If a patient has a low hemoglobin level pretreatment, should that patient be treated with EPO or transfusion before initiating HCV treatment? Dr. Kwo replied that ribavirin should be introduced by titration to find the appropriate dose for the particular patient. Dr. Sulkowski advised that the patient s anemia should be managed first, including an internal medicine examination to identify potential causes such as iron deficiency. He added that in such a situation clinicians should consider whether that patient in fact should receive HCV treatment at that time. How should a cirrhotic patient with thrombocytopenia be managed? Dr. Fried suggested that doing weekly platelet counts is essential and that in his own practice interventions are typically not considered until the platelet count reaches 25,000/mcL. At that level, clinicians may wish to consider use of a platelet growth factor. Dr. Kwo added that practitioners should adhere to futility rules rigorously for such patients. How should mild to moderate renal failure in HIV/HCV coinfected patients be managed? Dr. Kwo replied that patients with moderately reduced glomerular filtration rate (GFR) should be managed and monitored closely, as they can become anemic quickly. If HCV treatment is necessary, a PR lead in approach should be used, with the HCV PI added later. Dr. Sulkowski added that GFR should be checked pretreatment and before initiating treatment, clinicians should consult the ribavirin package insert since the information in one brand s insert provides directions for managing this situation. 29

30 Pharmacokinetics and Drug Interactions In his presentation, Pharmacokinetics and Drug Interactions, David J. Back, PhD, laid out the great challenges in understanding and managing the host of drug drug interactions (DDIs) associated with the use of the hepatitis C virus (HCV) protease inhibitors (PIs), telaprevir and boceprevir. These DDIs can change the levels of either the PI or the coadministered drug, possibly resulting in either toxicity or loss of efficacy of either. Key features of these direct acting antivirals (DAAs) include: Boceprevir o CYP metabolism: metabolized by and markedly inhibits CYP3A4 o Non CYP metabolism: metabolized by aldo keto reductase o P glycoprotein transporter: substrate Telaprevir o CYP metabolism: metabolized by and markedly inhibits CYP3A4 o P glycoprotein transporter: substrate of and inhibitor of Because approximately 50% of marketed drugs are metabolized by CYP3A4, the HCV PIs are inevitably involved in increasing the exposure of many other drugs. In Dr. Back s terms, telaprevir and boceprevir are both perpetrators and victims of DDIs. Because only targeted DDI studies are performed during drug development and, to a lesser degree, after licensing, understanding and managing the full range of DDIs remains an ongoing process. Contraindications Coadministration of boceprevir or telaprevir is contraindicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious or lifethreatening events. Examples include: Antiarrhythmics: amiodarone, bepridil, quinidine Antihistamines: astemizole, terfenadine Antipsychotics: pimozide Benzodiazepines: oral midazolam Ergot derivatives: dihydroergotamine, methylergonovine Lipid lowering agents: simvastatin, lovastatin, atorvastatin Phosphodiesterase (PDE)5 inhibitors for pulmonary arterial hypertension: sildenafil, tadalafil Coadministered medications that could markedly reduce the HCV PI concentration via enzyme induction are also contraindicated, particularly the anticonvulsants carbamazepine, phenobarbital, and phenytoin and the herb St. John s wort. Because telaprevir reduces the area under the curve of certain oral contraceptives, Dr. Back advised that additional nonhormonal contraceptives should also be used, particularly during and immediately after telaprevir treatment. Opioid Replacement Therapy Issues Since a very high proportion of HCV infected individuals have a history of substance use, with a number of them receiving opioid replacement treatment, interactions between the HCV PIs and either methadone or buprenorphine are a concern. 30

