December 11, 2013

Mark (Thursdays Child) Eckler: What a gift!!

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December 11, 2013

We sat in my car on a quiet night crying together but still alone. She was the woman I loved and also the one who I blamed for my infection. The last thing she ever said to me was " I will be your scape goat and this to shall pass". That made me so angry. I didn't need a scape goat for it was her who had done this to us right. That was the best my mind could offer me. Anger pain and fear witch i would live in for the next there years. It was dark indeed but what they say is it's always darkest just before the dawn. How true that is. What I couldn't see (or wouldn't see) at the time is that for her this was the other side of the coin. That the Boomerang of blame I was throwing in my anger and haste would one day turn in it's flight and come back to cut me down just as had happened to her. That everything I saw about the girl in my passenger seat that I despised I would one day become. Every line I drew in the sand to separate her actions from my own I would one day cross. I believe she knew then the pain I would have to walk through and the fear I would have to face going forward. I today think she wished she could help me but knew in her heart that she couldn't for I would only hold her as my hostage from now forward and use blame and fear as the tool to do it. How much she must have loved me to know that for her the only thing to do now was to walk away. What I am not sure if she knew is that I would in the end find happiness and true freedom directly due that very pain and fear. I don't think she knew that then or even knows that now for I am not sure if she has found the same. I hope she someday does. Did she give me HVC or did I get it from one of my basement tattoo sessions...who knows and who cares. All I know is at the time of my diagnoses I hadn't used IV drugs yet and she had it all along and hadn't been honest with me about it so I blamed her. I needed someone to blame. I needed a "Scape goat". But in time...that too would pass.

    My name is Mark and I am from a small town in Kentucky where everyone knows everyone and we party as herd as we work. We feel I believe that we had earned it. I was no different. I have spent the most of my days doing anything I can to earn a dollar playing some music cause it makes people smile and doing whatever it took to wipe away the pain and sorrow of a middle class young man. Most days back then where filled with 8 hours of making and serving chili at the local parlor, followed by several more hours of playing guitar drinking and doing drugs at one of the many local pubs. Witch pub depended on witch night. Life didn't seem to deep or meaningful to me at the time. Just try to be with friends,tell white lies and smile. I felt my life needed nothing else to be complete, needed no deeper meaning to be full. That is until she came back.

   Her name was Cassie. I had know her as a young teen. I could recall nights in my early high school years where her and I would play drinking games...one on one like true alcoholics until we passed out. Good times for 13 year old kids. I remember one night a friend of ours Kristie had suggested that one day we would be a couple. I wasn't fond of the idea at the time but it grew on me. Then one day when we where about 16 Cassie vanished. Someone told me she had a new boyfriend and she had been doing heroin. This shocked me. I had never even seen the stuff. How had she gotten into that. I heard no more of her for a 8yrs or more but the fond memory never left me. Until one day there she was at the local corner store I went to daily. She was with that same friend who had suggest we would be a couple. I was shocked. She didn't look like what I now knew to be a heroin addict at all. She was stunningly attractive. As we spoke she didn't sound like anything other than the well spoken young lady I had always known. I wanted to ask where she had been but figured it could wait. So I did what I know best and invited the girls out for drinks that night. And so it started.

   The girls showed at the bar where by now I was the door man and was well respected by my fellow drunks. We talked about old times over strong drink. (I was quite pleased to see Cassie still drank Kentucky bourbon and smoked Marlboro red cigarettes.) It was the great girl I remembered after all. I don't know if it was me the old memories or the drinks but something made quite the good impression for I was invited to an after party with the girls at closing time.) At the party we proceed to get much more drunk and then Cassie and I set off for a private room to fulfill the prophecy our friend had given all those years ago. It would be the start of the greatest love and greatest pain I have ever know in my life so far.

   In the following months and years even her and I did all the things partying couples do. Loved without holding back fight like cats and dogs and washed our pain away with drugs and drinks. That’s what normal couples do right. One thing I forgot to mention is during the time her and I had been apart heroin had became an epidemic in my town. It seemed everyone was on it but us. Her and I had talked about where she had gone for all that time. She told me about her experience with that awful drug, how she had gone to rehab and was better now. Seemed fine to me and also a good reason not to try it. I could kill the girl I loved. It took some time but the day came where her and I would start to do heroin together. I remember it like it was yesterday. We where sitting in the parking lot of a local dinner where  we met an old friend to buy 40$ worth of heroin. As we sat in my sky blue 1998 Buick regal I remember how hot it was. I remember thinking....only this once. We both snorted it this time (this wouldn't last long for her) like i did for the next five years because I didn't want to be like her. By the time I smoked a cigarette I knew...this feeling and this girl is all I needed for the rest of my days. That’s what I thought but it wasn't to be.

   Everything went alright for a while other than loosing our jobs , selling everything we owned , stealing from our families and everyone who cared about us and getting evicted from our home. Yes all was well indeed. Until one day her brother asked me if I was being carful with her...sexually. I didn't know what he really meant and replied."dude she's not going to get pregnant". And he said...Its not that I just don't want you to get hep-c. I was floored. I had heard rumors she had it but I had asked her and she denied it. (witch I now believe was out of fear of loosing the only comfort she had left..us) But here was her brother saying it was true. What to do now. Get tested I guess.

  I got tested a few days later and about a week later I found I was infected with HVC. I was at work when I got the phone call. I stepped outside to take it because I was at a new job and I didn't want to took stupid. As I found out i remember how bright it seemed outside and how my ears rang. What I heard was as follows. " You will be dead by Thursday and its that bitches fault. She used your love to kill you"  As we all know that’s not what was said but that’s what I heard. I then confronted her after work and she still denied it. So off we went to get her tested as well. She puts on a good show you know. The following day she told me the truth about the whole thing said she was sorry and asked if we could talk in person. Which leads us back to the dramatic intro paragraph.

   In the following years I was forced to face my own mortality daily it seemed. I always knew we died but had never really considered it much. I also couldn't quit drinking and doing heroin. At one point I was able to pull a few clean month together and get in to see a G.I. . It was here I started the combination therapy. The therapy made me very sick and after about six months I started to get high again. My doctor pulled me off treatment when he found out. By this time I knew drinking would kill me so I stuck to drugs mostly. I also felt my time was limited so I started to travel. By train, by plane, by car, by boat ,or by foot I set out to see the world while there was still yet time. In fact today as I write this I am sitting in the sun of Daytona Beach Florida hiding from the cold and still on my journey.

