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In This Issue:
The Year in Review
Alan Franciscus, Editor-in-Chief
HIV/HCV Coinfection at ICAAC and AASLD: Epidemiology and Hepatitis C Treatment
Lucinda Porter, RN
AASLD 2008—Drugs in Development: Part 2
Alan Franciscus, Editor-in-Chief
HCSP: 2008 in Review
Alan Franciscus, Editor-in-Chief
Excerpt from Making Sense of Medical Research and Medical Literature
Lucinda Porter, RN
HCV Advocate Eblast
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The Year in Review
—Alan Franciscus, Editor-in-Chief
At the top of the list for the most important news about hepatitis C is the discovery and development of many new drugs that have the potential to dramatically increase the chances for achieving HCV viral eradication and possibly shorten the duration of therapy at the same time. At the end of 2008 there were some 60 drugs in current clinical development. Of these, 19 are direct anti-viral medicines – HCV protease and HCV polymerase inhibitors. In addition to the development of new drugs to treat hepatitis C, there have been major advances in our understanding of the HCV replication process that could lead to the discovery and development of new medicines to treat hepatitis C. Of particular interest and importance was the conclusion and submission to the FDA of a rapid oral antibody test study that could help to identify the millions of Americans who have hepatitis C, but do not know it.
Top News of 2008
Without a doubt at the top of the list is telaprevir, being developed by Vertex. Clinical development of telaprevir, an HCV protease inhibitor, made great strides with the release of clinical data from 4 trials – either final or interim results. An important phase II study found that the combination of Pegasys, ribavirin and telaprevir (triple therapy) resulted in sustained virological response rates up to 69% in HCV genotype 1 treatment-naïve patients – with a shortened total treatment duration of 24 weeks. Interim results of two other phase II studies on people who did not achieve a sustained virological response to a course of pegylated interferon plus ribavirin found that 41- 43% of non-responders, 82% of partial responders, and 73% - 83% of relapsers treated with triple therapy became HCV negative (<10 IU/mL). Another study evaluated different doses of telaprevir used in combination with pegylated interferon plus ribavirin – the results in the arms that received telaprevir once every 12 hours was comparable to the results in the arms receiving telaprevir once every 8 hours. Stay tuned for the final results of the various studies on retreatment and less frequent dosing. Vertex also announced in March 2008 that phase III studies of HCV treatment-naïve patients began enrollment, and in October 2008 the initiation of a Phase III study of telaprevir for the treatment of prior null-responders, partial responders and relapsers began recruitment. The studies will include telaprevir, pegylated interferon, and ribavirin.
Schering also released promising data from their phase II study of boceprevir, PegIntron plus ribavirin combination therapy. In the study arm that included 103 patients, 74% of the patients were HCV RNA negative 12 weeks after completion of 48 weeks of triple therapy (SVR12). In May 2008, Schering announced that they were initiating a phase III study.
In the not so good news department, Human Genome Sciences (HGS) announced that, based on the assessment of an Independent Data Monitor Committee (DMC), the 1,200 mcg dose of albuferon was discontinued due to severe adverse events. This is bad news because this was the dose that was being studied for a possible once-a-month injection. The treatment arms that were given albuferon every two weeks are still in phase III studies, and, if the data is good and no major serious adverse events are seen, HGS could apply to the FDA for marketing approval in late 2009-2010.
For the first time, a combination therapy is being tested that does not include interferon. In 2008, Roche, InterMune, and Pharmasset began testing a triple combination of R7227, R7128 and ribavirin. Keep your fingers crossed on this one!
Final testing of OraSure Technologies’ Rapid HCV Antibody Test is complete, and OraSure has applied to the Food and Drug Administration for marketing approval. Hopefully, this test will be approved in early 2009 so HCV testing can be greatly expanded, and more people with hepatitis C can be identified. This technology will greatly improve prevention measures and hopefully get more people into much needed medical management and, possibly, HCV therapy, which will reduce the projected future disease burden of hepatitis C.
There were many other important discoveries made in 2008 that should also be noted including:
- Scientists at the Scripps Research Institute discovered a method to disrupt the replication of the HCV virus, which should lead to the development of more drugs to treat hepatitis C.
