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In This Issue:
Is It Cost Effective; to Treat HCV?;
Alan Franciscus, Editor-in-Chief
Direct-Acting Antiviral Drug Update from EASL: Part 2
HealthWise: Waiting for Better HCV Treatment: Living in the Gap
Lucinda Porter, RN
Editorial: Is it Safe to Wait?
Alan Franciscus, Editor-in-Chief
HCV Advocate Eblast
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Is It Cost Effective to Treat HCV?
—Alan Franciscus, Editor-in-Chief
Cost effectiveness of any therapy is a cornerstone for justifying treatment of a condition. There have been many models that have looked at and found that it is cost effective to treat people with hepatitis C based on the degree of HCV disease progression. A new study is building on the knowledge we already have about the need to treat people with cirrhosis, showing that treatment is cost effective and will limit the future costs associated with decompensation, liver cancer, liver transplantation and death from HCV.
Sammy Saab and colleagues studied the cost-effectiveness of treating people with HCV genotype 1 who had advanced HCV disease progression in order to determine at which point in disease progression treatment becomes cost effective. One thousand patients were enrolled in the study and the study participants evenly divided into 4 groups:
- Group 1: No treatment
- Group 2: Treatment for patients with compensated cirrhosis
- Group 3: Treatment for patients with decompensated cirrhosis
- Group 4: Treatment for patients with advanced fibrosis after transplantation
Groups 2, 3 and 4 received a 48-week course of pegylated interferon plus ribavirin. Group 1 was the non-treatment group used to compare treatment vs. no treatment. Response for the study participants was defined as sustained virological response (SVR) or no SVR. The measured outcomes of the study included the total cost per patient, the number of quality-adjusted life years (QALYs) saved, cost per QALY saved, number of deaths, number of cases of hepatocellular carcinomas (HCCs) or liver cancer, and the number of transplants required.
All groups that were treated showed some cost savings, but the most cost effective was Group 2 (compensated cirrhosis)—QALYs (0.95) and saved $55,314. Treatment of compensated cirrhosis also resulted in 119 fewer deaths, 54 fewer cases of liver cancer, and 66 fewer transplants. The authors reported that, although not as cost-effective, the treatment of decompensated cirrhosis and even severe recurrence of HCV post-transplant with antiviral therapy was still cost-effective.
The authors concluded that “[T]reatment of patients with compensated cirrhosis was found to be the most cost-effective strategy and resulted in improved survival and decreased cost in comparison with all other strategies.”
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Direct-Acting Antiviral Drug Update from EASL: Part 2
The 45th Annual Meeting of the European Association for the Study of the Liver (EASL) in April featured data on several experimental direct-acting antiviral drugs for hepatitis C. (For more information see “How Do Targeted Anti-HCV Drugs Work?” in the December 2009 HCV Advocate).
This report covers HCV polymerase inhibitors, NS4A inhibitors, and all-oral combinations. See last month’s HCV Advocate for coverage of HCV protease inhibitors.
Nucleoside Analog RG7128
E. Gane and colleagues reported on RG7128, the NS5B polymerase inhibitor being developed by Roche/Genentech and Pharmasset. Polymerase is a viral enzyme needed to copy genetic material. NS5B refers to the segment of the HCV genome that encodes the polymerase. RG7128 is a nucleoside analog, or defective mimic of natural DNA and RNA building blocks.
Researchers looked at RG7128 in combination with pegylated interferon plus ribavirin in 10 chronic hepatitis C patients with HCV genotype 2 and 15 people with genotype 3 who did not achieve sustained response with prior interferon-based therapy; most trials of direct-acting agents have focused on genotype 1, which is hardest to treat. Participants were randomly assigned to receive 1,500 mg RG7128 twice-daily or placebo with pegylated interferon alfa-2a (Pegasys) plus ribavirin for 28 days, followed by standard therapy for an additional 20-44 weeks.