  Though I can't tell you exactly how it happened here is what I know. Since the day I found out I have realized that our time is short. What a gift!! I have realized that what I do with that time is important and has a real effect on everything around me. What a gift!! I have been able to stop drinking and using drugs for some time now. What a Gift!! I can actually help people today because I don't think I am the most important thing on the planet. What a gift. I was able to go through everything I despised in Cassie including sleeping with someone without telling them I had HVC. I am not proud of that and I know the chance of that person contracting it are small. I wish I could find that person and tell them the truth. To be honest the way my life has been I wouldn't be surprised if it happened. Not the entire journey was bright but it was I believe exactly what had to happen for me to know what I today know. Today I can love Cassie again even though she won't speak to me. I can see she was acting out of fear just as I acted out of fear. Today I await affordable health care to kick in so I can again seek treatment. Its been 6 years since I was diagnosed and in that time I have learned to walk through fear because a great light awaits on the other side. To love all the way today because there may not be a tomorrow. I have a host of friends who know about my HVC and love me anyway. This is not the entire story because it would take too long. If you want to know more you can always contact me etown7077@hotmail.com or fb Mark J. Eckler. I will always be here for you like so many others have been there for me along the was. Because there is no me and you only us. Today I can honestly thank HVC because while it didn't make me mortal it made me realize I was. Only then was I truly able to try to learn how to live. How to use the limited time I have the best way i can for us... not for me. I hope someone has enjoyed this. I hope you can find your way as I have found mine. In closing all I can say it this. There will be pain and there will be fear on your journey. Face the fear and walk through the pain for the only thing I promise you is this. It is always darkest just before the dawn and there is a reason for this. I love all of you and I would love to hear about your journey for it is intact our journey towards the light together.

Mark (Thursdays Child) Eckler

Gilead's Sofosbuvir Gets New Name, Price, Headaches

Provided by The Motley Fool

By Todd Campbell | More Articles
December 11, 2013

The FDA didn't surprise anybody when it approved Gilead's (NASDAQ: GILD ) high-profile hepatitis C drug sofosbuvir in early December. The drug has enjoyed fanfare as the most promising drug in Gilead's pipeline ever since the company picked it up in its $11 billion acquisition of Pharmasset back in 2011. Now, with the FDA's blessing and a market-friendly name in hand, Gilead has an opportunity to make back some of that investment -- but it will have to leapfrog price objections first.

Out with the old, in with the new

Drugs are well known for their clunky, inefficient and difficult-to-pronounce names. So once the FDA gives the go-ahead, marketing teams crunch the data and scour the lists to find names that pass muster with regulators and consumers.

Those names get vetted pretty thoroughly in an FDA black-box process that makes sure companies don't sneak in hints of efficacy or safety. Those names also have to resonate with consumers enough to build a brand around.

Gilead hopes it's found the right formula in christening sofosbuvir as Sovaldi, a geographically neutral name that could stick globally once the drug wins approval in Europe.

Pricing is sky-high, but not as lofty as feared

Gilead also announced pricing for Sovaldi, and payers are happy to see that Gilead settled on a cost south of the rumored $100,000 mark. Still, there's little joy at insurers, given that its $84,000 bill for a course of treatment dwarfs the $15,000 to $20,000 a year they were paying a few years ago for Peg-interferon and ribavirin.

Sovaldi's stiff price tag is also a big jump from the $50,000-a-year price commanded byJohnson & Johnson's (NYSE: JNJ ) and Vertex's Incivek, and Merck's Victrelis.  Both of those drugs were recently approved in 2011, and Incivek was the fastest drug ever to reach $1 billion in sales.

Balking at paying

The decision to price Sovaldi higher than Johnson & Johnson's recently approved Olysio, formerly known as simeprevir, was bound to result in push back.

The first shove came from Express Scripts (NASDAQ: ESRX ) . The company suggests that it's willing to substitute lower priced competitors, even if those therapies come with a more unfriendly dosing schedule.

For now, that may prove an empty threat.

No other treatment, including Johnson's Olysio, is as effective across as large a patient pool as Sovaldi. Olysio, despite a solid showing in trials, struggled when treating patients with the Q80K polymorphism, which occurs in 50% of patients with hepatitis C, genotype 1a -- the most commonly occurring genotype in the United States.

That means Express Scripts has to hope AbbVie (NYSE: ABBV ) , with an up-and-coming multi-drug oral cocktail, will be willing to deal. So far, AbbVie's cocktail has enjoyed impressive results, including a 96% cure rate after 12 weeks in its most recent phase 3 trial.

Alternately, insurers could look to Bristol-Myers's  (NYSE: BMY ) daclatisvir, which is seeking approval in Japan as the first all-oral, interferon- and ribavirin-free treatment for the disease.

Foolishly creative math

The argument over pricing isn't a new debate for next-generation therapies. That means Express Scripts may be all bark and no bite. After all, hoping that AbbVie or Bristol-Myers will cut a deal to charge pharmacies less may prove a long shot, given that each has invested big money ushering its compound through clinical trials.

That's not to say there big buyers and big pharma can't strike deals behind closed doors. However, Gilead and Johnson's drugs, while more expensive, are also significantly better than predecessors. They cut the treatment time in half, with better outcomes. That suggests doctors and patients will embrace Sovaldi regardless of cost.

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Todd Campbell has no position in any stocks mentioned.  Todd owns E.B. Capital Markets, LLC.  E.B. Capital's clients may or may not have positions in the companies mentioned.  Todd also owns Gundalow Advisor's, LLC.  Gundalow's clients do not have positions in the companies mentioned. The Motley Fool recommends Express Scripts, Gilead Sciences, and Johnson & Johnson. The Motley Fool owns shares of Express Scripts and Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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Killing Pain: AGs Want FDA to Review Zohydro Approval

Published: Dec 11, 2013

By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today

Attorneys general from 28 states have asked the U.S. Food and Drug Administration to reconsider its approval of the powerful narcotic painkiller known as Zohydro (hydrocodone bitartrate).

