April 3, 2012

Hepatology. 2012 Mar 2. doi: 10.1002/hep.25688. [Epub ahead of print]

Perz JF, Grytdal S, Beck S, Fireteanu AM, Poissant T, Rizzo E, Bornschlegel K, Thomas A, Balter S, Miller J, Klevens M, Finelli L.

Centers for Disease Control and Prevention. JPERZ@CDC.GOV .

Abstract
BACKGROUND:

Reports of hepatitis B and hepatitis C virus transmission associated with unsafe medical practices have been increasing in the United States. However, the contribution of healthcare exposures to the burden of new infections is poorly understood outside of recognized outbreaks.

METHODS:

We conducted a case-control study at 3 health departments that perform enhanced viral hepatitis surveillance in New York and Oregon. Reported cases of symptomatic acute hepatitis B and hepatitis C occurring in persons aged ≥ 55 years from 2006-2008 were enrolled. Controls were identified using telephone directories and matched to individual cases by age group (55-59 years, 60-69 years, and ≥70 years) and residential ZIP code. Data collection covered exposures within 6 months prior to symptom onset (cases) or date of interview (controls).

RESULTS:

Forty-eight (37 hepatitis B; 11 hepatitis C) case- and 159 control-patients were enrolled. Case-patients were more likely than controls to report one or more behavioral risk exposures, including sexual or household contact with an HBV or HCV patient, >1 sex partner, illicit drug use or incarceration (21% of cases vs 4% of controls exposed; matched Odds Ratio [mOR]=7.1; 95%CI 2.1, 24.1). Case-patients were more likely than controls to report hemodialysis (8% of cases; mOR=13.0; 95%CI 1.5, 115); injections in a healthcare setting (58%; mOR=2.7; 95%CI 1.3, 5.3); and surgery (33%; mOR=2.3; 95%CI 1.1, 4.7). In a multivariate model, behavioral risks (adjusted OR [aOR]=5.4, 95%CI 1.5, 19.0; 17% attributable risk), injections (aOR=2.7, 95%CI 1.3, 5.8; 37% attributable risk) and hemodialysis (aOR=11.5, 95%CI 1.2, 107; 8% attributable risk) were associated with case status.

CONCLUSION:

Healthcare exposures may represent an important source of new HBV and HCV infections among older adults. (HEPATOLOGY 2012.).

Copyright © 2012 American Association for the Study of Liver Diseases.

Source

Addressing the HCV Referral and Treatment Bottleneck CME

From Medscape Education Infectious Diseases

Michael W. Fried, MD CME Released: 03/28/2012; Valid for credit through 03/28/2013

Introduction

Hepatitis C virus (HCV) infection has been called both the silent epidemic[1] and the silent killer;[2] it is both. Recent estimates are that there are at least 5.2 million people in the United States with HCV infection.[3] Although the Institute of Medicine report "Hepatitis and Liver Cancer" predates the availability of the HCV protease inhibitors for the treatment of genotype 1 chronic HCV infection, it underscores an important observation -- that advancements in the treatment of viral hepatitis in general will not in and of themselves decrease the burden of disease if people are not screened for both risk factors and presence of infection; diagnosed; or once diagnosed, referred to specialists and provided appropriate care.[4] In other words, the best treatments cannot benefit those who have no access to them, regardless of the reason. Lack of awareness among the general public and primary care providers (PCPs) about the prevalence of chronic HCV infection and failure to appreciate the serious burden of HCV will continue to impede efforts to prevent and control HCV infection in the era of the HCV protease inhibitors. The gap between the millions of people in the United States with untreated chronic HCV infection and the available treatments has been referred to as a treatment bottleneck, in which the capacity of healthcare providers with expertise in the treatment of these patients is overwhelmed. Thus, even when patients are screened and diagnosed, they may either not be referred for treatment, or if referred, they may wait as long as a 8 months for an appointment.[5]

Medscape spoke with Michael W. Fried, MD, Professor of Medicine and Director of Hepatology at the University of North Carolina School of Medicine, Chapel Hill, North Carolina, about various solutions to enhanced coordination of care and linkage of HCV-infected persons with treatment services.

Medscape: What is meant by the term "HCV bottleneck," and what problems does it create?

Michael Fried, MD: The HCV bottleneck can refer to several issues. Not everyone with chronic HCV infection is aware of his/her HCV status. When we talk about barriers to getting treatment for chronic HCV infection, 1 of the biggest barriers is that the vast majority of Americans living with chronic HCV infection have not been diagnosed.

A study published in the February 21, 2012 issue of Annals of Internal Medicine found that it was cost-effective to target HCV screening at the baby-boomer generation -- those born between 1945 and 1965.[6] It is very cost effective to use birth-cohort screening for HCV since, with the current program we are using -- a risk-based screening program -- very few of those patients are actually being identified as having HCV infection. By screening an age cohort, in which we know that older patients have the highest prevalence of chronic HCV infection, we might diagnose an additional 1 million cases that were not diagnosed otherwise.

Part of the bottleneck is the initial diagnosis. By the way, the issue with diagnosis is partly related to the lack of awareness of chronic HCV infection. Even though we had screening recommendations based on risk for many years, sometimes patients do not admit to risk factors that would trigger screening. Other times, primary care providers (PCPs) may not be familiar with the screening guidelines or the next steps in management. PCPs may not inquire about risk factors because they feel uncomfortable with asking these questions. Finally, PCPs may not test for HCV infection (even when they know that their patients have risk factors or even when they find an abnormal alanine transaminase level). Birth cohort screening would also obviate the need to inquire about risk factors and could lead to increased screening and diagnosis. The first steps in addressing the bottleneck issue are raising patients' and PCPs' awareness of chronic HCV infection and making the diagnosis in infected patients.

Still, once you identify all these patients, the questions then become, "What do you do with them? How do you get them into appropriate evaluation, provide education about the disease, and properly treat those patients who are candidates for therapy?" Those are also big challenges. There is a large backlog at most offices to see patients with chronic HCV infection; there are a lot of patients and there are not a lot of providers who will give the specialized care and treatment that are needed. Right now we can have a big impact on disease outcomes if we identify the patients at risk who have chronic HCV infection. There are strategies that PCPs can use to mitigate the disease while patients are waiting to be seen by specialists. PCPs can counsel at-risk patients on minimizing the risk for liver disease progression through lifestyle modification (eg, minimizing alcohol intake, maintaining an ideal body weight) to prevent the additive effects of fatty liver disease.

Medscape: Is the present model of liver specialist care sustainable? And if not, why?

