August 10, 2010

KERRY & HONDA: Disrupting a deadly disease

Hepatitis defense can save thousands of lives a year

By Sen. John Kerry and Rep. Michael M. Honda
The Washington Times
6:54 p.m., Tuesday, August 10, 2010

A silent killer is loose in America. It contributes to the death of 15,000 Americans a year and threatens the health of 5.3 million more. It is more common than HIV/AIDS. It is the leading cause of liver cancer - a cancer that is on the rise and continues to be a fatal and costly disease. Yet it remains unrecognized as a serious threat to public health.

This silent killer is viral hepatitis. Most people don't even know they have it until years later, when it causes cancer or liver disease. But we can help avoid such needless tragedies with prevention and surveillance programs and by educating Americans on the pervasive nature of hepatitis B and hepatitis C.

A first step is to change the way viral hepatitis is diagnosed and treated, and that is why we have introduced legislation in the Senate and the House to provide almost $600 million over the next few years to treat this deadly epidemic. Our legislation will make our health care system more efficient. More important, it will save lives.

The bills we have introduced closely mirror the recommendations in a recent report from the Institute of Medicine (IOM), "Hepatitis and Liver Cancer," which calls for a national strategy to prevent and control hepatitis B and C.

The report concludes that the current approach is not working: Americans at risk for hepatitis or living with it do not know it, and health providers are not screening for it. That should come as no surprise because there is no federal funding of core public health services for viral hepatitis. Nor is there any federally funded chronic hepatitis B and C surveillance system.

Not surprisingly, the IOM report recommends increased information and awareness about chronic viral hepatitis among health care providers, social service providers and the public; improved surveillance for hepatitis B and hepatitis C; and better integration of viral hepatitis services.

Our call for a national strategy is not unlike IOM's. Specifically, our bills increase interagency coordination between the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the National Cancer Institute (NCI), the Health Resources and Services Administration (HRSA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Agency for Healthcare Research and Quality (AHRQ) and the Department of Veterans Affairs (VA).

It sets up programs to improve understanding of hepatitis B and C and requires the CDC to integrate them into existing immunization, prevention and control programs and support counseling. It also expands current vaccination programs and establishes a national chronic and acute hepatitis B and C surveillance program to identify incidence and prevalence in viral hepatitis and liver cancer.

Hepatitis B is 100 times more infectious than HIV and, left untreated, can cause liver disease, liver cancer and premature death decades after infection. About 2 billion people worldwide have been infected with hepatitis B, and about 170 million people are chronically infected with hepatitis C. Tragically, two-thirds of those infected, on average, are unaware of their status, which increases the chance of spreading the disease.

We cannot afford to be silent anymore. Our fellow citizens are dying daily because our nation lacks a comprehensive prevention, education and medical management program. Each year, about 15,000 people die from liver cancer or liver diseases related to hepatitis B and hepatitis C. That's more than 40 deaths every day.

Beyond the tragic and preventable loss of human life, there is the economic cost. Although the costs of education, research and treatment are not trivial, they are substantially less than the annual health care cost attributable to viral hepatitis in the United States.

Without effective prevention and vaccination methods, chronic hepatitis B and C are expected to cost our country billions of dollars in the coming years. The baby-boomer population is estimated to account for two out of every three cases of chronic hepatitis C. As these Americans age and enter into Medicare, they are likely to develop complications and require expensive medical interventions. In the next decade, the costs of hepatitis C to commercial insurance and Medicare will more than double, and within 20 years, Medicare costs will increase fivefold. Projecting further out, over the next 20 years, total medical costs for patients with hepatitis C infection could increase more than 2.5 times - from $30 billion to more than $85 billion.

Contrast the costs for early detection and intervention with the costs for treatment post-infection. The costs for hepatitis B vaccinations vary but range from $75 to $165, whereas treatment can cost up to $16,000 per year. Screening for hepatitis C is also relatively inexpensive compared to treatment, which can cost up to $25,000 per year. Untreated, these infections will develop into liver disease that can cost up to $110,000 per hospital admission.

Moreover, the United States is entering an era of effective therapy for chronic viral hepatitis. Improvements in current treatment and therapies are likely to be approved in the next several years that can double cure rates and cut the length of treatment in half and could confer increasingly greater benefits.

Until then, though, we have no time to waste. Our legislation, along with strategic investments in public health and prevention programs, will save billions of dollars and the lives of tens of thousands of people all over America. We urge our colleagues to support activities that promote early detection and education. Our legislation will sound the alarm on this silent killer.

Sen. John Kerry is a Massachusetts Democrat, and Rep. Michael M. Honda is a California Democrat.

Source
publication pdf attached, figure 5 is very useful

"Rapid virological response was highly associated with SVR in all treatment groups. In the 28-week treatment groups, 82% (54/66) of patients in the PR4/PRB24 group and 74% (32/43) in the PRB28 group who had rapid virological response achieved SVR. In the 48-week treatment groups, 94% (62/66) of patients assigned to PR4/PRB44 and 84% (32/38) assigned to PRB48 who achieved undetectable hepatitis C virus RNA by week 4 of boceprevir achieved SVR. Achievement of undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy was also highly predictive of SVR in the 48-week treatment groups (table 3; figure 4). We noted a greater SVR in patients who cleared virus between weeks 4 and 12 of boceprevir in the PR4/PRB44 group compared with the PR4/PRB24 group (table 3).....

Thus, in the treatment of genotype 1 hepatitis C virus, nearly two-thirds of patients achieved undetectable hepatitis C virus RNA levels at week 4 of boceprevir therapy after PR4, and these individuals can be treated for 28 weeks with high SVR. Of the additional 18% (19/103) of patients who go on to achieve undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy, 79% (15/19) of patients benefit from extending therapy with peginterferon alfa-2b, ribavirin, and boceprevir to 48 weeks. Only one patient in the boceprevir groups who developed undetectable hepatitis C virus RNA after week 12 of boceprevir therapy went on to SVR."

"The lead-in (PR4) allowed us to examine the relation of peginterferon and ribavirin responsiveness at week 4 to SVR with boceprevir-containing regimens. In the PR4 28-week or 48-week groups, SVR was similar in participants with greater than 1·5 log10 reduction in hepatitis C virus RNA from baseline before the addition of boceprevir. Higher SVR was noted in participants who received PRB for 44 weeks with less than 1·5 log10 reduction from baseline at PR4 (figure 5). In patients with less than 1 log10 reduction with PR4, 55% (95% CI 32-76) SVR was noted in the PR4/PRB44 group.....

