Idenix: New HCV Drug Could Be A Blockbuster

Idenix: New HCV Drug Could Be A Blockbuster

Cris Frangold

Seeking Alpha

Idenix Pharmaceuticals, Inc. (IDIX) recently announced encouraging initial results from Phase IIb results for the treatment - namely, IDX184 and IDX719 - of the hepatitis C virus (HCV). Some reports about HCV say that it affects more than 170 million people globally, including over 4 million Americans. The global market for an effective treatment could reach as high as $100 billion by the year 2020.

HCV infects people who come in contact with contaminated blood that carries the virus, and is one of the main causes of chronic liver disease, which may end up as liver cancer. The result is also an increase in the number of liver transplants for people who contract the disease. The present treatment, which includes injections of the drug interferon alpha, cannot be tolerated by some patients, and can result in side-effects such as fever and depression.

Experts in the field say that this is a landmark moment in the treatment of HCV, because these results show that it is possible to treat the disease without using interferon. There is potential that these two drugs, with complementary profiles, can be given orally and eradicate the virus. The stage has been set for devising a treatment for effecting a complete cure among a large number of people. Experts also feel that the IDX 184 drug from Idenix can be used as a patch, and may overcome its deficiencies if it is combined with another potent drug such as Merck's (MRK) MK-5172/Victrelis (boceprevir), which has already been approved by the FDA.

With so many companies developing and testing treatments for HCV, it is worth our time to briefly survey the current developments. Idenix itself has produced some encouraging news about clinical trials for one of its new hepatitis C drug treatments, IDX719. The study measured a number of things, including the interaction between patient safety and food, and the effectiveness of the drug treatment.

In all, 40 volunteer patients took part in the trial, of which eight were given IDX 719. The volunteers reacted well to the drug, and have provided the company with positive feedback so that the trials can be continued. The company has also planned to begin trials with a combination of IDX 719 and IDX 184 towards the end of this year. Meanwhile, clinical trials on both drugs will continue to enable the company to gather as much data as possible before applying for FDA approval.

So many big companies are now involved in developing and testing drugs for HCV, that investors are asking whether they should invest in smaller companies, like Idenix, or look to larger pharmaceutical companies. Obviously, with the successful clinical trials to date, Idenix has to be taken seriously, but it may be appropriate to examine what the competition is doing. HCV drugs have recently become popular with investors because of the size of the potential market and the problems with the existing treatments for the disease. A successful treatment that would kill the virus, or at least keep it dormant, will help millions of people, and be extremely profitable for the company concerned.

Abbott Laboratories (ABT) has recently provided information on its pipeline drugs. Two short studies have shown recovery rates that are significant among the participants. The studies showed cure rates of 95% and 93%, respectively, for patients taking other HCV treatments, and 47% of patients not taking any other treatments. A cure rate refers to stopping or slowing down the spread of the virus, though the damage the virus has already caused cannot be reversed with these drugs. The company has started Phase II clinical trials, and will proceed to Phase III clinical trials before applying for FDA approval to manufacture and sell the drug treatment.

Gilead Sciences (GILD) also has a drug called GS-7977, which it took over when it acquired Pharmasset in late 2011. Gilead, is best known for its HIV drug treatments, Truvada and Viread. This HCV drug could become formidable competition for Index and other companies if it performs well in upcoming clinical trials. Gilead is under pressure, however, as its HIV drug treatments will lose patent protection by the end of the decade, and become vulnerable to low-cost generic producers.

Vertex Pharmaceuticals (VRTX) and Merck, two other companies developing new drug treatments for Hepatitis C, are also powerful competitors, and the recent problems that Vertex has had in respect of its data on Incivek do not take away from the effectiveness of the treatment. Finally, Medivir (MVIRB), working with Johnson & Johnson (JNJ), has reported good results with its drug TMC435. The company conducted a trial that resulted in an 80% 'cure' rate for volunteers who took the drug for 48 weeks and, within 24-weeks post-treatment, the virus disappeared.

Idenix has a robust drug pipeline centered on treatments for HCV. The company is investigating three separate classes of drugs. It has already been successful in developing and launching the licensed hepatitis B drug candidate, Telbivudine. The company has collaborations with other well-known companies, such as Novartis (NVS) and GlaxoSmithKline (GSK). These collaborations have produced several drugs such as IDX375 and IDX136. The company's best chance for a blockbuster is IDX184.

I have never believed that promising biotech investments can be identified with the use of conventional techniques and ratios involving past financial performance. A new blockbuster drug can be a complete game changer for a company. The kind of returns that are possible can easily outweigh the high risk and the process of waiting on FDA approvals. Idenix has a good track record, as well as a stellar product that could be a breakthrough in the potentially enormous HCV treatment market. If you can tolerate the risk of biotech investments, I would strongly recommend buying Idenix now.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

Source

Stress Management: How the Unfolded Protein Response Impacts Fatty Liver Disease

Stress Management: How the Unfolded Protein Response Impacts Fatty Liver Disease DOI: 10.1016/j.jhep.2012.06.018       Abstract PDF (591 KB) Abstract: Induction of the unfolded protein response (UPR) is recognized as central to fatty liver disease (FLD) pathophysiology. This pathway may be a potential therapeutic target for FLD, as well as...