HCV viral load decreased by an average of 5.0 log10 IU/mL at week 4 in the RG7128 arm compared with 3.7 log10 in the placebo arm. All but one patient (95%) receiving RG7128 and 60% in the placebo arm achieved rapid virological response, or undetectable HCV RNA at week 4 of therapy. Sustained virological response (SVR) rates 24 weeks after completion of treatment were 65% and 60%, respectively. Although the standard treatment duration for HCV genotypes 2 and 3 is 24 weeks, this study saw better outcomes for patients who received a longer course of RG7128 triple therapy (SVR 90% with 48 weeks, 67% with 24 weeks, and none who discontinued before 24 weeks). Response rates were similar for genotypes 2 and 3 (63% vs. 67%) and for prior nonresponders and relapsers (60% vs. 70%).
Roche/Genentech discontinued development of another nucleoside analog polymerase inhibitor candidate, RG1626 or balapiravir (the prodrug of RG1479), due to safety concerns. A Phase IIb study showed that the drug increased the likelihood of RVR at week 4 and complete early virological response (EVR) at week 12, but caused unexpected loss of neutrophils and lymphocytes¾an effect not seen with other nucleoside polymerase inhibitors.
RG7128 + RG7227
Gane also reported findings from INFORM-1, the first clinical trial of a combination oral hepatitis C regimen. This study looked at RG7128 in combination with the protease inhibitor RG7227, now named danoprevir. Combining agents that target different steps of the viral lifecycle may be more potent and make it harder for the virus to develop resistance.
INFORM-1 enrolled treatment-naive and treatment-experienced genotype 1 chronic hepatitis C patients. They were randomly assigned to receive RG7128 (500 or 1,000 mg twice-daily) and RG7227 (100 or 200 mg three-times-daily or 600 or 900 mg twice-daily), or else placebo, for 7 or 13 days, after which they continued on pegylated interferon/ribavirin for 24 or 48 weeks.
Outcomes were better with higher doses and longer duration of oral therapy. Treatment-naive patients receiving the high doses of both drugs achieved a 5.1 log10 IU/mL decline in HCV RNA by the end of dosing, while prior nonresponders and relapsers saw drops of 4.0-4.9 log10 IU/mL and placebo recipients showed no significant change. RVR rates were 88% for treatment-naive patients, 38% for prior partial responders or relapsers, and 13% for prior null responders; complete EVR rates at week 12 were 100%, 75%, and 38%, respectively. Among treatment-naive patients who received the high-dose regimen and were followed for 12 weeks after completion of therapy (SVR-12), 44% maintained an undetectable viral load. The researchers concluded that the large initial viral load reduction with RG7128/RG7227 prior to initiating standard therapy enhanced on-treatment and sustained virological response rates.
Nucleotide Analogs PSI-7977 and PSI-938
Nucleotide analogs are similar to nucleoside analogs but require less processing to make them active in the body. V. Zennou and colleagues from Pharmasset reported results from a laboratory study of two complementary nucleotide polymerase inhibitors, PSI-7977 (a pyrimidine analog) and PSI-938 (a purine analog). The combination demonstrated additive to synergistic antiviral activity in replicon models of wild-type (non-mutated) HCV and virus with various known resistance mutations. In addition, either PSI-7977 or PSI-938 plus a non-nucleoside polymerase inhibitor led to better viral clearance.
After EASL Pharmasset announced findings from a Phase IIa clinical trial of once-daily PSI-7977 in combination with Pegasys plus ribavirin for 28 days. In this study, which included 63 treatment-naive genotype 1 patients, 88% in the PSI-7977 100 mg arm, 94% in the 200 mg arm, and 93% in the 400 mg arm achieved undetectable viral load, significantly higher than the 21% in the placebo arm; safety and tolerability were comparable in the PSI-7977 and placebo arms and no serious adverse events were reported.
Anadys Pharmaceuticals presented findings from a Phase II trial of its non-nucleoside polymerase inhibitor ANA598 at EASL, with follow-up data announced in May. Non-nucleosides also interfere with the HCV polymerase enzyme, but do so by a different mechanism than nucleoside/nucleotide analogs, making the two classes suitable for combination therapy.
This ascending-dose study included 90 treatment-naive genotype 1 patients randomly assigned to receive 200 mg or 400 mg ANA598 twice-daily, or else placebo, in combination with Pegasys plus ribavirin for 12 weeks; they then continued on standard therapy for 24 or 48 weeks.
Response rates were similar in the 200 mg and 400 mg dose groups, with 73% and 75%, respectively, achieving complete EVR at week 12, compared with 63% in the placebo group. Tolerability was better and the frequency of skin rash was lower in the 200 mg arm, however, and the company will focus on this dose going forward.