In October, the FDA went against the recommendation of its own advisory committee and approved the drug, which will be the first hydrocodone-only drug in America. Hydrocodone is the opioid in drugs such as Vicodin which also include over-the-counter pain relievers such as acetaminophen or ibuprofen.

Zohydro ER will come in doses packing five to 10 times more heroin-like narcotic than traditional hydrocodone products. In addition, because it is designed to be released slowly over 12 hours, pleasure-seekers will be able to crush it, chew it, or mix it with alcohol to unleash its full punch at once because the drug does not have an abuse-limiting formulation.

In their letter to FDA Commissioner Margaret Hamburg, the 28 attorneys general said they did not want a repeat of the recent past when potent painkillers entered the market without abuse-deterrent formulas.

"This created an environment whereby our nation witnessed a vicious cycle of overzealous pharmaceutical sales, doctors overprescribing the narcotics, and patients tampering with these drugs, ultimately resulting in a nationwide prescription drug epidemic claiming thousands of lives," they wrote.

They said they wanted the FDA to reconsider its decision or to set a "rigorous time line" for Zohydro to be reformulated with abuse-deterrence.

Morgan Liscinsky, a spokesperson for the FDA, said the agency will review the letter and respond directly to the states' attorneys general.

The FDA's decision to approve Zohydro was the subject of a Journal Sentinel/MedPage Today investigative report that pointed to a November 2012 memo from the FDA's own staff warning that the drug will be abused more than traditional hydrocodone products. The memo compared what likely will occur with Zohydro to what happened with extended-release, oxycodone-containing opioids.

The most famous oxycodone product, OxyContin, for years was one of the most abused narcotics in America. In 2010, its maker, Purdue Pharma, reformulated its product to make it abuse-resistant.

Another Journal Sentinel/MedPage Today investigative report from October documented how, for years, FDA officials and executives of companies that make pain drugs held annual private meetings at expensive hotels through an organization funded by the drug companies. That article was based on emails obtained through public records requests and provided to the Journal Sentinel/MedPage Today.

One initiative that sprang from those meetings was a new FDA policy on how to conduct clinical trials of drugs. The new method, known as enriched enrollment, allows drugs companies to weed out people who don't respond well to a drug or who can't tolerate taking it before the actual clinical trial begins.

The approach has been described as cheating. Experts say that approach makes it much more likely a drug will prove effective and possibly win FDA approval. It's also cheaper for drug companies to conduct such trials.

Zohydro was approved using the enriched enrollment method.

The FDA approved the drug despite an 11-2 vote by its own advisory committee recommending that it not be approved.

"I am glad to see Attorneys General making their case directly to the FDA, but if the agency doesn't respect its own committee of experts, I doubt a letter will change their decision," said David Juurlink, MD, PhD, director of pharmacology and toxicology at the University of Toronto.

Jack Conway, the attorney general in Kentucky, a state that has been hit hard by opioid abuse, said that for decades it has fought the disastrous effects of the illegal marketing of the drug OxyContin.

"Zohydro ER has the potential to exacerbate the prescription pill epidemic, and given that abuse-deterrent properties are capable of being developed and required, the FDA's decision to approve the drug doesn't make sense," he said.

The U.S. already consumes 99% of the hydrocodone used in the world.

In 2010, Vicodin was the most prescribed medication in the U.S., with 131 million filled prescriptions. That same year, more than 16,000 people died of overdoses from narcotic painkillers, up from about 4,000 in 1999.

Vicodin comes in doses of 5, 7.5 and 10 mg of hydrocodone along with 300 mg of acetaminophen. Zohydro will come in six doses: 10, 15, 20, 30, 40 and 50 mg.

Kristina Fiore, MedPage Today, contributed reporting to this story.

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Alimentary Pharmacology & Therapeutics

B. Maasoumy, K. Port, B. Calle Serrano, A. A. Markova, L. Sollik, M. P. Manns, M. Cornberg, H. Wedemeyer

Aliment Pharmacol Ther. 2013;38(11-12):1365-1372.

Abstract and Introduction

Abstract

Background Drug–drug interactions (DDIs) in the treatment of chronic hepatitis C infection became a potential challenge with the introduction of direct-acting anti-virals (DAAs). Both currently approved DAAs, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), are substrates and inhibitors of P-glycoprotein and the cytochrome P450 3A4, which are regularly involved in DDIs.

Aim To analyse the risk for DDIs in patients with chronic HCV genotype 1 infection considered for PI treatment at a tertiary referral centre.

Methods The first 115 consecutive patients selected for a PI therapy at Hannover Medical School were included. All changes to co-medication before and during PI treatment were documented. Drugs were checked for DDIs with TVR and BOC using DDI websites and the respective prescribing information.

Results Out-patient medication contained 116 different drugs. Median number of drugs/patient was 2 (range 0–11). The risk for DDIs was substantial for 38% of the drugs affecting 49% of patients. Only 4% of the drugs were strictly contraindicated. DDIs between a PI and drugs newly prescribed during anti-viral therapy were considerable in 42% of the patients. Suspected DDIs were managed by dose adjustments and discontinuation of co-medication in 7% and 21% of the patients respectively.

Conclusions Many patients with chronic HCV genotype 1 infection are affected by potential DDIs if treated with a protease inhibitor, but only in a minority of cases co-medication is strictly incompatible. Overall, the challenge of DDIs is time-consuming, but well manageable by a careful review of the patient's drug chart and monitoring during treatment.