Dru Imrie, Kirsten C. Sadler

Discussion (In Press Accepted Manuscript)

25 June 2012

Organ Donation Has Consequences Some Donors Aren't Prepared For

Organ Donation Has Consequences Some Donors Aren't Prepared For

by Gretchen Cuda-Kroen

Listen to the Story
Morning Edition

Nearly a year and a half ago, Jeff Moyer donated a kidney. It's something he says changed his life forever. "Transplant surgery is a miracle," marvels Moyer. "I mean, to think that my kidney saved someone else's life — that's staggeringly wonderful."

His reaction is surprising given all he's been through. Like most surgical patients, when Moyer awoke, he was in a lot of pain. He was reassured that the post-surgical pain was normal and he'd be back on his feet again in a couple of weeks. But weeks, then months went by. His scars faded, and the pain didn't.

Today, Moyer says he has daily pain that leaves him virtually doubled over. It has affected his relationships and his ability to work. And yet doctors tell him they can find nothing wrong.

It's a story familiar to Vicky Young, who donated her left kidney to a friend seven years ago, only to develop kidney disease herself.

"All of a sudden I'm plummeting down to stage III chronic kidney disease, and that scared the hell out of me," says Young.

Moyer and Young represent only a small fraction of donors, but donors like them say they were unprepared financially and emotionally for the prospect of lifelong health problems. And they are frustrated by a transplant system that is primarily focused on the organ recipient, but isn't prepared to care for donors.

Young's kidney function eventually improved, but like Moyer, she suffered from chronic pain, numbness in her left leg and groin complications she says no one ever told her could happen.....

Continue Reading..

GlaxoSmithKline to pay $3 billion healthcare fraud settlement, U.S. says

GlaxoSmithKline to pay $3 billion healthcare fraud settlement, U.S. says

By Tiffany Hsu

Los Angeles Times

mercurynews.comJuly 2, 2012 9:38 PM GMTUpdated: 07/02/2012 02:37:07 PM PDT

Pharmaceutical drug maker GlaxoSmithKline will pay $3 billion and plead guilty to federal charges to resolve a slew of criminal and civil issues stemming from its use of kickbacks, mis-branding and other misconduct to market drugs such as Paxil, Wellbutrin and Advair, the U.S. government announced.

The agreement is the largest healthcare fraud settlement in history, spanning nearly every state, according to the Justice Department. It's also the largest payment ever by a drug company.
The settlement is "unprecedented in both size and scope," said James M. Cole, deputy attorney general, in a statement.

"Today brings to resolution difficult, long-standing matters for GSK," said Chief Executive Sir Andrew Witty in a statement. "Whilst these originate in a different era for the company, they cannot and will not be ignored. On behalf of GSK, I want to express our regret and reiterate that we have learnt from the mistakes that were made."

The British company illegally marketed depression drug Paxil to children and teens, even sponsoring dinners and spa programs in the drug's name, prosecutors said.......

Continue Reading....

NH hepatitis C outbreak grows to 27

NH hepatitis C outbreak grows to 27

 Jul 02, 2012 1:31 PM PDT EXETER, N.H.

(AP) - New Hampshire health officials have confirmed six more cases of hepatitis C as they continue to investigate an outbreak linked to Exeter Hospital's cardiac catheterization lab. Altogether, 27 people have tested positive for the same strain of the blood-borne viral infection, which can cause liver disease and chronic health issues. State officials suspect a worker's misuse of drugs led to the outbreak. Anyone who was treated at the lab since October 2010 has been asked to get tested, either at the hospital or at alternate sites in Hampton and Portsmouth. Copyright 2012 The Associated Press. All rights reserved.

This material may not be published, broadcast, rewritten or redistributed.

Exanthematous Drug Eruptions:Prescription and over-the-counter medications

Telaprevir approved by the FDA for the treatment of hepatitis C has been reported to cause cutaneous (skin) adverse events. Skin disorders in the triple therapy - (telaprevir plus PegIFN/RBV) has been reported more frequently and more severe than with PEG-IFN/RBV alone.

According to commentary in the - Journal Options-Hepatitis @ CCO, in clinical trials of telaprevir rash was experienced in 56% of patients, although as a rash management plan was implemented discontinuation of therapy in future trials improved.

An excerpt from CCO:

Strategies for Success: Management of Telaprevir-Associated Rash and Anorectal Symptoms

This rash management plan was implemented in the phase III studies of telaprevir with success.^[2] Although the overall incidence of rash remained similar in the phase III trials to that seen in the phase II trials, the rate of discontinuation of all medications due to rash fell to 1.1% in the phase III trials compared with a rate of 6.2% in the phase II trials. Thus, by using this management plan, most cases of rash can be effectively handled, allowing patients to remain on telaprevir therapy and maximizing the potential response to treatment.

 Read more here....

Last April Reuters reported on telaprevir-associated rash with information published in the 2012 March issue of  the Journal of Hepatology.  In the paper physicians reported during therapy with telaprevir, peginterferon, and ribavirin three patients out of 56, or 5 %  developed probable or definite DRESS.  According to the report; All cases managed successfully with discontinuation of medications, topical class I corticosteroids, and systemic antihistamines.

Excerpt;

In phase II and III clinical trials involving over 3,800 patients, 3.7% of telaprevir-treated patients developed severe cutaneous adverse events, the researchers note. The U.S. Food and Drug Administration approved telaprevir for treating HCV infection on May 23, 2011 and included DRESS among its warnings and precautions.

