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In This Issue:
Getting Closer – Telaprevir & VX-222
Alan Franciscus, Editor-in-Chief
HealthWise: Resilience and Hepatitis C
Lucinda Porter, RN
HIV/HCV Coinfection at CROI: Disease Progression
Disability & Benefits: Defining “Disabled” as It Applies to Benefits
Jacques Chambers, CLU
HCV Advocate Eblast
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Getting Closer – Telaprevir & VX-222
—Alan Franciscus, Editor-in-Chief
Recently, Vertex announced a new clinical trial which includes a combination of telaprevir (HCV protease inhibitor) and VX-222 (HCV polymerase inhibitor) that will be tested with and without pegylated interferon plus ribavirin.
Last year I reported on the first clinical trial of the first interferon/ribavirin-free therapy called INFORM-1. The study medications included an HCV protease inhibitor (RG7227) and an HCV polymerase inhibitor (RG7128)—these medications are in the very early stages of clinical development. They are also being tested individually in studies with pegylated interferon plus ribavirin. The INFORM-1 study results found that there was a very steep decline in HCV RNA or viral load. INFORM-2 was slated to begin earlier this year but has been cancelled due to adverse events (side effects). A new study—INFORM-3—is being designed that will include ritonavir to ‘boost’ the HCV protease inhibitor, which would allow for a lower dose of RG7227 and should lessen drug exposure and, hopefully, lower the side effects. The INFORM-3 study is expected to begin enrollment later this year once the optimal dose of ritonavir is established.
But back to the current study—the Vertex study will have 4 arms with 25 patients in each arm. Each arm of the study will contain Telaprevir (1125 mg BID-twice a day) and VX-222 (100 or 400 mg BID):
- Telaprevir plus VX-222 (100 mg BID)
- Telaprevir plus VX-222 (400 mg BID)
- Telaprevir plus VX-222 (100 mg BID) plus pegylated interferon and ribavirin
- Telaprevir plus VX-222 (400 mg BID) plus pegylated interferon and ribavirin
The current trial will be response guided—that is people who achieve undetectable (less than 10 IU/mL) HCV RNA or viral load at week 2 and week 8 will stop treatment at week 12. People who do not meet the response-guided criteria list above will continue on treatment of pegylated interferon plus ribavirin based on what study arm they were enrolled in: people in Arms 1 & 2 will stop the inhibitors (telaprevir and VX-222) and they will be treated with pegylated interferon and ribavirin for an additional 24 weeks; the people in Arms 3 & 4 who do not meet the above criteria will stop the inhibitors and will be treated with an additional 12 weeks of pegylated interferon plus ribavirin.
What is remarkable and a milestone in HCV treatment development is that the Vertex study includes an HCV protease inhibitor (telaprevir) in the later stages of development. The other drug VX-222 is a polymerase inhibitor that Vertex purchased from ViroChem Pharma Inc. that is in early clinical development. So at least one of the drugs is in later stages of development and this would indicate that the chances are better that this combination will be successful. This study is providing hope that we are a little bit closer to the much sought after goal of a treatment for HCV that does not contain pegylated interferon plus ribavirin.
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Healthwise: Resilience and Hepatitis C
—Lucinda K. Porter, RN
Merriam-Webster defines resilience as the “ability to recover from or adjust easily to misfortune or change.”1 This word applies to various situations and people. What does it mean to be resilient, how does one develop resilience, and how does resilience affect those with chronic hepatitis virus infection (HCV)?
Nearly everyone experiences some sort of trauma or pain, but some handle it better than others. For instance, not all children who experience brutality or violation are traumatized for life. Victims of rape and violence do heal. Soldiers and people who live in war-torn nations may experience post-traumatic stress, but not all of them do. Patients who are diagnosed with a potentially life-threatening medical condition may rise to the occasion or be devastated.
When I worked at Stanford, a thirty-five year old woman called me from time to time. She was told that she had HCV and basically stayed in bed for five years following her diagnosis. Although I encouraged her to take action to regain her strength, I also urged her to get further medical testing. Her HCV diagnosis had been based solely on an HCV-antibody test which is not conclusive. Eventually she got an HCV-viral load test which revealed she didn’t have HCV. That got her out of bed.
I’ve known other patients like this one and what they seem to lack is resilience. They don’t have the wherewithal to find their inner strength. The saying, when the going gets tough, the tough get going, does not apply to those without resilience.