It is probably not sustainable. Specialists -- ie, hepatologists, gastroenterologists -- are overwhelmed by the number of patients that are seeking care. One of the reasons for the increased number of patients seeking care is the availability of new treatments. With treatment using these new medications, many patients have an increased likelihood of achieving a sustained virologic response (SVR), so more patients are interested in hearing about new treatments.[7-10] We have to disseminate the care beyond the liver disease specialist, if possible.

Medscape: It goes back to the 2 prongs of the bottleneck that you outlined. People are not being diagnosed, and they are not being treated, so if you fix that problem of people being diagnosed, will you make the bottleneck worse?

Dr Fried: It increases 1 of the other problems: having the PCP capacity to see and to treat all these patients.

Medscape: Are you saying that the model is not sustainable because it already is not working?

Dr Fried: It is working to some extent, but it is clear that there are more people out there with chronic HCV infection. And even those who are diagnosed now have long wait times for appointments to see specialists. Fortunately, the natural history of chronic HCV infection is that it is not immediately life threatening. Although HCV can be appropriately self-concerning to patients when they are diagnosed, its natural history does not change in 1 week, 1 month, or even 1 year. So, patients can wait to see specialty providers. Again, as more and more people are diagnosed and more and more patients are interested in being treated, we need to find other ways to improve the capacity of PCPs to care for these patients.

Medscape: You mentioned mitigating disease progression; I find that very interesting. Most of the literature that I have seen talks about the 2 prongs: that people need to be aware of chronic HCV infection and that PCPs need to refer patients to specialists in order for patients to get linked to care. I have not seen much about the need for the PCPs to, as you said, mitigate disease progression. It is a really important point.

Dr Fried: It is. PCPs can do a lot. As I mentioned, PCPs can counsel about lifestyle; that is very important. It is also important to note that PCPs are not always aware that chronic HCV infection is not uniformly fatal -- that it is a slowly progressive disease that can be treated; those messages of hope need to be given to patients at the time of diagnosis. Secondly, when patients are diagnosed with chronic HCV infection, they are usually very concerned about the impact on their family, spouses, partners; it is very important to explain to patients that HCV infection is not easily transmitted outside of direct blood-to-blood contact. Reassuring patients about the small risk for transmission of HCV infection to sexual partners and the virtual absence of risk for transmission to household contacts and family members is really important. Then, PCPs can address making sure that appropriate contacts (eg, spouses, partners, children) are tested for HCV infection, if it is recommended. PCPs can also verify immunity to hepatitis A virus and hepatitis B virus and perform appropriate vaccinations in those patients. Those things, if done before referral, will help the specialists and also provide great reassurance to patients.

Medscape: Prevention and health maintenance strategies are right up the alley, so to speak, of the PCP. Why are those strategies being missed by PCPs?

Dr Fried: A lot of it is a question of education and time. I want to stress that there are a lot of really excellent PCPs who use these strategies to educate patients -- don't get me wrong -- but I think there needs to be a specific conversation, with the PCP saying, "You have chronic HCV infection; here are the things you need to know and here are the things I need to do. And when you get to the specialty care provider, he/she will have all of this information." It will help specialty care providers focus more on some of the positive messages about disease outcomes as well as the treatment issues.

Medscape: There are algorithms for diagnosis and treatment; is there something analogous to that for counseling during the evaluation and diagnosis process? For example, is there a pocket guide or an algorithm that PCPs can look up on their iPad or iPhone and say, "Okay, it is HCV. I need to ask about this, this, this, and this."

Dr Fried: That is a good point. I do not know of any resource other than the guidelines from the Centers for Disease Control and Prevention and specialty organizations, such as the American Association for the Study of Liver Diseases. I'm not familiar with the primary care literature, so I do not know what is out there.

Medscape: It is been suggested that physicians in other specialties (ie, primary care, infectious diseases) begin treating patients with chronic HCV infection. What are your thoughts about this as a potential solution to the bottleneck? Is it feasible for a PCP who sees 30 patients a day to add care of patients with chronic HCV infection to his or her practice?

Dr Fried: We touched upon this a bit. Those early stages of education and disease mitigation fall within the PCP's realm. At the present time, I do not believe that with the complexities of the treatment regimens that involve pegylated interferon plus ribavirin, and now the addition of a protease inhibitor -- either boceprevir or telaprevir -- to the regimen, that it is feasible for a PCP to treat chronic HCV infection.

Although the protease inhibitors substantially increase the SVR over dual-therapy regimens of peginterferon plus ribavirin, these regimens are complicated; there is a learning curve. There are a lot of adverse events that need to be very closely managed. Unless this is a major focus of their practice, I think it would be very difficult for a PCP to manage the treatment of patients with chronic HCV infection. It would certainly be feasible and important for PCPs to comanage their patients with chronic HCV infection on treatment.

That said, there are some interesting models being demonstrated to determine if PCPs, with the right mentoring, can provide highly specialized care. I think the most promising model is Project ECHO (Extension for Community Healthcare Outcomes)[11] developed by Sanjeev Arora, MD, at the University of New Mexico. Over the past year, this model has received a lot of interest from various stakeholders. Project ECHO involves a Web-based mentoring program where Dr Arora and his team discuss actual cases on a 2-way Webcam-based system; the PCPs in rural New Mexico are presenting cases to the specialty providers at the University of New Mexico. They have a team of people that they meet on a weekly basis, and they review all the cases. They do not actually see the patients, so this is not strictly telemedicine, in which a single doctor is providing Web-based care directly to a patient. It is telementoring, where the University of New Mexico team is working with what it calls "a knowledge network," to comanage these patients in the rural PCP practices.[11] Over time, because of this mentoring, the PCPs become more highly skilled at managing patients with chronic HCV infection.

Dr Arora compared outcomes of the specialty team at University of New Mexico to the Project ECHO rural PCPs;[5] PCP outcomes, in terms of SVR and adverse event management, were nearly identical to the outcomes of the University of New Mexico specialty teams. With effective mentoring, the PCPs can manage HCV. Initially, Project ECHO focused on treatment with pegylated interferon plus ribavirin. Dr Arora is now looking at how this mentoring is working with triple therapies, peginterferon plus ribavirin and the protease inhibitors. Triple therapy adds a level of complexity, and it will be a challenge.

Medscape: It has also been suggested that nurse practitioners (NPs) and physician assistants (PAs) could play a bigger role; what are your thoughts about this as a potential solution?

Dr Fried: Absolutely; those individuals are critical to managing chronic HCV infection, and I think that they do an outstanding job. No one comes into that job with a lot of experience managing chronic HCV infection, so if physicians spend the time mentoring NPs and PAs, NPs and PAs will do an outstanding job in the management of patients with chronic HCV infection. We use NPs and PAs extensively in our practice here at University of North Carolina. We are very fortunate to have 4 of these providers who work with patients with chronic HCV infection; I cannot say enough good things about their roles in managing this disease. If there is 1 group that I think we should particularly try to get involved in practices that have an interest in chronic HCV infection, it is certainly NPs and PAs. They are excellent healthcare professionals and ideally suited for managing chronic HCV infection.

