Roche (RHHBY) Scientists Uncover Unexpected Enzyme Activity in HCV RNA Polymerase

1/10/2013 2:27:59 PM

NUTLEY, NJ – January 10, 2013 – Today, Roche scientists detail the discovery of a new enzyme activity that allows HCV polymerase to remove nucleosides and nucleoside analogues from RNA molecules, which could have implications for future hepatitis C (HCV) drug development. In findings, presented online in the January 10th Early Edition issue of Proceedings of the National Academy of Science (PNAS)1, scientists uncovered that the HCV polymerase can use ATP and other abundant nucleoside triphosphates to cleave off the end nucleoside in newly formed RNA – similar to a reaction previously observed in HIV reverse transcriptase. This could lead to HCV polymerase counteracting the activity of nucleoside analogs and result in the development of pathways enabling HCV resistance.

“This new activity that we uncovered was quite unexpected,” said Klaus Klumpp, Ph.D., Vice President of Virology Discovery, at Roche. “We were very surprised by the finding that a viral RNA polymerase could so efficiently repair a blocked RNA molecule. The reverse transcriptase of HIV has shown the ability to respond to drug pressure by enhancing a similar mechanism and become resistant to nucleoside analogs such as AZT. As a result, we now have to look at viral RNA polymerases and investigate if such a pathway to nucleoside drug resistance could also be possible.”

The scientists developed a novel method to generate a stable elongation complex of HCV polymerase, which was published earlier in the Journal of Biological Chemistry2 , and were able to then characterize the enzyme activities of HCV polymerase. They found that HCV polymerase can remove nucleotides from its produced RNA strand using nucleotide triphosphates (NTP) such as ATP, as an excision mediator. Also, HCV polymerase can remove incorporated nucleoside analogs that block RNA replication, and thus rescue its RNA replication. ATP, which is abundant in cells, may mediate this rescue reaction in HCV replicating cells treated with nucleoside analogs. Another interesting finding from the research is that the byproducts of the reaction are Np4N molecules, which can modulate cell function.

“We were looking at the ability of HCV polymerase to make errors by incorporating the wrong nucleoside into the replicating RNA, but found that in many cases the enzyme started to remove nucleosides from the RNA,” said Zhinan Jin, Ph.D., who performed this work as a Postdoctoral Fellow at Roche. “I was particularly surprised by the efficiency of this excision reaction in the elongation complex, which was substantially higher than that reported previously for the HIV reverse transcriptase. Although it indicates the potential for HCV to develop resistance to certain nucleoside analog drugs, we believe this new knowledge will help scientists to develop drugs that circumvent resistance as well as new strategies to treat patients with better combination therapy.”

Nucleoside analogues are key components for the treatment of a large number of viral diseases, and may also become a cornerstone of future treatment of HCV infection. While nucleoside analogs have shown a high barrier to resistance in clinical trials to date, a few cases have been reported with viral load rebounds or relapse in the absence of known resistance mutations – the reason for treatment failure in these cases remained unexplained. These new findings raise the possibility of an RNA repair pathway to nucleoside resistance for consideration, as previously observed in HIV.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2011, Roche had over 80,000 employees worldwide and invested over 8 billion Swiss francs ($9 billion US) in R&D. The Group posted sales of 42.5 billion Swiss francs ($47.8 billion US). Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com or www.roche-nutley.com .

REFERENCES

1. Jin, Z., Leveque, V., Ma, H., Johnson, K. A. & Klumpp, K. NTP-mediated nucleotide excision activity of hepatitis C virus RNA-dependent RNA polymerase. Proc. Natl. Acad. Sci. U.S.A online Early Edition on January 10, 2013

2. Jin, Z., Leveque, V., Ma, H., Johnson, K. A. & Klumpp, K. Assembly, Purification, and Pre-Steady-State Kinetic Analysis of Active RNA-Dependent RNA Polymerase Elongation Complex. J. Biol. Chem. 287, 10674–10683 (2012)

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Accessing Hepatitis C Patients Who are Difficult to Reach

It Is Time to Overcome Barriers

P. Bruggmann

J Viral Hepat. 2012;19(12):829-835.

Abstract and Introduction

Abstract

With the arrival of simple, efficient and safe interferon-free treatment regimens, hepatitis C virus (HCV) therapy will have the potential to be successfully used for the majority of infected patients and prevent the associated morbidity and mortality. With the current treatment uptake rates, only a very small proportion of HCV-infected patients are reached. Paradoxically, treatment rates are lowest in the most affected at-risk group – people who inject drugs (PWID) – which is the major driving force behind the spread of HCV infection. To conquer the increasing problem of HCV-related liver disease, many existing but modifiable obstacles, which prevent detection, assessment and treatment uptake, have to be overcome in this population. This review article summarizes the existing literature on the most relevant barriers preventing HCV care and describes measures to overcome these obstacles.

Introduction

During the next decade, tolerability and efficacy of hepatitis C virus (HCV) therapy will improve remarkably. ^[1,2] With the expected interferon-free regimens, high treatment success rates for all genotypes will become available. Many barriers to treatment imposed by the side effects of interferon will disappear. However, one major barrier will remain, irrespective of increased efficacy and tolerability of future HCV treatment regimens: limited access to tests and therapy.

In the western world, the main driving force behind HCV infections is injecting drug use (IDU). Worldwide, about 10 million people who inject drugs (PWID) are HCV antibody positive. The mid-point HCV antibody prevalence in t\his at-risk group is 67.5%. ^[3]

People who inject drugs are affected by several comorbidities, such as alcohol dependence, HIV infections and mental diseases with concomitant chronic psychopharmacological medication. All of them compromise liver function and increase liver-related morbidity and mortality. ^[4–6] HCV, however, can be cured. The burden of advanced HCV-related liver disease among PWID is growing, ^[5,6] when it could in fact be reduced with higher treatment uptake rates. ^[7,8] Furthermore, mathematical models predict reduced transmission rates resulting from increased therapy rates. ^[9–11] Despite this, treatment uptake rates remain low in general ^[12] and in the drug-using population in particular. ^[13–17] With the current treatment uptake rates in the United States, antiviral treatments between 2002 and 2030 will prevent only 14% of liver-related deaths caused by HCV. ^[18] Hence, PWID as the major at-risk group and a virus reservoir are not yet reached well enough with HCV care. Besides developing highly efficient and well-tolerated HCV compounds, the main effort in global HCV care should focus on overcoming barriers to HCV testing, assessment and therapy. As PWID will be responsible for the main future burden of HCV-induced disease, improved access to this population should be the main goal.

To access patients, such as PWID, who are difficult to reach means breaking down barriers at healthcare system level, provider level, but also, indirectly, at individual patient level. Even if a person who uses drugs is ready for therapy, the provider (e.g. general practitioner (GP) or specialist) and/or the healthcare system are often not. ^[19] This review article gives an overview on modifiable factors preventing HCV care and describes different approaches and patient management settings to overcome these obstacles in the underserved population of PWID.

Testing: The First Step to Therapy

Improving access to therapy means first and foremost improving access to testing. Literature on HCV testing rates in PWID is scarce. Existing literature shows poor testing rates. ^[20–24] Half of the infected Americans are unaware of their infection. ^[18,20] In the canton of Zurich, 50% of all patients in opioid substitution therapies (OST) are inadequately tested for hepatitis C. ^[23] In their qualitative study, Swan et al. ^[25] assessed individual patient barriers to access HCV care. Most often mentioned obstacles were perceptions of HCV as a harmless disease, the fact that patients are not (yet) feeling unwell and a fear of intrusive tests. Due to the lack of symptoms, HCV patients without any other medical problems may not seek medical attention. According to a US investigation from 2009, patients lacking basic medical care (e.g. a GP) were 19 times more likely to be unaware of their diagnosis. ^[18]

Two studies carried out in the United States showed a lack of knowledge about risk factors and testing for hepatitis C among primary care physicians. ^[26,27] Rein et al. ^[28] presume that difficulties in implementing risk-based screenings are due to the limited time these primary care physicians have with patients and a reluctance to discuss behavioural risks. Another major barrier is the lack of specific medical care in substance abuse treatment programmes. ^[29] Furthermore, not having health insurance is associated with being unaware of one's HCV status, ^[18] and poorer geographical access to care is also associated with lower HCV detection rates. ^[30,31]

Barriers to HCV Assessment

Once tested for hepatitis C, only about 50% of patients are further assessed for treatment indication, ^[19,32] even less (about 20%) in PWID. ^[13,33] Once having tested positive for hepatitis C antibodies, only 77% of GPs performed a viral load determination. ^[34]

