June 27, 2010

DDW: Vitamin A Boosts Response to HCV Treatment

By John Gever, Senior Editor, MedPage Today
Published: May 05, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

NEW ORLEANS -- Early and sustained virologic responses to standard treatment for hepatitis C virus (HCV) infection were markedly improved when patients also received high doses of vitamin A, results of a small trial showed.
After 48 weeks of treatment with standard doses of pegylated interferon-alpha2b, ribavirin (Rebetol), and 30,000 IU/day of vitamin A, 61.7% of patients had achieved sustained virologic responses, compared with 42.9% of patients taking only the standard therapies without the vitamin, Shuichi Sato, MD, of Shimane University in Izumo, Japan, said here.

The addition of vitamin A also boosted early virologic response rates assessed after 12 weeks: 70% of patients taking vitamin A plus the standard drugs had no HCV genetic matter in circulation, whereas only about 40% of patients on standard therapy alone showed viral negativity at that point.

Despite the very high doses of vitamin A tested in the 42-patient trial -- the recommended daily intake of vitamin A in the U.S. ranges from 2,310 to 3,000 IU/day for adults -- Sato said it appeared to have no adverse effects in the trial.

"There is little or no risk in a high dose of vitamin A," he said at a press conference in advance of his formal presentation at Digestive Disease Week.

Sato and other researchers had reported in 2003 that retinoic acid compounds increased expression of interferon receptors on hepatoma cells in vitro. They followed that up last year with short-term clinical results suggesting that vitamin A increased the antiviral activity of interferon and ribavirin in patients with HCV infection.

At DDW, he will be presenting data on 42 patients who received a full course of PEG-interferon and ribavirin therapy in an open-label, multicenter study.

Patients with chronic hepatitis C were randomized to receive the high dose of vitamin A, or not, in addition to the standard therapy.

A little more than half the patients were men. Mean age was about 55 and 16 patients had previously received interferon treatment.

Study treatment lasted 48 weeks in most patients, although it was extended to 72 weeks in a few patients who achieved HCV negativity between weeks 12 and 36 of therapy.

About 5% of patients assigned to the vitamin A group and 10% of control patients failed to show a sustained response at week 48 but did achieve it by week 72, Sato reported.

Discontinuations were slightly more common in the vitamin A group but not significantly so: about 15% versus 10% in the control group.

Sato said a placebo-controlled trial is planned.

Press conference moderator Kelly Tappenden, PhD, of the University of Illinois in Urbana-Champaign, called the approach "promising" but said the findings need to be confirmed in a more rigorous study.

She said the very high vitamin A dose used in the trial was noteworthy and potentially a concern, as vitamin A is known to have toxic potential.

"They really need to look carefully at how to monitor the dosing schedule," Tappenden said. "It's an issue that needs to be sorted out for a practicing clinician who is not necessarily used to working with megadoses of vitamin A."
Primary source: Digestive Disease Week
Source reference:
Sato S, et al. "Retinol supplements antiviral action of pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C: Prospective pilot study" DDW 2010; Abstract T2004.


DDW: Telaprevir Said to Benefit Hardest HCV Cases

By John Gever, Senior Editor, MedPage Today
Published: May 08, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

NEW ORLEANS -- Adding an investigational protease inhibitor for hepatitis C virus (HCV) to standard treatment induced rapid and sustained virologic responses in many patients with poor responses to standard therapy alone, researchers said here.

In an open-label extension study, most patients with inadequate or no responses, or who showed renewed viral activity after an initial response to pegylated interferon and ribavirin, succeeded in achieving so-called sustained virologic responses to a second course of treatment that included telaprevir, reported Andrew Muir, MD, of Duke University.

Another analysis of one of these trials also showed that, among patients with inadequate initial responses to the standard regimen, even those with risk factors predicting especially poor responses did well when telaprevir was added, Muir said.

He presented the findings in two sessions here at Digestive Disease Week and at a press conference.

Telaprevir is one of two HCV protease inhibitors now in development, the other being boceprevir. These drugs are widely expected to be the first direct antiviral drugs made available for HCV, with FDA approval possible in 2011.