"The most feared complication of DRESS is end-organ damage, which in extreme cases can be life-threatening," Dr. Wu said, "so it is important to identify the syndrome early to stop the offending medications and monitor the disease."

"These are observations from a single institution during a finite amount of time," she added. "More information is needed to determine the true incidence of DRESS in telaprevir-treated patients, their prognosis, risk factors, and optimal treatment."

At this point there are no standard measures for preventing DRESS, according to Dr. Wu. "Future studies may involve genotyping those who have DRESS on telaprevir-based therapy and screening patients with associated HLA type or slow metabolism prior to receiving the medication," she said. "Although testing for human herpes virus 6 reactivation is not commonly done in this country, its association with DRESS has been made in other countries, and it may be worth screening for in the future."

Read more here....

Today on the blog is a case vignette from The New England Journal of Medicine which highlights cutaneous reactions from prescription and over-the-counter medications. The article discusses

the rare and more serious Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Hepatitis C patients, telaprevir, interferon alfa, and ribavirin is briefly mentioned.

Clinical Practice

Exanthematous Drug Eruptions

Robert S. Stern, M.D.

N Engl J Med 2012; 366:2492-2501

June 28, 2012

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.

A 50-year-old woman with bipolar depression presents with a widespread pruritic rash of 1 day's duration. She is afebrile and otherwise well. She has a history of childhood eczema and is allergic to sulfonamide antibiotics. Her medications include thyroxine daily, naproxen intermittently, and lamotrigine, which she began taking 3 weeks earlier. How should this case be evaluated and treated?
.
The Clinical Problem

In the United States, patients fill more than 300 million drug prescriptions and purchase millions of over-the-counter medications each month.1 In many cases patients are using these medications for the first time. Cutaneous reactions are among the most common adverse effects of drugs, including penicillins, cephalosporins, sulfonamide antimicrobial agents, and allopurinol (with an incidence of up to 50 cases per 1000 new users), and particularly the aromatic amine antiseizure medications, including carbamazepine, phenytoin, and lamotrigine (with an incidence of up to 100 cases per 1000 new users).2-7 Drug-related rash is reported for nearly all prescription medications, usually at rates exceeding 10 cases per 1000 new users. These reactions can range from asymptomatic mild eruptions to life-threatening conditions. Cutaneous reactions may be difficult to distinguish from common rashes that are unrelated to medication use, particularly viral exanthems.

Exanthematous drug eruptions (also called morbilliform or maculopapular drug eruptions) are the most common drug-induced eruptions.2,7 They and the much rarer and more serious Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) are idiosyncratic, T-cell–mediated, delayed (type IV) hypersensitivity reactions.8-11 Classically, antigen-presenting cells present haptens, composed of the drug or its metabolite bound to a protein or peptide, to naive T cells. These antigen-specific T cells proliferate, infiltrate the skin, and release cytokines, chemokines, and other proinflammatory mediators that are responsible for the signs and symptoms of the drug-related rash.12-15 According to an alternative theory known as the p-i (pharmacologic interaction of drugs with immune receptors) concept, small-molecule drugs or their metabolites, which are not complete antigens, activate T cells directly by binding to T-cell receptors.12,13 Irrespective of the mechanism that elicits a T-cell response to a drug, it is not known why only a minority of patients receiving a given drug have a clinical reaction to it, whereas others have immunologic reactivity without a rash.

Alterations in a patient's immune status, as well as genetic factors related to immune response, affect the risk of these drug reactions. Patients with human immunodeficiency virus (HIV) infection, bone marrow transplants, or certain infections for which they are taking particular medications are at especially high risk. 16,17 For example, most patients with infectious mononucleosis who are being treated with aminopenicillins have exanthematous eruptions, as compared with about 5% of patients without this disorder who are taking these drugs. Certain HLA alleles confer a much higher risk of some T-cell–mediated hypersensitivity reactions. Most often described in cases of severe cutaneous reactions, these associations are generally specific to the type of reaction, causative drug, and ethnic group (see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).18 In Europeans taking carbamazepine, HLA-A*3101 is reported to be associated with an increased risk of maculopapular exanthems.19

Most rashes due to medications are self-limited and only mildly symptomatic. The majority of skin events attributed to drugs are either exanthematous (maculopapular or morbilliform) eruptions (>80%) or urticaria (5 to 10%), but these percentages vary among medications and among patient groups.2,5,20 Among patients who are not immunologically compromised, severe cutaneous reactions to medications are rare (with an incidence of <1 case per 1000 new users), even with high-risk medications.8-11,20-23

Exanthematous eruptions present as a widespread, symmetrically distributed rash composed of pink-to-red macules and papules that may coalesce to form plaques (Figure 1A, 1B, and 1C 

Figure 1

Clinical Presentations of Common Drug Reactions and Measles.). Although mucous membranes are usually spared, redness without blistering may occur at these sites. Pruritus is frequent but highly variable in severity, and low-grade fever (temperature of <38.5°C) is common.