Introduction

Hepatitis C virus (HCV) infection majorly contributes to the increasing prevalence of liver cirrhosis and hepatocellular carcinoma worldwide.[1, 2] Anti-viral treatment may lead to clearance of the virus, defined as a sustained virological response (SVR). Achieving SVR lowers the risk for hepatic decompensation, hepatocellular carcinoma and reduces overall mortality.[3-5] The development of direct-acting anti-viral agents (DAAs) has significantly improved HCV therapy, as DAAs increase SVR rates and may soon even lead to interferon-free treatment options.[6] In 2011, the first generation of this new drug class was approved for the treatment of HCV genotype 1 infection: the protease inhibitors (PI) telaprevir (TVR) and boceprevir (BOC). Since then, the new standard of care for the treatment of chronic HCV genotype 1 infection became triple therapy consisting of pegylated-interferon alpha (Peg-IFN), ribavirin (RBV) and either telaprevir (TVR) or boceprevir (BOC) in many countries. Both PIs markedly improved the probability of SVR compared with previous dual therapy.[7] Under optimal conditions, up to 88% achieve SVR after 28–48 weeks of triple therapy.[8-10] However, new PI-containing triple therapies are also accompanied by new problems like a more complicated dosing regimen[8, 9] and a higher number of severe adverse events, in particular, in those with advanced liver disease.[11-13] Furthermore, with the introduction of DAAs, hepatologists are now facing drug–drug interactions (DDIs) as an additional challenge of HCV therapy. Both approved PIs are strong inhibitors of the cytochrome P450 CYP3A4. Furthermore, TVR and, to a lesser extent, BOC are metabolised by CYP3A4. In addition, both agents are also inhibitors and substrates of the membrane transporter P-glycoprotein (P-gp), which affects TVR more than BOC.[14, 15] As a result, there is a potential risk for DDIs with other drugs metabolised by the same pathways. An increase in drug concentrations may cause toxicity and lead to adverse events. On the other hand, a decrease in drug concentrations may lead to a loss of therapeutic efficacy and, if the PIs are affected, this may lead to treatment failure due to emergence of viral resistance and subsequently a virological breakthrough. Recently, there have been a couple of valuable review articles that indicated drugs that, in principle, should not be administered or only with caution due to anticipated DDIs.[14, 15] However, despite the relative attention DDIs have gained in the discussion of PI therapies, there are rather limited data on the extent that HCV patients are really at risk for DDIs due to their regular out-patient medication. Overall, it remains unclear to what extent DDIs reach clinical significance when HCV patients are considered for DAA treatment. We aimed to investigate the clinical significance of DDIs in a real-life cohort of patients with chronic HCV infection selected for PI treatment in a tertiary referral centre.

Patients and Methods

Patients

The first 115 consecutive patients who were selected to receive treatment with a PI, either TVR or BOC, at the hepatitis out-patient clinic of Hannover Medical School were selected for this study.

Assessment of Drugs Taken before and During PI Treatment

All 115 patients were routinely asked for their regular out-patient medication prior to the start of PI treatment, which importantly also included any kind of self-medication. For the assessment of the out-patient medication at baseline, we documented all drugs that were taken regularly, except for drugs started during Peg-IFN/RBV lead-in phase, which were considered drugs started during anti-viral treatment. In cases of combination products, e.g. ramipril/hydrochlorthiazide, each individual substance was counted separately. In contrast, mixtures of minerals or vitamins as well as herbal medication were counted as only one drug if they contained four or more ingredients. Of the 115 patients, 14 had to discontinue during or directly after the Peg-IFN/RBV lead-in phase due to a virological failure or treatment intolerance. As a result, only 101 patients were exposed to a PI. These 101 patients were followed during PI treatment and all drugs newly taken during or due to anti-viral therapy were assessed.

Estimation of the Risk for Drug-Drug-interactions

All drugs taken before or during PI therapy were carefully analysed for potential interactions with TVR and BOC using the web resource http://www.hep-druginteractions.org, the package label of TVR, BOC and the analysed drug, known interactions with other strong CYP 3A4 inhibitors (using ritonavir and the web resource http://www.hiv-druginteractions.org) as well as additional sources if more information was needed to draw a reliable conclusion. Drugs were categorised into four groups according to the suspected significance of interactions with the PIs: 'No clinically significant interactions expected' (Category 1), 'Interaction possible but in principle manageable by dose adjustments and/or closer monitoring' (Category 2), 'Not recommended for co-administration with a PI' (Category 3) or 'No classification possible due to a lack of information' (Category 0) (Figure 1). In doubt, or in cases of discrepancies between the two HCV PIs, the more sever risk category was chosen.

814983-fig1

Figure 1. The four different risk categories of drug–drug interactions with an HCV protease inhibitor: Category 1 (low-risk): 'No clinically significant interactions expected'; Category 2 (significant, but not severe risk): 'Interaction possible but in principle manageable by dose adjustments and/or closer monitoring'; Category 3 (severe risk): 'Not recommended for co-administration with a PI'; Category 0 (uncertain risk): 'No classification possible due to a lack of information'.

Ethics

This study was performed according to principals of good clinical practice as well as the declaration of Helsinki and approved by the local ethics committee of Hannover Medical School.

Results

Patient Characteristics and Anti-viral Treatment

The 115 patients who were selected to receive a PI had a mean age of 54 years and the majority had advanced liver fibrosis or cirrhosis. Overall, only 101 patients were treated with a PI due to a weak response or a poor tolerability to Peg-IFN/RBV therapy in the lead-in phase. A total of 69 patients were treated with TVR and 34 with BOC, including two patients who were switched from TVR to BOC during therapy due to TVR-related adverse events. The median observed PI treatment duration was 12 weeks (range: 4 days–48 weeks) (Table 1).

Table 1.  Baseline characteristics of the study cohort
Patient number 115
Age (mean ± s.d.) 54.4 (±10.3)
Gender
   Male 66 (57%)
   Female 49 (43%)
Used PI
   TVR 69 (60%)*
   BOC 34 (30%)*
   None 14 (12%)
Duration of PI exposure
   Median weeks 12
   Min–Max 4 days–48 weeks
Fibrosis stage
   F0–F2 24 (21%)
   F3/F4 89 (77%)
   n/a 2 (2%)
   Platelets (mean ± s.d.;/nL) 164 (±69)
   Albumin (mean ± s.d.; g/L) 40.8 (±4.3)

s.d., standard deviation; PI, protease inhibitor; TVR, telaprevir; BOC, boceprevir.
*Two patients were switched from TVR to BOC (exposed to both PIs).

Drug-Drug Interactions With the Regular Out-patient Medication Assessed at Baseline

Regular out-patient medication of the 115 patients included 116 different drugs. Almost one of four patients (23%) took more than four different drugs at baseline, while only 29 patients (25%) did not have any regular out-patient medication before HCV treatment was initiated (Figure 2a). Overall, the mean number of regular drugs was 2.7 with a maximum of eleven co-medications. Most commonly used drugs were selective beta-blocking agents, proton pump inhibitors and levothyroxine (Table 2).