Assessment Barriers at Patient Level

At patient level, barriers for assessment were the fear of a liver biopsy and treatment side effects as well as of the stigma associated with HCV. ^[25,35] Becoming symptomatic, learning that a HCV infection can cause serious liver disease and the desire to rid oneself of a virus associated with drug use were identified as assessment facilitators. ^[25]

Assessment Barriers at Provider Level

One of the main reasons for GPs in Switzerland to withhold referral for therapy is normal liver enzymes, ^[34] despite long-established evidence that such patients can still develop progressive liver disease. ^[36,37]

Having seen a general practitioner specifically about HCV is associated with a higher chance of a specialist assessment. ^[19,33,38]

Assessment Barriers at System Level

An Australian study showed that the younger the people, the higher the level of formal education on HCV assessments. ^[39] Being in OST and having low social support were associated with no specialist HCV assessment. ^[19,40]

Obstacles to Treatment Uptake

Although HCV therapy is proven to be safe and efficient for PWID, ^[41,42] treatment uptake is generally low in this population and lower than in other at-risk groups. ^{[13–15,17,33]} In PWID cohorts, treatment uptake levels vary between 1% and 6%. ^[13,15,33] Volk et al. ^[18] indentified lack of diagnosis as the primary barrier to treatment.

Treatment Barriers at Patient Level

Willingness to start treatment for HCV among PWID lies between 53% and 86%. ^[16,43–45] Yet, several modifiable barriers at individual patient level remain, such as lack of knowledge, low priority, lack of financial resources and fear of side effects. Most of them correspond with those mentioned as barriers to testing and assessment. ^[25,35,45] In their recent qualitative study carried out on patients receiving opioid agonist therapy who were offered HCV therapy, Zickmund et al. ^[46] described antiviral therapies, poor relations with health providers and the lack of access to health care as the remaining critical barriers despite intense educational efforts. Patients' negative perceptions of HCV therapy are mainly influenced by their peer networks. ^[25] Depression amplifies perceived barriers at patient level, ^[35] an important finding for a patient group with high prevalence of mood disorders. ^[47–49]

The knowledge of the potential consequences of HCV, knowing somebody who has died from HCV and being told by a doctor to start treatment are all factors that facilitate treatment uptake. ^[19]

Treatment Barriers at Provider Level

Many physicians are reluctant to treat PWID driven by concerns of adherence, medical comorbidities and the risk of re-infection. ^[34,50–52] Only 20% of HCV specialists would consider therapy for PWID. ^[53] Not more than 9% of addiction specialists in an US study provided HCV treatment and only 30% were motivated to do so with the appropriate training and resources. ^[51] The doctor–patient relationship plays a decisive role for patients whether or not they discuss HCV treatment with their GP. ^[25,39]

Receiving opioid substitution therapy and recent IDU were associated with not getting treated in a cross-sectional study carried out in New South Wales, Australia. ^[19] Furthermore, PWID face an increased risk of being stigmatized by healthcare professionals without specific training in addiction medicine. ^[54,55]

Treatment Barriers at System Level

People who inject drugs are often not able to adhere to the highly structured secondary or tertiary care settings, where HCV assessment and treatment is usually provided. The setting of HCV clinics is normally not adapted to the special, mainly psychosocial needs of the polymorbid population of PWID. ^[56] PWID face an increased risk of getting lost when transferred from primary to secondary or tertiary care. ^[56] Limited infrastructure for HCV therapies and long waiting lists for treatment have been indentified as further system level barriers. ^[52]

In some countries, health insurance can be a relevant system barrier to HCV treatment for underprivileged patients. In the United States, only one-third of patients with hepatitis C treatment indication had private medical insurance. ^[57] In this study, HCV infection was independently linked with being uninsured. Limited access to medical care and a lack of health insurance are associated with low treatment uptake rates according to the study of Volk et al. ^[18] In many regions, HCV treatment is not available at all due to the high cost of the medication.

Generally Improving Access to Care

The impact of new hepatitis C compounds will remain negligible as long as access to therapy cannot be expanded worldwide. ^[18,58] Scaling up access to therapy means improving detection rates, assessment of those tested positive and referral to therapy. From a global point of view, one of the most important measures is to provide HCV medication and testing kits at affordable prices to countries with low-income levels in analogy with the HIV field. At patient level, identification, assessment and treatment should be offered for free for underprivileged populations. The following measures have been studied to access underserved populations like PWID.

Improving Access to Testing

Measures at Provider Level

General practitioners and addiction specialists play a key role in screening PWID and referring them for assessment. ^[19] GPs often have low caseloads of HCV patients with an average of four patients per practice. ^[34] Addiction specialists often miss the opportunity to test their patients for hepatitis C and educate them accordingly as they focus their attention on drug-related and mental health issues. Specific training and education about HCV testing and diagnostic criteria should focus on these healthcare professionals. ^[19]

Measures at System Level

Hepatitis C virus screening rates could be significantly enhanced with birth cohort testing and a risk-based strategy. ^[59] Rein et al. ^[60] promote primary care-based birth cohort screenings for those born between 1945 and 1965 as a cost-effective solution. Better access to testing and screening for PWID could be achieved with specific, nurse-led HCV education and counselling for people at risk. ^[25] According to Volk et al., ^[18] scaling up diagnosis rates requires education of the public and physicians alike, as well as attention to the worsening problem of the uninsured. Patients without health insurance and low literacy may be more likely to seek care in emergency rooms than in clinics or GP practices – a finding with implications for programmes aimed at improving diagnosis among PWID. ^[57]

Improving Access to Assessment and Therapy

Measures at Patient Level

Many studies show how important knowledge of and readiness for HCV assessment and treatment is for HCV patients. Training for PWID should focus on the potential health implications of HCV. ^[25] But the education of patients is only one of several actions to be taken and has its limits. ^[46] Dealing with pronounced ambivalence – a common phenomenon in addicts – by using motivational interventions (cognitive behavioural therapy, motivational interviewing) can have positive effects on patients' readiness in the long run. ^[61]

As peers who have completed a HCV therapy have the potential to facilitate treatment willingness, peer involvement could be an important measure to enhance positive attitudes towards HCV assessment and therapy among PWID. Patients attending peer support groups showed high rates of HCV care engagement, assessment and treatment uptake. ^[62,63] Peer involvement can also improve the patients' knowledge. ^[62]

Hepatitis C patients should systematically be screened for depression, as it influences perceived barriers at individual patient level and inhibits pro-active help-seeking behaviour. Feelings of guilt, shame and social stigma are amplified by depression. ^[35] Untreated HCV patients of a younger age with a history of IDU, a population often not regularly attending healthcare services, should also be within the scope of a continuous education regarding treatment possibilities and the risks of untreated hepatitis C. ^[64]

Measures at Provider Level

Hepatitis C virus providers' treatment considerations for PWID are often driven by criteria that are lacking in evidence. Treating PWID has been proven safe with sustained virological response rates comparable to non-drug users, ^[41,65] adherence rates among PWID are similar to non-drug users, ^[66,67] most of the comorbidities of PWID are no contraindication per se for HCV treatment, ^[68] and re-infection has never been proven to be a relevant risk among PWID. ^[69] Evidence-based guidelines could help overcome the myths and misconceptions about HCV assessment and treatment among PWID.

The training of hepatitis specialists, which focuses on insights into addiction medicine, could address morally based misconceptions and stigmatization towards PWID. Provider education should focus on HCV in undergraduate and postgraduate medical education already. ^[2]

Two studies indicate a high acceptance among PWID of transient elastography to assess liver fibrosis. ^[70,71] Offering this technology may facilitate assessment and help clear the hurdle of fear of a liver biopsy. ^[25]

Implementing state-of-the-art telehealth technology to provide training and specialist support to general practitioners in rural areas for the management of so far underserved HCV patients has shown to be effective. ^[72] Patients have been treated by GPs who receive telehealth support with similar rates of treatment success as patients treated at tertiary care level. The authors of this telehealth study discuss several factors that potentially contribute to the success of this model: local community providers are more patient-centred, which improves the provider–patient relationship as well as patient education. Furthermore, they are able to offer more personal contact with the patient, hence enhancing adherence and side effect management. ^[72]

Measures at System Level

To extend HCV treatment to marginalized groups of PWID, implementation of integrated community-based treatment settings is needed. Reimer describes major principles for successful primary care community-based models such as rapid access to services, high ratio of community-based to office-based appointments, assertive engagement and shared care approach. ^[56] Because addiction treatment programmes offer an important point of contact, not only testing but the full range of hepatitis care, including counselling, testing, treatment and follow ups, could ideally be offered within this setting. ^[29]

Integrated primary care community-based treatment settings have the potential to overcome several barriers to HCV treatment for PWID, allowing successful HCV therapy in patients who would not be eligible for therapy in secondary or tertiary care-based settings. ^[73,74] Patients commonly excluded from therapy, such as the homeless or people with ongoing alcohol and/or injecting drug use, can be successfully treated within an integrated community-based setting. ^[73] Such settings simultaneously address drug dependence, social support, mental health care and infectious disease assessment and therapy under one roof. ^{[17,63,75–77]} Offering everything under one roof overcomes one of the major barriers to hepatitis C care for PWID: patients not attending appointments when referred to a specialist.