Urticaria (Figure 1D), photosensitivity, and fixed drug eruptions account for most of the remaining drug-associated eruptions in ambulatory patients. Urticaria shares pathophysiologic features with anaphylaxis and angioedema, both of which may be life-threatening. With most drugs, urticaria is an IgE–mediated, immediate (type I) hypersensitivity reaction. Urticaria due to nonsteroidal antiinflammatory drugs (NSAIDs) or angiotensin-converting–enzyme inhibitors usually reflects the pharmacologic effects of these medications rather than an immunologic reaction.24-26

Photosensitivity eruptions that accompany the use of systemic medications are almost always a consequence of ultraviolet- or visible-light activation of a drug, resulting in phototoxic injury to cells in the skin and a sunburn-like reaction that may blister in exposed areas27 (Figure 1E). Drugs commonly associated with phototoxicity include tetracyclines (particularly doxycycline), thiazide diuretics, quinolones, voriconazole, vemurafenib, amiodarone, and psoralens.28

Fixed drug eruptions present as small (usually <8 cm in diameter), red, round plaques that may sting, usually result in long-lasting pigmentation, particularly in persons with more skin pigment, and typically recur at the same sites (lips, genitalia, and acral skin) on reexposure to the causative medication (Figure 1F).29 Commonly responsible drugs include penicillins, NSAIDs, and acetaminophen.30

Strategies and Evidence
Evaluation and Diagnosis

In evaluating a patient with a new rash, the clinician should attempt to determine whether the rash is drug-related, whether it is likely to become severe, which medication or medications are most likely to be responsible, which medications can be discontinued, how the eruption should be treated, and what the patient should be told about future medication use. The appearance of the rash (its distribution and morphologic features and whether mucous membranes are involved), the time of its onset relative to the use of drugs, and an assessment of the patient for the presence of fever and other associated symptoms and signs (indicating involvement of other organs) and past reactions to medications, as well as other characteristics of the patient and any coexisting disorders, should guide decision making.

Any new, symmetric exanthematous eruption may be related to medication. Viral exanthems are often difficult to differentiate from drug-induced exanthems (Figure 1G). Viral illnesses are often characterized by the rapid onset of widespread, symmetric eruptions of pink-to-red macules and papules that may coalesce, with fever, malaise, sore throat, and conjunctivitis; however, these features may also be seen with a drug eruption. Viral exanthems are more common in children than in adults and are usually self-limited and mildly symptomatic.31 Table 1


Table 1

Selected Infections and Other Conditions that Often Include an Exanthem and Characteristics that Help Differentiate Them from an Exanthematous Drug Eruption. describes the characteristic features of some common viral exanthems that help distinguish them from drug eruptions. Patients with fever, sore throat, or malaise due to infections use many medications (particularly antibiotics and NSAIDs) that also cause exanthematous rash. Because of the time required for hypersensitivity to develop in a patient not previously sensitized to a particular drug, a rash that appears within 3 days after the drug has been initiated for these indications is more likely to be due to infection than to the drug.2,14,22
Most drug-induced exanthematous eruptions evolve rapidly, are symmetric and widespread, reach the maximal extent within 2 days after the elimination of the causative drug, and fade within a week after the drug is eliminated. Some drug eruptions start to fade even while the patient is still taking the causative agent.

The character of the individual lesions frequently varies according to the body site (e.g., confluent red plaques on the trunk and discrete pink macules and papules on the extremities). The rash is likely to be a deeper red and may even become purpuric in dependent areas. With the exception of patients who bleed easily, one should be able to cause blanching of the rash in nondependent areas. Skin eruptions that differ in appearance from exanthematous drug eruptions are common in patients treated with tyrosine kinase inhibitors (papulopustular eruptions) and patients with hepatitis C who are treated with telaprevir, interferon alfa, and ribavirin (eczematous eruptions).32,33

First-time exanthematous drug eruptions and T-cell–mediated severe cutaneous reactions typically begin to appear 4 to 21 days after the start of treatment with the responsible medication but may develop later in DRESS (Table 2

Table 2

Features of Selected Severe Cutaneous Adverse Reactions to Drugs.).2,11,22,23 Therefore, assessment of the timing of drug administration relative to the onset of rash and other symptoms is a key step. Resolution after a medication is stopped (known as a “dechallenge”) also helps identify the causative agent.

Since the likelihood of a drug-induced rash varies according to the medication, the population treated, and the indication for use, such factors should be considered in assessing the probability that the patient's rash is due to a specific drug. Aside from the genetic and disease factors discussed above, some groups of patients are at greatly increased risk for unknown reasons. For example, the rate of drug-related rash among young women treated with the antibiotic gemifloxacin (>20%) is about 10 times as high as the rate among other patients treated for the same indications.34 Organ-specific algorithms rather than algorithms that assess drug causality irrespective of the affected organ system may improve interrater reliability in the assessment of the cause of drug eruptions.35 Table S2 in the Supplementary Appendix provides an algorithm, adapted from one validated for SJS–TEN (another T-cell–mediated drug reaction), that may help identify the causative drug in cases of exanthematous drug eruptions,36 although it has not been validated for exanthematous reactions.

Assessing the Likelihood of a Severe Reaction

It is important to determine whether an exanthematous drug-induced rash is likely to be an early sign of a severe cutaneous reaction. Determining whether DRESS will develop in a patient with a widespread eruption and fever is particularly challenging. Table 2 summarizes the signs and symptoms associated with medication use for the three severe cutaneous reactions that together account for more than 90% of such reactions: DRESS (Figure 2A


Figure 2

Clinical Presentations of Severe Cutaneous Reactions to Drugs.), SJS–TEN (Figure 2B), and AGEP (Figure 2C). Table S1 in the Supplementary Appendix lists selected medications commonly associated with these reactions, as well as genetic risk factors.

