The REAL Drug to Beat in Treating Hepatitis C: Ribavirin

 REAL Drug to Beat in Treating Hepatitis C: Ribavirin , by Chris Barnes

By now, most of us are aware – some of us painfully so – that the Hepatitis C drug development market is red hot. Investors and developers alike need a scorecard to keep track of who is buying who and for what potential blockbuster drug in the race to make it big in treating Hepatitis C.  All of this hullabaloo is for good reason – the CDC estimates there are over 170 million people infected with Hepatitis C worldwide[1], a vast majority of them don’t know that they have it.  That is paradoxically both an enormous and lucrative problem. This means there are a lot of potential patients for pharmaceutical companies to treat with blockbuster anti-HCV drugs.

The names of the compounds in development are like alphabet soup – GS-7977, VX-222, BMS-790052, BI-201335, TMC 435, BL-8020… protease inhibitors, polymerase inhibitors, cyclophilin inhibitors… the list goes on and on. This is a good thing for both drug makers and patients. Drugs to treat Hepatitis C are becoming more potent and more tolerable.  And the race for the next blockbuster drug means there is no shortage of drugs and drug classes to choose from.  Drug developers may even realize the holy grail of Hepatitis C treatment – an all oral, interferon-free regimen consisting of 2-4 pills a day. That’s right, no shots, no interferon. This would potentially make treatment for Hepatitis C infinitely more tolerable for patients.

So the HCV drug development biz is booming… but the hottest drug to beat in Hepatitis C?  Ribavirin.  A cheap, generic anti-viral. It turns out that even with all the advances drug makers are realizing in interferon-free drug combinations, ribavirin is critical to the success in curing patients of Hepatitis C.   The trouble is that no one is really sure how ribavirin works. All we know is that treatment response rates are infinitely higher when it is part of a Hepatitis C antiviral regimen.[2][3][4]

Researchers are busy trying to find out just what makes ribavirin tick, but let’s look at a few of the current theories on how the drug works:

• Ribavirin may cause something called ‘error catastrophe’ in the lifecycle of the HCV virus.[5]Ribavirin is a nucleoside analog – this means that ribavirin can fool the virus into thinking that it’s one of the building blocks needed for the virus to replicate. So when the virus tries to replicate itself, it picks ribavirin as a building block instead of the real thing. This mucks up the replication process leading to ‘error catastrophe’ – in other words, the virus is no longer able to make copies of itself.

• Inosine monophosphate dehydrogenase (IMPDH). That’s a tongue-twister to be sure, but it’s also a cellular enzyme the human body makes and the HCV virus needs. Ribavirin may inhibit this enzyme, which consequently shuts down the energy supply the Hepatitis C virus requires to survive and replicate.[1]

• The Hepatitis C virus is sneaky. It has a peculiar knack for evading the body’s immune system[2], so anything that might disrupt that ability would be very valuable to an anti-HCV regimen. It turns out that ribavirin may have this unique ability by helping the body mount a specific anti-viral response to the Hepatitis C virus, which is essential in fully clearing the virus. [3]

While ribavirin’s exact mechanism of action remains a mystery, there is one thing we do know for certain – we need ribavirin to fight Hepatitis C. Paring ribavirin with the above new antiviral compounds currently in development – called Direct Acting Antivirals  or DAAs -  that target and disrupt numerous points in the lifecycle of the virus, lead to significantly better cure rates then just using the DAAs alone. While interferon may go the way of the buffalo, it appears that the lowly, unsexy ribavirin is here to stay.  This makes ribavirin the REAL drug to beat in the Hepatitis C drug development marketplace.

