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BASICS

hepatitis C

New HCV Antivirals and Drug Resistance

Alan Franciscus, Editor-in-Chief Lucinda K. Porter, RN

HCV acts like this. When you are newly infected, your immune system recognizes that an uninvited intruder (the hepatitis C virus) is in your body. Your immune system alerts your body to destroy HCV. However, HCV hurries to escape and makes a sloppy copy of itself, which outwits your immune system. Your immune system is patrolling for the original intruder, not realizing that the virus now looks a bit different. Now HCV can multiply at a faster rate. Eventually your immune system catches on and The Basics looks for the bad copy. In a hurry, HCV mutates again. Viruses are like rabbits; what This process may cycle through many, many mutations, they do best is multiply. making millions of different types of mutations. The term for this is viral replication. However, a virus One way to think about this is with Darwins theory of cannot survive on its own; evolution and survival of the fittest . In nature, the strong it can only survive inside of survive. The weak die and if they die before they reproanother living cell, known duce, their weak genetic material dies too. In this way, as a host cell. Viruses use it is more likely that strong genetic material is passed various pieces of the host along. Evolution applies to plants, animals and microcells genetic material in organisms.
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esearchers are investigating new antiviral medications to treat hepatitis C virus infection (HCV). Some of these drugs are referred to as direct-acting antivirals (DAAs), which are medications that specifically target the hepatitis C virus. However, unlike current HCV medications, direct antivirals carry the potential for resistance. This fact sheet will discuss the basics of HCV replication and why the hepatitis C virus becomes resistant to the DAAs.

order to reproduce, or make more copies of itself. Viruses survive because of their ability to constantly adapt and change when they are under attack from the immune system. Viruses still try to reproduce even while under attack. In a hurry to escape, a virus may make a bad copy of itself, which slightly alters its genetic make-up. The process of change actually produces a variation in the virus, known as a mutation or quasi-species.

Current Therapies
The current standard of care for treating hepatitis C is a combination of pegylated interferon (long-acting) plus ribavirin for genotypes 2 and 3, and the addition of an HCV protease inhibitor for genotype 1. How pegylated interferon works is not completely understood. What is known is this: 1) interferon boosts the ability of the bodys immune system to kill a virus, and 2) it protects non-infected cells from becoming infected. Interferon is used to treat a variety of diseases including hepatitis C. We also do not understand how ribavirin works against HCV, but, when used with interferon, it seems to interfere with HCVs ability to multiply, or replicate. Ribavirin alone is not effective against hepatitis C. It is known, however, that HCV protease inhibitors work by inhibiting or stopping the hepatitis C virus from replicating. Drug resistance does not develop with interferon and ribavirin since these drugs do not specifically target the enzymes of the virus used in the viral replication process. But now that the HCV protease inhibitors have been approved to treat hepatitis C, strict adherence to taking the medications as directed is an important strategy to increase the effectiveness of the triple combination therapies and prevent the emergence of resistance.

genetic material into smaller pieces before additional viral processing. If this process is interrupted, then the virus cannot make copies of itself. The HCV protease inhibitors recently approved will stop or interrupt the viral replication of HCV since there are many potential protease enzymes involved in the replication process of the hepatitis C virus. Even more potent HCV protease inhibitors are in development--TMC435 has progressed into phase III studies and it looks promising because of one-a-day dosing and higher cure rates.

Other materials that viruses depend on for replication are polymerase and NS5A enzymes. HCV cannot multiply without these enzymes. HCV inhibitors are drugs used to stop this The HCV Replication Process process. HCV inhibitors in human clinical trials and Direct Antivirals The hepatitis C virus is a single-stranded RNA virus of the include ABT-450, BMSflavivirus family with a very rapid turnover or replication rate. 790052, ABD GS-7977.

HCV enters the body and targets the liver the main replication site of HCV. The virus attaches itself to the outer coating of the liver cell or hepatocyte, and enters the cell. After entering the cell, HCV releases its genetic material and hijacks the cells internal processes.

Viral replication relies on the helicase enzyme to complete the process. There are no HCV helicase inhibitors currently in development. Most experts believe that it will be difficult, Now that HCV has taken over, it binds to various ribosome if not impossible, to develop sites within the cell. A ribosome is like a factory with printing helicase inhibitors. presses. If a master copy of a document has a mistake in it, all of the copies will have that same mistake. This is referred Resistance and to as translation. Drugs are being developed to interfere with this process, but so far, none have been found to be effective Direct Antivirals The new direct antivirals, in stopping the translation process. including the newly approved The next step involves an enzyme called the protease. HCV HCV protease inhibitors, work genetic material uses the protease enzyme to cut up the by inhibiting the entry of
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the virus or by inhibiting the specific enzymes during one of the replication processes. The medications in development that look the most promising are the HCV protease, polymerase and NS5A inhibitors. During the normal lifecycle of HCV, the bodys immune system exerts pressure on the replicating virus. This pressure produces mutations that escape the hosts immune response. In a similar way, drugs to treat hepatitis C will exert pressure on the virus to change and mutate in order to survive. For this reason, it is believed that most of the direct antiviral medications will eventually produce drug resistant mutations, especially if these drugs are taken for a long time. This in turn may make future medications ineffective in treating the new viral mutations.