Medscape: I think that most people understand the role of NPs and PAs. What do you think is the biggest value in making these providers an integral part of the patient care team for patients with chronic HCV infection?

Dr Fried: The initial evaluations are performed in a team environment; the attending physician, NPs, and PAs evaluate patients about their candidacy for treatment and develop a treatment plan. In our experience, NPs and PAs are often primarily responsible for managing patients with chronic HCV infection on a daily basis -- of course with our oversight and supervision -- and help make decisions about issues such as adverse-event management. They play a very pivotal role in the management of patients with chronic HCV infection; in my experience, they develop great rapport with the patients. I don’t think there is any other way to do it; the role of NPs and PAs should be expanded in the care of patients with chronic HCV infection.

Medscape: What about in states where NPs and/or PAs have prescriptive authority?

Dr Fried: In North Carolina, NPs and PAs have prescriptive authority. They work under the supervision of attending physicians. Management of chronic HCV infection during the treatment phase is very amenable to the role of NPs and PAs. Practitioners in other states would be familiar with their local regulations.

Medscape: The treatment algorithms are fairly clear?

Dr Fried: Yes, the treatment algorithms are clear, but -- make no mistake -- this is a complex disease with complex treatment and adverse-event management. You cannot just hand an algorithm to a clinician and say, "Here; go treat this patient with chronic HCV infection." They need to have backup support and ongoing mentoring because there are nuances to every case. Specialists have to continue to work with their team of multidisciplinary providers; everyone needs continuing medical education in this regard. As you do that, NPs and PAs become quite expert in managing this disease.

I think you can glean from my answers where we have to be; it is definitely a multidisciplinary model. As long as we are dealing with interferon-based therapies, it goes beyond just an NP or PA and the attending physician; because of drug-drug interactions, it is best to involve pharmacists and pharmacologists. Also, because all treatment including triple therapy is interferon based, there are issues related to the neuropsychiatric side effects of those drugs. Having a psychiatric healthcare provider (a psychiatrist or psychologist) can help with the evaluation and management of patients on interferon-based therapy. Multidisciplinary models are definitely important. How practical they are for solo providers is a different story, but at least they need to have resources in their communities that they know they can draw from.

Medscape: Treatment paradigms are changing: they are more complex on 1 hand, and the efficacy is greater on the other. What immediate changes are needed to optimize triple therapy? What will the future of treatment of chronic HCV infection look like?

Michael Fried, MD: We have been waiting a very long time for the introduction of the protease inhibitors into treatment. We are happy that they are here, because they improve SVR rates significantly over pegylated interferon plus ribavirin.[2-5] I mentioned that they represent treatment challenges due to adverse events, but nevertheless, they have also shortened the duration of therapy by 50% in patients with genotype 1 infection.[12]

Optimizing triple therapy involves understanding the treatment algorithms and knowing when these medications are not effective and need to be discontinued prematurely. This involves making sure that adherence to the medications is complete, optimizing management of side effects and adverse events, and optimizing therapeutic outcomes without premature discontinuation of these medications.

Researchers are also looking at certain subpopulations where perhaps even 6 months of therapy may be more than enough treatment; maybe we will be able to get away with shorter durations of treatment in certain populations -- for example, a patient with IL28B CC genotype who has mild disease. Maybe those patients only need 12 or 16 weeks of treatment; these studies are going on now.

Also, very exciting, is what is coming down the pipeline. We are talking about second-generation protease inhibitors that appear to have improved side effect profiles. They only need to be taken once or twice daily vs 3 times a day; that will help with adherence.

In 3 to 5 years we may be looking at all-oral regimens; that would be a complete game-changer. An all-oral regimen for chronic HCV infection will mean several things. First, PCPs could potentially treat chronic HCV infection because they would not be dealing with the interferon injectables and some of the adverse events. Of course, it will depend on the side-effect profiles of these all-oral regimens. Second, an all-oral regimen could extend treatment options for a large portion of the HCV-infected population that currently are not candidates for interferon-based regimens (eg, patients with underlying psychiatric disease). If you take interferon out of the mix, the treatment could be expanded quite extensively to patients who have no other contraindications to therapy. Once that occurs, there will be an even greater impact on the natural history of chronic HCV infection, and the likelihood of progression to cirrhosis, hepatocellular carcinoma, and the need for liver transplantation will be decreased. This will have a huge positive impact on the healthcare burden 10 and 20 years from now.

The possibility of all-oral regimens is very exciting, and it is happening faster than many of us predicted. However; a note of caution: although there are many drugs in the pipeline and researchers will ultimately discover which combinations will be very effective for most patients with chronic HCV infection, we are not there yet. Clinical trials are necessary to determine how to combine these medications to achieve the greatest efficacy with the least side effects, and in the most cost-effective ways in the most patients. We have a lot of work to do, but it is really exciting. I am very optimistic about the future of management of patients with chronic HCV infection.

References  Abbreviations

Source

Watch Achillion Pharmaceuticals For Upcoming Phase IIa Data

April 3, 2012

Brian L. Wilson

Achillion Pharmaceuticals (ACHN) is a development-stage pharmaceutical company developing treatments that combat the heptatitis C virus, which is estimated by the company's website to affect over 170 million worldwide.

If pharmas want to sell into emerging markets they will need a product list that includes HCV drugs, Behzad Aghazadeh of venBio told BioCentury this week.

"They have to sell into China with a full package - cardiovascular, diabetes, vaccine, hepatitis B and C," Aghazadeh said. "If they don't have it that weakens the portfolio selling opportunity; that's how you sell into China as opposed to in the U.S., where they are selling to individual doctors." Aghazadeh sees GlaxoSmithKline (GSK) plc and AstraZeneca plc (AZN) as among potential acquirers of HCV companies. According to the "2Q Financial Markets Preview" published for BioCentury subscribers, Idenix Pharmaceuticals Inc. and Achillion Pharmaceuticals Inc. are names several buy-siders said they have a position in or are watching closely. Each will present at the European Association for the Study of the Liver (EASL) meeting in Barcelona on April 18-22. Abstracts will be available starting on April 4.

Achillion's pipeline also includes one preclinical-stage drug being developed for bacterial infections, although the bulk of the company's resources are being spent on HCV (hepatitis C virus). Achillion have five separate HCV drugs in various stages of development, most notable is ACH-1625 which is classified as a protease inhibitor.