While the Phase II trial looked at ANA598 in combination with pegylated interferon/ribavirin, Anadys researchers also reported in vitro data at EASL showing that it demonstrates enhanced activity when combined with other direct-acting agents and retains activity against HCV with mutations conferring resistance to these drugs.
M. Rodriguez-Torres and colleagues presented data on Vertex’s non-nucleoside HCV NS5B polymerase inhibitor candidate VX-222. The researchers conducted a Phase Ib/IIa dose-ascending study that included 32 previously untreated genotype 1 chronic hepatitis C patients. Participants were randomly assigned to receive VX-222 at doses of 250 mg, 500 mg, or 750 mg twice-daily, or 1500 mg once-daily, or placebo for three days. They were then offered Pegasys plus ribavirin for 48 weeks.
HCV RNA decreased by about 3.0 log10 IU/mL in all VX-222 arms by day 4; the drug was active against both genotypes 1a and 1b. VX-222 was generally safe and well-tolerated with no serious adverse events. Vertex recently announced that it will test VX-222 in combination with telaprevir, the company’s HCV protease inhibitor, both as an all-oral regimen and in combination with pegylated interferon/ribavirin.
Filibuvir (PF-00868554) is Pfizer’s non-nucleoside polymerase inhibitor candidate. In a Phase II study, 35 treatment-naive genotype 1 patients were randomly assigned to receive filibuvir at doses of 200 mg, 300 mg, or 500 mg twice-daily, or else placebo, in combination with Pegasys plus weight-adjusted ribavirin for four weeks, then continuing on standard therapy for 44 more weeks.
Participants receiving the triple combination had RVR rates of 60%-75% at week 4, compared with none in the placebo arm, with the best results in the 300 mg dose arm. Filibuvir recipients maintained higher response rates at week 12 (up to 88%) and at the end of treatment (up to 75%). However, 20%-50% of filibuvir recipients relapsed after completing therapy, compared with none in the placebo arm, resulting in similar SVR-12 rates. The researchers suggested longer use of filibuvir may be needed for sustained response; a study of triple therapy for 24 weeks of treatment is underway.
BI 207127 is a non-nucleoside polymerase inhibitor being developed by Boehringer Ingelheim. D. Larrey and colleagues conducted a phase I study of 27 treatment-naive and 30 treatment-experienced genotype 1 patients randomly assigned to receive 400 mg, 600 mg, or 800 mg BI 207127, or else placebo, three times daily for 28 days in combination with pegylated interferon plus ribavirin, then continuing on standard therapy.
Among treatment-naive participants, the 600 mg and 800 mg BI 207127 doses had similar potency and worked equally well against genotypes 1a and 1b; among treatment-experienced patients, however, those with 1b had better response. All treatment-naive patients and about half of treatment-experienced patients who received BI 207127 experienced at least a 3.0 log10 IU/mL decrease in HCV RNA; median decreases in the two higher dose groups were about 5.5 log10 for treatment-naive patients and about 4.4 log10 for treatment-experienced patients. BI 207127 combination therapy was generally well-tolerated, but there was one case of serious rash in the 800 mg group.
Abbott also presented data on its non-nucleoside polymerase inhibitor ABT-333, and another further back in the pipeline, ABT-072. In a Phase IIa study, 30 genotype 1 hepatitis C patients received ABT-333 or placebo monotherapy for two days followed by the same agents with pegylated interferon plus ribavirin for 26 days. The triple combination produced about a 2.0 log10 greater reduction in viral load than standard therapy alone. Some drug resistance was detected, but this did not appear to compromise continued treatment response.
In addition to drugs targeting the HCV NS5B polymerase, researchers are also looking at agents that interfere with the nonstructural NS4A protein; the function of this protein is not fully understood, but it appears to play an important role in HCV replication.
S. Pol and colleagues conducted a Phase IIa trial looking at Bristol-Myers Squibb’s NS5A inhibitor BMS-790052. Treatment-naive genotype 1 patients (12 per arm) were randomly assigned to receive BMS-790052 at doses of 3 mg, 10 mg, or 60 mg once-daily, or else placebo, with Pegasys plus ribavirin for 48 weeks. Participants in all BMS-790052 arms had significantly higher response rates than placebo recipients, but the two higher doses were more effective. RVR rates at week 4 were 42% in the 3 mg arm, 92% in the 10 mg arm, and 83% in the 60 mg arm, compared with 8% in the placebo arm. Complete EVR rates at week 12 were 58%, 83%, and 42%, respectively. BMS-700952 was generally safe and well-tolerated.