Resilience may be part of our physiological fabric. Research is discovering various ways in which our neural circuitry influences how we adapt to stress.2 In short, resilience has a biological component and not everyone has the same genetic material that protects against life’s hard knocks.
However, that does not mean that biology is destiny. Resilience is like a muscle—it can be developed. Just like a muscle, it is developed under uncomfortable circumstances. We don’t learn how to be tough when life is easy. It’s on the job training. Psychotherapy may be helpful, particularly cognitive behavioral therapy. However, there is plenty you can do on your own.
Here is some advice on how to develop resilience, compiled from a variety of resources, including the Mayo Clinic3 and AARP magazine:4
- Connect with others
- Find purpose and meaning in your life
- Make health a priority
- Help others
- Make lemonade out of lemons
- Learn how to manage stress
Notice that last piece of advice: LAUGH. Those who have read my column before probably know where this article is going. April Fool Day is my favorite holiday. Perhaps it isn’t an official holiday, but it should be. Imagine if we took a day off to honor humor.
I advocate regular use of the funny bone. I could go into the science behind the benefits of humor, but if you need science to convince you to laugh, you need to have your seriousness excised. Research aside, laughing feels good, except if you’ve recently had abdominal surgery.
My heroes are those who can be on death’s door and still find a silver lining. Some recent stars in this arena are young adults with serious cancer. Iva Skoch “A Malignant Melanoma Walks Into a Bar”) and Kaylin Marie are giving hope and strength to others with cancer by treating hair loss and vomiting with hilarity. Now this is what I call resilience.
Inspired, I started a humor blog, The Hepatitis Comic. In all honesty, I don’t think it is very funny yet. I may like to laugh, but hepatic portal veins and jaundice don’t lend themselves to rollicking jokes. It’s my hope that readers will join in with their tales. Collectively we can use our funny bones to make our livers stronger. If we laugh at this together, we will be combining two of the recommended resiliency-builders on the list—staying connected and laughing.
As for resilience and HCV, Selmi and colleagues addressed this in their research titled, Resilience Affects the Quality of Life in Patients with Chronic Hepatitis C.5 They write, “Resilience is a term coined by physicists and applied by clinical psychologists to define the ability to recover from or adjust easily to a diagnosis.” Using this definition, Selmi’s team looked at the resilience of patients with HCV.
This study enrolled 149 HCV patients, none with cirrhosis or mood disorders: 55% were female, 42% had previously undergone HCV treatment and were either non-responders or relapsers. They used multiple questionnaires, surveying psychological well-being, health, quality of life, family and social relationships, job satisfaction, and other factors.
The results revealed that HCV patients are quite resilient. No significant differences were found between those who had undergone HCV treatment versus those who had not. Our social relationships and psychological well-being are generally strong and we maintain a good quality of life. Quality of life is affected by individual factors, particularly by the length of time one is infected. Selmi, et al. conclude, “informing patients regarding the disease natural history is critical to patient quality of life and should not be overlooked when new treatments are proposed.”
From this, I infer that how I feel from HCV may change the longer I have it. I may be resilient now because I am young and I have only had it for about 20 years. I may feel very differently 10 years from now. We’ll see how resilient I am then. In the meantime, I will continue to do what works for me, putting humor at the top of the list. Hope to see you in the funny papers.
2Psychobiology and Molecular Genetics of Resilience. Feder, Adriana; Nestler, Eric J.; Charney, Dennis S. Neuroscience 10, 446-457 June 2009 www.nature.com/nrn/journal/v10/n6/full
4The Secrets of Resilient People. Howard, Beth.
5Resilience Affects the Quality of Life in Patients with Chronic Hepatitis C. Selmi, C.; Giorgini, A. M.; Cocchi, C. A.; Meda, F.; Marta, S.; Monticelli, C.; Magrin, M.; Podda, M.; Zuin, M.2009 American Association for the Study of Liver Diseases meeting. Poster 1644.
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HIV/HCV Coinfection at CROI: Disease Progression
The 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010), held February 16-19 in San Francisco, featured several presentations on HIV/HCV coinfection.
This report looks at liver-related and HIV-related disease progression and outcomes among treated and untreated coinfected individuals; next month’s issue will include a report on factors predicting treatment response, inflammation, and associated conditions in this population.