- The side effects from current HCV therapy can be difficult. Researchers at the Duke Clinical Research Institute (DCRI) have discovered various proteins or peptides that will predict who will and who will not respond to therapy with a 90% accuracy rate. This knowledge could be a great motivator to start and stay on therapy.
- The medical strides that are being made in almost all areas of science are truly amazing. This year scientists using fluorescent proteins were able to image the hepatitis C replication process in live liver cells. What they found was that the hepatitis C virus sets up many large and small ‘viral factories’ in every cell it infects. http://newswire.rockefeller.edu:80
- Rockefeller’s Laboratory of Molecular Genetics and Immunology discovered the cell receptor that is responsible for the body’s inflammation process. This discovery could lead to the development of new medications that would help strengthen the immune response against viruses like HCV as well as mediate the damage that HCV causes. In addition this knowledge may help to understand and could lead to the discovery of drugs to treat autoimmune diseases.
- It was also reported in 2008 that scientists from the University of Pittsburg Graduate School of Public Heath and School of Medicine discovered a key enzyme that may explain how the hepatitis C virus causes fatty liver. It was also noted that blocking the expression of this enzyme resulted in a dramatic decrease in HCV RNA (viral load).
- Another group of scientists from Oklahoma Medical Research Foundation identified a gene in mice that causes fatty liver. If the same enzyme is found to cause fatty liver disease in humans, therapies could be developed to treat fatty liver – a condition that is expected to surpass HCV as the leading cause of liver transplants in the not too distant future.
In my opinion the worst of the worst news was about the unsafe practices (reused syringes and medicine vials) at the Endoscopy Center of Southern Nevada and the Desert Shadow Endoscopy Center. About 40,000 people were put at risk for acquiring HCV. To date some 114 people have been identified, but it is unclear if all of the infections are the result of unsafe procedures at the Las Vegas clinics or from a prior exposure. Expect more information about the outbreak as the Centers for Disease Control and Nevada health authorities will be releasing detailed findings of their investigations.
A special thanks to Mindy for helping to compile all the latest and greatest of the 2008 news.
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HIV/HCV Coinfection at ICAAC and AASLD: Liver Disease Progression and Immune Response
Last fall’s 59th annual meeting of the American Association for the Study of Liver Diseases (AASLD) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) both featured several presentations on HIV/HCV coinfection. This article covers studies looking at liver disease progression and immune response. See the December 2008 issue of the HCV Advocate for coverage of coinfection epidemiology and treatment.
Research indicates that HIV positive people with chronic hepatitis C tend to experience more rapid and severe liver disease progression, but study data are mixed, and coinfected people with well-preserved immune function may fare as well those with HCV alone. At the Liver Meeting (AASLD), R. Sterling and colleagues (AASLD abstract 27/1931) presented data from a prospective, longitudinal study of paired liver biopsies from 47 HIV/HCV coinfected patients in Virginia with no cirrhosis at baseline. Participants had well-controlled HIV disease, about 80% were on combination antiretroviral therapy for HIV (HAART), and the mean CD4 cell count was about 600.
Between the first and second biopsies, 34% of patients experienced fibrosis progression (including 13% with an increase of two or more points), 44% had unchanged fibrosis, and 21% experienced fibrosis regression (including 2% with a decrease of two or more points). In addition, 55% experienced worsened liver inflammation, 15% stayed the same, and 29% had improved inflammation. The average fibrosis progression rate was 0.132 units per year, while the annual inflammation progression rate was 0.174 units. No association was observed between speed of liver disease progression and ALT level, baseline liver damage, CD4 count, HIV viral load, use of HAART overall or any specific antiretroviral drugs, or response to interferon-based therapy for hepatitis C. Because no single factor predicted worsening liver histology, the researchers concluded that biopsies are necessary to identify coinfected patients experiencing disease progression. Even though the overall fibrosis progression rate was relatively low, Sterling recommended that all motivated coinfected patients should be offered hepatitis C treatment, since it is impossible to predict who will progress.