The lead-in can identify null responders to peginterferon alfa-2b and ribavirin, who seem to be at greatest risk for treatment failure with specifically targeted therapies and for development of resistance. However, in our cohort, a substantial proportion of null responders during the lead-in period went on to achieve SVR with the addition of boceprevir.....In the novel lead-in approach, we recorded increased SVR and a reduction in relapse and breakthrough, and allowed for potential determination of treatment duration on the basis of responsiveness to the PR4 lead-in. However, in the direct comparison between lead-in and non-lead-in groups, relapse reduction did not differ significantly, although the absence of a statistically conclusive result is not surprising since the sample size did not allow detection of modest differences between lead-in and non-lead-in groups. The mutations recorded in participants with viral breakthrough were consistent what those that have been previously reported with NS3 inhibitors with no new mutations noted.23-26 The clinical relevance of these mutations is unknown, and long-term follow-up is in progress."

"The SVR rate for black people in the PR48 control group was 13% (two of 16) and as high as 53% (eight of 15) in patients treated with boceprevir for 48 weeks (table 4). In patients with cirrhosis, the SVR rate was 67% (ten of 15) in the combined longer duration boceprevir groups versus 25% (two of eight) in the control group; in patients without cirrhosis, the SVR rate for the combined longer duration boceprevir groups was 71% (136/191) compared with 39% (37/96) for the control group."

"We also noted increased rates of SVR in patients who developed anaemia (haemoglobin <100 g/L) irrespective of treatment group. Epoetin alfa was used by 40% (236/595) of patients and was allowed at investigator discretion. The use of this drug in those with anaemia was also associated with an improved SVR (table 4).....

A study suggested that development of anaemia with haemoglobin less than 100 g/L is associated with increased SVR in patients receiving pegylated interferon and ribavirin; anaemia is potentially a surrogate marker of increased ribavirin concentration and the addition of epoetin alfa might allow patients to remain on therapy"

"These results are consistent with those recorded in two trials of another NS3 protease inhibitor, telaprevir, in combination with peginterferon and ribavirin, in populations that excluded those with histological cirrhosis and had fewer black people.17, 18 In one of these studies,17 undertaken in the USA, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 20% higher than in the control group of 48 weeks of peginterferon and ribavirin (61% [48/79] vs 41% [31/75]); and in the telaprevir group receiving 48 weeks of treatment with 12 weeks of telaprevir added to 48 weeks of peginterferon and ribavirin, the SVR rate was 26% higher than it was in the 48-week control group (67% [53/79] vs 41% [31/75]). In the other study,18 undertaken in Europe, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 23% higher than in the 48-week control group (69% [56/81] vs 46% [38/82]). Although the study designs and populations differed, in our study, SVR rates were 17-19% higher than in the control group in the 28-week boceprevir group, and 29-37% higher than control in the 48-week boceprevir groups."

Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial

The Lancet, Early Online Publication, 9 August 2010

Dr Paul Y Kwo MD a Corresponding AuthorEmail Address, Eric J Lawitz MD b, Jonathan McCone MD c, Prof Eugene R Schiff MD d, Prof John M Vierling MD e, David Pound MD f, Mitchell N Davis DO g, Joseph S Galati MD h, Stuart C Gordon MD i, Natarajan Ravendhran MD j, Prof Lorenzo Rossaro MD k, Frank H Anderson MD l, Prof Ira M Jacobson MD m, Raymond Rubin MD n, Kenneth Koury PhD o, Lisa D Pedicone PhD o, Clifford A Brass MD o, Eirum Chaudhri MD o, Janice K Albrecht PhD o

Summary

Background

Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin.

Methods

In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 µg/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670.

Findings

Patients in all four boceprevir groups had higher rates of SVR than did the control group

- (58/107 [54%, 95% CI 44-64], p=0·013 for PRB28;
- 58/103 [56%, 44-66], p=0·005 for PR4/PRB24;
- 69/103 [67%, 57-76], p<0·0001 for PRB48; and
- 77/103 [75%, 65-83], p<0·0001 for PR4/PRB44;
vs 39/104 [38%, 28-48] for PR48 control).

Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]).

Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.

Interpretation

In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone.

Funding
Merck.

Introduction

Chronic hepatitis C virus affects about 170 million people worldwide. Cirrhosis induced by hepatitis C virus is the most common indication for liver transplantation and is a major contributor to the worldwide increase in the incidence of hepatocellular cancer.1, 2 Standard-of-care treatment of genotype 1 hepatitis C virus is pegylated interferon and ribavirin for 48 weeks, which results in sustained virological response (SVR) in about 40-50% of individuals.3-5 SVR rates for black patients treated with standard of care are substantially lower; in two studies undertaken almost exclusively in genotype 1 individuals, 19-28% of black people achieved SVR versus 52% of non-Hispanic white people.6, 7 Those who achieve SVR can have long-term benefits with improvement in degrees of liver fibrosis, reduction in complications of chronic liver disease, and improved quality of life.8 Studies have shown that response-guided therapy can allow tailoring of duration of treatment, with week 4 viral clearance (rapid virological response) allowing shorter duration of therapy than for those who clear virus at week 12 (complete early virological response).9-12

Up until now, treatment for this disease has consisted of therapies to stimulate the immune system and interfere in a non-specific manner with viral replication. Research has focussed on therapies that inhibit hepatitis C virus proteins that are essential for intracellular replication; these drugs are referred to as direct-acting antiviral agents.13 Boceprevir is a novel peptidomimetic NS3 protease inhibitor that forms a covalent reversible complex with the NS3 protease in vitro and has shown potent antiviral activity in the hepatitis C virus replicon system, and in patients who previously showed no response to peginterferon administered with or without ribavirin.14, 15 In a dose-ascending study in null responders,16 boceprevir, when given in combination with peginterferon alfa-2b and ribavirin, was associated with a modest incremental haemoglobin reduction, as has been recorded with other direct-acting antiviral agents in the NS3 inhibitor class.17, 18 The NS3 protease inhibitor telaprevir has also shown significantly higher rates of SVR than has standard of care in patients with genotype 1 disease when given for 12 weeks in combination with regimens of peginterferon and ribavirin lasting 12, 24, or 48 weeks.17, 18 Although rates of SVR in the telaprevir groups were higher than were those recorded with standard of care, investigators noted higher drop-out rates due to increased side-effects.