Table 2.  The 10 most frequent drug classes in the regular out-patient medication at baseline
Drug class ATC code (3rd level) Number of patients (%)
Beta-blocking agents; selective
(i.e. bisoprolol)
C07AB 21 (18)
Proton pump inhibitors
(i.e. pantoprazole)
A02BC 19 (17)
Thyroid hormones
(i.e. levothyroxine)
H03AA 19 (17)
Angiotensin II antagonists
(i.e. candesartan)
C09CA 16 (14)
Dihydropyridine derivatives
(i.e. amlodipine)
C08CA 15 (13)
ACE inhibitors
(i.e. ramipril)
C09AA 15 (13)
Thiazides
(i.e. hydrochlorothiazide)
C03AA 11 (10)
Beta-blocking agents; nonselective (i.e. propranolol) C07AA 10 (9)
Biguanides
(i.e. metformin)
A10BA 9 (8)
Propionic acid derivatives
(i.e. ibuprofen)
M01AE9 9 (8)

The risk for DDIs with a PI was considered to be negligible (Category 1) for the majority of baseline drugs (62%), whereas for 29%, some DDIs were suspected, but dose modifications or careful monitoring may have been considered as sufficient for management (Category 2). Only 4% of the drugs were contraindicated for co-administration with a PI (Category 3). However, 10% of the patients took one of these contraindicated drugs. In the remaining 5% of the drugs, significant DDIs could not be excluded due to a lack of information (Category 0) (Figure 2b). This majorly affected herbal products and so-called alternative medicine. Overall, 49% of the patients were suspected to be at risk of experiencing significant DDIs, including the 7% of patients taking at least one drug belonging to risk category 0 (Figure 2c). Drug classes most often suspected to be involved in significant DDIs with a PI were thyroid hormones, dihydropyridine derivatives and herbal drugs/alternative medicine (Table 3).

Table 3.  The eight most frequent drug classes in the regular out-patient medication that were suspected to may cause significant drug–drug interactions with an HCV protease inhibitor
Drug class ATC code (3rd level) Number of patients (%)
Thyroid hormones
(i.e. levothyroxine)
H03AA 19 (17)
Dihydropyridine derivatives
(i.e. amlodipine)
C08CA 15 (13)
Alternative Medicine - 8 (7)
Beta-blocking agents, selective
(i.e. bisoprolol)
C07AB 8 (7)
Oestrogens
(i.e. ethinylestradiol)
G03CA 3 (3)
Alpha-adrenoreceptor antagonists
(i.e. tamsulosin)
G04CA 3 (3)
Glucocorticoids
(i.e. prednisolon)
H02AB 3 (3)
Selective serotonin reuptake inhibitors
(i.e. escitalopram)
N06AB 3 (3)

814983-fig2

Figure 2. Risk for drug–drug interactions between a protease inhibitor and the regular out-patient medication of the 115 patients prior to the initiation of anti-viral treatment: Number of different drugs in the regular out-patient medication (a). Percentage of the different drugs in the regular out-patient medication containing to risk category 1, 2, 3 and 0 for drug–drug interactions with an HCV protease inhibitor (b). Portion of patients with a high risk (taking at least one category 3 drug), an uncertain risk (no category 3, but one or more category 0 drug), significant, but no severe risk (one or more category 2, but no category 0 and 3 drugs) and those without any risk for drug–drug interactions with an HCV protease inhibitor (no or only category 1 drugs in the regular out-patient medication) (c).

Drug-Drug Interactions With Medication Started During Anti-viral Treatment

The included patients received 254 new drugs during PI treatment, mostly due to side effects of triple therapy. Most frequently, these new drugs were specific skin lotions, analgesics or antihistamines. Medications were usually prescribed by the HCV-treating physician, but also frequently by the patient's general practitioners or other physicians. In 8%, the name of the newly prescribed drug could not be evaluated retrospectively affecting 9% of the patients. In only 3% of the patients were new co-medications not suitable for co-administration with a PI. More than half of the patients (59%) either did not take any new drugs during treatment or only those considered to be safe in terms of significant DDIs with a PI (Figure S1a–c).

Impact of DDI Considerations Before and During PI Therapy

In 16% of the patients, at least one drug of the regular out-patient medication was stopped before PI treatment commenced due to suspected DDIs. In an additional 5% of cases, dose adjustments of the respective co-medication were applied before PI treatment was initiated. During PI treatment, discontinuation and dose adjustments of co-medication became necessary each in five cases (5%). Overall, suspected DDIs were managed by dose adjustments and discontinuation of co-medication before or during PI therapy in 7% and 21% of the patients respectively. In six patients (6%), a supposed treatment with certain drugs was either delayed until the end of PI therapy or an alternative medication was chosen due to DDI considerations.

Discussion

Management of drug–drug interactions (DDI) represents a challenge in the treatment of hepatitis C virus (HCV) infection. We here show, in a real-world cohort of patients treated in a tertiary referral centre, that DDIs represent a considerable risk if HCV protease inhibitors (PI) are used. However, DDIs can be managed if adequate medication adjustments and precautions are followed.

DDIs have not been considered a major problem in HCV therapy before HCV protease inhibitors have been introduced in 2011. However, it is certainly not surprising that many HCV patients take several drugs not related to the liver, as documented in our study. Similar to the non-HCV-infected population, HCV patients suffer from different common comorbidities like hypertension, dysliproteinaemia or atrial arrhythmia. Furthermore, some comorbidities like diabetes and thyroid disorders may even be overrepresented in the HCV-infected population, as they have been suspected to be extrahepatic manifestations of HCV infection.[16-18] Indeed, anti-hypertensive and anti-diabetic drugs as well as thyroid hormones belonged to the most frequent drugs in the regular out-patient medication of our study cohort. However, an important finding of our study was that, although some DDIs were expected in almost half of the patients, only a relatively small portion of patients took drugs that were strictly contraindicated for co-administration with a PI. In addition, a similar number of patients took drugs for which the available drug information was insufficient to exclude DDIs. However, these drugs mainly belonged to herbal products/alternative medicines and therefore a simple discontinuation may widely be considered. Overall, only a minority of patients (n = 23) required adjustments to their pre-treatment medication before or during PI therapy. Based on these findings a careful assessment of the regular out-patient medication and subsequent evaluation of potential DDIs with a PI are absolutely crucial to ensure drug safety in all treated patients. Importantly, this assessment must also include self-medication belonging to the group of herbal products/alternative medicine.