In a related study, C. Sagnelli and colleagues (AASLD abstract 502) compared outcomes in 30 Italian HCV monoinfected and 34 HIV/HCV coinfected patients with well-controlled HIV disease (mean CD4 count of about 560) who, over 18 months, had persistently normal ALT (a liver enzyme that indicates inflammation, but does not necessarily reflect fibrosis). Biopsies revealed that more that 90% of patients in both groups had relatively low histological activity index scores (< 8 using the 18-point Ishak scale), but the average fibrosis score was significantly higher in the coinfected compared with the HCV monoinfected group (2.1 vs. 1.4 on a 6-point scale). Furthermore, 24% of coinfected patients had advanced fibrosis (score of 3-6), compared with 7% in the HCV monoinfected group. There was an even larger difference in the number with a high degree of liver steatosis (fatty liver), 32% vs. 3%, respectively. The researchers concluded that, “Patients with HIV/HCV coinfection frequently show moderate or high liver fibrosis and deserve anti-HCV treatment,” even in the absence of elevated ALT.
Progression and HAART
At ICAAC, J. Pareja and colleagues from Spain (ICAAC abstract H-2319) presented further evidence that HAART can slow liver disease progression in HIV/HCV coinfected patients. This cross-sectional biopsy study included 119 coinfected participants, 80% of whom were on HAART. All had CD4 counts of at least 350 at the time of liver biopsy (median 550), but the median CD4 nadir (lowest-ever level) was about 200, indicating significant immune dysfunction.
One-quarter of study participants had at least moderate necroinflammatory activity (score of 3 or higher), 19% had advanced fibrosis (stage F3), and 3% had cirrhosis (stage F4). Participants with higher necroinflammatory scores were slightly more likely to be heavy alcohol users and to have steatosis, but were significantly less likely to be on HAART. Necroinflammatory scores did not correlate with HIV or HCV viral load, HCV genotype, or current or nadir CD4 count. “Use of HAART at the time of liver biopsy was associated with lower levels of necroinflammatory activity,” the researchers concluded. “Necroinflammatory activity was strongly associated with higher fibrosis scores. These results suggest that HAART might decrease hepatitis C activity in HIV/HCV coinfected patients with > 350 CD4 [cells].”
Because people with HIV receive routine HCV screening and regular liver function tests, acute or recent HCV infection is more likely to be detected, and outbreaks of apparently sexually transmitted acute hepatitis C have been reported among HIV positive gay/bisexual men in several cities. A. Uriel and colleagues from Mt. Sinai School of Medicine in New York (AASLD abstract 503) analyzed factors influencing spontaneous resolution of acute HCV and response to treatment in 22 HIV positive men (one of whom had two episodes). The group had well-controlled HIV disease (average CD4 count of about 500), most were on HAART, and all had HCV genotype 1.
Acute HCV infection was symptomatic about half the time, and four episodes (17%) resulted in spontaneous HCV clearance within six months. Of the 16 men with persistently detectable HCV who were treated with pegylated interferon plus ribavirin, 50% achieved rapid virological response at week 4, about 90% (all but one) achieved early virological response at week 12, and 70% achieved sustained virological response (SVR) 24 weeks after completing treatment. No significant differences were identified between patients with and without spontaneous HCV clearance, making it impossible to predict who would progress to chronic disease.
Disturbingly, among the 14 patients who underwent liver biopsy an average of four months after their first elevated ALT measurement, 12 (86%) already had moderate (stage F2) fibrosis – including three of the four who experienced spontaneous HCV clearance. “Moderately advanced liver fibrosis was seen during the acute phase and in the early chronic phase in almost every patient evaluated, suggesting far more rapid fibrosis progression than previously reported in patients with HIV infection, even in those who eventually had spontaneous clearance,” the researchers concluded. “It is therefore crucial to detect and treat acute HCV infections during the acute phase to take advantage of the higher cure rate (70%) and prevent further progression of the already moderately advanced liver disease.”
In another study, L. Jones and colleagues (AASLD abstract 1838) assessed the natural history and treatment outcomes of acute HCV infection in 30 HIV positive and 32 HIV negative individuals (including patients at Mt. Sinai and veterans in New York and Philadelphia). The HIV positive and HIV negative groups had similar peak ALT and maximum HCV RNA levels. Spontaneous HCV clearance occurred at a similar rate in both groups (13% vs. 19%), and patients with persistent infection who started interferon-based therapy had similar SVR rates (60% vs. 69%; both differences not statistically significant), leading the researchers to conclude that “HIV-associated CD4 T-cell dysfunction does not necessarily prevent HCV clearance.” These results conflict with other studies showing that HIV positive people are less likely to spontaneously clear HCV and do not respond as well to treatment, but this group had well-preserved immune function (median CD4 count of about 530).