Integrating professional counselling and case management by a psychologist into hepatology units can increase eligibility for HCV treatment of PWID who initially would have been deferred from therapy due to mental health and substance abuse-related comorbidities. ^[78]

The involvement of a clinical specialist psychiatric nurse in an integrated mental health and medical care setting can raise the rate of HCV assessments. ^[61] The duty of the specialist nurse in the setting as described by Knott et al. was to administer specific psychotherapies including cognitive behavioural and motivational therapies as well as prescribing psychopharmacological medication in collaboration with a psychiatrist.

Integration of specially trained nurses in rural health clinics in Canada providing counselling and interdisciplinary assessments together with the local physicians and addiction specialists enhanced the efficiency of HCV assessments as well as treatment uptake. ^[79]

A more widespread use of transient elastography would require licensing of this relatively new technology and the reimbursement by health insurances, two preconditions not yet met in many countries.

People who inject drugs have high rates of imprisonment. There are several successful models of HCV therapy for PWID in a prison setting. ^[80–83] HCV treatment in prisons is another possibility to receive HCV care for PWID.

Conclusion

There is not just one way to reach the goal of enhanced HCV detection, assessment and treatment uptake for people who use drugs. Many studies about possible measures to improve HCV management among PWID have been published and are described in this review. Accessing this HCV population that is difficult to reach needs an approach tailored to regional conditions and needs.

The approach of bringing HCV care to the patients instead of sending patients to secondary or tertiary care units is a very promising way of accessing PWID with the potential to overcome many current barriers. Evidence-based guidelines for HCV management for PWID are desperately needed to address myths about assumed contraindications and the supposed inefficiency of HCV treatment in this population. HCV education needs to be aimed at GPs and addiction medicine specialists and patients. The education of HCV specialists should focus on addiction and managing patients who are affected by addiction and its comorbidities.

To coordinate these efforts, they will have to be adapted to the needs of each individual country and applied nationwide. National coordination of action is needed. This action must start today in order to be ready in a few years when simple, well-tolerated and highly efficient HCV therapy regimens will become available.

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58. Thomas DL, Leoutsakas D, Zabransky T, Kumar MS. Hepatitis C in HIV-infected individuals: cure and control, right now. J Int AIDS Soc 2011; 14: 22.

59. Litwin AH, Smith BD, Drainoni ML et al. Primary care-based interventions are associated with increases in hepatitis C virus testing for patients at risk. Dig Liver Dis 2012; 44(6): 497–503.

60. Rein DB, Wittenborn JS, Weinbaum CM, Sabin M, Smith BD, Lesesne SB. Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States. Dig Liver Dis 2011; 43(1): 66–72.

61. Knott A, Dieperink E, Willenbring ML et al. Integrated psychiatric/medical care in a chronic hepatitis C clinic: effect on antiviral treatment evaluation and outcomes. Am J Gastroenterol 2006; 101(10): 2254–2262.

62. Sylvestre DL, Clements BJ. Adherence to hepatitis C treatment in recovering heroin users maintained on methadone. Eur J Gastroenterol Hepatol 2007; 19(9): 741–747.

63. Grebely J, Knight E, Genoway KA et al. Optimizing assessment and treatment for hepatitis C virus infection in illicit drug users: a novel model incorporating multidisciplinary care and peer support. Eur J Gastroenterol Hepatol 2010; 22(3): 270–277.

64. Treloar C, Hull P, Dore GJ, Grebely J. Knowledge and barriers associated with assessment and treatment for hepatitis C virus infection among people who inject drugs. Drug Alcohol Rev 2012; doi: 10.1111/j.1465–3362.2012.00468.x.

65. Bruggmann P, Falcato L, Dober S et al. Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients. J Viral Hepat 2008; 15(10): 747–752.

66. Mauss S, Berger F, Goelz J, Jacob B, Schmutz G. A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance. Hepatology 2004; 40(1): 120–124.

67. Robaeys G, Van VH, Mathei C, Van RM, Bruckers L, Buntinx F. Similar compliance and effect of treatment in chronic hepatitis C resulting from intravenous drug use in comparison with other infection causes. Eur J Gastroenterol Hepatol 2006; 18(2): 159–166.

68. Schaefer M, Capuron L, Friebe A et al. Hepatitis C infection, antiviral treatment and Mental Health: A European Expert Consensus Statement. J Hepatol 2012; doi:10.1016/j.jhep.2012.07.037.

69. Corson S, Greenhalgh D, Palmateer N, Weir A, Hutchinson S. Risk of Hepatitis C virus re-infection following spontaneous viral clearance in injecting drug users: a systematic review. Int J Drug Policy 2011; 22(2): 102–108.

70. Foucher J, Reiller B, Jullien V et al. FibroScan used in street-based outreach for drug users is useful for hepatitis C virus screening and management: a prospective study. J Viral Hepat 2009; 16(2): 121–131.

71. Moessner BK, Jorgensen TR, Skamling M et al. Outreach screening of drug users for cirrhosis with transient elastography. Addiction 2011; 106(5): 970–976.

72. Arora S, Thornton K, Murata G et al. Outcomes of treatment for hepatitis C virus infection by primary care providers. N Engl J Med 2011; 364(23): 2199–2207.

73. Wilkinson M, Crawford V, Tippet A et al. Community-based treatment for chronic hepatitis C in drug users: high rates of compliance with therapy despite ongoing drug use. Aliment Pharmacol Ther 2009; 29(1): 29–37.

74. Jack K, Willott S, Manners J, Varnam MA, Thomson BJ. Clinical trial: a primary-care-based model for the delivery of anti-viral treatment to injecting drug users infected with hepatitis C. Aliment Pharmacol Ther 2009; 29(1): 38–45.

75. Litwin AH, Harris KA Jr, Nahvi S et al. Successful treatment of chronic hepatitis C with pegylated interferon in combination with ribavirin in a methadone maintenance treatment program. J Subst Abuse Treat 2009; 37(1): 32–40.

76. Belfiori B, Ciliegi P, Chiodera A et al. Peginterferon plus Ribavirin for chronic hepatitis C in opiate addicts on methadone/buprenorphine maintenance therapy. Dig Liver Dis 2009; 41(4): 303–307.

77. Harris KA Jr, Arnsten JH, Litwin AH. Successful integration of hepatitis C evaluation and treatment services with methadone maintenance. J Addict Med 2010; 4(1): 20–26.

78. Evon DM, Simpson K, Kixmiller S et al. A randomized controlled trial of an integrated care intervention to increase eligibility for chronic hepatitis C treatment. Am J Gastroenterol 2011; 106(10): 1777–1786.

79. Hill WD, Butt G, Alvarez M, Krajden M. Capacity enhancement of hepatitis C virus treatment through integrated, community-based care. Can J Gastroenterol 2008; 22(1): 27–32.

80. Boonwaat L, Haber PS, Levy MH, Lloyd AR. Establishment of a successful assessment and treatment service for Australian prison inmates with chronic hepatitis C. Med J Aust 2010; 192(9): 496–500.

81. Farley JD, Wong VK, Chung HV et al. Treatment of chronic hepatitis C in Canadian prison inmates. Can J Gastroenterol 2005; 19(3): 153–156.

82. Allen SA, Spaulding AC, Osei AM, Taylor LE, Cabral AM, Rich JD. Treatment of chronic hepatitis C in a state correctional facility. Ann Intern Med 2003; 138(3): 187–190.

83. Skipper C, Guy JM, Parkes J, Roderick P, Rosenberg WM. Evaluation of a prison outreach clinic for the diagnosis and prevention of hepatitis C: implications for the national strategy. Gut 2003; 52(10): 1500–1504.