The hepatitis C virus, in order to replicate, needs particular protease enzymes to construct new virions which allow the disease to continue to attack the body. ACH-1625 is an inhibitor of the HCV NS3 protease, which means this drug should prove effective if it can prevent this protein from functioning. The NS3 protein that is targeted by ACH-1625 has been studied extensively, and serves critical functions in the HCV infection process. All non-structural proteins with regards to HCV are processed by NS2 and NS3, and due to their necessary interaction, inhibition of NS3 should hypothetically be a nearly-insurmountable obstacle for HCV replication. As of now, ACH-1625 has passed Phase I trials which have validated its relative safety and lack of side-effects. Phase II trials will give further insight into the efficacy of the drug against viral replication by HCV.

ACH-2684 is a broader protease inhibitor being developed to suppress the natural variants of the hepatitis C virus by the same mechanism. According to the company, the compound is also potent against standard genotypes of HCV which means it could be just as (if not more) effective than inhibition of just the NS3 protein, although the company claims that it has actually been tailored to affect the NS3 protease. The efficacy of this broader ranged protease inhibitor is difficult to determine at this stage, since it has only proven potency in the "low pico-molar range" (an incredibly small volume), but the fact that it might target mutant strands of HCV makes it worthwhile.

The third drug in the pipeline that has begun its clinical trials is ACH-2928, which acts through another mechanism by inhibiting HCV NS5A. This protein actively antagonizes a cell's response to a viral infection through RNA-binding, and research is being done to investigate its suspected role in genome replication. The second generation version of this, ACH-3102, is being developed with enhanced abilities to fight off resilient strains of HCV that would be less susceptible to ACH-2928.

ACH-1625 will be releasing results of its Phase IIa clinical trials on April 18-22, at the International Liver Conference being hosted in Barcelona. Shares have already rocketed up at the start of 2012, but there's reason to believe that some early confirmation of ACH-1625's efficacy in a larger sample size could be immensely beneficial for the stock. News may be slow after this since many fresh studies are being started this year, but investors may jump the gun if the data on this generation of protease inhibitors gives hope on stopping HCV.

That being said, from a purely technical perspective (see chart) , the market could be hinting that a move like we saw earlier in the year might occur when details of those results come.

Source

Christian Voitenleitner1, Jill Bechtel1, Ann Arfsten2, and Robert Hamatake1

1GlaxoSmithKline, Research Triangle Park, NC, USA
2InterMune, Brisbane, CA, USA

BioTechniques, Vol. 52, No. 4, April 2012, pp. 273–275

 Full Text (PDF)

Hepatitis C virus (HCV) is a plus-strand RNA virus in the Flaviviridae family with replication restricted to hepatocytes of humans and chimpanzees. HCV infects more than 3% of the world population, leading to increased risk of liver cirrhosis and hepatocellular carcinoma. The search for HCV model systems has been hampered by the fact that HCV isolates taken from patients replicate poorly, if at all, in in vitro cell culture systems. The first selectable subgenomic replicon capable of replicating autonomously—generated in the laboratory of Ralf Bartenschlager (1)—revealed a series of so called adaptive mutations that allow this construct to replicate in tissue culture (2-4). These subgenomic HCV replicons have proven to be powerful tools for studying viral replication or performing drug screening, and additional mutations have been reported that enhance the fitness of stable genotype 1a systems (5). Given the error prone nature of the RNA-dependent RNA polymerase NS5B, resistance to direct acting antivirals develops rapidly necessitating the ability to screen a compound against a panel of resistant replicons during drug development. Since keeping stable replicon cell lines of all these mutant replicon systems is prohibitive, mutant replicons are often used in transient assays rather than in stable cell lines. In transient assays, the hepatoma cell line Huh7-Lunet (6) is electroporated with in vitro transcribed HCV RNA that contains a luciferase reporter. The transfected cells are transferred onto 96-well plates containing compounds of interest in a dilution series. Luciferase activity is measured after 72 h to establish EC50 values of compounds against certain replicons (Figure 1A). The genotype 1a-H77 subgenomic replicon (7), which contains a luciferase/neomycin (neo) reporter cassette as well as the structural proteins NS3 through NS5B and two adaptive mutations in NS3/4A and NS5A, P1496L and S2204I, respectively, has very low luciferase levels after 72 h resulting in a low signal to noise ratio (Figure 2A).

BTN_A_000113841_O_F_177914b

Figure 1. Schematic of transient transfections. (Click to enlarge)

BTN_A_000113841_O_F_177915b

Figure 2. The 1a-fit replicon shows enhanced fitness in transient assays. (Click to enlarge)

This low signal makes it difficult to obtain robust data on the potency of compounds against the 1a-H77 replicons, especially those resistance mutant replicons exhibiting even further diminished replication capacity.

In order to quickly evaluate lead compounds against our large panel of resistance mutations, we needed to create a system with a quick luciferase reporter readout that had a robust signal to noise ratio at the assay readout time of 72 h. An additional advantage of a transient system is that there is no additional accumulation of mutations as can happen in a stable cell line propagated for several cell division cycles. In order to achieve this goal, we started with a replicon system that originated from a resistance screen with an HCV inhibitor targeting NS4B and revealed a mutation in NS4B, E1726G, which conferred fitness to the 1a-H77 replicon. Replicons carrying this mutation manifested higher luciferase units at the 72 h time point of a transient transfection (Figure 2A), yet did not impact the activity of HCV inhibitors to various targets (Figure 2C). Furthermore, a publication from Stan Lemon's laboratory reported several mutations that enhanced replication of the 1a-H77 replicon (8). We chose the mutation in the NS4A gene, K1691R, for minimal interference with our compound targets, while still displaying increased fitness in the 1a replicon. In an effort to further improve the luciferase signal resulting from transient transfection of the 1a-H77 replicon, we introduced both mutations into the 1a-H77 subgenomic replicon. Site-directed mutagenesis using the Quikchange Kit from Stratagene resulted in the 1a-fit (1a-H77-K1691R/ E1726G) replicon (Figure 1B).

In order to assess and compare the robustness of these replicons, we performed a transient transfection, followed by a time course up to the assay readout time of 72 h (Figure 2A). After the initial burst of luminescence at 4 h, which stems from translation of the luciferase gene from the transfected RNA rather than replicated RNA, we saw an initial decline in all samples, which indicated the lag until proteins from the replicated RNA begin to be made. At 48 h, 1a-E1726G showed higher signal than 1a-H77; this difference continued through the 72 h time point. The 1a-fit vector consistently showed the highest luminescence, with a 10-fold higher readout than the 1a-E1726G and a hundred-fold higher readout than 1a-wt at 72 h. Some mutations obtained from resistance screens and introduced into the replicon system are known to reduce replicon fitness significantly. One example is the NS5B site IV mutation in 1a, C316Y, which has only 7% replication capacity compared with 1a-wildtype (9). We tested this mutant replicon and showed that, although replication fitness is still impaired relative to wildtype, the luciferase units of 1a-fit-C316Y after 72 h are high enough (>300,000 RLU) to give a robust signal to noise ratio (Figure 2B). This signal represents a vast improvement when compared with the signal of C316Y in the original 1a-H77, which ranged from about 1500 to 3000 RLU.