SVR Reduces AIDS Progression
HIV positive people coinfected with hepatitis C virus tend to experience more rapid liver disease progression than individuals with hepatitis C alone; some research also shows that coinfection accelerates HIV disease progression. Successful interferon-based therapy is known to decrease the likelihood of liver disease progression and liver-related death. Now, a new study has shown that hepatitis C treatment can also reduce illness and death due to AIDS and other non-liver-related causes in HIV/HCV coinfected people.
Juan Berenguer and colleagues (abstract 167) analyzed 1,428 coinfected participants in the Spanish GESIDA 3603 cohort who started interferon-based therapy between January 2000 and July 2007. More than 80% were also on antiretroviral therapy (ART) for HIV, about 60% had undetectable HIV viral load, and the median CD4 T-cell count was high, at over 500. A majority had high HCV viral load, 30% had advanced liver fibrosis, and 60% had hard-to-treat HCV genotypes 1 or 4.
Overall, 36% of participants achieved sustained virological response (SVR) (58% for genotypes 2 or 3; 24% for genotypes 1 or 4). After a median follow-up period of about four years, people who achieved SVR had better outcomes than non-SVR patients (including both nonresponders and relapsers). The overall mortality rate was significantly lower among sustained responders compared with non-SVR patients, 0.31 vs. 1.71 per 100 person-years (PY).
As expected, sustained responders had significantly lower rates of liver disease complications including decompensation, hepatocellular carcinoma (HCC), and liver-related death. In addition, those who achieved SVR were significantly less likely than non-SVR patients to experience new AIDS-defining conditions or AIDS-related death, and were also less likely to die of other (non-liver and non-AIDS) causes. Looking at a combined outcome of new AIDS-defining conditions and all non-liver-related death, sustained responders reduced their risk by about two-thirds compared with non-SVR patients (0.47 vs 1.54 per 100 PY, respectively).
After controlling for other factors, the SVR group was about three times less likely to develop a new AIDS-defining condition (adjusted hazard ratio [HR] 3.24) and more than twice as likely to die of a non-liver-related cause (adjusted HR 2.60) compared with the non-SVR group.
Asked whether treatment that does not result in SVR might still have beneficial effects, Berenguer said while these data are not yet fully analyzed, there were “some hints” that people who achieved an end-of-treatment response but then relapsed also had improved clinical outcomes.
Outcomes of Moderate Liver Fibrosis
While advanced liver fibrosis typically precedes adverse clinical outcomes such as liver cancer and end-stage liver disease (ESLD), these can occur among HIV/HCV coinfected individuals with even moderate fibrosis, according to a study by Mark Sulkowski and colleagues (abstract 166).
The investigators analyzed 637 HIV/HCV coinfected adults seen at the Johns Hopkins HIV clinic between July 1993 and March 2009.
A majority were men and 80% were black. About 60% were on ART, more than half had undetectable HIV viral load, and one-third had a CD4 cell count of at least 500. Almost all (94%) had HCV genotype 1. According to baseline liver biopsies, 32% had no fibrosis (Metavir stage F0), 41% had mild fibrosis (F1), 9% had significant fibrosis (F2), 7% had advanced fibrosis (F3), and 11% had cirrhosis (F4).
The likelihood of ESLD, HCC, or death due to any cause was significantly greater among individuals with any fibrosis stage above F1. Incidence rates for the three outcomes combined were 21 and 27 per 1,000 PY, respectively, for people with stages F0 and F1, rising to 50 and 59 per 1,000 PY for stages F2 and F3, and finally to 71 per 1,000 PY for stage F4. After adjusting for other factors, stage F1 fibrosis was not significantly associated with more adverse outcomes relative to stage F0 (incidence rate ratio [IRR] 1.23), but all higher stages increased the risk (IRR 2.29, 2.29, and 3.12, respectively, for stages F2, F3, F4).
Among participants treated for hepatitis C (about 25% of those with stages F0-F1 and half of those with stages F2-F4), the SVR rate was only about 15% in this hard-to-treat population. But sustained responders experienced fewer adverse outcomes than either non-responders or untreated individuals, even if they had cirrhosis.