Abbreviations
GP, general practitioner; HCV, hepatitis C virus; IDU, injecting drug use; OST, opioid substitution therapies; PWID, people who inject drugs.

J Viral Hepat. 2012;19(12):829-835. © 2012 Blackwell Publishing

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Heat-inactivated HIV promising in treatment study

Published on January 9, 2013 by Paul Tinder

Injecting heat-inactivated human immunodeficiency virus may stimulate the immune system in some patients, allowing for the temporary freedom from drugs, according to a recent study.

Felipe Garcia, the study’s co-author and an infectious disease physician at the University of Barcelona, said that the combination of immune system cells – dendritic cells – and inactivated HIV, aroused the immune system to attack the live virus that circulated in the bodies of patients.

The research team selected 22 patients at random and administered a vaccine of the patients’ own dendritic cells and their inactivated HIV. Twelve of the 22 patients experienced a 90 percent drop in virus levels over 12 weeks. The immunity to HIV diminished and virus levels eventually increased. After 48 weeks, only three participants receiving the experimental vaccine maintained the 90 percent virus level drop.

Patients in the control group who received unchanged HIV and dendritic cells appeared to receive little benefit. Before the study, all participants were receiving treatment with standard antiretroviral therapy.

Garcia suggested that a therapeutic vaccine could be beneficial, even if it only offered temporary effects. He said that dropping virus levels down extremely low could mean the patients would not need drugs, would not show symptoms and would be unlikely to transmit the disease to others.

The study was published in a January edition of Science Translational Medicine.

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FDA calls for lower-dosing of sleeping pills

The Food and Drug Administration says that the current recommended doses for the prescription sleep medication Ambien and its generics should be cut in half for women and for some men. (Tim Boyle / Getty Images / January 30, 2008)

By Melissa Healy

January 10, 2013, 6:53 p.m.

The Food and Drug Administration, citing safety concerns, has called on manufacturers of the drug Ambien and its generic equivalents to lower the standard dosages of the insomnia drug now sold, and it is warning physicians that at current dosages, some patients are at risk of impairment in the morning.

The agency cited new data showing that the morning after taking the medication, some patients continued to have blood levels of zolpidem, the active ingredient in Ambien, that could disrupt driving and other activities that require alertness. That problem is more common for women, who clear the medication from their systems more slowly, and for those who use the extended release form of the medication, the FDA said in a statement.

In prescribing the immediate-release form of zolpidem to patients with sleep difficulties, physicians should routinely recommend that women take a 5-milligram dose instead of a standard dose of 10 milligrams, the FDA recommended. For men, a standard dose would be between 5 and 10 milligrams. These forms of zolpidem are marketed as generic medications under names such as Edluar and Zolpimist as well as under the name Ambien.

The current standard dose for extended-release Ambien -- which is not available as a generic medication -- is 12.5 milligrams, but should be cut in half -- to 6.25 milligrams for women, the FDA recommended. For men, the new standard dose can start at 6.25 milligrams but go up to 12.

In driving simulators and laboratory studies, 15% of women and 3% of men who took a 10-milligram dose of Ambien still had worrisome concentrations of the drug in their blood eight hours later. Among those who took a 12.5-milligram extended-release tablet of Ambien, the problem was even more common: 1 in 3 women and 1 in 4 men had blood concentrations of Ambien that would raise the risk of a motor vehicle accident eight hours later.

At the lower dose of extended-release Ambien now recommended by the FDA, 15% of women and 5% of men still had high levels of the drug in their system in the morning.

The FDA's latest step follows a litany of reports to the agency about "hangover" effects after the use of zolpidem. Some have reported engaging in routine activities such as eating or cooking while in a trance-like state under the medication's influence.

Between 6% and 10% of Americans use prescription sleep medications, a class of drugs called hypnotic sedatives. A recent study found that those who took any of these medications had a slightly higher risk of cancer as well, and that the heaviest users of sleep aids were 35% more likely to be diagnosed with cancer.

Despite evidence that they may not add much to a night's sleep, Americans in 2010 filled about 66 million prescriptions for "hypnotics and sedatives," according to IMS Health, which tracks drug trends. That makes sleep aids the 20th most used class of prescription therapies.

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Decline in Available Liver Transplants Expected

Liver Transplantation

Vol 19 (12 Issues in 2013)

Edited by: John Lake and John Roberts

Print ISSN: 1527-6465 Online ISSN: 1527-6473

Published on behalf of American Association for the Study of Liver Diseases

Impact Factor: 3.386

January 10, 2013

Lower Liver Quality from Donation after Cardiac Death Linked to Drop

A new study, funded in part by the National Institutes of Health (NIH) and Health Resources and Services Administration, and published in the January 2013 issue of Liver Transplantation, a journal of the American Association for the Study of Liver Diseases (AASLD), found that the non-use of donor livers climbed through 2010 due to a worsening of donor liver quality, primarily from donation following cardiac death. Diabetes, donor age, and body mass index (BMI) were also linked to a decrease in use of organs.

“For patients with end-stage liver disease, transplantation is the only option for extending life, but organ availability places constraints on the transplant community,” explains Dr. Eric Orman with the University of North Carolina School of Medicine in Chapel Hill. “One of the methods to increase the donor pool is to include donors with less than ideal health status—those with fatty livers, older donors, and donation after cardiac death.”

In an attempt to increase available livers for transplant, the transplant community has gradually extended donation criteria. However, previous research shows that poor outcomes may occur following transplant of more inferior organs. In fact, studies have shown an increased recipient morbidity and mortality risk with donation after cardiac death (when circulation ceases) than with standard donation following brain death in which donor circulation is sustained.

For the present study researchers used data from the Organ Procurement and Transplantation Network (OPTN) to indentify 107,259 deceased donors in U.S. between 1988 and 2010. Donors were 18 years of age and older who had a least one organ (liver, heart, intestine, kidney, lung or pancreas) used for transplantation. The mean donor age was 44 years; 41% were female and 68% were white. Split liver donations and donors with BMI less than 14 kg/m² or more than 50 kg/m² were excluded.

Analysis indicates that 41,503 donations occurred after June 30, 2004 with 82% of livers used for transplant and 18% unused. The number of unused livers decreased from 1,958 (66% of donors) in 1988 to 841 (15%) in 2004, and then increased to 1,345 (21%) in 2010. Liver non-use was independently linked to older donor age, greater BMI, diabetes prevalence and donation after cardiac death—all of which are on the rise in the U.S.

Researchers reported a four-fold increase in the odds of non-use of livers from donation following cardiac death donors between 2004 and 2010, with the proportion of nonuse climbing from 9% to 28% during the same time period. “Our findings show nonuse of livers for transplantation is steadily rising, and is primarily due to donation after cardiac death,” concludes Dr. Orman. “If these trends continue, a significant decline in liver transplant availability would be inevitable.”

In a related editorial also published in Liver Transplantation, Dr. Anton Skaro from the Feinberg School of Medicine at Northwestern University in Chicago, Ill. concurs, “Utilization of livers donated after cardiac death increases risk of biliary complications, greater costs and higher graft failure rates, resulting in a reduction of liver transplants using organs donated after cardiac death in the U.S. since 2006.” Dr. Skaro suggests that liver transplantation using organs donated after cardiac death should be encouraged for recipients who would have poor outcomes by remaining on the waitlist.

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Also See: Study finds increase in unused transplant livers

Scientists Discover New Gene That Affects Clearance of Hepatitis C Virus........A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus

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Download the PDF here

.........Scientists have discovered a gene that interferes with the clearance of hepatitis C virus infection. They also identified an inherited variant within this gene, Interferon Lambda 4 (IFNL4), that predicts how people respond to treatment for hepatitis C infection.

......Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians.......It has been reported that rs12979860 predicts early viral kinetics in HCV-infected patients receiving IFN-α-free treatment52. This genotype has also been associated with the response to IFN-α-based treatment of chronic hepatitis B virus (HBV) infection in some studies53, 54. Furthermore, IFN-α therapy is used for a number of other clinical conditions, including some forms of cancer55. Thus, therapeutic inhibition of IFNL4 might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy.

...........By analyzing data from hepatitis C-infected African-Americans and European-Americans participating in clinical studies, the authors found that the presence of the IFNL4 protein is associated with poorer clearance and response to treatment than the form that does not produce IFNL4. The deletion variant is more common in people of African ancestry, which helps partially explain why African-Americans have a lower response to current hepatitis C treatments than patients of Asian and European ancestry.