References

[1] Perz JF, et al. The contribution of hepatits B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 529-38

[2] Vertex Pharmaceuticals, Inc. (2010)  Vertex adds ribavirin in additional treatment arm in ongoing phase II VX-222 & Telaprevir combo trial. [Press Release] Retrieved fromhttp://viralmatters.blogspot.com/2010/11/vertex-adds-ribavirin-in-additional.html

[3] Hezode, Christopher, et al. (2009) Telaprevir and Peginterferon with or without Ribavirin for chronic HCV Infection. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa0807650

[4] Smith, M. (2012). New Combo KOs HCV Without Interferon, Ribavirin  [Online article] Retrieved from:http://www.medpagetoday.com/InfectiousDisease/Hepatitis/30739

[5] Maag D, et al. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc. Natl. Acad. Sck.2001; 98: 6895-900

About the Author

Chris Barnes

Chris Barnes is a 18 year veteran of medical affairs and commercial functions of the biopharma and pharmaceutical industry, with expertise in Hepatitis and HIV. He actively follows Hepatitis C drug development through his blog and LinkedIn discussion group, Viral Matters. He can be contacted at christopherjbarnes10@gmail.com

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L Drug to Beat in Treating Hepatitis C: Ribavirin

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Is HCV Infection a Neurologic Disorder?