Turning to immune response, N. Rallon and colleagues (AASLD abstract 1047) analyzed HCV-specific CD4 and CD8 T-cell responses in 30 interferon-naïve Spanish chronic hepatitis C patients with and without HIV. A majority of the HIV positive participants were on HAART and the median CD4 cell count was 390. Coinfected patients had a higher average HCV RNA level (5.7 vs. 6.4 log IU/mL), but similar large percentages in both groups (more than 80%) had detectable CD4 and/or CD8 response against five HCV proteins; the extent of total anti-HCV CD4 and CD8 responses were also similar. In both groups, the predominant response was CD4 cells that produced only tumor necrosis factor alfa (TNF-alfa), but the HIV negative patients had more CD4 cells that exclusively produced interleukin 2 (IL-2). “The ability of CD4 T-cells to produce IL-2 against HCV is impaired in HIV-coinfected patients,” the researchers concluded, adding that this might contribute to poorer control of HCV replication in this group.
In another study, C. Koerner and colleagues from Germany (AASLD abstract 1076) compared CD4 cell apoptosis (programmed cell death or “cell suicide”) in HCV monoinfected, HIV monoinfected, and HIV/HCV coinfected patients. Not surprisingly, untreated HIV monoinfected people had more CD4 cell apoptosis (3.2%) than healthy individuals, while apoptosis rates in HCV monoinfected and healthy people were the same (both 0.9%). The coinfected patients, however, had significantly greater apoptosis (6.2%) than either monoinfected group. Effective HAART led to a substantial reduction in CD4 cell apoptosis in HIV monoinfected patients, but even more so in coinfected patients, bringing them down to a similar level (2.0% and 2.1%, respectively). The researchers suggested that increased apoptosis could underlie accelerated HIV disease progression in HIV/HCV coinfected people, but that HAART “abolishes the additional effect of HCV coinfection on CD4 T-cell apoptosis” in this population.
For complete conference coverage, see:
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—Lucinda Porter, RN
In the 1840’s, a French physician looked at a diseased liver and coined the word cirrhosis from the Greek kirrhos for tawny. A common myth is that cirrhosis is caused solely by alcoholism. Actually, there are many causes. Examples are hepatitis B, C, and D, fatty liver disease, excess iron, certain drugs and supplements, and other liver diseases.
One in five people with chronic hepatitis C virus infection (HCV) will develop cirrhosis. It starts when the liver tries to eliminate HCV, by producing more liver enzymes. But for some, the liver can’t keep up with the pace and it builds scar tissue. This scar tissue is called fibrosis. Most with HCV have fibrosis and will not progress past this stage. If the damage becomes severe, the liver hardens into cirrhosis. If it happens, the process usually takes twenty or more years.
One way to describe cirrhosis is to picture a drip coffee maker. If you lived in a place where the water is hard, mineral deposits will build up in the holes the water passes through. In time, deposits accumulate so that water can’t pass through. Your coffee maker would have cirrhosis.
“Cirrhosis has been linked to as little as 2-3 daily glasses of alcohol for healthy women and 3-4 for men, according to the National Institute of Diabetes, Digestive, and Kidney Disease.”
There is a problem with this analogy. The mineral deposits can be cleaned out with various solutions, such as white vinegar. Although the liver acts as a filter, fibrosis and cirrhosis aren’t simply clogged up vessels. The liver is damaged because the constant assault from inflammation actually changes the architecture of the tissue. For this reason, products that promise to cleanse the liver are misleading because it is not an organ that can be “flushed out” with herbs or supplements.
Signs & Symptoms
The liver is referred to as a non-complaining organ. Although twinges are common, most patients don’t run to the clinic, writhing with liver pain. Typically patients find out they have HCV via a routine lab test, such as when applying for insurance or attempting to donate blood. Or, labs may be ordered to address vague complaints such as fatigue.
This silent feature is good news for those who abhor pain and bad news for those who can’t stand uncertainty. If the disease is silent, how does someone know if they have cirrhosis? There may be symptoms such as fatigue, appetite loss or nausea. However, these are symptoms of a host of other conditions, including HCV. So again, how does one know if they have cirrhosis? Your health provider can tell you.