To verify that the two newly introduced mutations had no effect on compound potency of HCV inhibitors hitting various targets, we tested and compared a series of inhibitors against the 1a-H77, the 1a-E1726G and the 1a-fit replicons (Figure 2C). When tested against a variety of compounds targeting protease, NS4B, NS5A, and various sites of NS5B, the 1a-fit replicon resulted in the same compound potency as the 1a-H77 or the 1a-E1726G replicon, suggesting that neither of these two newly introduced mutations altered compound potencies, but were merely conferring fitness to the replicon.

In summary, we have shown that introducing two mutations in NS4A and NS5B, respectively, could enhance replication fitness and increased the signal to noise ratio about 100-fold compared with the 1a-H77 replicon, resulting in more robust data for HCV inhibitors. This newly described replicon construct provides a quick reporter gene response through its Luciferase readout, as well as a robust signal for reliable determination of compound potencies. Because of the relative ease of introduction of mutations into the replicon, this system can be used to quickly profile a large number of compounds on a panel of resistance mutations against various HCV targets.

Acknowledgments

The authors would like to thank Ermias Woldu at GlaxoSmithKline for his technical assistance.

Competing interests

The authors declare no competing interests.

Correspondence
Address correspondence to Christian Voitenleitner, GlaxoSmithKline, 5 Moore Drive HCV DPU, N3.3235C, Research Triangle Park, NC, USA. Email: christian.a.voitenleitner@gsk.com

References

1.) Lohmann, V., F. Korner, J. Koch, U. Herian, L. Theilmann, and R. Bartenschlager. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110-113.

2.) Krieger, N., V. Lohmann, and R. Bartenschlager. 2001. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J. Virol. 75:4614-4624.

3.) Lohmann, V., F. Korner, A. Dobierzewska, and R. Bartenschlager. 2001. Mutations in hepatitis C virus RNAs conferring cell culture adaptation. J. Virol. 75:1437-1449.

4.) Lohmann, V., S. Hoffmann, U. Herian, F. Penin, and R. Bartenschlager. 2003. Viral and cellular determinants of hepatitis C virus RNA replication in cell culture. J. Virol. 77:3007-3019.

5.) Robinson, M., H. Yang, S.C. Sun, B. Peng, Y. Tian, N. Pagratis, A.E. Greenstein, and W.E. Delaney. 2010. Novel hepatitis C virus reporter replicon cell lines enable efficient antiviral screening against genotype 1a. Antimicrob. Agents Chemother. 54:3099-3106.

6.) Blight, K.J., J.A. McKeating, and C.M. Rice. 2002. Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J. Virol. 76:13001-13014.

7.) Blight, K.J., J.A. McKeating, J. Marcotrigiano, and C.M. Rice. 2003. Efficient replication of hepatitis C virus genotype 1a RNAs in cell culture. J. Virol. 77:3181-3190.

8.) Yi, M., and S.M. Lemon. 2004. Adaptive mutations producing efficient replication of genotype 1a hepatitis C virus RNA in normal Huh7 cells. J. Virol. 78:7904-7915.

9.) McCown, M.F., S. Rajyaguru, S. Kular, N. Cammack, and I. Najera. 2009. GT-1a or GT-1b subtype-specific resistance profiles for hepatitis C virus inhibitors telaprevir and HCV-796. Antimicrob. Agents Chemother. 53:2129-2132.

10.) van den Hoff, M.J., A.F. Moorman, and W.H. Lamers. 1992. Electroporation in ‘intracellular’ buffer increases cell survival. Nucleic Acids Res. 20:2902.

Source

Crosstalk between HIV and Hepatitis C Virus during co-Infection

Published on: 2012-04-03

An estimated one-third of HIV+ individuals are also infected with hepatitis C virus (HCV). Chronic infection with HCV can lead to serious liver disease including cirrhosis and hepatocellular carcinoma.

Liver-related disease is among the leading causes of death in HIV+ individuals and HIV/HCV co-infected individuals are found to progress more rapidly to serious liver disease than mono-infected individuals. The mechanism by which HIV affects HCV infection in the absence of immunosuppression by HIV is currently unknown.

In a recent article published in BMC Immunology, Qu et al. demonstrated that HIV tat is capable of inducing IP-10 expression.

Further, they were able to show that HIV tat, when added to cells, was able to enhance the replication of HCV. Importantly, the increase in HCV replication by tat was found to be dependent on IP-10.

This work has important implications for understanding the effect HIV has on the outcome of HCV infection in co-infected individuals and the findings of Qu et al may inform the design of intervention and treatment strategies for co-infected individuals.Please see related article: http://www.biomedcentral.com/1471-2172/13/15

Author: Paul J RiderFenyong Liu
Credits/Source: BMC Medicine 2012, 10:32

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Also See: The Tat protein of HIV-1 enhances hepatitis C virus replication through interferon gamma-inducible protein-10

Public release date: 3-Apr-2012

Contact: Steve Graff
stephen.graff@jefferson.edu
215-955-5291
Thomas Jefferson University

 

Longer tips on chromosomes may be new noninvasive biomarker for hepatitis B patients, say Jefferson's Kimmel Cancer Center researchers

CHICAGO— Hepatitis B-infected patients with significantly longer telomeres—the caps on the end of chromosomes that protect our genetic data— were found to have an increased risk of getting liver cancer compared to those with shorter ones, according to findings presented by researchers at Jefferson's Kimmel Cancer Center at the American Association for Cancer Research (AACR) Annual Meeting 2012.

The relative telomere length in hepatitis B-infected cases with liver cancer was about 50 percent longer than the telomere length of the cancer-free hepatitis B-infected controls.

A strong correlation between telomere length and non-cirrhotic hepatocellular carcinoma (HCC), a liver cancer commonly caused from hepatitis B and C viral infections, could help physicians better stratify the hepatitis B population in an effort to better prevent and treat the disease.

Previous reports have suggested telomere length plays a role in cancer prediction; however, there have been conflicting results and the majority of the studies measured telomere length in liver cells (hepatocytes) and white blood cells.

Here, Hushan Yang, Ph.D., of the Division of Population Science at the Department of Medical Oncology at Thomas Jefferson University and Jefferson's Kimmel Cancer Center, and colleagues used circulating cell-free serum DNA from an existing and ongoing clinical cohort at the Liver Disease Prevention Center at Thomas Jefferson University Hospital.