Presidio Pharmaceuticals is developing another NS5A inhibitor, PPI-461. R. Colonno and colleagues reported that PPI-461 demonstrated potent activity against all HCV genotypes in a replicon model and showed good tolerability and oral bioavailability in animal studies, suggesting the feasibility of once-daily dosing.
Idenix and Tibotec Combination Therapy
In an effort to delay the emergence of drug resistance¾and ultimately enable people to use direct-acting agents without interferon¾pharmaceutical companies are now testing combinations of candidates from different drug classes early in the development process.
Idenix Pharmaceuticals presented data on agents from multiple classes alone and in combination. J. Lalezari and colleagues evaluated the safety, antiviral activity, and pharmacokinetics of the nucleotide analog polymerase inhibitor IDX184. In a Phase IIa ascending-dose trial, sequential groups of 20 previously untreated genotype 1 patients received IDX184 at doses of 50, 100, 150, or 200 mg once or twice daily, or else placebo, for 14 days; participants also received Pegasys plus ribavirin during the IDX184 dosing period and for 14 days thereafter.
After 14 days, HCV viral load decreased by 2.7 log10 IU/mL in the 50 mg once-daily IDX184 arm, 4.0 log10 IU/mL in the 50 mg twice-daily arm, and 4.2 log10 IU/mL in the 100 mg once-daily arm, compared with just 1.2 log10 IU/mL in the placebo arm. By the end of dosing, half the patients in the 50 mg twice-daily and 100 mg once-daily arms achieved undetectable viral load. Most participants experienced viral rebound after the last day of IDX184 dosing, however, even though they remained on pegylated interferon/ribavirin. The drug was generally well-tolerated and no participants discontinued treatment early.
M. La Colla and colleagues from Idenix evaluated various two- and three-drug regimens containing IDX184, the protease inhibitor candidate IDX320, the non-nucleoside polymerase inhibitor IDX375, and a prototype NS5A inhibitor known as IDX-NS5A in a genotype 1b laboratory replicon model. Over three days IDX320 + IDX375 demonstrated additive activity, while IDX320 + IDX-NS5A produced additive to synergistic activity. Triple combinations of IDX184 + IDX320 + either IDX375 or IDX-NS5A produced clear synergistic activity. Over 14 days, IDX184, IDX320, and IDX375 individually produced viral load reductions of about 0.5-1.5 log10 IU/mL. Any two-drug combination demonstrated additive activity, with a reduction of about 2.0 log10; combining all three drugs led to a decrease of nearly 4.0 log10.
Researchers from Tibotec likewise tested combinations of the HCV NS3/4A protease inhibitor TMC435 with a nucleoside analog or non-nucleoside polymerase inhibitor in a replicon model. Both combinations showed additive or synergistic antiviral activity and a higher genetic barrier to resistance than the drugs used alone. The investigators concluded that combining all three agents at low concentrations resulted in a “pronounced reduction in replicon HCV RNA and the most efficient replicon clearance.”
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HealthWise : Waiting for Better HCV Treatment: Living in the Gap
—Lucinda K. Porter, RN
In 1997, I muddled through 3 months of treatment for chronic hepatitis C virus (HCV) infection. The prescribed medication was interferon, self-administered three times weekly. Since I have genotype 1, my chances of eliminating the virus were low (less than 10%), so it was no surprise when I didn’t respond to treatment. Waiting for better treatment was my best option.
A year later, combination therapy of interferon and ribavirin was introduced, along with better success rates. I decided to wait for better HCV drugs based on my resistant genotype and my recent experience with interferon therapy. In 2002, a modified version of interferon known as pegylated interferon or peginterferon, became available; this new version administered with ribavirin gave me a nearly 50% chance of success, so I took the plunge. I responded to treatment, and went through a 48-week course. The bad news was that the virus returned after treatment was discontinued; the good news was that the condition of my liver improved dramatically.