..........We have identified a new inducible human protein-coding gene, IFNL4, which is related to but distinct from known IFNs and other class 2 cytokines. The 179 amino-acid ORF of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860. In individuals of African ancestry, the IFNL4-generating ss469415590[∼G] allele is superior to the rs12979860[T] allele in predicting poorer response to pegIFN-α/RBV treatment of CHC. Within IFNL4, we identified three nonsynonymous variants, rs73555604 (p.Cys17Tyr), rs142981501 (p.Arg60Pro) and rs11764844 (p.Pro70Ser), which are present on haplotypes with the ss469415590[∼G] allele. The effects of these variants on IFNL4 biological function and their impact on HCV clearance in different populations should be further explored.

.......We assessed the associations of ss469415590 and rs12979860 with HCV clearance in 1,436 African-American and 1,480 European-American individuals from 4 studies. In Virahep-C32 and HALT-C33, we evaluated the response to pegIFN-α/RBV therapy in individuals with CHC (Supplementary Table 5). There were differences in the rates of sustained virological response (SVR) among the subjects from these studies, which reflect well-known ancestry-related differences in response to treatment and the differing selection criteria for these clinical trials: Virahep-C (European-American), 52%; Virahep-C (African-American), 28%; HALT-C (European-American), 18%; and African-American, 7%. We evaluated spontaneous HCV clearance in injection drug users enrolled in two studies, UHS34 and ALIVE35 (Supplementary Table 6). The decrease in the amount of HCV RNA during the first 28 d of treatment is a powerful early predictor of ultimate treatment response that is strongly associated with rs12979860 genotype36, 37. In African-American Virahep-C participants, the decline in HCV RNA levels after 28 d of treatment was more strongly associated with ss469415590 genotype than with rs12979860 genotype (P = 0.015, difference in mean values; Fig. 3 and Supplementary Table 7). In the same study, we observed a stronger association for ss469415590 than for rs12979860 with other measures of treatment response (week 24 response, end-of-treatment response and SVR; Table 2), although these differences did not reach statistical significance. The association pattern was similar in African-American individuals from the HALT-C study, with a stronger association for ss469415590 than for rs12979860 (week 20 response, end-of-treatment and SVR; Table 2). Spontaneous HCV clearance in African-Americans was evaluated using the area under the receiver operating curve (AUC). In UHS participants, the AUC value was greater for ss469415590 (0.62) than for rs12979860 (0.58) (Table 3). In the ALIVE study, the AUC values were similar for rs12979860 (0.64) and ss469415590 (0.64) (Table 3).

P = 0.015 for the mean differences in HCV RNA levels at day 28 for each of the three genotype groups at ss469415590 relative to the respective rs12979860 genotype groups.

Scientists Discover New Gene That Affects Clearance of Hepatitis C Virus

Jan. 9, 2013 - Scientists have discovered a gene that interferes with the clearance of hepatitis C virus infection. They also identified an inherited variant within this gene, Interferon Lambda 4 (IFNL4), that predicts how people respond to treatment for hepatitis C infection.
The results of this study, by investigators at the National Cancer Institute (NCI), part of the NIH, and their collaborators at NIH and other institutions, were published online in Nature Genetics on Jan. 6, 2013.

Chronic infection with hepatitis C virus is a cause of liver cirrhosis and liver cancer. Up to 80 percent of people who are acutely infected with hepatitis C fail to clear the virus and develop chronic hepatitis C infection, and of these, approximately 5 percent develop liver cancer. Individuals of African ancestry do not respond as well to current treatments of hepatitis C infection compared to patients of European or Asian ancestry.

Previously, results from genome-wide association studies (GWAS) identified common inherited genetic markers that were associated with response to hepatitis C virus treatment and spontaneous clearance of the infection. Those markers are located on chromosome 19 near a known interferon gene, IFNL3 (IL28B). However, molecular investigations into IFNL3 did not explain the GWAS association with spontaneous virus clearance or treatment response. To find the new gene, the investigators used a technology involving RNA sequencing on human liver cells treated to mimic hepatitis C virus infection.

"By using RNA sequencing we looked outside the box to search for something beyond what was already known in this region. We hit the jackpot with the discovery of a new gene. It is possible that other important genes may be discovered using this approach," said co-lead investigator Ludmila Prokunina-Olsson, Ph.D., of the Laboratory of Translational Genomics in NCI's Division of Cancer Epidemiology and Genetics (DCEG).

The researchers found that the IFNL4 region harbors a variant that is found in two alternative forms. One form, called deltaG, results in a deletion in one of the four bases that comprise DNA. The change creates an alteration known as a frameshift, which produces the IFNL4 protein, while the form without the deletion does not produce IFNL4. By analyzing data from hepatitis C-infected African-Americans and European-Americans participating in clinical studies, the authors found that the presence of the IFNL4 protein is associated with poorer clearance and response to treatment than the form that does not produce IFNL4. The deletion variant is more common in people of African ancestry, which helps partially explain why African-Americans have a lower response to current hepatitis C treatments than patients of Asian and European ancestry.

"Our work fulfills several promises of the genomic era," said NCI's Thomas R. O'Brien, M.D., Infections and Immunoepidemiology Branch, DCEG. "One, a better understanding of biology; two, personalized medicine; and three, new potential treatments. We deliver immediately on the first two. We've identified a new gene that may help us better understand response to viral infection and the new genetic marker may transition to clinical practice because it predicts treatment outcome for African-American patients better than the current genetic test. For the third, the INFL4 protein may be used as a novel therapeutic target for hepatitis C virus infection, and possibly other diseases."

The new gene belongs to what is now a family of four interferon-lambda protein-encoding genes, three of which were discovered more than ten years ago (IFNL1, IFNL2 and IFNL3) The mechanism by which the IFNL 4 protein impairs hepatitis C virus clearance remains unknown. Further studies will explore molecular function of this novel protein in normal and disease conditions.

This study was conducted collaboratively with the National Institute of Diabetes and Digestive and Kidney Diseases at NIH, as well as the U.S. Food and Drug Administration, and a number of universities and research institutions. Funding was provided by NCI grant Z01 CP005782.

-----------------------------------------
A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus

Nature Genetics Jan 6 2013

Ludmila Prokunina-Olsson1, Brian Muchmore1, Wei Tang1, Ruth M Pfeiffer2, Heiyoung Park3, Harold Dickensheets4, Dianna Hergott1,5, Patricia Porter-Gill1, Adam Mumy1, Indu Kohaar1, Sabrina Chen6, Nathan Brand1, McAnthony Tarway1, Luyang Liu1, Faruk Sheikh4, Jacquie Astemborski7, Herbert L Bonkovsky8, Brian R Edlin9,10, Charles D Howell11, Timothy R Morgan12,13, David L Thomas7,14, Barbara Rehermann3, Raymond P Donnelly4 & Thomas R O'Brien5

ABSTRACT

Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ∼G), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[∼G] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

Introduction

More than 3% of the world population is infected with HCV1. Up to 80% of acutely infected individuals fail to clear the virus and develop chronic hepatitis C (CHC)2, with as many as 5% eventually progressing to liver cancer3. Success of CHC treatment with pegylated interferon-α with ribavirin (pegIFN-α/RBV) depends on HCV genotype and reaches 50-80% in patients of European ancestry but only 30% in patients of African ancestry. Adding a direct-acting antiviral (DAA) agent to this regimen increases the success rate but may result in adverse effects from pegIFN-α/RBV4 and DAA treatment. If this treatment fails, there is an increased risk of the selection of resistant HCV strains that may compromise future treatment options5, 6.
Recent genome-wide association studies (GWAS) have identified the rs12979860 and rs8099917 SNPs on chromosome 19q13.13 near the IFNL3 gene (formerly known as IL28B) as variants associated with both spontaneous HCV clearance7, 8 and response to pegIFN-α/RBV treatment7, 8, 9, 10, 11. Within this region reside the three interferon-λ genes, IFNL1, IFNL2 and IFNL3 (formerly IL29, IL28A and IL28B, respectively), which encode the type III IFNs12, 13. Type I IFNs (IFN-α and IFN-ß) and type III IFNs (IFN-λs) induce antiviral activity and suppress HCV replication in vitro14, 15 and in vivo16 through activation of the JAK-STAT pathway and upregulation of interferon-stimulated genes (ISGs)14, 17, 18. The molecular phenotype of this genetic association remains unclear. The GWAS markers have not consistently been associated with hepatic IFNL3 mRNA expression19, 20, 21, and a nonsynonymous IFNL3 variant, rs8103142 (encoding a p.Arg70Lys alteration), which is in strong linkage disequilibrium (LD) with rs12979860 in all HapMap populations (r2 = 0.8-1.0), does not seem to affect the function of the IFNL3 protein22.