One of the studies Muir presented involved 117 participants in three earlier trials in the PROVE series who were in the standard-therapy arms and failed to show sustained virologic responses. They were categorized by the type of poor response: null responders (those with little or no change in viral loads), partial responders (initial decrease of at least two logs in HCV RNA but virus still detectable at week 24), and relapses and breakthroughs.

These patients underwent a second round of treatment with PEG-interferon and ribavirin at standard doses with the addition of telaprevir at 750 mg every eight hours. All three drugs were given for 12 weeks, with interferon and ribavirin continued for an additional 12 weeks.

Patients not showing complete responses at week 24 received an additional 24 weeks of interferon and ribavirin.

Muir said more than half of patients, 59%, had sustained virologic responses to the 12 weeks of telaprevir and 24 weeks of standard therapy.

Among the 35 who ended up taking interferon and ribavirin for the full 48 weeks, 52% had sustained responses.

The shorter regimen was not very effective in the subgroup with null responses to standard therapy during the PROVE studies. Only 13% of these patients developed sustained virologic responses during the first 24 weeks. But 57% of those who stayed on therapy for 48 weeks achieved sustained responses, according to Muir.

Among the other subgroups, response rates to the 24-week regimen ranged from 60% to 92%. Only seven patients in those subgroups received 48 weeks of treatment, of whom two obtained sustained responses.

The other study presented by Muir was a post hoc subgroup analysis of responses in "difficult to cure" patients in one of the earlier trials, PROVE3. These were patients who had one or more risk factors previously known to predict poor responses to interferon and ribavirin.

These included:
  • HCV genotype 1
  • Age
  • High baseline viral load
  • Male gender
  • Obesity
  • Bridging fibrosis in the liver 
Participants in PROVE3 had all received prior unsuccessful treatment for HCV, so it was not surprising that, of the 342 patients included in the analysis, most had at least one of these risk factors.

PROVE3 was a randomized trial that assigned patients to interferon and ribavirin at standard doses for 48 weeks with or without 12 weeks of telaprevir, or to 24 weeks of the standard therapy plus 12 weeks of telaprevir. There was also a fourth arm, combining telaprevir and interferon without ribavirin, that was excluded from the new analysis.

Muir reported that, in each major risk-factor group, patients in both telaprevir arms did far better than those receiving the standard therapy alone.

Sustained viral responses were achieved in 44% to 61% of patients receiving telaprevir, compared with 10% to 15% of those receiving only the standard regimen (P<0.0001 for all comparisons), for the following subgroups: males, those older than 50, those with body mass index values of 25 to 30, those with BMI over 30, those with initial viral loads of more than 800,000 IU/mL, and those with bridging fibrosis or cirrhosis.

Patients with the risk factor associated with the worst outcomes -- those with no response at all to initial interferon and ribavirin treatment -- also did better with telaprevir, with 38% obtaining sustained responses.

Multivariate analysis indicated that adding telaprevir increased the chances of achieving a sustained response by nearly nine-fold (odds ratio 8.7, 95% CI 4.6 to 16.7).

In his presentations here, Muir spent little time addressing adverse effects. However, earlier reports from the PROVE series indicated that anemia and skin rashes and pruritus were relatively common with telaprevir.

Philip Schoenfeld, MD, of the University of Michigan in Ann Arbor, who moderated the press conference where Muir spoke, said the results with HCV protease inhibitors have been highly encouraging.

"These agents offer the opportunity for a revolution in the treatment of hepatitis C virus patients, achieving successful eradication of the virus in substantially more patients," he said.

In particular, Schoenfeld added, boceprevir and telaprevir offer "new hope for patients who have failed conventional therapies."

Primary source: Digestive Disease Week
Source reference:
Muir A, et al "Final results of a rollover study assessing telaprevir in combination with peginterferon alfa-2a and ribavirin in chronic HCV patients with well-characterized null response, partial response, viral breakthrough, or relapse after prior PR treatment" DDW 2010; Abstract 311.

Additional source: Digestive Disease Week
Source reference:
Muir A, et al "Improved sustained virologic response (SVR) in "difficult-to-cure" patients treated with telaprevir (T) in combination with peginterferon alfa-2a (P) and ribavirin (R): An analysis from the PROVE3 study" DDW 2010; Abstract T2002


Also See: DDW: New Drug Treatments Hold Promise for Hepatitis C Patients

Overlooked Reason That Physical Activity Fights Hepatitis C

Many don't realize how critical lymphatic fluid movement is for staying healthy with Hepatitis C infection - and that physical activity is the best way to promote lymph flow.

by Nicole Cutler, L.Ac.