The aim of the hepatitis C virus SPRINT-1 (Serine Protease Inhibitor Therapy-1) study was to establish the safety and efficacy of boceprevir when added to peginterferon and ribavirin. We investigated treatment durations of 28 weeks versus 48 weeks, with and without a 4-week lead-in of peginterferon alfa-2b and ribavirin before the addition of boceprevir for 24 or 44 weeks, and the efficacy of low-dose ribavirin. The rationale for the 4-week lead-in was to allow pegylated interferon and ribavirin to reach steady-state concentrations before the addition of boceprevir such that backbone drug concentrations would be at an optimum and potentially reduce the likelihood for emergence of drug-resistant mutations by reducing viral levels.19-21 Part 2 of this study, which was added after enrolment in part 1 was completed, was undertaken to assess the possibility of use of a lower dose of ribavirin to reduce treatment complications, mainly anaemia. Since boceprevir and other NS3 protease inhibitors have been associated with a modest reduction in haemoglobin, weight-based low-dose (400-1000 mg per day) versus standard-dose (800-1400 mg per day) ribavirin was assessed to establish whether efficacy could be maintained while reducing anaemia. Lastly, we examined the rates of viral clearance and SVR.

Results

765 patients were screened and 595 were enrolled in 43 US, four Canadian, and 20 European Union sites. All efficacy and safety analyses were based on 595 patients who were randomly assigned and received at least one dose of medication. Table 1 shows baseline characteristics, and figures 2 and 3 show patient disposition for all groups.

Table 2 shows virological response. Irrespective of treatment duration or use of PR4 as lead-in, SVR rates in all four boceprevir groups in part 1 were significantly better than were those in the PR48 control group. In the 28-week treatment groups, the SVR was 56% (95% CI 46-66) in the PR4/PRB24 group (p=0·005 vs control) and 54% (44-64) in the PRB28 group (p=0·013 vs control). In the 48-week treatment groups, the SVR was 75% (65-83) in the PR4/PRB44 group (p<0·0001 vs control) compared with 67% (57-76) in the PRB48 group (p<0·0001 vs control). In part 2, the SVR for low-dose PRB48 was 36% (24-49).

We noted significantly lower relapse rates in the 48-week treatment groups compared with PR48 control (PRB48, p=0·0079; PR4/PRB44, p=0·0002; table 2). Although the relapse rates were higher in the 28-week than in the 48-week treatment groups, patients in the 28-week groups who had rapid hepatitis C virus RNA clearance at week 4 of boceprevir had substantially lower relapse rates than did those who did not have rapid viral clearance (p<0·0001; table 2). Low-dose PRB was associated with high relapse rates. Of note, we recorded no viral breakthrough in control groups that did not contain boceprevir (table 2). In the boceprevir groups, the lead-in groups were associated with a modestly lower rate of breakthrough than were the groups with no lead in. Combining across treatment groups, the rate of breakthrough in the boceprevir lead-in groups was 4% (nine of 206) compared with 9% (19/210) in the boceprevir groups with no lead in (p=0·057). By population sequencing, the major mutations (in >25% of samples) were V36M, T54S, and R155K, with less common (in 5% to <25%) mutations including T54A, V55A, R155T, A156S, V158I, and V170A (data not shown). Infrequent mutations (in <5% of samples) included V36A, V36L, and I170T (data not shown).

Rapid virological response was highly associated with SVR in all treatment groups. In the 28-week treatment groups, 82% (54/66) of patients in the PR4/PRB24 group and 74% (32/43) in the PRB28 group who had rapid virological response achieved SVR. In the 48-week treatment groups, 94% (62/66) of patients assigned to PR4/PRB44 and 84% (32/38) assigned to PRB48 who achieved undetectable hepatitis C virus RNA by week 4 of boceprevir achieved SVR. Achievement of undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy was also highly predictive of SVR in the 48-week treatment groups (table 3; figure 4). We noted a greater SVR in patients who cleared virus between weeks 4 and 12 of boceprevir in the PR4/PRB44 group compared with the PR4/PRB24 group (table 3).

Table 3 Rates of sustained virological relapse by time to first undetectable hepatitis C virus RNA


The lead-in (PR4) allowed us to examine the relation of peginterferon and ribavirin responsiveness at week 4 to SVR with boceprevir-containing regimens. In the PR4 28-week or 48-week groups, SVR was similar in participants with greater than 1·5 log10 reduction in hepatitis C virus RNA from baseline before the addition of boceprevir. Higher SVR was noted in participants who received PRB for 44 weeks with less than 1·5 log10 reduction from baseline at PR4 (figure 5). In patients with less than 1 log10 reduction with PR4, 55% (95% CI 32-76) SVR was noted in the PR4/PRB44 group.

A multivariate regression analysis of pooled boceprevir groups in part 1 of the study was done by investigation of baseline factors associated with SVR. These factors included low viral load (²600 000 IU/mL), non-black race, lower platelet count, and genotype 1b. In the control group of this study which received the standard of care, black people and those with cirrhosis had a lower SVR than did participants of non-black race and with no cirrhosis (table 4). The SVR rate for black people in the PR48 control group was 13% (two of 16) and as high as 53% (eight of 15) in patients treated with boceprevir for 48 weeks (table 4). In patients with cirrhosis, the SVR rate was 67% (ten of 15) in the combined longer duration boceprevir groups versus 25% (two of eight) in the control group; in patients without cirrhosis, the SVR rate for the combined longer duration boceprevir groups was 71% (136/191) compared with 39% (37/96) for the control group.

We also noted increased rates of SVR in patients who developed anaemia (haemoglobin <100 g/L) irrespective of treatment group. Epoetin alfa was used by 40% (236/595) of patients and was allowed at investigator discretion. The use of this drug in those with anaemia was also associated with an improved SVR (table 4).

The most common adverse events in the boceprevir groups, as reported by investigators, were fatigue, anaemia, nausea, and headache-a side-effect profile generally similar to that recorded in patients receiving PR48 control. The rate of dysgeusia and anaemia was higher in the boceprevir groups than in other groups (table 5). In the boceprevir groups, we detected nadir haemoglobin concentrations of 85-100 g/L in those who developed anaemia; and haemoglobin concentrations less than 85 g/L were rare (table 6). Dose modifications of ribavirin were similar in boceprevir groups compared with the PR48 control group, and boceprevir dose modifications were rare (table 7). We recorded an overall higher discontinuation rate in the boceprevir groups than in the control group (table 7). Treatment discontinuations attributable to adverse events ranged from 9% to 19% in the groups receiving boceprevir therapy compared with 8% for the PR48 group, with two patients discontinuing treatment because of anaemia in the boceprevir groups (table 7). The rate of adverse events categorised as skin and subcutaneous tissue disorders was similar in boceprevir-containing regimens (159/416, 38%) and the control group (38/104, 37%).