Is HCV Infection a Neurologic Disorder?
	Download the PDF here Gastroenterology March 2012 CYRILLE FERAY Service d'HEpatogastroentErologie Hotel-Dieu Hospital Nantes, France Hepatitis: Brain endothelial cells support HCV entry and replication - (01/27/12) HCV SVR Improves Quality of Life & Brain Function - (01/27/12) from Jules: this topic of does HCV have a neurological effect & cause neurological symptoms has been controversial with many clinicians over the years doubting that this is true and with conflicting research, for example in HIV researchers have reported from studies not finding HCV caused cognitive impairment in HIV+ coinfected individuals. In the recent year or so there have been a number of research papers just like this finding that HCV enters the brain & can cause damage. There was research years ago from Pegasys studies showing improvement in neurological symptoms in patients achieving SVR. It is clear to me this is true. After achieving an SVR about 10 yrs ago I realized how much fatigue & cognitive impairment I had previously but before achieving the SVR I had no idea how much fatigue & cognitive impairment I had & I certainly did not appreciate it could be associated with HCV. After finishing HCV therapy & achieving an SVR the I started to feel improved energy & improved cognitive abilities. And over the next several years I experienced ongoing continuing further improvements. So there is no doubt that HCV can be associated neurological impairment and that it can improve. Now I had cirrhosis before achieving SVR so having a more severe stage of HCV disease may be more associated with experiencing cognitive impairment but I think earlier HCV disease can also be associated with fatigue, depression and cognitive impairment. Hepatitis C is known to induce chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The absence of symptoms is common even when the disease has reached the stage of cirrhosis or hepatocellular carcinoma. For this reason, infection with hepatitis C virus (HCV) is frequently called a "silent killer." Fatigue is the most frequent complaint in infected subjects. HCV infection has also been associated with cognitive dysfunction and depression, which are not correlated with the severity of liver disease and cannot be explained by hepatic encephalopathy or drug abuse. Numerous extrahepatic disorders have been attributed to or are more frequent during HCV infection. The most common mechanism underlying these disorders is autoimmunity.Thyroiditis, arthropathies, lymphocytic sialadenitis with or without sicca syndrome, and diabetes have long been known to be more frequent with HCV.1, 2 The second most frequent disorder associated with HCV infection is type II or III cryoglobulinemia. Cryoglobulins contain immune complexes made of HCV virions and anti-HCV antibodies and are highly prevalent in infected subjects. This can lead to symptomatic vasculitis with purpura, arthralgias, and asthenia, as well as peripheral nervous system and kidney involvement. Cryoglobulins are considered to be the result of B-cell proliferation owing to chronic antigenic stimulation, and B-cell lymphomas have been reported to be slightly more common in this population.3 A direct role of HCV is suggested by the fact that antiviral therapies have an antitumoral effect.4 The third group of extrahepatic symptoms associated with HCV infection could be a direct consequence of HCV infection of components of the central nervous system. Indeed, HCV RNA has been detected at autopsy in brain tissues.5, 6, 7, 8 Recently, an elegant study using microdissection in brain tissues from HCV-positive patients obtained at autopsy combined with measurement of cytokine mRNA in cells that were positive for the HCV nonstructural 3 protein suggested that brain macrophages/microglia cells were activated in HCV-infected patients. The purpose of the paper by Fletcher et al,9 published in this issue of Gastroenterology, was to explore the original hypothesis that HCV could infect and alter the function of blood-brain barrier (BBB) endothelial cells. The authors first demonstrated that all of the known viral receptor molecules (CD81, claudin-1, occludin, LDLR, and scavenger receptor-B1) are expressed at the surface of BBB endothelial cells. It is important to note that scavenger receptor-BI expression was restricted to the microvascular endothelium, whereas other receptors were expressed by astrocytes. In a second step, the authors convincingly showed that HCV replicates in 2 distinct cell lines derived from these BBB endothelial cells. Hepatitis C is known to infect nonhepatocyte cells. There are numerous reports in the literature describing the presence of HCV RNA in immune cells10 as well as in the brain.11 In immune cells (mainly B-cells)12 and in the central nervous system,13, 14 the detection of viral sequences different from those found in the blood or the liver illustrates the compartmentalization of viral quasispecies and supports the idea that replication takes place in these extrahepatic sites. Indeed, in the absence of local replication, the presence of HCV RNA would be because of the adsorption or internalization of circulating viral particles produced in the liver; thus, no phylogenetic differences would exist with majority variants present in the serum (unless selection of liver-generated viral variants takes place at the cell receptor level). In almost all studies, the level of extrahepatic replication of HCV has been reported to be low, so that the contribution of these sites to circulating virions is limited. The HCV genome is positively stranded, meaning that it is directly translated into the viral polyprotein in the cell cytoplasm. The detection of negatively stranded HCV RNA in tissues or cells demonstrates that viral proteins have been translated and the HCV replication complex is functional, at least for the synthesis of negatively stranded HCV RNA. This intermediate of replication has frequently been detected in extrahepatic sites. There are, however, numerous technical issues that challenge the specificity of such detection. The detection of viral proteins in tissues or cells is also difficult because of their low level of expression. However, their presence has been convincingly reported recently in lymph nodes from the liver pedicle15 and in the brain.16 The most important information in the article by Fletcher et al9 is that human cell lines derived from BBB endothelial cells can be infected by HCV. The authors first tested HCV binding using HCV pseudoparticles (HCVpp) formed by the incorporation of the envelope glycoproteins E1 and E2 into lentiviral core particles. HCVpp closely mimic the functionality of wild-type viruses during the early steps of the viral lifecycle. HCVpp binding to endothelial cells was quantitatively similar to that observed with hepatocyte cell lines. The authors then used the JFH1 strain, the only HCV strain that effectively infects and replicates in primary human hepatocytes and in the hepatocyte cell line Huh7.5.17 Not surprisingly, HCV replicated at much lower levels in endothelial cells than in hepatocytes. Definitive confirmation of viral replication in endothelial cells was provided by using specific HCV protease inhibitors, which decreased the amount of HCV RNA in these cells. Micro-RNA (miR)-122 is hepatocyte specific and its fixation at 2 sites in the 5' untranslated region of the virus genome is required for efficient HCV replication. As expected, miR-122 was not detected in endothelial cell lines. The transfection of these cells to express functionally active miR-122 RNA duplexes failed to promote HCV replication, demonstrating that replication is miR-122 independent in endothelial cells. Indirectly, this result also suggested that liver-specific factors are required for the action of miR-122 on HCV replication in hepatocytes. Another important group of findings in this paper was the observation of functional consequences of HCV infection of endothelial cells. Indeed, HCV increased endothelial cell permeability and this effect was reversed when replication was inhibited by antiviral molecules. Neutralization of HCV infection with pooled anti-HCV immunoglobulins also restored endothelial cell permeability, demonstrating the direct effect of HCV on this parameter. Furthermore, the authors noted that HCV-infected endothelial cell lines expressing nonstructural protein NS5A were TUNEL positive, suggesting an effect of infection on brain endothelial cell apoptosis. Altogether, these findings suggest that the infection of endothelial cells by HCV and HCV replication in these cells in vivo are highly plausible. These findings raise the important question of the impact of HCV replication in BBB endothelial cells on neurocognitive and psychological symptoms frequently reported by subjects infected by this virus. This issue has been evaluated in case-control and in longitudinal studies assessing patients before and after a sustained virologic response to antiviral therapy. In these works, neurologic involvement was evaluated by means of neurocognitive tests combined with quality-of-life questionnaires or by measuring magnetic resonance spectroscopy (MRS) signals. Such case-control studies raise the issue of matching patients with HCV infection who know their status and have past or present addictive behaviors and HCV-negative controls. Despite these limitations, most studies reported more fatigue, more depression, and less effectiveness in HCV-infected patients than in controls. The longitudinal approach also has drawbacks. Subjects know the results of therapy and have experienced the adverse effects of antiviral drugs for many months. Although numerous studies have reported an improvement of the quality of life after achieving a sustained virologic response,18 only a few recent papers investigated changes in neurocognitive functions and MRS in relation to the response to therapy. The results of these studies are conflicting. In 1 study, the authors concluded that HCV eradication had a beneficial effect on cerebral metabolism and selective aspects of neurocognitive functions, especially in patients with mild disease.19 In contrast, another comparable study concluded that HCV had a measurable effect on brain integrity in patients screened for other medical and/or psychiatric comorbidities, but that these abnormalities did not improve after viral eradication.20 Both studies were based on a very small number of patients and the evaluation of neurocognitive functions and MRS were performed early after viral clearance. The second study20 questioned the reversibility of brain involvement once HCV infection is cured. Indeed, because brain cells have a very low rate of regeneration, the effect of HCV infection could be prolonged by months or years after the virus has been cured. The main interest of the article by Fletcher et al9 is to show that the brain is a likely target for HCV. More important, the results with BBB endothelial cells suggest that other endothelial cells could be targeted and altered by HCV. For example, a study in an Egyptian population showed higher carotid intimal media thickness in HCV-infected than in noninfected patients.21 If this is confirmed, the possibility that HCV infection could induce brain or vascular disorders could modify the current indications for therapy, which are essentially based on the severity of liver disease or the presence of extrahepatic manifestations of immune origin, such as symptomatic cryoglobulinemia or B-cell lymphoma. Further studies are thus needed in the field of HCV neuroinvasion to better define the actual consequences of infection and their reversibility if infection is eradicated. However, it must be emphasized that the effects of HCV on neurocognitive functions, depression, or fatigue are generally mild. Many HCV-infected patients are highly successful and creative. Because stigmatization of HCV infected people exists, the notion of a brain involvement in these patients could have devastating consequences. The results of the present study should therefore be interpreted as what they are, certainly not overinterpreted as the demonstration that HCV infection leads to severe brain disease (Figure 1).