Cutaneous leukocytoclastic vasculitis is characterized by erythematous and purpuric papules predominantly on the lower extremities (Figure 2D). Although most cases are associated with infection or autoimmune disorders, about 20% are due to drugs.37 More than 100 drugs have been implicated, particularly propylthiouracil.38
Serum sickness–like reactions have a variety of cutaneous manifestations, including exanthematous and urticarial eruptions, as well as fever, lymphadenopathy, arthralgia, and inflammation of other organs. Foreign proteins, including biologic agents, minocycline, and cephalosporins, have been associated with these reactions.

Further Evaluation

In most cases of exanthematous drug reactions, a structured clinical evaluation will identify the most likely causative drug (or drugs), which can be withdrawn and avoided in the future (Table S2 in the Supplementary Appendix). Occasionally, greater certainty is needed to establish the causative drug. Whereas in vitro detection of specific IgE antibodies may assist in identifying cases of urticaria, angioedema, and anaphylaxis due to beta-lactam antibiotics and some other drugs, these tests are not relevant to T-cell–mediated drug eruptions, including DRESS and SJS–TEN.39
Various tests have been advocated for establishing the causative drug in cases of exanthematous eruption, but all the tests have limitations. Patch testing has long been used to document the cause of allergic contact dermatitis, a T-cell–mediated delayed hypersensitivity reaction. However, standardized reagents for patch testing are lacking, and sensitivities below 10% have been reported.40 The lymphocyte transformation test attempts to quantify in vitro activation of T cells in response to a drug or its metabolites, but the test is cumbersome and not sufficiently standardized for clinical decision making.40 Drug provocation testing relies on the controlled readministration of a suspected drug to determine causality. Such testing is rarely used in clinical practice because it is not well standardized, may have false positive or false negative results, and carries a risk of triggering a new and possibly more serious drug reaction.
Skin biopsy may help identify SJS–TEN or AGEP in their early phases, but specific histopathological features that would distinguish exanthematous eruptions from DRESS and viral exanthems early in their course are lacking. 41 Phototoxic reactions have characteristic features on biopsy.

Management

Whenever feasible, identification and prompt withdrawal of the suspected drug constitute the cornerstone of management for drug-induced eruptions. This is particularly important for drugs with a short half-life (<24 hours) when an exanthematous rash may represent the early sign of SJS–TEN, since prompt withdrawal of drugs with a short (but not long) half-life has been associated with reduced mortality.42 Patients with signs and symptoms suggesting that the rash may be an early manifestation of a severe reaction should be closely monitored and are often hospitalized until a severe reaction can be ruled out. If the drug is essential and the reaction is not severe, desensitization after recovery may be attempted, but this process is rarely required and is cumbersome.
Sedating antihistamines such as diphenhydramine and hydroxyzine may provide symptomatic relief from pruritus. Potent topical glucocorticoids (which should not be used on the face or in intertriginous areas) may reduce signs and symptoms of the rash, but data from randomized trials of their efficacy in this setting are lacking. Data from a retrospective review and an open-label study, respectively, suggest that early treatment of SJS–TEN with systemic glucocorticoids or cyclosporine is associated with reduced mortality.43,44 The role of intravenous immune globulin in the treatment of SJS–TEN is controversial. The benefits of systemic glucocorticoids relative to their risks in the treatment of exanthematous drug reactions are not clear.

Subsequent Care of Patients with a History of an Exanthematous Drug Reaction

Although in many patients, rechallenge with a drug thought to be responsible for a prior drug-related rash does not result in a new eruption, it should generally be avoided because an eruption on reexposure to the drug may be more severe than the previous eruption. The exception is infectious mononucleosis; if a rash develops in association with the use of aminopenicillin in a patient with this disorder, the risk associated with readministration is only slightly higher than it is for first-time users of the drug.
Exposure to chemically related compounds is also a concern among patients with a prior drug exanthem. However, in many cases, the related drug is tolerated. Among patients who have had an exanthematous (non-IgE–mediated) rash in association with a penicillin antibiotic, the risk of a reaction to a beta-lactam antibiotic is probably less than 10%, and cross-reactivity between cephalosporins with different side chains is infrequent.45 Sulfonamide antimicrobial agents are frequent causes of drug eruptions. The structures of nonantimicrobial sulfonamides, including diuretics, some NSAIDs, and antidiabetic agents, differ sufficiently from the structures of sulfonamide antibiotics that cross-reactivity with sulfonamide antibiotics is unlikely.46 Cross-reactivity is frequent among aromatic amine antiepileptic agents.47 Irrespective of the agent causing an initial drug reaction, persons with a history of drug hypersensitivity are about twice as likely to have hypersensitivity reactions to any other medication as are those without such a history.46

Areas of Uncertainty

Limited information suggests that HLA haplotypes and other genetic factors may be useful in predicting the risk of exanthematous reactions to certain drugs, but more data are needed to improve the identification of persons at high risk for such reactions. In addition, a better understanding is needed of factors that mediate differences in the extent and severity of exanthematous drug reactions among affected patients exposed to the same medication. Finally, the usefulness of systemic glucocorticoids and other treatments for exanthematous drug reactions remains uncertain.