Discussion

The results of this phase 2 trial have shown that an optimum dose of boceprevir (800 mg three times a day), when added to the standard of care for treatment of chronic genotype 1 hepatitis C virus, significantly increased SVR in both 28-week and 48-week regimens compared with the control of peginterferon alfa-2b and ribavirin. Responses in the 48-week boceprevir groups were substantially higher than were those in the 28-week groups, with a near doubling of SVR in the PR4/PRB44 group. The use of low-dose ribavirin in combination with peginterferon and boceprevir, while reducing haematological toxic effects, did not improve SVR rates compared with control.

These results are consistent with those recorded in two trials of another NS3 protease inhibitor, telaprevir, in combination with peginterferon and ribavirin, in populations that excluded those with histological cirrhosis and had fewer black people.17, 18 In one of these studies,17 undertaken in the USA, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 20% higher than in the control group of 48 weeks of peginterferon and ribavirin (61% [48/79] vs 41% [31/75]); and in the telaprevir group receiving 48 weeks of treatment with 12 weeks of telaprevir added to 48 weeks of peginterferon and ribavirin, the SVR rate was 26% higher than it was in the 48-week control group (67% [53/79] vs 41% [31/75]). In the other study,18 undertaken in Europe, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 23% higher than in the 48-week control group (69% [56/81] vs 46% [38/82]). Although the study designs and populations differed, in our study, SVR rates were 17-19% higher than in the control group in the 28-week boceprevir group, and 29-37% higher than control in the 48-week boceprevir groups.

In black participants and in those with cirrhosis, the addition of boceprevir to standard of care improved SVR. These preliminary results in a fairly small number of patients suggest that the addition of boceprevir to peginterferon alfa-2b and ribavirin will improve SVR in these difficult-to-treat populations. This study assessed the use of a PR4 lead-in before the addition of boceprevir, as well as the effect of starting all three drugs concomitantly, and compared these groups with PR48 control. In the novel lead-in approach, we recorded increased SVR and a reduction in relapse and breakthrough, and allowed for potential determination of treatment duration on the basis of responsiveness to the PR4 lead-in. However, in the direct comparison between lead-in and non-lead-in groups, relapse reduction did not differ significantly, although the absence of a statistically conclusive result is not surprising since the sample size did not allow detection of modest differences between lead-in and non-lead-in groups. The mutations recorded in participants with viral breakthrough were consistent what those that have been previously reported with NS3 inhibitors with no new mutations noted.23-26 The clinical relevance of these mutations is unknown, and long-term follow-up is in progress.

The viral response during the lead-in could help to predict best possible treatment duration. Patients achieving less than 1·5 log10 reduction in viral level after PR4 benefit most from a treatment duration of 48 weeks, whereas those with greater than 1·5 log10 reduction show similar SVR irrespective of treatment duration of 28 weeks or 48 weeks. The lead-in can identify null responders to peginterferon alfa-2b and ribavirin, who seem to be at greatest risk for treatment failure with specifically targeted therapies and for development of resistance. However, in our cohort, a substantial proportion of null responders during the lead-in period went on to achieve SVR with the addition of boceprevir.16, 27

In all groups, rapid virological response was highly predictive of SVR. We also recorded high rates of rapid virological response in the 48-week treatment groups. Participants who cleared virus between weeks 4 and 12 of boceprevir therapy were more likely to go on to SVR if they received 48 weeks of treatment rather than 28 weeks. Thus, in the treatment of genotype 1 hepatitis C virus, nearly two-thirds of patients achieved undetectable hepatitis C virus RNA levels at week 4 of boceprevir therapy after PR4, and these individuals can be treated for 28 weeks with high SVR. Of the additional 18% (19/103) of patients who go on to achieve undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy, 79% (15/19) of patients benefit from extending therapy with peginterferon alfa-2b, ribavirin, and boceprevir to 48 weeks. Only one patient in the boceprevir groups who developed undetectable hepatitis C virus RNA after week 12 of boceprevir therapy went on to SVR.

We noted no new adverse events or treatment-limiting toxic effects associated with boceprevir-containing regimens in this trial compared with those recorded in patients receiving peginterferon and ribavirin. No increases in skin or subcutaneous adverse events were noted in the boceprevir-containing groups compared with the control groups. Higher rates of both anaemia and dysgeusia were noted in the boceprevir-containing regimens than in the control group, although stopping treatment for anaemia was rare. Haemoglobin reductions in the PRB48 low-dose group were less than those in the control group and in any of the full-dose PRB groups in part 1, and similar to the haemoglobin reduction in the PR48 group of part 1 of the study. In this study, use of epoetin alfa was allowed at the investigator's discretion and was associated with improved SVR. A study suggested that development of anaemia with haemoglobin less than 100 g/L is associated with increased SVR in patients receiving pegylated interferon and ribavirin; anaemia is potentially a surrogate marker of increased ribavirin concentration and the addition of epoetin alfa might allow patients to remain on therapy.28 In our study, the development of anaemia and the use of epoetin alfa were associated with improved SVR in the boceprevir-containing regimens. However, since there was no randomisation for use of epoetin alfa in this study, the contributions of anaemia and epoetin alfa use to improved SVR with boceprevir remains to be established. The role of epoetin alfa as an adjuvant in patients receiving pegylated interferon and ribavirin in addition to therapy with direct-acting antiviral agents deserves further study. We recorded a higher drop-out rate in the boceprevir-containing groups than in the control group, as has been noted when other direct-acting antiviral agents are added to peginterferon alfa-2b and ribavirin.17 This findings suggests that treating physicians might need experience with these agents to ensure patient adherence and manage side-effects, as was noted with the introduction of ribavirin to interferon therapy for hepatitis C virus infection.17, 18

There are potential limitations of this study which deserve mention. This was an open-label study with regard to the administration of boceprevir because of the complex study design with comparisons of lead-in and non-lead-in groups, and differing treatment durations. However, all assays were done by an independent commercial laboratory that did not have access to participant treatment assignments. The primary and other key study endpoints were based on hepatitis C virus RNA level-an outcome that is not subject to bias. Another possible limitation concerns the stratification of patients as with or without cirrhosis. We required a liver biopsy sample to be taken within 5 years of enrolment into the study. A patient who tested negative for cirrhosis 5 years before the beginning of the study could have developed cirrhosis in the intervening years. Thus patients with cirrhosis could have been mischaracterised as being non-cirrhotic, biasing the results in favour of the population with this disease. Therefore, the promising results obtained in patients with cirrhosis who received boceprevir will need confirmation in larger trials that are in progress.