In contrast to the pre-existing baseline medication, the majority of newly prescribed drugs during PI treatment were supposed to counter adverse events of anti-viral therapy. Here, it seems to be feasible to handle potential DDIs by establishing standard algorithms for the management of frequent adverse events like depression or rash. In such standard algorithms, drugs with well-manageable DDIs or, even better, those without any risk for DDIs with a PI should be preferred. As a result of this strategy and careful DDI consideration prior to new drug prescriptions, the risk for DDIs was lower for the newly prescribed medications during PI therapy. Still, of note and importantly, even during PI therapy, some drugs not allowed for co-administration were prescribed by other physicians and, in some cases, drug names were even unknown. This emphasises the need for a close collaboration between different physicians involved in the management of hepatitis C patients.

DDI assessment is certainly rather time-consuming if it is based on several different sources as applied in this study. Still, concentrating exclusively on the prescribing information of BOC and TVR may be insufficient as the provided data are limited. In our experience, web-based DDI interaction tools like http://www.hep-druginteractions.org represent the most feasible and comprehensive way for an assessment of potential DDIs. However, although this web resource is updated regularly and already includes a huge number of drugs, many drugs taken by our study cohort could not be found. This underlines the challenge of generating clinically useful information when comparatively few DDI studies have been performed. Therefore, more studies investigating DDIs with DAAs need to be performed in the future.

This study was not designed to compare the risk of DDIs between TVR and BOC regimens. It is well known that, in general, interactions may be more prominent for TVR. However, overall risk categories of co-medications did not differ between TVR and BOC. In a few cases of doubt or discrepancies between the two HCV PIs, the more severe risk category was chosen, which may have lead to a slight overestimation of the overall risk for DDIs. Certainly, it has to be considered that the current patient cohort may differ from those in smaller centres and may not be representative for all HCV patients due to the referral tertiary setting. As shown in a recently published analysis, patients selected for currently available triple therapy tend to be those with the more urgent need for anti-viral treatment presenting with more advanced liver disease.[11] However, this shows that, even in a complicated, difficult-to-treat cohort, the challenge of DDI appeared to be manageable. Nevertheless, risk of DDIs must not be neglected. Although only a minority was infected by a severe risk for DDIs, this still requires cautiousness and a careful evaluation of the patient's drug chart. Otherwise, there is a risk for even life-threatening complications. Severe adverse events caused by drug interactions, in particular, through the CYP3A4 pathway are reported frequently.[19-21] There also have been cases of anti-viral treatment failure in HIV patients due to DDIs.[22] Lately, there has been a case of renal failure in an HCV-infected liver transplant patient receiving TVR treatment in combination with tacrolimus.[23] In addition, a possible limitation of our study is that information on number and type of drugs widely depended on patient information. Therefore, some drugs may have been missed and risk for DDIs may have been underestimated in our study.

The next wave of DAAs including the protease inhibitors faldaprevir and simeprevir as well as the NS5B nucleotide inhibitor sofosbuvir may be available in early 2014 and more will follow in the upcoming years. Risk for DDIs differ between the various future DAA classes. The nucleotide NS5B inhibitor sofosbuvir does not seem to be involved in significant DDIs.[24, 25] In contrast, DDIs have to be considered for several nonnucleotide NS5B inhibitors.[15] DDIs may also play a role for some NS5A inhibitors. Daclatasvir is substrate and inhibitor of P-glycoprotein and substrate of CYP3A4. However, pharmacokinetic data suggest that risk for significant DDIs is far lower compared with using protease inhibitors.[15] Soon-available PIs faldaprevir and simeprevir are also both inhibitors and substrates of CYP3A4 and it has already been shown that drug levels are altered in the presence of other strong inhibitors or inducers of CYP3A4.[15] Taken together, it can be assumed that the challenge of DDIs will certainly accompany HCV therapy in upcoming years, in particular, as combination treatments with several DAAs will most likely be necessary to finally achieve an efficient interferon-free anti-viral treatment.[6, 26]

In summary, we have shown that DDIs in HCV patients are manageable, as only a minority of drugs may be unsuitable for co-administration. Still, the patients' drug charts need to be checked carefully, including self-medication, which is time-consuming and requires sufficient interaction studies provided by the pharmaceutical companies. Drug interaction websites can be regarded as an important tool to aid in the management of DDIs in clinical practice. We believe that continued support of these websites would be very useful.

References

  1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol2011; 55: 245– 64.

  2. Maasoumy B, Wedemeyer H. Natural history of acute and chronic hepatitis C. Best Pract Res Clin Gastroenterol2012; 26: 401–12.

  3. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol2011; 9: 509–16.e1.

  4. van der Meer AJ, Veldt BJ, Feld JJ, et al.Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA2012; 308: 2584–93.

  5. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med2013; 158: 329–37.

  6. Wedemeyer H. Hepatitis C in 2012: on the fast track towards IFN-free therapy for hepatitis C? Nat Rev Gastroenterol Hepatol2013; 10: 76–8.

  7. Rowe IA, Houlihan DD, Mutimer DJ. Despite poor interferon response in advanced hepatitis C virus infection, models of protease inhibitor treatment predict maximum treatment benefit. Aliment Pharmacol Ther2012; 36: 670–9.

  8. Maasoumy B, Manns MP. Optimal treatment with boceprevir for chronic HCV infection. Liver Int2013; 33 (Suppl 1): 14–22.

  9. Jesudian AB, Jacobson IM. Optimal treatment with telaprevir for chronic HCV infection. Liver Int2013; 33 (Suppl 1): 3–13.

  10. Ramachandran P, Fraser A, Agarwal K, et al.UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther2012; 35: 647– 62.

  11. Maasoumy B, Port K, Markova AA, et al.Eligibility and safety of triple therapy for hepatitis C: lessons learned from the first experience in a real world setting. PLoS ONE2013; 8: e55285.

  12. Joshi D, Carey I, Agarwal K. Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients. Aliment Pharmacol Ther2013; 37: 659–71.