Data from Phase 2 Study of an INCIVEK® Combination Regimen Showed 74% of People Co-Infected with Hepatitis C and HIV Had Undetectable Hepatitis C Virus 12 Weeks After Treatment Ended (SVR12)

Data from Phase 2 Study of an INCIVEK® Combination Regimen Showed 74% of People Co-Infected with Hepatitis C and HIV Had Undetectable Hepatitis C Virus 12 Weeks After Treatment Ended (SVR12)

- INCIVEK was well tolerated with commonly used Atripla- and Reyataz-based HIV treatment regimens, and no patients experienced HIV breakthrough -
 

- Enrollment is ongoing in Phase 3 study evaluating 24- and 48-week treatment durations in people who are co-infected -
 

SEATTLE--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results from an ongoing Phase 2 study designed to evaluate the safety and tolerability of INCIVEK^®(telaprevir) tablets in combination with pegylated-interferon and ribavirin in people who are co-infected with genotype 1 hepatitis C virus and human immunodeficiency virus (HIV). Data showed 74 percent (28/38) of patients who were treated with INCIVEK (in-SEE-veck) combination therapy had undetectable hepatitis C virus (HCV RNA) 12 weeks after the end of all study treatment (SVR12) compared to 45 percent (10/22) who were treated with pegylated-interferon and ribavirin alone. INCIVEK was well tolerated with commonly used Atripla^®- and Reyataz^®-based HIV treatment regimens. Changes in CD4 counts were similar between the treatment groups and no HIV viral load breakthroughs were observed in either treatment group during the study.