I have options. I could try a daily course of consensus interferon or a 72-week course of peginterferon and ribavirin. These seem extreme to me given the condition of my liver. Knowing that science is working on better treatments, and there are some very promising ones in the pipeline, I prefer to wait.
Graceful waiting is an act of courage and patience. I cling to the fact that my liver is in excellent condition. Simultaneously, I am acutely aware that record damage from HCV is forecasted, due to the fact that the majority of those with HCV, the aging Baby Boomers, have lived with this virus for a long time. The number of those with HCV-related advanced liver disease will quadruple in the next 10 years—from 30,000 to 150,000. Those with liver cancer will triple from 5,000 to 15,000; mortality rates are rising.
Waiting for the next round of HCV treatment feels like living in a gap, straddling the past and a future that I try to imagine. As someone with vast experience of living in the gap, I have picked up some tips for how to live well while waiting for science to discover better treatment for HCV:
- Tip #1: Don’t be a victim—be your own hero. Waiting is an active process. While waiting for better treatment, a frustrated patient once told me, “I feel like I am sitting around and doing nothing while the hepatitis C is eating away at my liver.” Don’t sit back and let this happen. Use this time to assess your choices and design a plan for how to live well. Commit to this plan and act on it today.
- Tip #2: Take care of your entire body. You may have a liver disease, but statistically you are more likely to die of an unrelated medical condition. While you are at it, take care of your mind and spirit too.
- Tip # 3: Get a life. It’s easy to dwell on HCV, especially when we are first diagnosed. However, after awhile, thinking about HCV all the time can become an obsession that may hurt more than help. Strike a balance between the need to stay current and the need to be free from thinking about HCV.
- Tip # 4: Imagine health. Visualization, positive self-talk, and imagination are powerful tools. We can use them to our advantage or detriment. If all we can think about is how tired and befuddled we are, it doesn’t leave room for much else.
- Tip # 5: Stay connected. Find people, with or without HCV, who are vital and wise. I found it necessary to let go of unhealthy relationships, and surrounded myself with people who had gumption. Someone wrote, “Life isn’t about waiting for the storm to pass. It’s about learning to dance in the rain.” If I was going to dance in the rain, I wanted to be with other dancers.
- Tip # 6: Strive for the healthiest lifestyle you can. This is courage in action. Lao Tzu said, “A man with outward courage dares to die: A man with inward courage dares to live.” Start small. I don’t smoke or use alcohol. I eat well, maintain my weight, am active, and I meditate. This took years to achieve. I gave up alcohol first, then cigarettes. Exercise came next. I am still working on meditation. It’s a process. If I tried to change all of me at once, I would have given up.
- Tip # 7: Live in health, not fear. HCV is scary, and it is reasonable to freak out about it. However, fear and worry don’t help, so when you are ready, consider giving up fear. Amy Tan wrote, “If you can’t change your fate, change your attitude.” Attitude can change everything.
- Tip # 8: Surround yourself with positive messages. Mary Kay Ash, founder of Mary Kay Cosmetics said, “If you think you can, you can. And if you think you can’t, you’re right.”
- Tip # 9: Live in gratitude. There is a Chinese proverb that states, “We count our miseries carefully, and accept our blessings without much thought.” Are you counting your blessings or your troubles?
- Tip # 10 Keep your sense of humor. The English poet, Lord Byron wrote, “Always laugh when you can. It is cheap medicine.” In addition to scientifically-proven health benefits, humor lightens even the heaviest load.
It takes stamina to live in the gap, and sometimes I get sidetracked from my determination.
When I feel sorry for myself, I think about Lance Armstrong. He survived testicular cancer that had metastasized to his brain and lungs, later going on to win the Tour de France seven times. Even more impressive is Lance’s return from retirement. He said, “Anything is possible. You can be told that you have a 90-percent chance or a 50-percent chance or a 1-percent chance, but you have to believe, and you have to fight.”
The reality is that new and better treatments are always going to be around the corner. I’ve seen enough change that although I appreciate the progress; I don’t get overly excited about the next great thing in the pipeline. What I want to see are hard core results. While waiting for the evidence, my priority is to stay healthy, no matter what.
Living in the gap is much like being in training. It is a declaration of intent to stay healthy no matter what. It is medicine without taking drugs. When we dare to live well, we serve others by honoring ourselves.