In conclusion, boceprevir, in combination with pegylated interferon and ribavirin, achieved high SVR rates with 28 weeks of therapy in most patients and is safe and effective for use up to 48 weeks in the few patients who benefit from longer duration of therapy. We also recorded increased response rates in difficult-to-treat groups, including black participants and those with cirrhosis. The use of PR4 lead-in before the addition of boceprevir improves SVR over a 48-week duration, and reduces viral breakthrough and relapse. A large confirmatory trial is in progress and will define the best treatment regimen for the use of boceprevir in the treatment of genotype 1 chronic hepatitis C virus infection.

Source
publication pdf attached, figure 5 is very useful

Andrew J. Muir 1,2,*,, Mitchell L. Shiffman 3, Atif Zaman 4, Boris Yoffe 5, Andrew de la Torre 6, Steven Flamm 7, Stuart C. Gordon 8, Paul Marotta 9, John M. Vierling 10, Juan Carlos Lopez-Talavera 11, Kelly Byrnes-Blake 12, David Fontana 12, Jeremy Freeman 12, Todd Gray 12, Diana Hausman 12, Naomi N. Hunder 12, Eric Lawitz 13

Hepatology Article first published online: 14 MAY 2010

"The findings from this study offer evidence that PEG-IFN-λ, given QW for 4 weeks, exhibits potent antiviral effects against HCV with the potential for an improved tolerability profile with respect to that traditionally observed for PEG-IFN-α. These results are being tested in larger randomized controlled trials enrolling treatment-naive patients."

ABSTRACT

Interferon lambda 1 (IFN-λ1) is a type III IFN that produces intracellular responses similar to those of IFN-α but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-λ) at 1.5 or 3.0 µg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-α-based treatment. Part 2 evaluated weekly doses of PEG-IFN-λ ranging from 0.5 to 2.25 µg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-λ at 1.5 µg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-λ dose levels (from 0.5 to 3.0 µg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-λ. Most DLT occurred in patients with high PEG-IFN-λ exposure. Conclusion: Weekly PEG-IFN-λ with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV. (HEPATOLOGY 2010;)

The World Health Organization estimates that 180 million people worldwide (3% of the world population) are infected with hepatitis C virus (HCV), and 130 million of these are chronic HCV carriers.1 Chronic HCV infection is responsible for 50% to 76% of all liver cancer cases, two-thirds of all liver transplants in the developed world, and considerable morbidity and mortality. Identifying effective treatments for chronic HCV infection is therefore a global health priority.1

Consensus guidelines for the treatment of hepatitis C recommend a regimen of pegylated interferon alfa (PEG-IFN-α) and ribavirin (RBV).2 However, this treatment regimen results in sustained virological response (SVR) rates of only 40% in patients with genotype 1 HCV, and associated adverse events include flu-like symptoms, fatigue, depression, anxiety, and bone marrow suppression, which results in anemia, neutropenia, and thrombocytopenia.2-6 PEG-IFN-α is contraindicated in patients with major uncontrolled depressive illness and should be used with caution in patients with any psychiatric illness.2, 5-7 Other contraindications for the use of interferon alpha (IFN-α)-based regimens include hepatic decompensation, autoimmune disease, and severe concurrent medical disease such as chronic obstructive pulmonary disease, congestive heart failure, or significant coronary artery disease.2, 6, 7 In addition to the negative impact on quality of life, adverse events and laboratory abnormalities often lead to dose reductions or discontinuation of IFN-α therapy, which further compromises efficacy.2, 3, 8, 9

IFN-λ1, also known as interleukin-29 (IL-29), is a type III IFN with functional similarities to type I IFNs, which include IFN-α and IFN-ß. Like IFN-α and IFN-ß, IFN-λ1 is induced in response to viral infections such as hepatitis C and has demonstrated antiviral activity in vitro, including inhibition of HCV RNA replication in the replicon model.10 IFN-λ1 interacts with the structurally unique IFN-λ1 receptor complex to stimulate an intracellular response through phosphorylation of the Janus kinase/signal transducer and activator of transcription pathway (similar to the mechanism of action of IFN-α) and leads to the up-regulation of IFN-stimulated genes and an antiviral effect.11, 12 Unlike the widely distributed IFN-α receptor, expression of the IFN-λ1 receptor is more restricted. Although all cell types in the liver express the IFN-α receptor, the IFN-λ1 receptor is found only in hepatocytes. Similarly, although all peripheral blood leukocytes, including B, T, and natural killer cells, neutrophils, and monocytes, express the IFN-α receptor, messenger RNA of the IFN-λ1 receptor is not expressed in hematopoietic cells with the exception of B lymphocytes.10, 13 The limited distribution of the IFN-λ1 receptor suggests the potential for reduced adverse events with IFN-λ1-based therapy in comparison with IFN-α-based therapy along with preservation of the antiviral effect in HCV.

PEG-IFN-λ, a conjugate of a recombinant form of human IFN-λ1 and a 20-kDa linear polyethylene glycol chain, is currently under development for the treatment of chronic HCV infection. A phase 1a, placebo-controlled, dose escalation study of single subcutaneous doses of PEG-IFN-λ in healthy subjects was recently completed.14 PEG-IFN-λ was well tolerated at pharmacologically active doses without the toxicities typically associated with PEG-IFN-α. The estimated half-life was 50 to 80 hours, and the time to the maximum concentration was 8 to 24 hours. PEG-IFN-λ, starting at the 1.5 µg/kg dose, demonstrated dose-dependent biological activity with the induction of increases in serum ß2-microglobulin (ß2M). Here we describe the results of a three-part study assessing the safety and antiviral activity of PEG-IFN-λ with or without RBV over 4 weeks in patients infected with genotype 1 chronic HCV.

Patients and Methods

Study Design.

This was a three-part dose and schedule escalation study of PEG-IFN-λ administered subcutaneously as a single agent or in combination with RBV in patients chronically infected with HCV genotype 1 who had relapsed after IFN-α-based treatment (parts 1 and 2) or who were naive to treatment (part 3). Part 1 of the study evaluated escalating doses of PEG-IFN-λ monotherapy administered either every 2 weeks (Q2W) or weekly (QW) for a total of 4 weeks. Parts 2 and 3 of this study evaluated a range of doses of PEG-IFN-λ administered QW in combination with RBV twice daily for 4 weeks. All patients were followed for at least 4 weeks after the completion of treatment.