The most common adverse events in the INCIVEK arms of the study were fatigue, pruritis (itching), headache, nausea and rash. No cases of severe rash were reported and there were no discontinuations due to rash. Interim results from this study are being presented at the Conference on Retroviruses and Opportunistic Infections (CROI), March 5 to 8, 2012 in Seattle.

"Hepatitis C generally progresses faster, leads to more long-term liver complications and has been harder to cure among people who also have HIV," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "These new INCIVEK data are important as we work toward our goal of helping cure more people with hepatitis C. We're actively enrolling co-infected patients in a Phase 3 study and expect that data from this study will be included in a submission for a supplemental approval of INCIVEK."

The Phase 2 study includes two parts: Part A is evaluating people who are not currently being treated with antiretroviral therapy (ART) for HIV infection and Part B is evaluating those who are taking an Atripla- or Reyataz-based regimen for HIV. This study enrolled patients who were new to hepatitis C treatment (treatment naïve). Patients who were randomized to receive INCIVEK were treated with 12 weeks of INCIVEK, pegylated-interferon and ribavirin, followed by 36 weeks of pegylated-interferon and ribavirin alone. Interim data also showed that 68 percent (26/38) of patients treated with INCIVEK combination therapy in this study had a rapid viral response (RVR, undetectable hepatitis C virus at week 4 of treatment) compared to none (0/22) of the patients who received pegylated-interferon and ribavirin alone.

"There is a great need for treatments that are well tolerated and offer co-infected patients a better chance at a cure for hepatitis C while maintaining suppression of their HIV," said Douglas Dieterich, M.D., Professor of Medicine in the Division of Liver Diseases, Mount Sinai School of Medicine, New York City. "It's very encouraging that nearly three out of four people had undetectable hepatitis C virus 12 weeks after stopping INCIVEK combination therapy and that their HIV medicines continued to work during treatment."

Interim Study Results 
Sixty-two people 18 and older were enrolled in this Phase 2 study and 60 received at least one dose of study drug. This analysis was conducted 12 weeks after patients completed all treatment. The ART regimens evaluated in this study were selected based on current HIV treatment guidelines from the U.S. Department of Health and Human Services, International AIDS Society and drug-drug interaction studies of INCIVEK with commonly used ART medicines.

Click On Image To Enlarge

The majority of adverse events in this study were mild or moderate. Adverse events that occurred more frequently in the INCIVEK arms compared to placebo (≥10 percent difference) were pruritis (itching), headache, nausea, rash, fever, and depression. Three patients, all in Arm B, discontinued all study treatment due to adverse events (one each due to gall stones, hemolytic anemia and nausea/vomiting).

About this Phase 2 Study 
Vertex and its collaborator Janssen conducted extensive drug-drug interaction studies with INCIVEK and commonly used HIV medicines prior to initiating a development program in people co-infected with hepatitis C (HCV) and HIV. This Phase 2 study is a two-part (A and B), randomized, double-blind, placebo-controlled, parallel group, multi-center study in people chronically infected with both HCV and HIV who were new to HCV treatment. The primary endpoint of the study is to evaluate the safety and tolerability of INCIVEK combination therapy in people co-infected with HCV and HIV. A secondary endpoint is to evaluate rates of sustained viral response (SVR) 12 and 24 weeks after the end of treatment. The study is being conducted by Vertex in collaboration with Janssen.

Phase 3 Study Actively Enrolling 
Enrollment is ongoing in a Phase 3 study evaluating 24- and 48-week response-guided regimens of INCIVEK combination therapy in people co-infected with HCV and HIV. Patients who are either new to treatment for HCV, or who had relapsed after at least one prior course of therapy with pegylated-interferon and ribavirin alone, will receive 24 or 48 weeks of INCIVEK combination treatment, based on their antiviral response. Patients who had not responded to a prior course of treatment (partial responders and nulls) will receive 48 weeks of INCIVEK combination treatment. A similar study is also being initiated by Janssen in its territories.