Guidelines

Guidelines for the identification and management of cutaneous drug reactions have been published by the American Academy of Dermatology (most recently in 1996)48; the American Academy of Allergy, Asthma, and Immunology49; and the British Society for Allergy and Clinical Immunology.50 The British guidelines put greater emphasis on skin testing to determine causative drugs than do the recommendations presented here, which are otherwise consistent with these guidelines.

Conclusions and Recommendations

The patient described in the vignette almost certainly has an exanthematous drug eruption due to lamotrigine. Fortunately, she has no signs or symptoms suggestive of a severe cutaneous reaction, but she should be informed that if fever, mucosal symptoms, blisters, or malaise develops, she should seek immediate medical attention. She should also be advised to stop taking lamotrigine and to ask her psychiatrist to prescribe an alternative agent that is not an aromatic amine. Since lamotrigine has a long half-life, the patient should be informed that the eruption may take a week or longer to fade. I would recommend that she apply emollients and take sedating antihistamines at bedtime. If the rash is very itchy, I would recommend treatment with a potent topical glucocorticoid for 1 week; although data from randomized trials are lacking, clinical experience suggests that this treatment should reduce secondary skin inflammation and pruritus. Oral glucocorticoids are not indicated, and no further tests are necessary. She should be counseled to avoid this drug and other aromatic amines, including phenytoin and carbamazepine.

Dr. Stern reports receiving consulting fees for the assessment of skin reactions associated with drugs under development from Vertex, InterMune, Johnson & Johnson, Boehringer Ingelheim, and Takeda and its Millennium Division, and for serving on a drug-safety panel for Takeda and as an expert witness in product liability litigation relating to skin reactions for Johnson & Johnson and Mutual, as a consultant to Audet Partners in litigation unrelated to cutaneous drug reactions, and as an expert in patent litigation for Nycomed. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

I thank Drs. E. Hawryluk and S. Huang for their helpful comments and clinical photographs, Drs. T. Nijsten and Gail A. Howrigan for their helpful comments, and Drs. R.A. Johnson and P.A. Wu for clinical photographs.

Source Information

From the Department of Dermatology, Beth Israel Deaconess Medical Center, Boston.
Address reprint requests to Dr. Stern at the Dermatology Department, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Gryzmish 522A, Boston, MA 02215, or at rstern@bidmc.harvard.edu.

Key Clinical Points

EXANTHEMATOUS DRUG ERUPTIONS

	• Exanthematous drug eruptions, also called morbilliform or maculopapular drug rashes, occur in 1 to 5% of first-time users of most drugs.
	• These often pruritic skin reactions typically appear 4 to 21 days after a person starts taking the causative medication and are characterized by symmetrically distributed, pink-to-red macules and papules that spread rapidly and may coalesce.
	• Patients with human immunodeficiency virus infection or bone marrow transplants are at increased risk.
	• Identifying and discontinuing the causative drug are the most important steps in management; symptomatic treatment with antipruritic agents and potent topical glucocorticoids may be helpful.
	• Signs and symptoms that should alert the clinician to the possibility of a severe cutaneous reaction include mucous-membrane involvement, temperature above 38.5°C, blisters, facial edema and erythema, and lymphadenopathy.

 http://www.nejm.org/doi/full/10.1056/NEJMcp1104080

IL28B Genotyping in the Management of Chronic HCV

Michael Charlton

MBBS, FRCP

Hepatology Director and Medical Director of Liver
Transplantation, Mayo Clinic, Rochester, MN

Dr. Charlton is a council member of the International Liver Transplantation Society. He is also a member of AASLD’s practice guidelines writing group and the United Network for Organ Sharing’s Liver and Intestinal Organ Transplantation Committee.

IL28B Genotyping in the Management of Chronic HCV

"There are exciting data regarding IFN-free treatment protocols with combinations of direct-acting antivirals and RBV. Whether IL28B polymorphism will remain relevant in the context of IFN-free treatment protocols is not known and seems unlikely."

In the years following the identification of hepatitis C virus(HCV), the efficacy of interferon (IFN)- and ribavirin(RBV)-based therapies reached a peak of approximately 45 percent for the most prevalent HCV genotype, genotype 1.

Predicting response to IFN, bound to polyethylene glycol(PEG) or otherwise, and RBV has been frustrating. Profound differences in the frequency of virological cure(sustained virological response [SVR]) following IFN- and RBV-based therapy exists between ethnic groups. Among patients within an ethnic group, the likelihood of SVR could not be predicted accurately by any single or combination of host or virological parameters.

As the treatment of HCV infection is both expensive and difficult, with frequent toxicities, estimating the likelihood of success is important. Virological factors that influence response to treatment include viral genotype (the most predictive single factor) and viral load
(view table at http://www.gastro.org/charlton83).

Patients infected with HCV genotype 1 who are treated for 48 weeks with pegylated IFN (PEG-IFN) and RBV have an approximately 40 to 54 percent1 likelihood of achieving an SVR, whereas patients with genotypes 2 or 3 virus have an SVR rate of approximatley 65 to 82 percent. Host characteristics predictive of response to treatment include ethnicity, gender, age, weight, insulin resistance, hepatic steatosis and liver fibrosis stage.