Discussion

We have identified a new inducible human protein-coding gene, IFNL4, which is related to but distinct from known IFNs and other class 2 cytokines. The 179 amino-acid ORF of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860. In individuals of African ancestry, the IFNL4-generating ss469415590[∼G] allele is superior to the rs12979860[T] allele in predicting poorer response to pegIFN-α/RBV treatment of CHC. Within IFNL4, we identified three nonsynonymous variants, rs73555604 (p.Cys17Tyr), rs142981501 (p.Arg60Pro) and rs11764844 (p.Pro70Ser), which are present on haplotypes with the ss469415590[∼G] allele. The effects of these variants on IFNL4 biological function and their impact on HCV clearance in different populations should be further explored.

Analysis of the genomic sequences of 45 species for which the sequence of the IFNL4 region is available in the UCSC Genome Browser showed that the unfavorable IFNL4-generating ss469415590[∼G] allele is an ancestral variant present in all species. The existence of IFNL4 protein could be predicted only in the genomes of macaques (marmosets and rhesus), orangutans, chimpanzees and humans (Supplementary Fig. 9). The beneficial insertion ss469415590[TT] allele seems to be a recently derived variant, which became common in all human populations (93% frequency in Asians, 68% frequency in Europeans and 23% frequency in Africans, according to HapMap samples), suggesting positive selection for this allele. The introduction of frameshifts is considered to be an evolutionary mechanism for the rapid emergence of new proteins49, 50, but, in this case, an insertion allele that abrogates IFNL4 seems to have been selected during evolution.

We found that the IFNL4 protein of 179 amino acids induces STAT1 and STAT2 phosphorylation, activates the ISRE-Luc reporter and ISGs, and generates antiviral response in hepatoma cells. The mechanisms by which IFNL4 induces these responses but nevertheless impairs HCV clearance are currently under investigation. IFNL4 and IFNL3 have similar residues in the area that is known to interact with the primary receptor of IFNL3 (IFNLR1) but differ in the region of IFNL3 that interacts with the second chain of the IFNL receptor complex, IL10R2. Thus, it is possible that IFNL4 activates JAK-STAT signaling through a unique receptor complex consisting of IFNLR1 and a currently undefined second receptor chain or that IFNL4 functions as a decoy cytokine competing with type III IFNs for the binding of IFNLR1. We also found that the IFNL4-caused preactivation of interferon signaling prevents further activation by type I and type III IFNs. We used an allele-specific mRNA expression assay (Supplementary Fig. 10) and explored endogenous IFNL4 expression in PHHs, where it was induced by polyI:C, IFN-α (but not IFNL3) treatment and in vitro infection with HCV (Supplementary Fig. 11). However, no IFNL4 mRNA expression was induced by polyI:C, IFN-α or IFNL3 in several transformed cell lines that carry the ss469415590[∼G] allele (HepG2, HeLa, 293T, A549 and HH29). Experiments aimed at elucidating the triggers of IFNL4 expression in diverse conditions and cell types and its receptor components are ongoing and may provide greater insight regarding its mechanism of action.

Previous studies found that individuals with CHC who carry rs12979860[T], which marks the ss469415590[∼G] allele, before treatment have somewhat higher hepatic expression of ISGs but poorer ISG response to pegIFN-α/RBV treatment19, 41, 42, 43, 44. The rs12979860[T] variant has also been associated with lower HCV RNA levels in the absence of treatment9, 51. Our in vitro experiments in HepG2 cells showed that IFNL4 induced activation of ISGs, which was not further enhanced by exogenous treatment with IFN-α or IFNL3. Taken together, these data suggest that IFNL4 induces weak expression of ISGs that provides an antiviral response that might lower the HCV load, although it also reduces the responsiveness to type I and type III IFNs that is needed for efficient HCV clearance.

It has been reported that rs12979860 predicts early viral kinetics in HCV-infected patients receiving IFN-α-free treatment52. This genotype has also been associated with the response to IFN-α-based treatment of chronic hepatitis B virus (HBV) infection in some studies53, 54. Furthermore, IFN-α therapy is used for a number of other clinical conditions, including some forms of cancer55. Thus, therapeutic inhibition of IFNL4 might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy.

Results

A genetic variant creates IFNL4, a novel interferon protein

We performed sequencing of mRNA (RNA-seq) in primary human hepatocytes (PHHs) treated with polyinosinic:polycytidylic acid (polyI:C), which is a synthetic mimic of double-stranded HCV RNA. The PHH sample was from a liver donor who was heterozygous for rs12979860 (C/T) and uninfected with HCV. Hepatocytes were treated with polyI:C for 0, 1, 2, 4, 8 or 24 h, and induction of the IFN-λ genes (IFNL1, IFNL2 and IFNL3) was confirmed by TaqMan expression analysis before performing RNA-seq. An analysis of RNA-seq data that focused on a 150-kb region centered on rs12979860 showed concordance with the TaqMan expression results-there was no expression of IFN-λ genes without polyI:C treatment, and these genes were induced after 2-24 h of activation by polyI:C (Fig. 1a).

We also observed transient activation of a novel transcribed region upstream of IFNL3, with the highest levels of expression detected at 2 and 4 h after treatment (Fig. 1b). Analysis of paired-end RNA-seq reads identified one major splice junction site. Using this common sequence as a starting point for 5' rapid amplification of cDNA ends (5'RACE), we mapped a transcription start site, followed by a unique protein translation start site 277 bp downstream. Within exon 1 (at amino acid 22), we detected a novel compound dinucleotide variant, denoted ss469415590 (TT>∼G), comprised of a one-base insertion or deletion (indel) polymorphism (loss of T, rs67272382) and a one-base substitution variant (T>G, rs74597329). Using polyI:C-stimulated PHHs from five additional liver donors and the primers described in Supplementary Table 1, we cloned and annotated ten individual transcripts created by a combination of the ss469415590 alleles and inclusion of several alternative exons (Fig. 1c,d; NCBI accession numbers are presented in Supplementary Table 2). The location of these novel transcripts 3 kb upstream of and in the same orientation as IFNL3 raised the possibility that they were alternatively spliced forms of IFNL3 or fusions. However, the presence of a CTCF transcriptional insulator site23, 24 between the two transcribed regions (Fig. 1b), the results of the RACE experiments and the inability to generate an RT-PCR product covering IFNL3 and the novel transcribed region confirmed the independence of these loci. Despite high overall similarity with a genomic region upstream of IFNL2, the novel transcripts and ss469415590 are specific for the region upstream of IFNL3 (Supplementary Fig. 1).

Of the ten novel transcripts, four were interrupted by premature stop codons and, thus, are likely to be eliminated by nonsense-mediated mRNA decay25. The remaining six transcripts were predicted to produce full-length proteins of 143 amino acids (p143) and 124 amino acids (p124) from transcripts with the ss469415590[TT] allele and 179 amino acids (p179), 170 amino acids (p170), 131 amino acids (p131) and 107 amino acids (p107) from transcripts with the ss469415590[∼G] allele (Fig. 1c). A global protein BLAST search found homology only for p179, with 29.1% amino-acid identity and 40.8% amino-acid similarity with IFNL3. However, the p179 and IFNL3 cDNA sequences were not similar enough to be aligned using the BLAST bl2seq tool. On the basis of its protein sequence homology with type III IFNs (Table 1), the International Society of Interferon and Cytokine Research (ISICR) and the nomenclature committee of the Human Genome Organization (HUGO) designated p179 as interferon λ4 protein (IFN-λ4, IFNL4). IFNL3 and p179 (IFNL4) proteins are most related within the sequences that correspond to the A and F helices of IFNL3, which constitute the core area for the interaction of IFNL3 and other type III IFNs with their primary receptor, IFNLR1 (also known as IL28R1). However, IFNL4 differs in the area corresponding to the D helix of IFNL3, which is the area of interaction of type III IFNs with the second chain of the IFN-λ receptor complex, IL10R2 (Fig. 2)26, 27, 28, 29.