31 Coadministration of telaprevir and methadone in a clinical trial reduced R methadone C min by 31% and the free fraction of R methadone by 26%. However, no change was observed in the effective concentration of R methadone. A small trial of telaprevir in HCV negative subjects receiving buprenorphine/naltrexone treatment found that telaprevir was associated with a relatively minor decrease in buprenorphine C max ; no subjects experienced withdrawal symptoms. With many other potential DDIs besides those listed above, coadministration of other medications requires close monitoring, potentially involving alteration of dosage or timing of administration. In the absence of data regarding particular drugs, Dr. Back advised, guidance needs to be derived from knowledge of the drugs pharmacology. This approach can be found in this still evolving resource: druginteractions.org, where the guidance is color coded: Red do not coadminister Amber use caution when coadministering Green coadministration is safe Antiretroviral DDIs One particular area of concern, explained Dr. Back, is HIVpositive patients who are receiving antiretroviral therapy, who represent a relatively high proportion of HCV infected patients. The polypharmacy that many coinfected patients are receiving means that they are at a high risk of DDIs. Recently presented drug interaction data regarding telaprevir and boceprevir have reinforced initial concerns that management of coinfected patients poses a significant set of challenges. Early preclinical data had indicated that ritonavir used to boost the concentration of nearly all HIV PIs would increase telaprevir and boceprevir exposures. However, investigators have since realized that in clinical practice boosted PIs e.g., lopinavir/ritonavir, darunavir/ritonavir, and atazanavir/ritonavir in fact cause a reduction in telaprevir and boceprevir levels; the mechanisms for this effect are not clearly understood. A further complication is that nearly all of these interactions are 2 way, so that the exposure to the HIV PI is also altered. The current recommendation for telaprevir is that atazanavir/ritonavir (the least interacting HIV PI) or the HIV integrase inhibitor raltegravir (which is not metabolized by CYP3A4 and has no significant interaction) can be used with no dose adjustment and that if the non nucleoside reverse transcriptase inhibitor efavirenz is used, the telaprevir dose needs to be increased from 750 mg 3 times daily to 1125 mg 3 times daily. For boceprevir, the magnitude of the interaction with lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir means that coadministration of boceprevir and any of these HIV PIs is not recommended. Coadministration of boceprevir and efavirenz is also not recommended. However, raltegravir can be coadministered with boceprevir without dose adjustment. The resource should be consulted for potential interactions relating to other antiretrovirals. Dr. Back stressed, however, that all of the pharmacokinetic interaction studies of HCV PIs and antiretrovirals were conducted in healthy volunteers and that data from HCV infected patients are greatly needed. 31 All of the pharmacokinetic interaction studies of HCV PIs and antiretrovirals were conducted in healthy volunteers, and data from HCV-infected patients are greatly needed.

32 Next Generation of DAAs The investigational HCV PI simeprevir (TMC435) has a weak inhibitory effect on CYP3A, suggesting that there may be less potential for DDIs. Data available to date indicate: No effect on methadone No effect on the antidepressant escitalopram Efavirenz coadministration contraindicated No dose adjustment needed: o Rilpivirine o Raltegravir o Tenofovir DDI data concerning most other DDAs that are likely to become available in the next several years are still being evaluated. Key questions that are yet to be answered include: Will the magnitude of an interaction observed in a healthy volunteer be the same in an HCVinfected patient? Does the magnitude of an interaction change with the degree of hepatic impairment? How does the interaction seen in plasma relate to the actual interaction in the liver? Dr. Back summarized the gamut of interaction issues with HCV PIs in a concise expression: Think DDIs for the DAAs. Think DDIs for the DAAs. Clinical Implications of Resistance In his presentation, Clinical Implications of Resistance, Stuart C. Ray, MD, aimed to suggest some of the implications for studying hepatitis C virus (HCV) resistance that may be available from investigators much more extensive experience with HIV and hepatitis B virus (HBV) resistance. Lessons learned earlier could shed light on challenging issues such as: The clinical implications of resistance At what point during disease progression and treatment it is appropriate to do resistance testing The mechanisms of resistance and potential long term implications of archived resistance variants Commonalities and Differences HIV and HBV replication predictably rebound after treatment discontinuation, whereas HCV is curable with treatment. The development of resistance, Dr. Ray explained, is a form of evolution, requiring both diversification and selection. Worldwide, the HCV genome is significantly more diverse than those of HIV or HBV. Direct acting antivirals (DAAs) for both HIV 1 and HBV are active against all viral subtypes. With HCV, however, DAA activity varies across genotypes: Telaprevir and boceprevir primarily in genotype 1 NS5B non nucleoside inhibitors genotype 1 NS5B nucleoside analogs several genotypes 32

33 In addition, HCV diversification is particularly extensive, due to its extreme dynamics and unique aspects of its life cycle, during which the genome replicates multiple times per cell. Although mutations occur randomly, the likelihood of mutation to a resistant genotype (i.e., the genetic barrier ) can differ among strains. For all 3 viruses, characteristics such as replication dynamics, genomic diversity, genetic barrier to resistance, plasticity at resistance sites, pharmacodynamics, and adherence determine the pace and character of resistance. Drug concentration at the site of action is a key factor in whether a virus can overcome the genetic barrier and evolve toward resistance underscoring the importance of pharmacology and adherence. Dr. Ray listed some key commonalities and differences: Therapy that is nonsuppressive generates resistance. Combination therapy: o Reduces the risk of resistance with HIV and HCV. o Is not required for HBV, as monotherapy is effective. Permanence of resistance: o HIV yes o HBV yes o HCV not yet fully determined Pretreatment Resistant Variants The HCV viral population in each patient is a mixture of genetically distinct but closely related virions. Most resistant variants are comparatively unfit and cannot be detected before initiation of therapy by current technologies. Preclinical data from individuals receiving boceprevir detected high level resistance associated variants (RAVs) in 4% of them before initiation of treatment. Telaprevir RAVs were detected at baseline in 5% of the samples from combined clinical trials, although no conclusions could be made about their potential clinical impact. Continued viral replication in the presence of drug will likely lead to further evolution of a patient s viral population, which could lead to a more fit, drug resistant population. This can be prevented by 33