In 2009, Ge et al3 reported that variation in and near the IL28B gene is strongly predictive of response to treatment of chronic HCV infection with PEG-IFN and RBV. The p value for the association of rs12979860 with SVR was approximately 10,2, 4 with an associated 2.5-fold higher relative rate of SVR among non-Hispanic Caucasian subjects carrying the responsive C/C genotype compared to the T/T genotype. The C/C genotype is also associated with higher likelihood of SVR in Hispanics, Asians and African Americans. IL28B genotype accounts for essentially all of the variability in SVR between ethnic groups. IL28B genotype is also highly predictive of spontaneous clearance of acute HCV infection and outcomes following liver transplantation.

How should IL28B genotyping, which costs about $300, be incorporated into current treatment algorithms now that addition of a protease inhibitor, boceprevir or telaprevir to PEG-IFN and RBV is the new standard of care in the treatment of genotype 1 HCV infection? Is there a role for IL28 genotyping in non-1 genotypes or acute HCV infection?  I present my interpretation and a rational possible approach.

Genotype 1 (and possibly 4)

If the decision of whether or not to treat HCV infection is dependent upon likelihood of SVR, IL28B genotyping should be considered (view figure at http://www.gastro. org/charlton83). In patients in whom treatment is planned, IL28B genotyping can be useful in guiding duration of treatment with PEG-IFN and RBV, as the C/C genotype confers a nine-fold increase in likelihood of rapid virological response (RVR).

Among those who do not achieve RVR, patients with C/C genotype are more than five times as likely to achieve SVR. Adding boceprevir and telaprevir to PEG-IFN and RBV reduces, but does not eliminate, the association between IL28B genotype and treatment outcome. In treatmentnaïve patients with HCV genotype-1 infection, IL28B genotype continues to be significantly predictive of SVR.

As the protease inhibitors do not significantly increase efficacy among patients who achieve RVR or patients with IL28B C/C genotype, a case could be made for performing IL28B genotyping to identify patients who are likely to achieve SVR without protease inhibitors.

IL28B C/C genotype patients who do not achieve RVR could have boceprevir added to PEG-IFN and RBV, thus still adhering to the response-guided triple therapy protocol for boceprevir, which includes a four week lead-in phase of boceprevir-free therapy. Telaprevir is also effective with a PEG RBV lead-in. Such an approach might maximize patient-specific likelihood of response while potentially limiting cost.

The potential for cost savings may be magnified if generic PEG-IFNs become available (an event that is hard to predict for biologic agents). The benefit of the protease inhibitors in patients with IL28B C/C genotype is to allow shorter treatment duration while maintaining SVR rates above 80 percent, not to increase SVR. Non-CC IL28B genotype patients clearly benefit from the addition of protease inhibitors, with SVR rates doubling among treatment-naïve patients when compared to PEG-IFN and RBV alone.

There are exciting data regarding IFN-free treatment protocols with combinations of direct-acting antivirals and RBV. Whether IL28B polymorphism will remain relevant in the context of IFN-free treatment protocols is not known and seems unlikely.

Genotypes 2 and 3

IL28B genotype has been only variably and modestly predictive of SVR for patients with HCV genotypes 2 and 3, for whom SVR rates are 65 to 82 percent.

IL28B genotyping thus has little role in decision making regarding treatment initiation. Although IL28 genotype predicts SVR at 24 weeks in patients without RVR, the role for IL28B genotyping is not clear at a practical level.

While it is possible that IL28B genotyping may be of utility in determining optimal duration of antiviral therapy in patients with HCV genotypes 2/3 (e.g., 24 weeks for C/C and 48 for non-C/C), the data are too weak to make a firm practice recommendation

References

1. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS.
Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.
N Engl J Med 2009;361:580-9
2. Mangia A, Thompson AJ, Santoro R, Piazzolla V, Tillmann HL, Patel K, Shianna
KV, Mottola L, Petruzzellis D, Bacca D, Carretta V, Minerva N, Goldstein DB,McHutchison JG.
An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response.
Gastroenterology  2010;139:821-7, 827 e1.
3. Ge D, Fellay J, Thompson AJ, Simon JS,Shianna KV, Urban TJ, Heinzen EL, QiuP, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB.
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
Nature 2009;461:399-401.

June/July 2012 issue of AGA Perspectives

Also In AGA Perspectives: Worth the Wait? Should chronic hepatitis C patients be treated now or wait for promising therapies?

Scripps Research Institute Scientists Develop Alternative to Gene Therapy

Carlos Barbas

The technique points to safer, simpler potential HIV treatment

LA JOLLA, CA – July 1, 2012 – Scientists at The Scripps Research Institute have discovered a surprisingly simple and safe method to disrupt specific genes within cells. The scientists highlighted the medical potential of the new technique by demonstrating its use as a safer alternative to an experimental gene therapy against HIV infection.

"We showed that we can modify the genomes of cells without the troubles that have long been linked to traditional gene therapy techniques," said the study's senior author Carlos F. Barbas III, who is the Janet and Keith Kellogg II Professor of Molecular Biology and Chemistry at The Scripps Research Institute.

The new technique, reported in Nature Methods on July 1, 2012, employs zinc finger nuclease (ZFN) proteins, which can bind and cut DNA at precisely defined locations in the genome. ZFNs are coming into widespread use in scientific experiments and potential disease treatments, but typically are delivered into cells using potentially risky gene therapy methods.

The Scripps Research scientists simply added ZFN proteins directly to cells in a lab dish and found that the proteins crossed into the cells and performed their gene-cutting functions with high efficiency and minimal collateral damage.