Drug resistance is expected. However, scientists are looking for ways to prevent or interfere with drug resistance. For instance, drug resistant mutations may be identified earlier in the process, such as during the test tube development phase.

Preventing and Reducing Drug Resistance

The reduction or prevention of drug resistance depends on a number of factors. Some of these are:

Eradicating or Curing HCV: Unlike HIV and HBV, hepatitis

C does not become part of the host cell. We have been able to rid HCV from the body with the use of current medications pegylated interferon plus ribavirin, and an HCV protease inhibitor. Since HCV does not integrate into the host cells DNA, as mentioned above, it will be easier to eliminate HCV without the risk of the virus changing or mutating.

BASICS
Executive Director Editor-in-Chief, HCSP Publications Alan Franciscus Webmaster C.D. Mazoff, PhD Design and Production HCSP The information in this fact sheet is designed to help you understand and manage HCV and is not intended as medical advice. All persons with HCV should consult a medical practitioner for diagnosis and treatment of HCV. This information is provided by the Hepatitis C Support Project a non-profit organization for HCV education, support and advocacy 2012 Hepatitis C Support Project Reprint permission is granted and encouraged with credit to the Hepatitis C Support Project.

hepatitis C

Combination of direct and indirect antivirals: Direct antivirals can be given for a shorter period of time this reduces the chances for the virus to resist the drug. When used in combination with indirect antivirals peginterferon and/or ribavirin, the chances of the virus developing resistance to the drug is lower. An example of this is extending the duration of treatment with peginterferon and/ or ribavirin after stopping the direct HCV antiviral. This may prevent drug resistance while allowing for continual and hopefully complete viral suppression. For instance, telaprevir and boceprevir used in combination with pegylated interferon plus ribavirin have been approved by the FDA to treat hepatitis C. It was found that treatment duration could be reduced for some people who responded to the new medications early on in treatment and that the total treatment duration could be reduced from 48 weeks to 24, 28 or 36 weeks for some people. Potent direct antivirals: The development of potent direct antivirals that quickly distribute throughout the body and reach high blood concentrations in a short time period will put enough pressure on the virus before it has a chance to mutate. If the drugs are not potent enough, the escaped viral mutations may become the dominant virus, rendering the antiviral medication ineffective. Combination direct antivirals: The use of direct antivirals that inhibit several different enzymes at the same time will reduce the viruss ability to mutate.
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 Adherence: Current
HCV medications require adherence to prescribed doses and durations t o b e m o re e f f e c t i ve in treating HCV. The n ew l y a p p rove d H C V protease inhibitors will require strict adherence to the new medications. Talk with your medical provider to find out the correct dosing schedule either every 7-9 hours or 3 times a day with food. Doses that are skipped or forgotten could lead to viral mutations and drug resistance. HCV research has benefited from what we know about HIV and HBV drug resistance and hopefully will be able to contribute to this body of knowledge. As we begin this era of new HCV medications, now is the right time to develop strategies to make HCV therapy more effective. Now is also the time to reduce the chances of the surfacing of drug resistance that could potentially reverse some of the benefits of new therapies. The best strategy for moving forward depends on using knowledge from the past in order to discover the future.

For more information about drugs in development to treat hepatitis C, visit our HCV Drug pipeline. www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html For information about current clinical trial enrollment visit: www.clinicaltrials.gov

Fo o d : R i b a v i r i n and the HCV protease inhibitors should be taken with food. When taking ribavirin and boceprevir (Victrelis), eat a light meal or snack. When taking telaprevir (Incivek), eat food that has at least 20 grams of fat. (See HCSP Fact Sheet Incivek (Telaprevir): 20 Grams of Fat) www.hcvadvocate. org/hepatitis/factsheets_ pdf/Incivek_20%20 Grams.pdf Fo o d i m p r o v e s t h e absorption of the drugs; high fat food improves the absorption of telaprevir. Improved absorption raises the concentration in the blood, maximizing the chances of eradicating or curing HCV. This will also help prevent drug resistance.

Visit the HCV Advocate Web Site: www.hcvadvocate.org

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