Figure 1 summarizes the treatment schema for the three parts of the study. PEG-IFN-λ doses ranging from 0.5 to 3.0 µg/kg were evaluated. PEG-IFN-λ was supplied at a concentration of 10 mg/mL, and a two-step dilution was required to achieve the final dose for subcutaneous administration. No dose modifications were allowed. In parts 2 and 3, RBV (Copegus, Roche Laboratories, Inc., Nutley, NJ) was administered orally twice daily to achieve a total dose of 1000 mg for patients < 75 kg or 1200 mg for patients ≥ 75 kg. The primary endpoints of the study were safety and tolerability. Secondary endpoints included HCV RNA reduction and pharmacokinetic analysis of PEG-IFN-λ serum concentrations.

Each cohort consisted of at least six evaluable patients. To be considered evaluable, a patient had to have completed all study visits through day 29 (Q2W cohorts) or day 36 (QW cohorts) unless the reason for not doing so was PEG-IFN-λ-related toxicity. A dose level or schedule was considered not tolerated if two or more patients experienced dose-limiting toxicity (DLT) or if two or more patients were unable to receive all planned doses because of treatment-related toxicity. Data from each cohort were reviewed by a safety monitoring committee.

Patients.

Parts 1 and 2 enrolled patients with chronic HCV infection who had relapsed after at least 12 weeks of prior treatment for HCV with either PEG-IFN-α or another IFN-α in combination with RBV. Part 3 enrolled treatment-naive patients. Patients had HCV genotype 1 infection and serum HCV RNA levels ≥ 100,000 IU/mL at enrollment. Inclusion criteria included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 2.5 times the upper limit of normal with no evidence of decompensated liver disease or hepatocellular carcinoma and documented liver biopsy within 2 years of study enrollment with an Ishak score ≤ 4.15 Patients were excluded if they had significant cardiac disease or a medical condition requiring immunosuppressive therapy. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practice guidelines and requirements of the regulatory authorities at each institution. All patients provided written, informed consent.

Safety Assessments.

All patients who received at least one dose of PEG-IFN-λ were included in the safety analyses. The evaluation of safety included adverse event monitoring, physical examination, clinical laboratories (hematology and serum chemistry), electrocardiogram, and echocardiogram. The National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) was used to evaluate adverse event severity and laboratory toxicities.

DLT included any clinical adverse event ≥ grade 3 in severity that was at least possibly related to PEG-IFN-λ treatment, with the exceptions of transient (<72-hour) grade 3 fatigue, fever, or rigor. In addition, a >5-fold increase in ALT or AST levels from the baseline (≥grade 2) or a >2-fold increase in ALT or AST levels from the baseline (≥grade 2) with a grade 2 elevation in bilirubin was considered DLT. If the ALT or AST level increased to more than 3 times the baseline (≥grade 2) or more than 7 times the upper limit of normal, but the bilirubin level or international normalized ratio did not increase to grade 2, PEG-IFN-λ was to be held until the ALT or AST level returned to less than 2 times the baseline value.

Pharmacokinetics.

Pharmacokinetic samples were collected at selected time points throughout the study. Samples were analyzed with a fully validated method developed at ZymoGenetics with mesoscale discovery electrochemiluminescent technology to quantify the PEG-IFN-λ serum concentration. The lower limit of quantification of the assay was 0.125 ng/mL in human serum. The PEG-IFN-λ serum concentration versus time profile for each patient was evaluated by noncompartmental methods with the software WinNonlin 5.2.1 (Pharsight Corp., Cary, NC). The maximum serum concentration (Cmax) and the area under the curve (AUC0-t) were estimated for each patient.

Immunogenicity.

Serum samples for evaluating antibody responses directed against PEG-IFN-λ were collected and analyzed with a fully validated method developed at ZymoGenetics with mesoscale discovery electrochemiluminescent technology to detect antibodies to PEG-IFN-λ1. Analysis was performed by a tiered approach designed to confirm reactivity, quantify the antibody titer, and demonstrate specificity. Samples that were confirmed to be reactive and demonstrated specificity to the drug product were assayed for neutralizing activity in a cell-based assay. The lower limit of assay detection was 0.1 µg/mL. The cell-based neutralizing bioassay was qualitative in nature.

Pharmacodynamics.

Samples were collected for pharmacodynamic studies at selected time points during the study. ß2M levels were assessed with a competitive binding assay (R&D Systems, Minneapolis, MN). The lower limit of assay quantification was 0.4 µg/mL.

Efficacy Assessments.

HCV RNA levels were measured with the COBAS TaqMan HCV test (version 2.0, Roche Molecular Diagnostics, Pleasanton, CA) with a lower limit of detection of 25 IU/mL. A central laboratory with expertise in the serial measurement of HCV RNA levels was used (Covance, Indianapolis, IN).

Data Analysis Methods.

No formal hypothesis was proposed; however, a cohort size of six patients would allow for a greater than 80% probability of detecting an event with a true population incidence of 25% and allow an evaluation of antiviral activity. The presented data represent an intent-to-treat population. All statistical analyses were performed with SAS (version 9.1.3 or higher, SAS Institute, Inc., Cary, NC) or other commercially available validated software.

RESULTS

Patient Demographics and Baseline Characteristics.

Fifty-six patients were enrolled from 10 sites in the United States: 24 with treatment-relapse disease in part 1, 25 with treatment-relapse disease in part 2, and 7 with treatment-naive disease in part 3 (Fig. 1). All but one patient completed the study through day 59. One patient in the cohort receiving 1.5 µg/kg PEG-IFN-λ QW plus RBV discontinued dosing after receiving PEG-IFN-λ through day 8 because of an adverse drug reaction to meperidine that was deemed unrelated to PEG-IFN-λ. Data from this patient were excluded from the efficacy assessment.

Patient demographics are shown in Table 1. All treatment-relapse patients had received at least one previous course of therapy with a PEG-IFN-α plus RBV except for two patients, one of whom had previously received treatment with albinterferon alfa-2b plus RBV and one of whom had previously received interferon alfacon-1.

Safety and Tolerability.