For more information on how to stay healthy while living with HCV, check out: A Guide to Healthy Living with HCV.
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EDITORIAL: Is it Safe to Wait?
—Alan Franciscus, Editor-in-Chief
It is projected that there will be one million cases of cirrhosis due to HCV in 20201 – yes that’s one million people with HCV who will progress on to cirrhosis – a life-threatening disease. Can we wait until the newer therapies are approved before we start to aggressively treat the HCV population? Are people with HCV playing with a ticking bomb by waiting until the new drugs are approved? The answer is NO we can’t wait and YES, it is a gamble that people with HCV should take very seriously.
The big picture issue is that in order to reduce the number of cases of cirrhosis, severe disease progression and the deaths that are projected to occur in the next ten years we must take a more aggressive approach to identifying, managing and treating people with HCV now—not when the new therapies become available. But looking at an individual who is living with hepatitis C the issue about waiting it is a much more complicated one—read on.
In this month’s HealthWise column Lucinda K. Porter discusses a different aspect of the issue—the actual waiting itself.
The cost justification for treating people with cirrhosis was proved in the Saab study, but I think the bigger issue is that we need to treat people with hepatitis C (HCV) sooner than later to prevent the serious disease progression and the complications that can result from being infected with HCV.
Most everyone agrees that people with moderate to severe fibrosis, and compensated cirrhosis should be treated now, but for people who have mild damage the decision to treat isn’t as straightforward. In the past, it was believed that HCV disease progression was a slow process that took many years or decades. For some people this hypothesis has been proven to be a fact, but this is not true for all people who have decided to wait. For instance, many people living with HCV were told to hold off on treatment until better therapies became available and they were promised that their health wouldn’t be compromised. Now, we are learning that this is not necessarily the case as more people are finding out that their liver has become more damaged in the years they have been waiting for the new drugs. The ‘wait and see’ attitude is rapidly being replaced by more careful monitoring and a more aggressive consideration of current HCV therapy.
In regards to people with little or no liver damage the “treat now” approach is tricky. In a perfect world everyone should be treated—it’s a viral disease that can be potentially eradicated. But the reality is that some people have work, insurance and/or support issues that prevent them from going on treatment. When you add in patient and/or medical provider reluctance to treat because of the many side effects of HCV therapy it’s not surprising that so many people and their medical providers have decided to delay treatment until the new and improved therapies become available.
These newer HCV medications promise an increased efficacy and possibly even a shorter duration of treatment. But the increase in efficacy will also come with an added burden—more monitoring, stricter adherence to taking the medications to increase efficacy and prevent drug resistance. Better side effect management will also be needed to manage the new triple combination HCV therapies. As a result, the new and improved treatment scenario will become more difficult for patients and medical providers to deal with.
The media trumpets these new HCV direct antiviral medications and they tell us that these new drugs will be available in the very near future. The reality is a much different story. We don’t really know when these new drugs will be approved. The current estimate and best case scenario is that telaprevir and boceprevir triple combination therapies will be approved in 2011 or 2012. However, under the Obama administration the ‘new’ Food and Drug Administration (FDA) has become more concerned about drug safety and has taken a more conservative approach in the drug approval process. In many ways this is a really good approach because it protects us from the potentially harmful side effects of any new medications. But in other (obvious) ways it could delay approval of drugs that could save many lives. If the FDA decides to sit on the marketing applications or requests more clinical data it could potentially push out the approval and availability date even farther.
Waiting is a strategy that some people with hepatitis C should not take—especially people with moderate to severe fibrosis. To me it’s a no-brainer: Regardless of cost effectiveness, people who have moderate to severe fibrosis should be treated as soon as possible with pegylated interferon plus ribavirin therapy, and most people should not postpone treatment. Consider that even after the FDA approves the new therapies, it will take time for the pharmaceutical companies to gear up for production and distribution. Add in the time it will take to educate medical providers and patients about the new therapies and I think you get the picture.
Gambling that HCV disease progression will not occur during this period is a risk that no one with HCV should take without very careful consideration and discussion with a medical provider and their loved ones.
1Gastroenterology. 2010 Feb;138(2):513-21, 521.e1-6. Epub 2009 Oct 25. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW.
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