The liver is normally soft and smooth. On exam, if your liver feels hard and coarse, this is a sign. The spleen may be enlarged. You may have red, spidery blotches, usually on upper body and face, called spider nevi.
The signs and symptoms of cirrhosis may be caused by other conditions, some of which are very minor. For instance, a red spider vein on the face may be just that. Don’t assume, don’t panic, don’t self-diagnose.
Lab tests are critical. Some typical lab abnormalities include:
• Decreased platelets – the sticky part of the blood that helps clotting
• Increased blood clotting times
• Low cholesterol
Lab abnormalities that occur later in cirrhosis may include low albumin and high bilirubin,both produced by the liver.
Ultrasound and other imaging studies may be ordered but are not reliable diagnostic tools. A liver biopsy is the surest way to confirm cirrhosis. For most, the risk of liver biopsy-related complications is low. This risk increases if there is cirrhosis, so make sure the physician performing the biopsy is experienced. If the procedure is done in a hospital during July, ask if a new resident will be doing the biopsy. If the answer is yes, ask yourself if you are comfortable with this since this is the start of rotation for new residents.
If lab tests point to a bleeding risk, a safer option is to have a transjugular biopsy. This procedure is done under sedation. A long, thin tube is guided to the liver through an incision made in the neck’s jugular vein. Liver tissue is obtained via a biopsy needle threaded through the tube. If there is accidental bleeding, the blood flows into the liver’s own vein rather than leaking into the abdomen.
Two Stages of Cirrhosis
Sometimes the symptoms of cirrhosis are not subtle. A friend found out she had cirrhosis after vomiting blood. Her liver was severely damaged. She probably had cirrhosis for awhile. I’ll explain the bleeding in a moment.
Cirrhosis is categorized as compensated or decompensated. Compensated cirrhosis means that the liver is performing relatively well in spite of the damage. Decompensated cirrhosis means that the liver is not functioning properly. Decompensated cirrhosis is also known as end-stage liver disease (ESLD). About one in five of those with HCV-induced cirrhosis will progress to a decompensated stage.
Let’s go back to the coffee maker analogy. Imagine that the holes through which the water passes are starting to get clogged from mineral deposits. This happened gradually. You probably didn’t notice that it took longer to brew. Maybe you thought the coffee maker was getting old. But it worked and every morning you still had coffee, so there was no reason to suspect anything. Then one day, the holes are completely clogged to the point that everything gushes back out the top of the machine. You have a mess of steam, water, and coffee grounds.
It is similar with cirrhosis. Blood flow eventually backs up into the liver’s portal vein. The circulatory system tries to push blood through the damaged organ. The blood pressure in the portal system increases. This is known as portal hypertension.
At this point, everything in the area is affected. The spleen gets bigger because blood backs up into it. Splenomegaly is the term for an enlarged spleen. Platelets get trapped in the spleen, reducing the body’s ability to clot. Also because of the increased pressure, varicose veins called varices form in the esophagus and stomach. These can burst, as in the case of my friend who vomited blood. The body’s decreased clotting ability combined with bleeding varices is potentially life-threatening.
“Compensated cirrhosis means that the liver is performing relatively well in spite of the damage. Decompensated cirrhosis means that the liver is not functioning properly.”
The liver has over 500 functions, so portal hypertension affects nearly every bodily system. Here are some of the complications of advanced cirrhosis:
• susceptibility to bodily bruising and bleeding
• severe itching
• osteoporosis – bone loss
• increased infections
• cachexia – loss of muscle mass
• increased or decreased blood sugar
• breast enlargement in men along with atrophy of testes
• menstrual irregularities
• kidney abnormalities
• ascites – fluid retention, particularly abdominal and ankle swelling
• jaundice – yellowing of eyes and skin
• cola-colored urine and/or clay-colored stools
• varices – esophageal and gastrointestinal bleeding
• hepatic encephalopathy – mental changes caused by accumulation of toxins in the brain, such as poor memory and concentration or impaired sleep
As stated earlier, the liver will compensate for the decreased function of 80% of those with HCV-induced cirrhosis. This means that the majority of those with cirrhosis are able to function despite cirrhosis. Most of these haven’t progressed enough to warrant a referral for liver transplant evaluation. Many will live long and active lives. These patients need regular medical visits to monitor their health, particularly because those with HCV and cirrhosis have an increased risk of liver cancer. Early diagnosis is a critical factor in liver cancer survival rate.