PEG-IFN-λ was well tolerated by most patients. Four of 56 patients (7%) had one or more doses withheld because of treatment-related toxicity. Most adverse events were mild or moderate in severity. Table 2 summarizes adverse events occurring in at least three patients in all cohorts combined. The most common adverse events were fatigue (29%), nausea (12%), myalgia (11%), and headache (9%). Among treatment-relapse patients, fatigue, nausea, myalgia, headache, diarrhea, irritability, pruritis, and insomnia were more commonly observed in patients treated with PEG-IFN-λ in combination with RBV versus those receiving single-agent therapy. PEG-IFN-λ plus RBV therapy was very well tolerated by treatment-naive patients, with fatigue, headache, and chills each reported by one of seven patients (14%) and with no patients reporting nausea, myalgia, diarrhea, irritability, pruritis, anorexia, influenza-like illness, or insomnia. The incidence of adverse events did not appear to be dose-related; adverse events were reported in 33.3%, 50%, 50%, and 50% of patients in part 1 cohorts receiving 1.5 µg/kg PEG-IFN-λ Q2W, 3.0 µg/kg PEG-IFN-λ Q2W, 1.5 µg/kg PEG-IFN-λ QW, and 3.0 µg/kg PEG-IFN-λ QW, respectively. Similarly, in part 2 (PEG-IFN-λ plus RBV), adverse events were reported in 83.3%, 83.3%, 85.7%, and 83.3% of patients receiving 0.5 µg/kg PEG-IFN-λ Q2W, 0.75 µg/kg PEG-IFN-λ Q2W, 1.5 µg/kg PEG-IFN-λ QW, and 2.25 µg/kg PEG-IFN-λ QW, respectively. Adverse events were reported in 42.9% of treatment-naive patients receiving 1.5 µg/kg PEG-IFN-λ QW plus RBV.


Two patients experienced other clinically important events considered related to PEG-IFN-λ. One patient treated with 3.0 µg/kg PEG-IFN-λ QW as a single agent experienced grade 3 idiopathic thrombocytopenic purpura, which occurred 2 weeks after the final dose; this event was considered DLT. The patient responded rapidly to therapy with oral prednisone. Another patient, treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV in part 2, experienced elevated ALT, AST, and bilirubin levels, which met the protocol-defined criteria for withdrawing therapy. However, this patient received an additional dose of PEG-IFN-λ in violation of the protocol and subsequently experienced further elevation of ALT, AST, and bilirubin levels, which resulted in suspected medication-associated hepatotoxicity, pruritis, and elevated lipase and amylase levels (without associated clinical symptoms of pancreatitis).

Clinical Laboratory Evaluations.

Five patients experienced aminotransferase elevations that met the protocol-defined criteria for DLT, and an additional patient met the criteria for temporarily holding of a dose of PEG-IFN-λ (Table 3). Of these patients, four were in cohorts receiving the highest PEG-IFN-λ dose evaluated [3.0 µg/kg QW (n = 3) or Q2W (n = 1)], and two were in cohorts receiving 1.5 µg/kg PEG-IFN-λ QW with RBV (n = 1) or without RBV (n = 1). In three patients, the ALT and AST elevations were accompanied by a bilirubin elevation. All elevations in ALT, AST, and bilirubin were reversible, generally at or before the end of the study visit (day 59).

Grade 3 or 4 elevations in lipase and/or amylase not associated with abdominal pain or nausea were observed in four patients during the study; all were resolved after the withholding or discontinuation of PEG-IFN-λ. One patient had the day 15 dose held and was subsequently successfully treated on day 22, with no loss of antiviral effect observed that was related to the interruption. No other clinically important changes were noted in serum chemistry values.

Mean absolute neutrophil counts and platelet counts over time in cohorts receiving PEG-IFN-λ plus RBV are displayed in Fig. 2(A1,A2), respectively. There were no clinically significant changes in absolute neutrophil counts. Three patients with baseline absolute neutrophil counts in the low normal range of 2.04 to 2.30 x 109/L had decreases to 1.62 to 1.80 x 109/L; these were all isolated values that required no change in the studied therapy. One patient (described previously) experienced a grade 3 decrease in platelets during the posttreatment follow-up period, and this was concurrent with a diagnosis of idiopathic thrombocytopenic purpura; platelet decreases were not observed in other patients. Figure 2(B1,B2) displays the mean hemoglobin values in the cohorts that received PEG-IFN-λ as a single agent and PEG-IFN-λ plus RBV, respectively. No significant changes were observed in patients treated with single-agent PEG-IFN-λ, whereas decreases in hemoglobin consistent with the known effects of RBV were observed in patients treated with combination therapy.

Antiviral Activity.

Virological responses are summarized in Table 4. Antiviral activity was observed at all PEG-IFN-λ dose levels. Among the 43 patients dosed QW and evaluable for efficacy, all but 4 achieved a >1-log10 decline in HCV RNA during the study. The first day of treatment yielded a rapid decline in HCV RNA that continued in a biphasic manner from days 4 through 29; this was similar to the pattern observed with IFN-α.16 Higher PEG-IFN-λ doses were associated with greater declines in HCV RNA when PEG-IFN-λ was used both as a single agent and in combination with RBV (Fig. 3). At PEG-IFN-λ doses ≥ 1.5 µg/kg QW with or without RBV, 23 of 24 treatment-relapse patients (96%) achieved a >2-log10 decline in HCV RNA levels, and 4 of 24 (17%) achieved undetectable HCV RNA. Among treatment-naive patients, six of seven patients (86%) achieved a >2-log10 decline in HCV RNA levels, and they included two (29%) who achieved undetectable HCV RNA. Among patients dosed QW with PEG-IFN-λ with or without RBV, a >2-log10 decline in HCV was achieved by 21 of 28 white patients (75%), 8 of 8 African American patients (100%), and 6 of 7 Hispanic patients (86%).


Four treatment-relapse patients who received PEG-IFN-λ QW did not achieve a >1-log10 reduction in HCV RNA. Three of these patients were in the lowest PEG-IFN-λ dose cohorts; two were treated with 0.5 µg/kg PEG-IFN-λ QW plus RBV, and one was treated with 0.75 µg/kg PEG-IFN-λ QW plus RBV. The remaining patient without a detectable antiviral response was treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV; this patient had preexisting neutralizing antibodies against PEG-IFN-λ and very low or undetectable serum levels of the study drug throughout the study period.

Pharmacokinetics.