"This work removes a major bottleneck in the efficient use of ZFN proteins as a gene therapy tool in humans," said Michael K. Reddy, who oversees transcription mechanism grants at the National Institutes of Health's (NIH) National Institute of General Medical Sciences, which helped fund the work, along with an NIH Director's Pioneer Award. "The directness of Dr. Barbas's approach of 'simply' testing the notion that ZFNs could possess an intrinsic cell-penetrating ability is a testament to his highly creative nature and further validates his selection as a 2010 recipient of an NIH Director's Pioneer Award."

Questioning Assumptions
ZFNs, invented in the mid-1990s, are artificial constructs made of two types of protein: a "zinc-finger" structure that can be designed to bind to a specific short DNA sequence, and a nuclease enzyme that will cut DNA at that binding site in a way that cells can't repair easily. The original technology to make designer zinc finger proteins that are used to direct nucleases to their target genes was first invented by Barbas in the early 1990s.

Scientists had assumed that ZFN proteins cannot cross cell membranes, so the standard ZFN delivery method has been a gene-therapy technique employing a relatively harmless virus to carry a designer ZFN gene into cells. Once inside, the ZFN gene starts producing ZFN proteins, which seek and destroy their target gene within the cellular DNA.

One risk of the gene-therapy approach is that viral DNA—even if the virus is not a retrovirus—may end up being incorporated randomly into cellular DNA, disrupting a valuable gene such as a tumor-suppressor gene. Another risk with this delivery method is that ZFN genes will end up producing too many ZFN proteins, resulting in a high number of "off-target" DNA cuts. "The viral delivery approach involves a lot of off-target damage," said Barbas.

In the new study, Barbas and his colleagues set out to find a safer ZFN delivery method that didn't involve the introduction of viruses or other genetic material into cells. They experimented initially with ZFN proteins that carry extra protein segments to help them penetrate cell membranes, but found these modified ZFNs hard to produce in useful quantities. Eventually, the scientists recognized that the zinc-finger segments of ordinary ZFNs have properties that might enable the proteins to get through cell membranes on their own.

"We tried working with unmodified ZFNs, and lo and behold, they were easy to produce and entered cells quite efficiently," Barbas said.

New Strategy Against HIV
Next, the team showed how the new technique could be used in a ZFN-based strategy against HIV infection.

The AIDS-causing retrovirus normally infects T cells via a T cell surface receptor called CCR5, and removing this receptor makes T cells highly resistant to HIV infection. In 2006, an HIV patient in Berlin lost all signs of infection soon after receiving a bone marrow transplant to treat his leukemia from a donor with a CCR5 gene variant that results in low expression of the receptor. Disrupting the CCR5 gene in T cells with a ZFN-based therapy might be able to reproduce this dramatic effect.
"The idea is to protect some of the patient's T cells from HIV, so that the immune system remains strong enough ultimately to wipe out the infection," said Barbas.

A gene therapy that uses ZFNs to disrupt CCR5 genes in T cells and reinfuses the modified T cells into patients is currently in clinical trials. Barbas and his team showed that they could achieve the same effect with their simpler ZFN-delivery method. They added ZFN proteins directly to human T cells in a culture dish and found that within hours, a significant fraction of the ZFN-treated cells showed sharp reductions in CCR5 gene activity.

After several applications of ZFNs, aided by a special cooling method that improves the ability of the proteins to get across cell membranes, the scientists were able to inactivate CCR5 genes with an efficiency approximating that of the gene therapy-based approach, Barbas said.
The new approach also appeared to be safer. A DNA-based method the team used for comparison or the viral-based methods reported in the literature by others ended up producing ZFNs for up to several days, causing a significant amount of off-target DNA damage. But the directly delivered ZFN proteins remained intact within cells for only a few hours, causing minimal off-target damage.
"At some off-target locations where the gene therapy approach frequently causes damage, we saw no damage at all from this new technique," said Barbas.

Hope for 'Tiny Factories' of Health
The team tested its direct ZFN-delivery technique with a variety of other cell types and found that it works with particularly high efficiency in human skin "fibroblast" cells. Researchers now are working on advanced therapies in which they harvest such fibroblasts from patients and reprogram the cells' gene-expression patterns so that they effectively become stem cells. These induced stem cells can then be modified using ZFNs and other genome-editing techniques. When reinfused into a patient, they can produce millions of therapeutic progeny cells over long periods.
Such techniques may one day be used to treat a vast array of diseases. Barbas, who has been developing anti-CCR5 strategies for more than a decade, wants to start with a ZFN-based therapy that disrupts the CCR5 gene in hematopoietic stem cells. These blood-cell-making stem cells, reinfused into an HIV patient, would become tiny factories for producing HIV-resistant T cells.
"Even a small number of stem cells that carry this HIV-resistance feature could end up completely replacing a patient's original and vulnerable T cell population," he said.

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The other authors of the paper, "Targeted gene knockout by direct delivery of ZFN proteins," are first author Thomas Gaj, and Jing Guo, Yoshio Kato, and Shannon J. Sirk, all members of the Barbas laboratory during the study.
The research was funded by NIH grants R01GM065059, DP1OD006990, and T32GM080209 and by the Skaggs Institute of Chemical Biology at Scripps Research.

http://www.eurekalert.org/pub_releases/2012-07/sri-sri062812.php