Tapping into a cohort of almost 2,600 Korean Americans, a population disproportionately infected with hepatitis B, the team analyzed blood samples from over 400 hepatitis B-infected patients to compare relative telomere length using quantitative real-time polymerase chain reaction (qRT-PCR).

This nested case-control study included 140 hepatitis B-HCC cases and 280 cancer-free hepatitis B controls. Demographic and clinical data were obtained for each patient through medical chart review and consulting with treating physicians.

All participants were restricted to Korean hepatitis B patients to control the confounding effects of ethnicity and HCC etiology. The large majority of the patients were infected at birth or childhood, making this population an ideal resource to study the long-term outcome of hepatitis B infection at the population level.

The hepatitis B-HCC cases were found to have a relative telomere length about 50 percent longer than the cancer-free controls (0.31 versus 0.20, P=0.003), a statistically significant difference.

The difference, however, was also only evident in males and in non-cirrhotic patients, and not cirrhotic patients, possibly because that the effect conferred by telomere length was overshadowed by the strong association between cirrhosis and HCC. There were also no statistical differences between cohorts with respect to age and smoking status.

"This is the first study to demonstrate that relative telomere length in circulating cell-free serum DNA could potentially be used as a simple, inexpensive and non- invasive biomarker for HCC risk," said Dr. Yang. "This sets the stage for further retrospective and prospective investigations, in-depth molecular characterizations, and other assessments to determine the clinical value of serum DNA telomere length in risk prediction and early detection of HCC."

###

Co-authors of the study were Shaogui Wan, Xiaoying Fu, Ronald Myers, Ph.D., Division of Population Science, Department of Medical Oncology, Thomas Jefferson University; Hie-Won Hann, M.D., Richard Hann, Jennifer Au, M.D., Division of Hepatology and Gastroenterology, Department of Medicine, Thomas Jefferson University; and Jinliang Xing, Department of Cell Biology, Fourth Military Medical University in China.

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Patients with liver cancer more likely to be on transplant waitlist

According to Arthur Caplan, the list is 'heavily oriented' toward the sickest patients

By Laura Cofsky · April 2, 2012, 9:21 pm

To the surprise of many in the medical community, patients with both liver disease and a certain kind of liver cancer are eight times less likely to die than those who just suffer from the disease.

The reason, according to a Perelman School of Medicine study, is that patients with both illnesses may receive an unfair advantage on the organ transplant waitlist. The study has prompted the United Network for Organ Sharing to reevaluate some of its policies toward the liver transplant waitlist.

Between 2005 and 2009, Department of Gastroenterology professor and lead author David Goldberg and his team analyzed data from 10,000 adults suffering from liver disease. Some patients had been diagnosed with both liver disease and hepatocellular carcinoma — the type of cancer — while others were only struggling with liver disease.

They found that 24 percent of patients suffering from the disease alone were removed from the transplant waitlist because of the severity of the illness or because many patients died while on the waitlist.

Only 3 percent of cancer patients had the same fate. The results of the study are published in the April issue of Liver Transplantation.

“The current list is heavily oriented toward who’s sickest, who’s more likely to die,” bioethicist and medical ethics and policy professor Arthur Caplan said. “I think this study is surprising because many think those with liver cancer are very sick, and this study shows that those with both liver failure and cancer aren’t necessarily sicker.”

On the national waitlist, patients with the disease “are ranked according to how likely they are to die,” explained Goldberg. “They can develop liver cancer. They may not be as ‘sick,’ but they can be moved up the list.”

“Even though they have the risk of getting sicker from the cancer, the priority they were given on the list didn’t match up with real life,” he added.

Every HCC patient receives a lab value and is ranked according to their likelihood of death within a three month period, according to Ann Harper, UNOS’s Liver and Intestinal Organ Transplantation Committee spokesperson.

Goldberg said the current scoring system was adopted by UNOS in 2002, when HCC patients were given waitlist priority. To combat this, UNOS revised the scoring system in 2003, and again in 2005.

Since 2010 there has been an accumulating body of evidence showing that HCC patients still receive an unfair advantage, Harper said.

“Sometimes it takes a few years to see issues with policies,” Harper said. “Sometimes the committee needs to make adjustments to policies.”

Harper’s committee meets several times a year to review its policies, transplant statistics and outside research. Based on the review, they will release a recommendation for public comment, and then the UNOS board of directors will vote on it. Currently, the group is trying to obtain public feedback pertaining to the transplant policy.

Caplan agrees with Goldberg’s proposal that the scoring system be changed. “I think what they’re calling for is ethically and medically sensible. You want to use evidence to see who has the greatest need.”

“This is something that a lot of people have recognized on their own but it’s never been put out there,” Goldberg said.

Yet Caplan hopes people remain cognizant of the bigger issues — the lack of livers, the need to have more people sign donor cards and engage in healthier habits and the possibility of building mechanical organs.

“You don’t want to lose sight of solutions to prevent or treat liver failure, although prioritization is important,” he said.

Last updated April 2, 2012, 10:14 pm

Filed under:News
Permanent link: http://thedp.com/r/78d77225

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Published on: 2012-04-03

Co-infection with human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) is associated with faster progression of liver disease and an increase in HCV persistence. However, the mechanism by which HIV-1 accelerates the progression of HCV liver disease remains unknown.

Results: HIV-1/HCV co-infection is associated with increased expression of interferon gamma-induced protein-10 (IP-10) mRNA in peripheral blood mononuclear cells (PBMCs).

HCV RNA levels were higher in PBMCs of patients with HIV-1/HCV co-infection than in patients with HCV mono-infection. HIV-1 Tat and IP-10 activated HCV replication in a time-dependent manner, and HIV-1 Tat induced IP-10 production.

In addition, the effect of HIV-1 Tat on HCV replication was blocked by anti-IP-10 monoclonal antibody, demonstrating that the effect of HIV-1 Tat on HCV replication depends on IP-10. Taken together, these results suggest that HIV-1 Tat protein activates HCV replication by upregulating IP-10 production.

Conclusions: HIV-1/HCV co-infection is associated with increased expression of IP-10 mRNA and replication of HCV RNA.

Furthermore, both HIV-1 Tat and IP-10 activate HCV replication. HIV-1 Tat activates HCV replication by upregulating IP-10 production.

These results expand our understanding of HIV-1 in HCV replication and the mechanism involved in the regulation of HCV replication mediated by HIV-1 during co-infection.Please see related article: http://www.biomedcentral.com/1741-7015/10/32

Author: Jing QuQi ZhangYouxing LiWeiyong LiuLvxiao ChenYing ZhuJianguo Wu

Credits/Source: BMC Immunology 2012, 13:15

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PR-Logo-GlobeNewswire

PRESS RELEASE

April 3, 2012, 10:29 a.m. EDT

NEW YORK, Apr 3, 2012 (GlobeNewswire via COMTEX) -- Investigative journalism by TheStreet, a leading digital financial media company, has caused a prominent European medical association to enact a major change in its disclosure policy, a move that will help level the playing field for ordinary investors.