Data from In Vitro Evaluation of INCIVEK and HIV Protease Inhibitors 
Also being presented at CROI this week are data from an in vitro evaluation of the anti-HIV activity of four HIV protease inhibitors (amprenavir, darunavir, lopinavir and atazanavir) in combination with INCIVEK. In the study, no antagonistic effects on the antiviral activity were observed when INCIVEK was used in combination with amprenavir, darunavir, and lopinavir, and slight antagonistic effects were observed on the antiviral activity of atazanavir.

About INCIVEK 
INCIVEK ^® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication. INCIVEK is the most prescribed direct-acting antiviral for the treatment of adults with genotype 1 chronic hepatitis C and has been used to treat more than 30,000 people in the United States. 
INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for people with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO^® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic^®. 
INCIVEK^® is a registered trademark of Vertex Pharmaceuticals Incorporated. 
PEGASYS^® and COPEGUS^® are registered trademarks of Hoffmann-La Roche. 
Reyataz^® is a registered trademark of Bristol-Myers Squibb. 
Atripla^® is a registered trademark of Bristol-Myers Squibb and Gilead Sciences, LLC.

About Hepatitis C 
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹ 
Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.²However, approximately 60 percent of people do not achieve SVR,^3,4,5 or viral cure,⁶ after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^7,8 
More than 170 million people worldwide are chronically infected with hepatitis C.⁶ In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.⁹ Hepatitis C is four times more prevalent in the United States compared to HIV.⁹ The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.¹⁰ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.^11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.⁹
  
About Hepatitis C and HIV Co-Infection 
There are 1 million people living with HIV in the United States, and an estimated 300,000 people living with HIV/AIDS in the United States are also infected with hepatitis C. ¹³ There have been dramatic improvements in the treatment of HIV and the prognosis for people living with HIV. However, liver disease progresses more rapidly in people co-infected with hepatitis C and HIV, with an increased rate of progression to cirrhosis, decompensated liver disease, hepatocellular carcinoma and death. ^{14, 15, 16, 17} The hepatitis C cure rate with a 48-week treatment of pegylated-interferon and ribavirin, the current standard of care for people with co-infection, is approximately 29 percent.¹⁸

  
About Vertex 
Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives. 
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases. 
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, andScience magazine named Vertex number one on its 2011 list of Top Employers in the life sciences. 
Vertex's press releases are available at http://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.vrtx.com&esheet=50192600&lan=en-US&anchor=www.vrtx.com&index=1&md5=18a7237549906d05df8bb2b8fe97be6f.

Special Note Regarding Forward-Looking Statements 
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including Dr. Kauffman's statements in the second paragraph of this press release and statements regarding ongoing and planned Phase 3 studies of INCIVEK combination therapy in people co-infected with HCV and HIV. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the outcomes from future clinical trials of INCIVEK combination therapy in co-infected patients may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at http://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.vrtx.com&esheet=50192600&lan=en-US&anchor=www.vrtx.com&index=2&md5=dc1126ed302dd955953363f13e08c651. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

IMPORTANT SAFETY INFORMATION 
Indication 
INCIVEK^® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information 
INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK. 
INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements. 
INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com. 
(VRTX-GEN)

References: 
¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at:http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed February 22, 2012. 
² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900. 
³ Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. 
⁴ Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med.2002;347:975-982. 
⁵ McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. 
⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40. 
⁷ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115). 
⁸ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684. 
⁹ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at:http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed February 22, 2012. 
¹⁰ Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at:http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed February 22, 2012. This report was commissioned by Vertex Pharmaceuticals, Inc. 
¹¹ Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755. 
¹² Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression.Gastroenterology. 2010;138:513-521. 
¹³ HIV Advocate. HIV/HCV Coinfection. Available at:http://www.hcvadvocate.org/hepatitis/factsheetspdf
Accessed February 28, 2012. 
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