Regardless of a person's specific health concerns, experts seem to universally proclaim that exercise is the solution to just about everything. This is especially true when it comes to battling the Hepatitis C virus. While there are several reasons that exercise is beneficial to those with Hepatitis C, its function of encouraging movement in the lymphatic system is often overlooked.

Most people have a general understanding of what the cardiovascular system is and how it functions. This is not the case for the lymphatic system. Despite its importance to our health, a majority of us have little to no concept of the lymphatic system - including where it is, what it does and how it relates to Hepatitis C.

A Brief Overview of the Lymphatic System

The lymphatic system consists of lymph vessels, nodes and organs for circulating lymph fluids. While it helps maintain fluid balance and transport fats and nutrients to the circulatory system, its most important function is to support immune function.

Considered to be one of the most important aspects of our immune system, the lymphatic system carries cellular waste, toxins and pathogens away from the tissues. It can accomplish this seemingly impossible task, because lymphatic fluid:

· bathes every one of our cells

· collects unwanted substances

· removes unwanted substances by transporting it away in its own network of lymph vessels

Connecting the lymphatic system together, the lymph vessels are akin to a microscopic, fine net laced throughout the entire body.

Lymph Flow

Blood vessels and lymph vessels are often next to one another. However, blood and lymphatic fluid's movement through their respective vessels is very different. Blood courses through its vessels because it is pumped by the heart. Unlike the cardiovascular system, the lymphatic system has no pump.

Lymph fluid depends on skeletal muscle contractions to move through lymph vessels. Thus, physical activity is the best way to transport cellular debris, pathogens, cancerous cells and toxins away for removal. Without adequate movement, the cells are left stewing in their own waste products and starving for nutrients, a situation which could only worsen chronic Hepatitis C infection. This is especially problematic for those who lead a relatively inactive lifestyle, such as those who sit in a vehicle driving all day or are parked in front of a computer screen for a majority of their waking hours. In contrast, vigorous exercise has been reported to increase lymph flow by 15 to 30 times more than inactivity.

Applied to Hepatitis C

For those individuals who must manage Hepatitis C infection, one of the goals is to help the liver process its toxic load in any way possible. Aiding the circulation of lymphatic fluid is one small way to accomplish that goal.

Because the livers of those with Hepatitis C may have some degree of impaired function, this organ may not be as effective in its role of detoxification. Thus, those with liver damage commonly have a backup of cellular waste and toxins in their bloodstream - a situation that can lead to more liver damage, cancer or hepatic encephalopathy.

Hepatic encephalopathy occurs when toxic substances normally removed by the liver accumulate in the blood and impair the function of brain cells. Hepatic encephalopathy can lead to decreased cognition, coma and can ultimately be fatal.

By keeping active, those with chronic Hepatitis C can help their liver manage the continual onslaught of waste and toxins. Physical movement is necessary for moving unwanted debris along lymph vessels. This is just one reason why exercise helps reduce demand on the liver and helps keep the immune system healthy - a benefit for anyone regardless of his or her Hepatitis C status.

http://en.wikipedia.org/wiki/Hepatic_encephalopathy, Hepatic Encephalopathy, Retrieved October 17, 2009, Wikimedia Foundation Inc., 2009.

http://infectiousdiseases.about.com/od/glossary/g/lymphatic_system.htm, Definition of Lymphatic System, Ingrid Koo, PhD, Retrieved October 17, 2009, About.com, 2009.

http://lumologie.com.au/Page/TheLymphaticSystem, The Lymphatic System, Retrieved October 16, 2009, Lumologie Pty Ltd 2009.

http://www.cbass.com/lymph.htm, Healthy Lymph System, Healthy Body, Retrieved October 17, 2009, Clarence and Carol Bass, 2009.

http://www.healingdaily.com/exercise/rebounding-for-detoxification-and-health.htm, Why rebounding is so beneficial, Retrieved October 16, 2009, Healing Daily, 2009.

http://www.naturalalternativeshealth.com/lymphatic-therapy.html, Lymphatic Therapy, Retrieved October 16, 2009, Natural Alternatives, 2009


Twenty four-week pe-ginterferon plus ribavirin after interferon-b induction for geno-type 1b chronic hepatitis C

Issue date: 2010-06-26

AIM: To investigate the possibility of shortening the duration of peginterferon (Peg-IFN) plus ribavirin (RBV) combination therapy by incorporating interferon-b (IFN-b) induction therapy.