As reported by TheStreet biotechnology reporter Adam Feuerstein on March 20, 2012 ( www.thestreet.com/story/11462003/1/easl-gives-wall-streets-privileged-investors-sneaky-preview-to-key-hep-c-data.html ), the European Association for the Study of the Liver (EASL) was set to selectively disclose, to a group that includes hedge funds and sell-side equity analysts, potentially market moving data involving clinical studies of experimental treatments for hepatitis C -- three weeks before the data was going to be announced to the public at EASL's International Liver Congress gathering to be held April 18-22. The conference will include reports on important studies by Gilead Sciences (GILD), Bristol-Meyers Squibb (BMY), Abbott (ABT), Idenix Pharmaceuticals (IDIX), Vertex Pharmaceuticals (VRTX) and Merck (MRK), among others.

TheStreet's article pointed out that many medical and scientific groups, such as the American Society of Clinical Oncology, make research abstracts publicly available in advance of major conferences in light of ability of such information to cause significant movement to the share price of various public medical industry companies.

Two days after TheStreet's exposure of EASL's unfair selective disclosure policy, EASL reversed course and announced that the research abstracts would be disclosed by making the data publicly available online on April 4 -- see http://www.thestreet.com/story/11465904/1/easl-backs-down-will-publicy-disclose-key-hep-c-data.html .

TheStreet commends EASL on taking appropriate action and changing its unfair policies.

About TheStreet

TheStreet, Inc. is a leading digital financial media company that distributes its content through online, social media, tablet and mobile channels. The Company's network of brands include: TheStreet, RealMoney, RealMoney Pro, Stockpickr, Action Alerts PLUS, Options Profits, ETF Profits, Chat on TheStreet, MainStreet and Rate-Watch. For more information on TheStreet's business, visit www.t.st . For financial and business news, actionable trading ideas, stock quotes and more, visit TheStreet.com via your web browser, follow TheStreet on Facebook and Twitter, visit TheStreet.mobi from your mobile device and access TheStreet through all major tablet platforms.

The TheStreet, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=11420 

This news release was distributed by GlobeNewswire, www.globenewswire.com 

SOURCE: TheStreet, Inc.

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Provided by ICT Infection Control Today

A recent article posted online ahead of print in the journal Hepatology by the CDC’s Dr. Joseph Perz identifies medical injections as a potential risk factor for having hepatitis B or hepatitis C infection.

In this week’s Annals of Internal Medicine, an editorial highlights how unsafe injection practices and other infection control breaches result in transmission of hepatitis C virus.

The editorial also mentions the need for the national One and Only Campaign led by the CDC and the Safe Injection Practices Coalition to promote safe injection practices and describes the increasing role of public health departments in healthcare-associated infection prevention.

This week, the One and Only Campaign announces the release of a new Health Department Toolkit that provides information and tips on ways to implement the One and Only Campaign.

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Scientists Find Promising Vaccine Targets on Hepatitis C Virus

Provided by ICT Infection Control Today

A team led by scientists at The Scripps Research Institute has found antibodies that can prevent infection from widely differing strains of hepatitis C virus (HCV) in cell culture and animal models.

HCV’s very high rate of mutation normally helps it to evade its host’s immune system. The newly discovered antibodies, however, attach to sites on the viral envelope that seldom mutate. One of the new antibodies, AR4A, shows broader HCV neutralizing activity than any previously reported anti-HCV antibody.

“These antibodies attach to sites on the viral envelope that were previously unknown, but now represent promising targets for an HCV vaccine,” says Mansun Law, an assistant professor at Scripps Research. Law is the senior author of the new report, which appears online this week in the Proceedings of the National Academy of Sciences.

An effective HCV vaccine is desperately needed. The World Health Organization (WHO) estimates that the virus has established mostly silent infections in 130 to 170 million people worldwide—nearly 3 percent of the human population—and spreads to 3 to 4 million new people annually. HCV principally infects liver cells, and is thought to cause chronic, often-unnoticed liver inflammation, which eventually can lead to serious liver ailments. The virus already is responsible for about a quarter of annual US cases of liver cirrhosis and primary liver cancer, and it is the leading cause of liver transplants. In some developing countries, HCV prevalence is extremely high; studies suggest that in Egypt, as many as 22 percent of the population is infected—apparently due to poor screening of blood products and past re-use of syringes. Even in developed countries, HCV infections represent a looming public health crisis. In the United States and Europe, up to 14 million people are now HCV-positive, and each year an estimated 150,000 people are newly infected.

The current leading treatment for HCV infection involves a 12- to 36-week course of the immune-stimulating protein interferon-alpha, the antiviral drug ribavirin and HCV protease blocker. But it is not completely effective, and it causes significant adverse side effects—aside from being very expensive. To fully stamp out the HCV pandemic, especially in developing countries, scientists will have to develop a cheap preventive vaccine.

Yet an effective HCV vaccine has so far been elusive. The virus mutates very rapidly, and thus, antibodies raised against one isolate of HCV typically won’t protect against a subsequent HCV infection. Hospital samples of HCV suggest that the virus’s genes, and the proteins for which they code, are highly variable even within an individual patient.

“One of the big goals of HCV vaccine development has been to find an accessible spot on the virus that doesn’t change constantly,” saya Law.

To find such vulnerable spots, researchers sift through antibodies sampled from infected people and look for those antibodies that can neutralize a broad range of viral strains. The locations on the virus where those broadly neutralizing antibodies bind mark the vulnerable viral structures that can be used as the bases of a broadly effective, antibody-stimulating vaccine. Previous studies, including a 2008 study in Nature Medicine, for which Law was lead author, have found some broadly neutralizing HCV antibodies. But for the present study, Law and his colleagues used a more thorough approach, known as “exhaustive panning,” to see if they could find new and even more broadly neutralizing antibodies. “Exhaustive panning is a powerful technique for finding rare antibodies that might otherwise go undetected,” Law said.

HCV employs a complex of two envelope glycoproteins, E1 and E2, to grab and fuse with target cells. Erick Giang, a research assistant in Law’s lab, harvested this viral E1-E2 complex from HCV-producing cells in a lab dish and used it as “bait” for a panel of antibodies derived from the blood of a person with chronic HCV infection. The exhaustive panning technique involves exposing this bait protein to different anti-HCV antibodies in sequence, so that the known antibody-binding sites on the complex are progressively covered until only new ones are left.