Although this subject is frightening, take comfort in this: 1) The majority of us with HCV will not progress to cirrhosis. 2) Of those that do progress, the majority can still live full, productive lives. Next month’s column will go into more detail, concluding with how to help ourselves live with cirrhosis or avoid it altogether.
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AASLD 2008—Drugs in Development: Part 2
Alan Franciscus, Editor-in-Chief
In last month’s HCV Advocate newsletter I wrote about many new drugs in development to treat hepatitis C that were presented at the American Association for the Study of Liver Diseases (AASLD) conference. The report included four studies on telaprevir as well as the results on boceprevir, nitazoxanide, R7128, and ITMN-191. This month I will report on studies of drugs that are in an earlier phase of clinical development: TMC435, BI 201335, PF-00868554, GI-5005 (a DNA based HCV vaccine) and farglitazar (anti-fibrotic).
TMC435 (formerly TMC435350) is a new HCV protease inhibitor that is being developed by Tibotec Pharmaceuticals Ltd. One poster presented data on cloned HCV genotype 1 through 6 proteases that found TMC435 was a potent inhibitor of the serine protease in all genotypes tested.
In another poster two groups of patients were studied – healthy patients and patients infected with hepatitis C.
In the group of healthy volunteers the once-a-day 200 mg dose was to evaluate the safety, antiviral activity and pharmacokinetics (absorption, distribution, metabolism and excretion) of TMC435. The 200 mg capsule formulation reached a steady state in 7 days.
In yet another study, 48 HCV-infected patients received either the 25 mg or 75 mg dose (once a day) given as a monotherapy or in combination with pegylated interferon plus ribavirin. After 7 days of treatment there was a mean viral load reduction of 2.63 log10 IU/mL in the 25 mg arm and 3.43 log10 IU/mL in the 75 mg/day arm both given as monotherapy. The triple combination arm (TMC435, pegylated interferon, ribavirin) given for 28 days produced a mean viral load reduction of 3.47 log10 IU/mL in the 25 mg arm and 4.55 log10 IU/ml in the 75 mg/day arm.
The most common adverse events reported were nausea, diarrhea, and headache – no serious adverse events were reported.
Boehringer Ingelheim’s BI 201335 is an HCV protease inhibitor that is in early clinical development. Information about the safety, antiviral activity and pharmacokinetics of BI 210335 in HCV genotype 1 treatment-naïve patients and treatment-experienced patients were presented.
The treatment-naïve study was divided into two parts, the first part of which was a monotherapy study evaluating 4 doses of BI 201335 (20, 48, 120, 240 mg or placebo) for 14 days. If a patient had ≥ 1 log10 decrease in HCV RNA they were rolled over to the second part of the study that included BI 201335 plus Pegasys and ribavirin from day 15 through day 28. All of the patients in the study (except one patient in the 20 mg arm) achieved greater than 2.8 log10 drop in HCV RNA. The maximal HCV RNA reduction was 2.9 log10 (20 mg) to 4.0 log10 (240 mg) which was achieved within 2-4 days. The drug was generally safe and well-tolerated with no dose dependent increase in adverse events. The only case for concern was a dose dependent change in bilirubin.
The second study included 19 treatment experienced patients who did not achieve more than a 2 log10 reduction in HCV RNA with a previous course of pegylated interferon plus ribavirin. The patients were given doses of 48, 120, or 240 mg (once daily) in combination with Pegasys plus ribavirin for 28 days. The maximal HCV RNA reduction was 5.0 log10 (48 mg) to 5.3 log10 (240 mg) during the 28 days of treatment. BI 201335 was found to be safe and well-tolerated with no severe adverse events except the usual side effects seen in people who receive pegylated interferon plus ribavirin.
The antiviral activity of the once a day dose of BI 201335 was remarkable and further clinical trial development is expected.
Pfizer’s entry into HCV drug development is an HCV polymerase inhibitor PF-00868554. Two studies were released at AASLD – one was on the safety, tolerability and pharmacokinetics of PF-00868554 dosed in healthy volunteers, and the other poster measured the antiviral activity in HCV genotype 1 infected patients.