Association of genetic variants in IFNL4 with HCV clearance

The GWAS markers rs12979860 and rs8099917 are located 367 bp downstream (intron 1) and 4 kb upstream of ss469415590, respectively. Analysis of data from the HapMap Project30 (Supplementary Table 3) and the 1000 Genomes Project31 (Supplementary Table 4) showed that the IFNL4-creating ss469415590[∼G] allele is perfectly correlated with the unfavorable rs12979860[T] allele in Asians (Han Chinese in Beijing, China (CHB) and Japanese in Tokyo, Japan (JPT) sets, r2 = 1.00) and well correlated in Europeans (Utah residents of Northern and Western European ancestry (CEU) set: HapMap, r2 = 0.92; 1000 Genomes Project, r2 = 0.83). In Africans, however, this correlation is only moderate (Yoruba from Ibadan, Nigeria (YRI) set: HapMap, r2 = 0.71; 1000 Genomes Project, r2 = 0.65), even though rs12979860 is the best surrogate for ss469415590 of all markers within the 100-kb region. Correlation between ss469415590 and rs8099917 was high in Asians (r2 = 0.91) and moderate in Europeans (r2 = 0.44) but very low in Africans (r2 = 0.008) (Supplementary Table 3).

We assessed the associations of ss469415590 and rs12979860 with HCV clearance in 1,436 African-American and 1,480 European-American individuals from 4 studies. In Virahep-C32 and HALT-C33, we evaluated the response to pegIFN-α/RBV therapy in individuals with CHC (Supplementary Table 5). There were differences in the rates of sustained virological response (SVR) among the subjects from these studies, which reflect well-known ancestry-related differences in response to treatment and the differing selection criteria for these clinical trials: Virahep-C (European-American), 52%; Virahep-C (African-American), 28%; HALT-C (European-American), 18%; and African-American, 7%. We evaluated spontaneous HCV clearance in injection drug users enrolled in two studies, UHS34 and ALIVE35 (Supplementary Table 6). The decrease in the amount of HCV RNA during the first 28 d of treatment is a powerful early predictor of ultimate treatment response that is strongly associated with rs12979860 genotype36, 37. In African-American Virahep-C participants, the decline in HCV RNA levels after 28 d of treatment was more strongly associated with ss469415590 genotype than with rs12979860 genotype (P = 0.015, difference in mean values; Fig. 3 and Supplementary Table 7). In the same study, we observed a stronger association for ss469415590 than for rs12979860 with other measures of treatment response (week 24 response, end-of-treatment response and SVR; Table 2), although these differences did not reach statistical significance. The association pattern was similar in African-American individuals from the HALT-C study, with a stronger association for ss469415590 than for rs12979860 (week 20 response, end-of-treatment and SVR; Table 2). Spontaneous HCV clearance in African-Americans was evaluated using the area under the receiver operating curve (AUC). In UHS participants, the AUC value was greater for ss469415590 (0.62) than for rs12979860 (0.58) (Table 3). In the ALIVE study, the AUC values were similar for rs12979860 (0.64) and ss469415590 (0.64) (Table 3).

Virahep-C, HALT-C and UHS also enrolled European-American participants. In these subjects, ss469415590 and rs12979860 showed similar associations for both treatment-induced and spontaneous HCV clearance (Supplementary Tables 7-10). Taken as a whole, our results show that, in African-American individuals, ss469415590 is a better marker than rs12979860 for predicting response to pegIFN-α/RBV treatment of CHC and possibly for spontaneous HCV clearance, whereas these variants are similarly informative in European-Americans.

By sequencing IFNL4 in 270 HapMap samples, we annotated 3 nonsynonymous variants, rs73555604 (p.Cys17Tyr) in exon 1 and rs142981501 (p.Arg60Pro) and rs117648444 (p.Pro70Ser) in exon 2, as well as 4 synonymous variants, rs150891559 (p.Ala11Ala) and rs4803221 (p.Ser30Ser) in exon 1 and rs12971396 (p.Ser149Ser) and rs137902769 (p.Ser175Ser) in exon 5 (Fig. 2, Supplementary Fig. 2 and Supplementary Tables 11 and 12). On the basis of a haplotype analysis of 16 markers from the 8-kb IFNL3-IFNL4 region, we identified 8 markers that captured all haplotypes present in the HapMap sets (Supplementary Table 13). These eight markers were also tested in European-American and African-American individuals from Virahep-C. In all populations, the unique favorable haplotype included the ss469415590[TT] allele, which eliminates the IFNL4 protein. The unfavorable ss469415590[∼G] allele was found on a number of haplotypes, including two haplotypes that were reported as being neutral in Europeans despite carrying the unfavorable rs12979860[T] allele38, 39; these two haplotypes included minor alleles of either of the rs73555604 and rs11764844 nonsynonymous variants. It is possible, therefore, that these variants modify the risk in carriers of the unfavorable ss469415590[∼G] allele and are the source of the haplotype heterogeneity previously reported in Europeans38, 39; however, data from Virahep-C are too sparse to confirm this theory (Supplementary Table 13).

IFNL4 induces expression of ISGs

We evaluated the functional properties of the six novel protein isoforms created by alleles of ss469415590. For an analysis of 45 signaling pathways, HepG2 hepatoma cells were transiently transfected with expression constructs for all six isoforms or treated with recombinant IFN-α, IFNL3 or IFNL4 (with the latter two produced in the sfs9 baculoviral expression system). Only transfection with construct expressing IFNL4, as well as treatment with IFN-α or IFNL3, induced activation of an interferon-stimulated response element luciferase reporter (ISRE-Luc), which contains STAT1- and STAT2-binding sites responsive to type I and type III IFN signaling and the IRF1 reporter (Fig. 4a). These results were validated in HepG2 cells transiently (Fig. 4b), as well as stably (Fig. 4c), expressing ISRE-Luc reporter constructs. The effect was comparable when the cells were transfected with constructs expressing IFNL4 that generated proteins with either a Halo or a Flag tag (Supplementary Fig. 3). Similarly, only transient transfection with the construct expressing IFNL4 decreased HCV RNA replication in hepatoma cells stably expressing a subgenomic luciferase-expressing hepatitis C virus replicon40 (Fig. 4d) and induced STAT1 and STAT2 phosphorylation (Fig. 4e). Transfection with IFNL4 activated the ISRE reporter in HepG2 and 293T cells but not in HeLa cells (Supplementary Fig. 4).

Recombinant IFNL4 protein expression was detectable in the cells and cell lysates of transfected HepG2 and 293T cells by confocal imaging and protein blots, respectively, with antibodies specific for IFNL4 and tag proteins (Supplementary Figs. 5 and 6). We also detected weak expression of recombinant IFNL4 in the medium of transfected HepG2 cells but not 293T cells (Supplementary Fig. 7). In polyI:C-stimulated PHHs from liver donors not infected with HCV, the endogenous expression of IFNL4 protein was detected by confocal imaging in carriers of the unfavorable ss469415590[∼G] allele but not in a homozygous carrier of the favorable ss469415590[TT] allele (Fig. 5). In hepatocytes from the donor heterozygous for ss469415590[∼G], we detected endogenous expression of IFNL4 in cells treated with polyI:C and after in vitro infection with the JFH1 HCV strain (Supplementary Fig. 6d). In fact, in hepatocytes from one of these donors (∼G/TT genotype), we observed low IFNL4 expression, even without polyI:C treatment or in vitro HCV infection (at the time point at 0 h). Although preliminary, these results suggest that IFNL4 might be expressed in conditions unrelated to HCV infection.

To further explore the functional consequences of IFNL4 expression, we performed RNA-seq in HepG2 cells transiently transfected with empty vector or construct expressing IFNL4 (Supplementary Fig. 8a) and found that the top canonical pathways induced by IFNL4 were related to the activation of interferon signaling (Supplementary Fig. 8b). We validated the RNA-seq results by quantitative RT-PCR (qRT-PCR) analysis and showed that IFNL4 induced the expression of many ISGs in a pattern similar to that induced by IFN-α and IFNL3 (Supplementary Fig. 8c). Previously, many of these ISGs have been shown to be expressed at higher levels in liver biopsies taken before treatment from HCV-infected patients who do not respond to pegIFN-α/RBV treatment; these individuals tend to carry the unfavorable genotypes at rs12979860 and rs8099917 (ref. 19,41,42,43,44), which mark the ss469415590[∼G] allele that produces IFNL4. To mimic this clinical phenotype, we transfected HepG2 cells with empty vector or IFNL4 expression constructs and/or treated cells with 10 ng/ml of recombinant IFN-α or IFNL3. In these samples, we validated the RNA-seq data by qRT-PCR analysis and showed that IFNL4 induced expression of selected ISGs (STAT1, ISG15, IFIHI1-MDA5, OAS1, MX1 and DHX58-RIG-I) in a pattern similar to that induced by IFN-α and IFNL3 (Supplementary Fig. 8d). Furthermore, treatment with IFN-α or IFNL3 of cells already expressing IFNL4 did not induce additional activation of ISGs (Supplementary Fig. 8d). Some genes known as markers of HCV-induced liver damage, such as the chemokine CCL5 (also known as RANTES)45 and the proto-oncogene FOS46, 47, 48, were induced by IFNL4 but not by IFNs (Supplementary Fig. 8d), suggesting a functional role for IFNL4 distinct from the roles of IFN-α and IFNL3.