METHODS: A one treatment arm, cohort prospective study was conducted on seventy one patients. The patients were Japanese adults with genotype 1b chronic hepatitis C, HCV-RNA levels of ≥ 5.0 Log IU/mL or 100 KIU/mL, and platelet counts of ≥ 90 000/mL. The treatment regimen consisted of a 2 wk course of twice-daily administration of IFN-b followed by 24 wk Peg-IFN plus RBV combination therapy. We prolonged the duration of the Peg-IFN plus RBV therapy to 48 wk if the patient requested it.

RESULTS: The patients, including 44% males, were characterized by an median age of 63 years (range: 32-78 years), an median platelet count of 13.9 (range: 9.1-30.6) × 104/mL, 62% IFN-na├»ve, and median HCV-RNA of 6.1 (range: 5.1-7.2) Log IU/mL. The sustained virologic response (SVR) rates were 34% (Peg-IFN: 1-24 wk, n = 61, 95% confidence interval (CI): 24%-47%) and 55% (Peg-IFN: 20-24 wk, n = 31, 95% CI: 38%-71%, P < 0.001; vs Peg-IFN: 1-19 wk). The SVR rate when the administration was discontinued early was 13% (Peg-IFN: 1-19 wk, n = 30, 95% CI: 5%-30%), and that when the administration was pro­longed was 50% (Peg-IFN: 25-48 wk, n = 10, 95% CI: 24%-76%, P < 0.05; vs Peg-IFN: 1-19 wk). In the patients who received 20-24 wk of Peg-IFN plus RBV, only the higher platelet count (≥ 130 000/mL) was significantly correlated with the SVR (odds ratio: 11.680, 95% CI: 2.3064-79.474, P = 0.0024). In 45% (14/31) of the patients with a higher platelet count (≥ 130 000/mL) before therapy, the HCV-RNA level decreased to below 3.3 Log IU/mL at the completion of IFN-b, and their SVR rate was 93% (13/14) after 20-24 wk administration of Peg-IFN plus RBV.

CONCLUSION: These results suggest the possibilities of shortening the duration of Peg-IFN plus RBV combination therapy by actively reducing HCV-RNA levels using the IFN-b induction regimen.

Okushin H, Morii K, Uesaka K, Yuasa S. Twenty four-week pe­ginterferon plus ribavirin after interferon-b induction for geno­type 1b chronic hepatitis C. World J Hepatol 2010; 2(6): 226-232 Available from: URL: http://www.wjgnet.com/1948-5182/full/v2/i6/226.htm DOI: http://dx.doi.org/10.4254/wjh.v2.i6.226


Hepatoma Cell Line That Can Be Infected with Both Hepatitis C and Human Immunodeficiency (HIV-1) Viruses

Posted by Ross Jackson on Sunday, June 27, 2010, 9:56

It is estimated that 250,000 HIV patients in the U.S. are chronically infected with hepatitis C virus (HCV). Co-infection of HCV and HIV is associated with increased morbidity and mortality relative to mono-infection with either virus. Compared to HCV mono-infected individuals, HCV/HIV co-infected individuals experience rapid progression of liver disease, have higher HCV RNA viral levels, decreased cure rates, and increased toxic reactions to anti-HCV therapy. Understanding how these two viruses interact has been difficult because a cell culture system that supports HCV growth in the laboratory was not available. Recently, a continuous culture system to propagate HCV was discovered, however these cells do not express receptors that allow for infection by HIV. The inventors were able to genetically transform these cells (liver cancer) to express HIV receptors and successfully infect them with both viruses. This modified cell culture system will be useful for studying the interactions between HCV and HIV within the same cell and will serve as a model to understand the pathogenesis of HCV/HIV co-infection.