In the first study of healthy volunteers, 33 male patients were randomized to receive 50,100, and 300 mg BID (twice a day), and one group received 300 mg TID (three times a day) for 14 days. The researchers found that the drug was safe and well-tolerated at all doses and drug plasma concentrations were achieved that would be expected to inhibit HCV RNA replication.
The second study included 32 HCV treatment-naïve genotype 1 male patients who received the same doses listed above for 7 days. The drugs were found to be safe and well-tolerated and the HCV antiviral activity was dose dependent with mean reductions in HCV RNA from -0.97 to -2.13 log10. Based on these results Pfizer has initiated a study of PF-0086854 in combination with pegylated interferon alpha-2a and ribavirin.
GlobeImmune’s therapeutic vaccine study of GI-5005, used with and without pegylated interferon plus ribavirin in 140 HCV genotype 1 treatment-naïve and non-responders was presented in a poster. In the monotherapy phase of the study no patients discontinued therapy due to adverse events. In the pegylated interferon/ribavirin therapy (without GI-5005), 5 patients discontinued therapy due to side effects. In the triple therapy arm 3 patients discontinued therapy due to side effects, but the investigators did not attribute the side effects to GI-5005.
The authors reported that in the triple therapy arm that was given to HCV patients with a high viral load (>600,000 IU/mL) the patients showed a 2.6-fold improvement in RVR rates compared to those who received just pegylated interferon/ribavirin. Based on these results the authors suggested that GI-5005 may increase the rate of HCV clearance.
Given the amount of people who do not respond to current HCV therapies it is of the utmost importance that other options to help with HCV disease progression are developed. An area that is vitally important is the development of anti-fibrotic medications to treat moderate to severe HCV disease progression. There are currently clinical trials underway on a variety of anti-inflammatory and anti-fibrotic drugs such as PF-03491390, MitoQ, CTS-1027, and farglitazar. Unfortunately, the results from a trial of farglitazar (G1262570) in 177 people with chronic hepatitis C who had moderate fibrosis did not show any benefit when given various doses of Farglitazar. Hopefully, the other drugs in current clinical development and new anti-fibrotic drugs will be developed to help stop or reverse disease progression.
There are currently clinical trials underway on a variety of anti-inflammatory and antifibrotic drugs such as PF-03491390, MitoQ, CTS-1027, and farglitazar.
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HCSP: 2008 in Review
Alan Franciscus, Editor-in-Chief
In 1997, the Hepatitis C Support Project (HCSP) was founded to address the lack of information, support, services, and resources available at the time to the HCV community. In the eleven years since the founding of HCSP, we have grown to become one of the most well-respected organizations in the hepatitis C community and our services are accessed by thousands of patients, medical providers and HCV service providers in the United States and around the world.
Our services include information and educational resources about hepatitis C, hepatitis B, and HIV/HCV coinfection.
In 2008 we saw a tremendous growth in the services that we provide and we also expanded our collaborations with other HCV service organizations, CDC Adult Hepatitis Coordinators, local, state and national health organizations, as well as with people who are living with hepatitis C.
HCSP continues to provide important resources via our HCV Web site, HCSP’s Training workshops, and HCSP educational materials.
Major accomplishments of HCSP in 2008 include:
• Web Site: Average weekly web hits grew from 400,000 in 2007 to 425,000 in 2008.
• Educational Material Distribution: 290,000 pieces distributed in 2008. This is not including the educational materials downloaded from the web site.
Listed below are some examples of our most popular publications and the amounts we distributed throughout the United States:
• African Americans & HCV – 18,000
• Are You At Risk for HCV Poster – 16,000
• Coping with Depression and Hepatitis C – 19,000
• Hepatitis B – 17,000
• Hepatitis C Basics – 5,000
• HIV/HCV Coinfection Facts – 18,000
• HIV/HCV Coinfection Poster – 8,000
• HIV/HCV Coinfection Poster (Spanish) – 6,500
• Lo que necesita saber (Hepatitis C: What You Need to Know) – 16,000
• Needle Exchange – 16,000
• Tattoo You 2 – 24,000
• Testing Positive – 28,000
• The Liver: The Basics – 34,000
• National Training Program: In 2008 we conducted 40 HCV training workshops throughout the United States. The overall participant rating of various topics covered ranged from 4.61 to 4.93 on a scale of 1 (lowest) to 5 (highest). Since the program’s inception HCSP has certified over 8,000 HCSP Basic Educators. We conservatively estimate that if every educator reaches 50 people that we will reach over 400,000 people in just one year.