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Study finds increase in unused transplant livers

By Andrew M. Seaman

NEW YORK | Thu Jan 10, 2013 4:40pm EST

(Reuters Health) - The number of donor livers thrown away in the U.S. has increased since 2004 due - in part - to a population growing older and heavier, according to a new study that also points to changes in medical practice that may make some donor livers less viable.

"The rationale for looking at this question in the first place is that the number of liver transplants done in the U.S. has gone down," said the study's lead author Dr. Eric Orman, a fellow at the University of North Carolina at Chapel Hill.

To identify factors that might explain the trend, Orman and his colleagues used a national database of all organ donations beginning in late 1987 to see how many livers from donors of at least one organ were discarded, and why.

They found that the proportion of unused livers fell dramatically, from 66 percent in 1988 to 15 percent in 2004. After that, however, the percentage of unused livers began to rise again, hitting 21 percent in 2010.

Between 1988 and 2010, about 107,000 people donated their livers. Nearly 42,000 of those were after 2004. Of those post-2004 donations, about 33,900 livers were used and about 7,600 were not.

When the researchers, who published their results in the journal Liver Transplantation, looked at the differences between the livers that were used and those that weren't, they found a few possible links.

Specifically, livers from older, heavier and sicker patients were more likely to be thrown out between 2004 and 2010.

"That wasn't too surprising because a lot of those donors are more likely to have fatty livers. Those livers are avoided because they can lead to worse outcomes after transplant," said Orman.

And the proportion of older, heavier donors increased during the study period.

Between 1988 and 2010, the average donor age rose by almost 10 years, and the proportion of donors who were over age 50 grew from 16 percent to 38 percent. The proportion who were obese rose from 15 percent in 1995 to just over 30 percent in 2010. And donors with diabetes and high blood pressure grew from three percent in 1995 to almost 23 percent in 2010.

The findings suggest that overall population aging and rising obesity led to a decline in the quality of livers being harvested, and ultimately to an increase in the percentage of unused organs, the researchers write.

They also found that the number of livers donated after so-called cardiac deaths rose during the study period, and that those livers were more likely not to be used.

In traditional donations after brain death, the body's heart is still pumping and supplying blood to organs because it's still attached to life-support machines. In donation after cardiac death, those machines have been disconnected.

Because livers donated after cardiac death have sometimes been linked to worse outcomes after transplant compared to brain-death donations, the fact that more cardiac-death organs were discarded did not surprise the researchers.

They found that cardiac death livers made up a quarter of all unused livers by 2010, whereas in 1995 they were just one percent.

"The problem is that the standard (or brain death) donors seem to be decreasing over the last few years, and the number of (cardiac death) donors is increasing," said Orman.

One possible explanation, the researchers write, is that machines keeping the heart beating are being removed earlier, which would turn a potential brain death donation into a "less desirable" cardiac death donation. Though, there is no evidence to support this concern, Orman cautioned.

Orman told Reuters Health that one limitation of the new study is that he and his colleagues cannot say for certain why livers were discarded

"We couldn't look at the actual reasons, but we could look at associations," he said.

Dr. David Reich, professor and chief of transplantation at Drexel University and Hahnemann Hospital in Philadelphia, said he agrees that organ donors are older, sicker and more obese, but he does not think cardiac deaths are "cannibalizing" the supply of potential brain-death livers.

Rather, he told Reuters Health, brain deaths are declining because of the advancement of neurological techniques.

"The cardiac deaths are growing because of changes in management by neurologists and neurosurgeons," he said. "That's good for patients but it's going to cost us some donors."

SOURCE: bit.ly/Wvzs4l and bit.ly/WvzhWS Liver Transplantation, online December 27, 2012.

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Dueling HCV Screening Recommendations

By Joann Kwah, Editorial Intern, Medpage Today

Published: December 27, 2012

As part of the Year in Review series, MedPage Today reporters are revisiting major news stories and following up with an analysis of the impact of the original report, as well as subsequent news on the topic. Here's what's happened since we published the first 2012 piece on hepatitis C screening recommendations. In a nutshell: There's been controversy and concern.

Until recently, HCV screening was recommended only for those with elevated liver function tests or who were at risk for the virus. Risk factors included a history of injection drug use, blood transfusions before 1992, or long-term hemodialysis.

But in May, the CDC suggested updating its HCV screening recommendations to include a one-time test for all those born from 1945 through 1965 -- the "baby boomers" -- given the high burden of disease in this population. That suggestion, after some public comment, was made final in August.

The U.S. Preventive Services Task Force had a different opinion.

After reviewing a study on the clinical outcomes of HCV screening, by Roger Chou, MD, and colleagues published online in the Annals of Internal Medicine, the task force concluded in November that the evidence did not support the recommendation for the one-time screening.

But, given the higher prevalence of HCV in this population, the group made a weaker recommendation: to consider offering screening for HCV to the baby boomers.

The differences have divided the medical community. While some agree with the task force, many fear missing opportunities for diagnosis and treatment in a population that is largely unaware of the issue.

The CDC's recommendations were made because the agency estimated that between 45% and 85% of adults with chronic HCV do not know they are infected. HCV is often asymptomatic and without risk factors for screening, the infection could go undiagnosed until after the liver has sustained significant damage.

What's more, baby boomers account for 76.5% of all HCV infections in the U.S., even though they make up only 27% of the population, according to CDC data reported online in the Annals of Internal Medicine in August.

In that report, CDC researchers led by Bryce Smith, PhD, suggested that including birth between 1945 and 1965 as a risk factor for screening would detect the infection in those who otherwise would not have been screened.

The CDC estimates that a one-time HCV test for those born from 1945 to 1965 could identify more than 800,000 additional people with the virus, prevent the costly consequences of liver cancer and other chronic liver disease, and save more than 121,000 lives.

On the other hand, Chou and colleagues concluded that there was no direct evidence that screening asymptomatic people for the virus improves clinical outcomes, and there was no published evidence on the long-term effectiveness of treatment.

But there was evidence, they found, to support screening based on the risk factors with small numbers needed to screen of less than 20 to identify one case of HCV.

As a result, the USPSTF issued a draft recommendation – and gave it a "B" grade – urging that all people deemed to be at high risk for HCV be tested. For the baby boomers, the task force draft recommendation (with a "C" grade) said screening would yield only a small net benefit and therefore was not recommended, but the task force stated that clinicians could consider screening those patients.

These draft recommendations were open to public comment until Dec. 24 with the final recommendations to follow after further review.

The Infectious Diseases Society of America (IDSA) responded by saying it was "gravely concerned that an estimated 800,000 baby boomers may not realize they have a potentially deadly virus" if the USPSTF recommendations are adopted.

In that statement, issued by society president David A. Relman, MD, the society urged the task force to revise its final recommendations to align with those of the CDC.

The American Association for the Study of Liver Diseases took a similar tack. President Guadalupe Garcia-Tsao, MD, said on the society's website that if the "recommendation is allowed to stand, many people in the group most likely to be impacted (those born between 1945 and 1965) will not be tested."

She appealed to physicians to give feedback to the task force urging them to amend their recommendation.

A number of public advocacy groups, including the National Viral Hepatitis Roundtable, have also encouraged the public to urge the task force to strengthen its recommendation for the baby-boomer generation, arguing that -- in an age where new drugs show response rates as high as 70% and 80% -- the opportunity to make an impact on the virus is great.

Those who agree with the USPSTF say there is not enough evidence to support one-time screening, arguing that prospective studies are needed to better understand the effects of HCV screening strategies on clinical outcomes before making any changes, because screening can have direct harm including labeling, anxiety, and stigmatization.

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