Among individuals with fibrosis stages F0-F1, combined ESLD/HCC/death rates were 27 and 22 per 1,000 PY, respectively, for untreated patients and nonresponders, while no relapsers or sustained responders experienced any of these outcomes. Among patients with stages F2-F4, untreated individuals had a combined incidence rate of 82 per 1,000 PY, falling to 57 for non-responders, 22 for relapsers, and zero for sustained responders. Higher CD4 cell count and lower HIV viral load were also independently associated with decreased risk.
Based on these findings, the researchers recommended that liver disease staging should be routine for coinfected patients. The study also suggests that HIV/HCV coinfected individuals may benefit from earlier initiation of both ART and hepatitis C treatment.
Rapid Liver Disease Progression
Studies continue to produce conflicting evidence about how rapidly liver disease progresses in HIV/HCV coinfected people.
Juan Macias and colleagues from several centers in Spain (abstract 659) used the non-invasive transient elastography method (FibroScan) to assess liver fibrosis progression in 441 coinfected patients not receiving hepatitis C treatment.
Almost all (97%) were on ART during follow-up, 75% had undetectable HIV viral load, and the median CD4 count was 444. About three-quarters had HCV genotypes 1 or 4, about 20% had received previous anti-HCV therapy, and the median baseline FibroScan liver stiffness value was 6.9 KPa—above the 6.0 cut-off for mild (F1) fibrosis, but below the 9.0 threshold for significant (F2) fibrosis.
Among 179 participants with follow-up FibroScan measurements at 18-24 months, 16% showed fibrosis regression, 54% showed no change, and 30% progressed by at least one liver stiffness fibrosis category (including 4% who progressed by two categories). HIV suppression and increasing CD4 count were associated with a lower risk of worsening liver damage. But despite effective ART, the researchers concluded, “liver fibrosis progresses in a significant proportion of HIV/HCV coinfected patients over a short period of time.”
In a related analysis, Martin Vogel and colleagues (abstract 642) prospectively evaluated liver fibrosis progression—also using FibroScan—among 30 participants in the European NEAT cohort (mostly men who have sex with men) who acquired acute hepatitis C after they were already HIV positive.
Again, most participants were on ART and the median CD4 cell count was 444. While 80% had HCV genotype 1, most of the rest had genotype 4. A majority (67%) had elevated ALT, 27% showed symptoms of acute infection, and 10% developed jaundice (yellowing of the skin and eyes).
Over a median follow-up period of 4-5 months, the calculated fibrosis progression rate—that is, the difference in fibrosis scores divided by amount of follow-up time—was very high, at 3.8 Metavir fibrosis units per year (assuming stage F0 prior to HCV infection). Plotting the fibrosis progression rate over time revealed a logarithmic association between observation time and calculated fibrosis progression rate, with short observation times strongly correlated with high progression rates.
“Calculated high fibrosis progression rates after acute HCV infection in HIV positive individuals are probably influenced by short observation periods,” the researchers concluded. “Higher liver stiffness in the acute phase of HCV infection may be at least partially explained by higher inflammatory activity which has been shown to increase stiffness leading to overestimation of fibrosis.” They added that a linear model of fibrosis progression “should be used with caution in the setting of acute HCV infection.”
Of note, other European teams using FibroScan have not observed unusually rapid fibrosis progression among coinfected individuals. But using liver biopsies—considered the “gold standard” for staging liver disease—Daniel Fierer’s group at Mt. Sinai Medical Center in New York City has reported unexpectedly advanced fibrosis in HIV positive men coinfected with HCV for only a short time.
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Disability & Benefits: Defining “Disabled” as It Applies to Benefits
—Jacques Chambers, CLU
Persons living with a chronic medical condition are often concerned about what would happen to them if they became “disabled.” But what do they really mean? What is the definition of disability?
According to Merriam-Webster, disabled means: “incapacitated by illness or injury; also: physically or mentally impaired in a way that substantially limits activity especially in relation to employment or education.” And that is a good, generic definition; however, someone contemplating leaving work due to disability cannot count on that definition when it comes to obtaining disability benefits. In fact, “disabled” and “disability” have several meanings that will vary depending on how and where they are used. That’s why your doctor writing a letter stating you are disabled won’t automatically get you disability benefits.
First, recognize that the term “disabled” is most frequently used as short-hand for the phrase “Totally Disabled” – and it usually means someone who is “unable to work at all.” But even that is not specific enough for the various disability benefit programs. Additionally there are other types of disability, partial or residual disability, as well as permanent disability.