In this way, Giang catalogued 73 new anti-HCV antibodies, which bind to five distinct “antigenic regions” on the E1-E2 complex. In standard cell culture tests of HCV-neutralizing ability, several of these antibodies showed an ability to neutralize infection by a wide range of HCV strains. One, AR4A, turned out to bind to an almost-unvarying spot on E1-E2 complex, close to the surface of the virus’s outer coat of fat molecules. AR4A showed significant neutralizing ability against all 22 HCV strains in a test panel—not only in tests in Law’s lab, but also in confirmatory tests at the University of Copenhagen.

The new antibody thus is more broadly protective than the previous top contender, AR3A, which Law described in his 2008 Nature Medicine paper. “This human antibody AR4A has the broadest HCV-neutralizing activity known to the field,” Law says.

Collaborating researchers at Rockefeller University, who recently engineered a line of HCV-infectable mice, showed that AR4A antibodies protected these mice from two widely different HCV strains. A combination of half-doses of AR3A and AR4A antibodies worked less well.

The next step for Law and his colleagues is to start making and testing prototype vaccines based on the vulnerable HCV binding sites that have been revealed by these antibody studies. The researchers also plan to use the new antibodies to study the structure and function of HCV proteins such as the all-important E1-E2 complex.

Anti-HCV antibodies such as AR4A and AR3A could have some therapeutic use, too. Although they wouldn’t be able to clear existing HCV infections and would be too expensive and difficult to use on a large population to prevent new infections, they could be useful in preventing new HCV liver infections in liver transplant patients. Such infections can spread from HCV reservoirs in the patient’s body to the newly transplanted liver tissue.

“Antibody-based treatment has worked extremely well for liver transplants to patients with hepatitis B virus, and we hope the new HCV antibodies can be just as helpful to HCV liver transplant patients,” Law says.

In addition to Law and Giang, contributors to the paper, “Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus,” were Marcus Dorner, Charles M. Rice, and Alexander Ploss of Rockefeller University in New York; Jannick C. Prentoe and Jens Bukh of the University of Copenhagen; Matthew J. Evans of the Mount Sinai School of Medicine; and Marlène Dreux and Dennis Burton at Scripps Research.

The Law laboratory’s research is supported by the National Institutes of Health.

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ICVH 2012: Highest-Risk Individuals Missed by Current HCV Screening

From Medscape Medical News

Neil Canavan

April 3, 2012 (New York, New York) — An analysis involving more than 30 million medical claims from a commercial insurance provider and from Medicare suggest that current recommendations for hepatitis C virus (HCV) testing are not being followed.

In fact, the adult demographic with the lowest incidence of HCV infection — young women — is the most likely to be tested, according to data presented here at the International Conference on Viral Hepatitis 2012.

"The CDC is looking at changing the HCV guidelines to mandate a 1-time HCV antibody test for everybody born between 1945 and 1965," said lead analyst Camilla Graham, MD, who is vice president of global medical affairs for Vertex Pharmaceuticals.

Recent studies have suggested that the 1945 to 1967 birth cohort accounts for 81% of all people diagnosed with HCV infection. "This study was done to look at who is actually getting tested for HCV in the United States under current risk-based screening recommendations."

The analysis was performed using records from the Thomson Medstat MarketScan commercial database, a resource comprising medical and outpatient pharmacy claims from employer-sponsored health insurance plans and including more than 30 million commercially insured and 3 million Medicare supplemental-insured individuals. Claims made from 2004 to 2008 were used for this study.

People who had undergone HCV testing were identified on the basis of Current Procedural Technology codes for HCV antibody or HCV RNA testing, birth cohort, and sex. People diagnosed with HCV infection after testing were identified with International Classification of Diseases, Ninth Revision (ICD-9) codes. "Filters were also employed to find people newly identified with HCV as of 2008," said Dr. Graham, "to get a sense of diagnosis trends."

For 2008, only 1.1% of individuals in the payer population and 1.7% in the Medicare population had been tested for HCV. "This is actually an increase from 2004, and a maximum for the study period," Dr. Graham noted.

"When we look at the commercial database, we see that there are more women being tested than men [62% vs 38% in 2008]," she said. The sex distribution in the Medicaid population was about even for men and women (51% vs 49%).

Although this finding seems balanced on the surface, data continue to accrue showing that men have higher exposure to HCV and a greater likelihood of having chronic HCV infection. Of the currently identified 800,000 HCV-related cases of cirrhosis in the United States, 75% are men.

Current testing practices do not reflect actual rates of HCV infection as indicated by birth cohort, Dr. Graham said. Only 32.8% of people born from 1945 to 1964 have been tested, even though this cohort has the highest rate of infection. In contrast, 48.2% of people born from 1970 to 1989 have been tested, although their rate of HCV infection is known to be much lower.

"Interestingly, in this younger group, almost twice as many women as men are being tested," she said.

An analysis of HCV diagnosis during the study period illustrates a displaced diligence in HCV screening. "When we look at the people who were actually diagnosed, young women have a much lower prevalence than older men."

For the birth period of 1945 to 1954, 3.5% of women and 7.4% of men were diagnosed with HCV. For 1955 to 1964, 2.9% of women and 5.7% of men were diagnosed with HCV.

"Medicare is a more complicated population," because some patients are enrolled on the basis of disability rather than age, said Dr. Graham. "But again, you see a shockingly high prevalence of HCV in men." Medicare data show that 16.1% of men and 10.4% of women in the 1945 to 1954 cohort and 19.1% of men and 13.3% of women in the 1955 to 1974 cohort are HCV-positive.

"Is Medicare aware of this serious HCV problem as the leading edge of the boomers are entering the program?" she wondered.

The precise reason for the tilt toward the more prevalent HCV testing of women is not known, but Dr. Graham speculated that the driver is prenatal testing.

Findings "Not a Surprise"

"I've looked at the data from my own institution," said Natalie Kil, MPH, project manager in the division of general internal medicine at Mount Sinai Hospital in New York City. "I can tell you that it is not at all common for a primary care doctor to order a routine hep C test. They're only doing it by way of known risk factors, and most clinicians, from my understanding, are not really asking about risk factors."

Through Kil's involvement in Mount Sinai's community outreach program to help identify HCV-infected individuals, she has noted no small measure of misplaced trust.

"We find that when we go out and do hep C testing, most people who are in care somewhere, who have a regular primary care doctor, think that they have already been tested. People say, 'Oh my doctor is wonderful, he tests me for everything,' but you can see from these data that this is simply not happening," Kil explained.

Dr. Graham is an employee of Vertex Pharmaceuticals. Ms. Kil has disclosed no relevant financial relationships.

International Conference on Viral Hepatitis (ICVH) 2012: Abstract 79332. Presented March 26, 2012.

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