Shaded-in states are those where HCSP has conducted trainings
• Support Group Project: HCSP distributed materials and tools to about 300 support group leaders in the United States. The distribution of education materials and tools included our HCV playing cards and HCSP Guides. In addition, we make every effort to make sure our Web site support group data base is up to date by contacting the support groups every quarter.
• Newly Diagnosed Patient Kits: Distributed over 2,500 kits to patients, support group leaders, and medical and service providers. The kit includes a variety of publications, such as Making Treatment Decisions, Preparing for Treatment, A Guide to Help You Stay on Treatment, After HCV Treatment, and Healthy Living with Hepatitis C.
• AIDS Service Organizations (ASO): HCSP distributed educational materials to over 1800 ASO’s in the United States and has continued to distribute educational materials, such as HCSP’s HIV and Hepatitis Coinfections Pocket Guide, HIV/HCV Coinfection Facts, HIV/HCV Coinfection Poster, and Staying Healthy with Hepatitis B.
• Prisons: In 2008 HCSP sent out over 500 comprehensive information packets to prisoners and worked with various prison peer support group leaders from various prisons across the country who have ordered bulk newsletters and brochures to distribute to inmates. We now provide over 265 inmates with a ‘free’ subscription to the HCV Advocate newsletter so that they can share it with and educate other inmates.
• HEP Quiz, HCV Learning Courses, and CME Courses: HCSP continued to provide a Web-based game – Hep Quiz – in English and Spanish on topics such as hepatitis C and hepatitis B. We also provided educational courses such as “A Basic Overview of Hepatitis C,” “Making Treatment Decisions,” “Disability Programs from Social Security,” and “An Overview of HCV Diagnostic Tests.” In total over 9,000 people took our on-line quizzes and courses.
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Excerpt from Making Sense of Medical Research and Medical Literature
Lucinda K. Porter, RN
Phases of Clinical Trials
In order to find treatments for chronic hepatitis C that are safe and effective, new drugs, including interferons, must undergo rigorous testing. Drug research involves many stages. Much of the knowledge about drugs is derived from initial laboratory research in animals. Animals are used during the drug development phase, primarily to confirm lack of toxicity. If laboratory tests show that a drug has potential therapeutic value without major toxicity, it may advance to the next stage. The next step involves an extensive process of applying to the FDA for permission to proceed. After careful review of the preliminary data, if the FDA gives its approval, then drug testing – clinical trials – can begin on humans.
Clinical trials may have up to four phases. The initial introduction of an investigational new drug using humans occurs in Phase I. The subjects in this phase are usually healthy volunteers (usually 20 to 80 subjects). Sometimes the subjects are those with the disease that is being studied. The goals of a Phase I trial are to evaluate safety and tolerability (i.e., lack of major side effects) as well as the dosage range. This is determined by testing a range of doses (called a dose-ranging trial). Study participants initially receive a low dose of the drug; this is gradually increased as long as the drug appears to be safe. Phase I studies may provide early indications of the drug’s effectiveness, but whether or not a drug works is the primary focus of Phase II and Phase III studies.
In Phase II trials, clinical studies are conducted using patients with the disease that is being tested. The goal of this phase is to obtain preliminary data on the effectiveness (also known as efficacy) of the test drug. This phase also allows further collection of data on the common short-term side effects and risks associated with the drug. A relatively small number of participants enroll in Phase II studies (100 to 300 subjects).
After confirming preliminary evidence of effectiveness in Phase II studies, the goal of Phase III studies is to gain additional information on effectiveness and safety. In this phase, the several hundred to several thousand subjects receive the test drug. In Phase III studies, the new drug is often compared to current standard therapy.
After the drug is approved and marketed, the FDA may require a company to obtain more information about the drug. These studies occur as Phase IV trials. Examples are the safety and efficacy of varying doses, how the drug interacts with other drugs, or how it works in people with other diseases. Phase IV trials may include small or large numbers of subjects and may reveal uncommon side effects that are too rare to show up in Phase II or III studies.
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