Totally Disabled/Total Disability
Insurance companies and the Social Security Administration use the term “Totally Disabled.” Both, however, apply specific definitions to the term and it is important to know the specific definition as that is the yardstick with which a claimant’s medical condition is measured to see if they qualify for benefits.
Social Security defines “totally disabled” as:
- “You have a physical or mental health condition which is expected to last for a continuous period of not less than 12 months or to result in death, and
- “Because of that medical condition, you must be unable to perform your job and any job for which you are qualified based on your age, education and work experience.”
Notice that Social Security immediately eliminates coverage for brief periods of disability by including the “12 month” limitation. Also, the disability does not have to have lasted 12 months, only that it is expected to last that long. Also an exception is made for those with a terminal illness that might cause death within 12 months.
Also, under Social Security rules, you are not necessarily disabled just because you can’t perform your regular job. Instead, if you can’t do your prior job, they look to see if there is another occupation for which you might qualify either by past experience or training or education.
For example, they may expect a 35 year old with a college degree who can no longer perform his prior job, to be able to move to another job that he is able to do, both physically and mentally. At the other extreme, a 55 year old who has only a high school diploma and spent his entire career in one, relatively unskilled job may be eligible for benefits just because he can no longer perform his old job.
Private Disability Insurance
Benefits paid under either employer provided disability plans or individually purchased disability policies are all paid according to the terms of the disability plan document or the insurance contract. Each policy will define “totally disabled/totally disability” in the contract so anyone contemplating leaving work due to disability should know how the particular plan defines it.
Although each plan’s definition may vary, there are some basic provisions that are usually included in the definition in one form or another:
- Inability to work – Most definitions include a phrase such as: “due to medical condition, the claimant is unable to perform the material and substantial duties of an “occupation.” This provision has some variants:
- “His regular occupation” – If this is used in the definition, then a person is disabled only if he is unable to do the job he was doing when he became disabled; or
- “Any occupation for which he is suited based on education, training, or experience.” This is similar to Social Security in that they are looking for any job the claimant might be able to do based on the claimant’s background.
- Most employer provided disability plans use both of the above definitions of inability to work. They look only at the “regular occupation” during the first two or three years of the claim and then shift to “any suitable occupation” for the remainder of the claim. This is one reason many claimants are dropped from benefits after the first couple of years.
- Loss of income – Some plans define disability as “due to a medical condition, the claimant has lost at least twenty percent of his prior earnings.” Such plans will only pay full benefits if the claimant has lost 80% or more of his income. If the income loss is between 20% and 80% of prior earnings, then only a proportionate benefit is paid. Some plans use this provision without an “inability to work” provision; most, however, will use a combination of the two effectively requiring inability to work AND a loss of income.
- Under medical care – Most definitions include a requirement that the claimant be under the ongoing care of a physician, although some contracts waive that requirement if there is nothing medically to be done by further treatment.
The way insurance companies define “Totally Disabled” has a profound effect on who will get benefits, and knowing what definition a claimant has to meet should help him and his physician clearly document the medical record to reflect the claimant’s condition in the light of the definition used. Some older contracts written on professionals such as doctors and dentists defined disability so narrowly that they were obligated to pay full benefits even though the claimant was able to do other types of full-time employment. The days when those policies were written are long gone.
Partially Disabled, sometimes called Residual Disability, is not defined or used by Social Security. Their disability programs, both Social Security Disability (SSD) and Supplemental Security Income (SSI) have programs for persons “working while disabled” that effectively provides coverage for a partial disability. Note that the rules for working while disabled vary dramatically between SSD and SSI.
Partially Disabled is used in disability insurance plans, both individual Disability Income and group Long Term Disability. Usually, they provide a proportionate benefit to the claimant based on the amount of wages they are able to earn compared with what they earned prior to disability, adjusted for inflation. For example a person who can do some work and earn 40% of their prior earnings would be eligible to get 60% of the total disability benefit. At least that is a “typical” partial disability provision. The contract should be checked as they do vary.
Permanently disabled is really a non-term when referring to disability benefits. Other than Social Security’s requirement of lasting at least one year, benefit plans are more concerned with how total the disability is not how long it will last.
However, the term “permanently disabled” is occasionally used in some pension plans as the grounds for a disability retirement designation. To be honest, to say someone is permanently disabled is simply a prediction that may or may not be true. No disability plan makes you promise never to work again.
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