  13. Hezode C, Fontaine H, Dorival C, et al.Triple therapy in treatment-experienced patients with hcv-cirrhosis in a multicentre cohort of the french early access programme (anrs co20-cupic) - nct01514890. J Hepatol2013; 59: 434– 41.

  14. Burger D, Back D, Buggisch P, et al.Clinical management of drug-drug interactions in HCV therapy: challenges and solutions. J Hepatol2013; 58: 792– 800.

  15. Kiser JJ, Burton JRJ. Everson GT. Nat Rev Gastroenterol Hepatol: Drug-drug interactions during antiviral therapy for chronic hepatitis C, 2013.

  16. Antonelli A, Ferri C, Ferrari SM, Colaci M, Sansonno D, Fallahi P. Endocrine manifestations of hepatitis C virus infection. Nat Clin Pract Endocrinol Metab2009; 5: 26–34.

  17. Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB. Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach. Dig Liver Dis2007; 39: 2–17.

  18. Eslam M, Khattab MA, Harrison SA. Insulin resistance and hepatitis C: an evolving story. Gut2011; 60: 1139–51.

  19. Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother2006; 40: 753–7.

  20. Pollack TM, McCoy C, Stead W. Clinically significant adverse events from a drug interaction between quetiapine and atazanavir-ritonavir in two patients. Pharmacotherapy2009; 29: 1386–91.

  21. Hoover WC, Britton LJ, Gardner J, Jackson T, Gutierrez H. Rapid onset of iatrogenic adrenal insufficiency in a patient with cystic fibrosis-related liver disease treated with inhaled corticosteroids and a moderate CYP3A4 inhibitor. Ann Pharmacother2011; 45: e38.

  22. Hugen PW, Burger DM, Brinkman K, et al.Carbamazepine–indinavir interaction causes antiretroviral therapy failure. Ann Pharmacother2000; 34: 465–70.

  23. Werner CR, Egetemeyr DP, Lauer UM, et al.Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. Liver Transpl2012; 18: 1464–70.

  24. Mathias A, Cornpropst M, Clemons D, Denning J, Symonds WT. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS- 7977) and the immunosuppressants cyclosporine A or tacrolimus in healthy volunteers. Hepatology2012; 56 (Supplement): 1063A.

  25. Kirby B, Mathias A, Rossi S, Moyer C, Shen G, Kearney BP. No clinically significant pharmacokinetic drug interaction between sofosbuvir (GS- 7977) and HIV antiretrovirals atripla, rilpivirine, darunavir/ritonavir, or raltegravir in healthy volunteers. Hepatology2012; 56(Supplement): 1067A.

  26. Manns MP, von Hahn T. Novel therapies for hepatitis C – one pill fits all? Nat Rev Drug Discov2013; 12: 595–610.

Source

 

By Scott O’Brien, November 2013

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States: nearly four million persons are chronically infected.1 HCV infection is cleared in fewer than 20% of infected people, with the majority developing chronic HCV infection leading to increased risk of liver cirrhosis, hepatocellular carcinoma (HCC), liver failure, and related morbidities.1 HCV-related morbidity and mortality is further driven by the estimates that, due to the asymptomatic nature of infection and slow disease progression, 45% to 85% of infected patients are unaware of their HCV infection until they present with liver disease.1 Currently, there is no effective vaccine for HCV; clinical efforts are focused on prevention of infection, identification of infected individuals, and therapeutic treatment of infected individuals. Decisions to treat HCV-positive individuals are based upon the severity of the patient’s clinical features. The HCV genotype is used to aid in treatment decisions and determine the type of treatment, dosage, and duration of therapy, and to estimate the likelihood of response.2-3

HCV-associated morbidity and mortality

Upon infection, some people note fatigue, loss of appetite, muscle aches, or fever. In most individuals, the immune system is unable to clear the infection and HCV chronic infection progresses over decades, which may lead to liver inflammation and elevated liver enzyme levels. An estimated 20% of individuals infected with HCV will progress to cirrhosis 20 years after infection.1 Up to 5% of persons with chronic HCV infection per year will progress to advanced cirrhosis and die from HCV-associated liver disease.1

HCV infection is the leading indication for liver transplant and accounts for 50% of hepatocellular carcinoma cases. Due to the slow progression of HCV disease, 73.4% of HCV related deaths occur in persons aged 45-64 years,1 one to four decades after initial infection.

Screening and diagnosis of HCV infection

Traditionally, HCV testing has been recommended for individuals at high risk for HCV transmission. High risk for HCV transmission includes individuals who have participated in injection drug use, undergone chronic hemodialysis, or received blood transfusions or organ transplants before 1992 or clotting factor concentrates manufactured before 1987.3This risk-based testing strategy has had limited success in accurately diagnosing HCV-positive individuals, with 45% of persons with HCV reporting no known exposure risk.1

In an effort to diagnose more HCV-positive individuals prior to development of liver disease, the U.S. Centers for Disease Control and Prevention (CDC) recently released new age-based HCV screening guidelines. The CDC study determined that the prevalence of anti-HCV antibodies, which indicate exposure, was highest among persons born during 1945-1965 (at 3.25%), roughly five times higher than adults born in other birth cohorts. Another CDC HCV surveillance study found that persons born between 1945 and 1965 accounted for 58.5% of those who were HCV antibody-positive and 67.2% of those who were HCV RNA-positive.4 The recent CDC birth cohort screening recommendation states that adults born between 1945 and 1965 should receive one-time testing for HCV, regardless of risk. In an independent review, the U.S. Preventive Services Task Force (USPSTF) also supports the recommendation for birth cohort screening to drive improved health outcomes. The benefits of amended HCV diagnosis guidelines are to identify more infections prior to the onset of liver disease and thus better enable accurate diagnosis of active chronic HCV infection.

Individuals who are screened for or suspected of having acute or chronic HCV should initially be tested for the presence of anti-HCV antibodies. A positive HCV antibody test should be followed with an HCV RNA test to confirm active HCV infection versus prior exposure to HCV. A person with a positive HCV antibody test, but who has a negative HCV RNA, should be considered negative for HCV infection.4

The recommendation for a diagnostic HCV RNA test is supported by a CDC HCV surveillance study, which found that half of reported HCV infections did not have a positive HCV RNA test.4 As a result, it was not possible to determine whether the reported HCV infection was an active or previously resolved infection.

The overall goal of the updated CDC recommendation is to improve awareness of HCV infection and drive improved healthcare outcomes. The adoption of birth cohort screening at the same compliance rate as colorectal screening recommendations could identify 400,000 new HCV-infected individuals in the next three years. The use of HCV RNA testing may also improve the accuracy of HCV diagnosis and lead to follow-up medical evaluation.

HCV treatment guidelines

Once diagnosis is confirmed with a nucleic acid HCV RNA test, treatment decisions are based on multiple factors, including the severity of liver disease, the presence of other health issues, patient readiness for treatment, and potential for treatment side effects. The goal of antiviral therapy is to achieve Sustained Virological Response (SVR), defined as undetected HCV virus 24 weeks after completion of therapy. The treatment regimen varies by HCV genotype (Table 1).

MLO201311-CE-Sidebar-table1

Table 1. Current HCV testing guidelines

Duration of treatment for genotype 1 and 4 is based on specific stopping rules related to early virologic response to therapy determined by RNA viral load drop during the first 4 to 24 weeks of therapy. Genotype 1 patients receive triple therapy with pegylated interferon (PEG-IFN), ribavirin (RBV), and one of the FDA-approved protease inhibitors. No formal therapy guidelines exist for genotype 5 and 6 patients, but the typical treatment regimen is PEG-IFN and RBV. Genotype 2 and 3 patients are typically given, and respond well to, PEG-IFN/RBV therapy, with SVR rates of approximately 70%.

The evolution of HCV treatment

HCV therapy in the early 1990s focused on stimulating the patient’s innate antiviral immune response with interferon (IFN) therapy. By the 2000s, therapy that included the nonspecific antiviral drug ribavirin in combination with IFN improved SVR rates in genotypes 1-3 two- to threefold.6

The first antivirals that specifically targeted HCV, direct acting antivirals (DAAs), were approved in 2011. Two hepatitis C DAAs approved in 2011 prevent viral replication by inhibiting HCV’s NS3/NS4 proteases required for hepatitis C virus protein processing. The approval of protease inhibitor DAAs for HCV genotype 1, used together with PEG-IFN and RBV, improved SVR rates from 30% to approximately 60% to 70% SVR.5 Some persons do not reach SVR due to emergence of HCV drug resistance mutations to the protease inhibitors. In particular, HCV genotype 1, subtype A is more prone to developing resistance mutations that can reduce SVR.7 Other potential targets for HCV DAAs include HCV’s RNA-dependent RNA polymerase (NS5B) and the viral cofactor protein NS5A, which is required for viral replication.

At present, there are more than 25 drug candidates in phase II or phase III clinical trials targeting HCV infection. Three of the leading drug candidates in phase III trials (Sofosbuvir, Faldaprevir, and Simeprevir), used in combination therapy with PEG-IFN plus RBV (P/R), show 80% to 90% SVR rates in individuals with HCV genotypes 1a/1b (Table 2). Sofosbuvir is being evaluated on multiple genotypes, which may lead to DAA treatment options for non-genotype 1 individuals. Triple DAA therapy with ABT-450/267/333 plus ritonavir is being evaluated without PEG-IFN to reduce adverse treatment side effects while still delivering ~90% SVR.8

MLO201311-CE-Sidebar-table2

Table 2. Investigational phase II/III HCV therapies8

Numerous DAA drug candidates are in late-stage trials, and some are currently under priority marketing review, which may lead to FDA approval of these drugs by 2014. Future combination DAA therapy trials are focused on shorter treatment course, activity to all HCV genotypes, and elimination of PEG-IFN and ribavirin from the therapy. Ultimately, if these goals are achieved, the results would be reduced side effects from therapy, reduced drug resistance, and simplified therapy regimens to improve patient compliance through the course of treatment. The rapid advances in DAA development and the large number of clinical trials will likely deliver 8-to-12 week therapy for all genotypes, with SVR rates exceeding 90%, in the coming years.

Importance of accurate HCV genotyping

Hepatitis C virus genotyping is currently used as an aid in determining dose and duration and estimating therapeutic response. Based on the current standard of care, it is critical for patients to receive an accurate genotype, particularly in the case of patients with HCV genotype 1, as they are eligible for combination therapy with FDA-approved protease inhibitors. While the standard of care does not require subtyping of genotype 1, there is significant evidence indicating HCV genotype 1a is more likely to develop drug resistance mutations than genotype 1b.7 As a result, accurate genotype 1a and 1b subtyping may contribute to clinical decisions, such as beginning therapy immediately or waiting for more effective DAA combination therapy in the near future. It is possible that some of the new DAAs will be approved with genotype-specific indications with variation in dosage or duration for treating specific genotypes.

It is estimated that 3% of the world’s population is chronically infected with HCV.6 In the United States, HCV is an increasing cause of morbidity and mortality and the leading indication for liver transplant. In the last few years the CDC has expanded HCV screening efforts and recommended a new HCV diagnostic algorithm to drive HCV awareness just as new HCV therapies are nearing FDA approval. Expanded screening efforts with early and accurate diagnosis and genotyping are now more important than ever as delivering an effective and accessible cure for HCV becomes a reality.

References

  1. CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR. 2012;61(RR-4).
  2. CDC. Hepatitis C Information for Health Professionals.http://www.cdc.gov/hepatitis/hcv. Accessed September 28, 2013.
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  4. CDC. Vital signs: evaluating of hepatitis C virus infection testing and reporting–eight U.S. sites, 2005-2011. MMWR. 2013;62(18).
  5. Feld JJ, Shah H. Hepatology–management of hepatitis C infection.http://www.clinicaloptions.com/inPractice/Hepatology/Hepatology/ch8_Mgmt_of_Hep_C_Infection/Pages/Page%201.aspx. Accessed September 28, 2013.
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  7. Cento V, Mirabelli P, Salpini R, et al. HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors.http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039652. Accessed September 28, 2013.
  8. Muir AJ. HCV: Highlights from EASL 2013.http://www.chronicliverdisease.org/disease_focus/ppts/ch/HCV_Highlights_from_EASL_2013_Muir.pdf. Accessed September 28, 2013.

Source