The first-dose Cmax and AUC0-t values are summarized in Table 5. Two patients were excluded from the pharmacokinetic analyses; one patient who received PEG-IFN-λ (1.5 µg/kg) was excluded because of premature discontinuation of the study, and one patient who received 0.5 µg/kg PEG-IFN-λ was excluded because of Cmax and AUC0-t values grossly inconsistent with the nominal dose administered.


Overall, the exposure of PEG-IFN-λ appeared to be dose-dependent and ranged from a mean AUC0-t value of 11.6 h*ng/mL at the 0.5 µg/kg dose level to 148 h*ng/mL at the 3.0 mg/kg dose level. Normalization of AUC0-t by dose (µg/kg) appeared to remove the effect of dose on exposure, and this suggested that exposure may increase linearly with dose. A modest accumulation from week 1 to week 4 was observed with average patient Cmax and AUC0-t accumulation index values of 1.12 and 1.34, respectively. No obvious effect of RBV on the exposure to PEG-IFN-λ was detected. To explore the effect of body weight on exposure, AUC0-t/dose (µg) estimates were compared to the body weight. No trend was detected, and linear regression analysis indicated no apparent effect of weight on exposure.

Although there was no continuous relationship between exposure and change in ALT, very high exposure was observed in patients who demonstrated significant ALT elevations. Among patients dosed QW, six had a PEG-IFN-λ AUC0-t value > 225 h ng/mL; four of these patients (67%) experienced DLT. Conversely, there appeared to be a continuous relationship between PEG-IFN-λ exposure and decreases in HCV RNA, with robust antiviral activity observed at exposures both above and below 225 h*ng/mL (Fig. 4).

Pharmacodynamics.

A rapid rise in ß2M levels was observed after the first dose of PEG-IFN-λ; levels peaked on day 4 and decreased toward the baseline values by day 8. Increases in ß2M were observed at all dose levels, and this confirmed pharmacological activity. A potential relationship between ß2M induction and decreases in HCV RNA was observed. In general, patients who had the greatest HCV RNA decline on day 8 had the strongest induction of ß2M. In addition, minimal or no induction of ß2M was observed in patients with only minimal changes in HCV RNA on day 8, and this suggested that the lack of a virological response in these patients was likely related to an absence of pharmacological activity.

Immunogenicity.

Low-titer antibodies specific to PEG-IFN-λ developed in 3 of 56 patients (5.4%) during the study (all in the treatment-relapse group). Neutralizing activity was observed on day 59 in one of these patients (1.8%); this patient achieved a ≥2-log decrease from the baseline in HCV RNA on days 22 and 29.

Two additional treatment-relapse patients had detectable antibodies to PEG-IFN-λ prior to treatment and throughout the study period; neither had a titer increase during the study. One of these patients had neutralizing antibodies and had very low or unmeasurable PEG-IFN-λ serum levels and no antiviral response throughout the study period. The second patient had preexisting but nonneutralizing antibodies to PEG-IFN-λ and had measurable serum levels of PEG-IFN-λ as well as an antiviral response (a 3.81-log10 decrease on day 29).

DISCUSSION

This study was the first designed to assess the safety, tolerability, and efficacy of PEG-IFN-λ in patients chronically infected with genotype 1 HCV. The results indicate that a broad range of PEG-IFN-λ doses exhibit antiviral activity with limited toxicity when it is administered QW, and this supports the hypothesis that PEG-IFN-λ may be a useful agent in future HCV treatment regimens

SVR, the most definitive measure of antiviral activity, was not evaluated in this study because patients received only 4 weeks of therapy with PEG-IFN-λ with or without RBV. However, relationships between early viral kinetics and long-term response are well established and add clinical relevance to the 4-week antiviral results observed in the current study. Predictive markers of response, including rapid virological response (defined as undetectable HCV RNA at week 4) and early virological response (defined as a >2-log10 decrease in HCV RNA by week 12), have been demonstrated to predict response in treatment-naive patients treated with PEG-IFN-α plus RBV and in treatment-relapse patients as well.17-21 A recent report demonstrated that a ≥2-log10 decrease in HCV RNA by week 4 had a positive predictive value of 52% and a negative predictive value of 94% for predicting SVR in treatment-relapse patients receiving PEG-IFN-α in combination with RBV.19

Parts 1 and 2 of the study included patients who had previously responded to therapy with PEG-IFN-α, and this allowed a close examination of the safety profile in a group of patients who were expected to demonstrate antiviral activity (proof of concept) within a short treatment period. As anticipated, antiviral activity was observed in the majority of treatment-relapse patients, especially in those who received a dose of PEG-IFN-λ ≥ 1.5 µg/kg QW with or without RBV, with 23 of 24 patients (96%) achieving at least a >2-log10 decrease in HCV RNA. Although information on the viral kinetics of the patients' previous responses to IFN-α-based therapies was not collected as part of the study, this magnitude of HCV RNA decrease in the first 4 weeks of therapy indicates clear antiviral activity potentially comparable to that of PEG-IFN-α.

Unambiguous antiviral activity was also observed in the cohort of treatment-naive patients who were all treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV. Six of the seven treatment-naive patients (86%) achieved a >2-log10 decrease in HCV RNA, and two of seven (29%) achieved undetectable HCV RNA; this was an encouraging result despite the small sample size. Historically published rates of >2-log10 decreases in HCV RNA or undetectable HCV RNA after 4 weeks of therapy with PEG-IFN-α plus RBV in treatment-naive patients range from 42% to 67% and from 7.4% to 11.7%, respectively.3, 16, 22

Recent evidence indicates that the viral response to PEG-IFN-α plus RBV may have a genetic basis.23, 24 Single nucleotide polymorphisms upstream from the IL-28B gene on chromosome 19 have been found to be associated with SVR to PEG-IFN-α plus RBV treatment as well as natural clearance of HCV infection.23-27 These links to IL-28B were initially found through genome-wide association studies, so the mechanism of action was not determined. The connection to PEG-IFN-λ is of interest because IL-28B is also a type III IFN known as IFN-λ3, which shares approximately 70% sequence identity with IFN-λ1 and shares the same receptor with IFN-λ1. The genes for IFN-λ1 (IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B) are all located in this same region of chromosome 19. It is possible that the IFN-λ family has unique antiviral effects important to the control of HCV infection, and studies to assess the impact of the different polymorphisms on the antiviral response to PEG-IFN-λ plus RBV are being conducted.

Overall, PEG-IFN-λ, given QW for 4 weeks, was safe and was well tolerated by most patients. Minimal constitutional symptoms or hematologic effects were observed with PEG-IFN-λ as a single agent. As expected, the addition of RBV increased the incidence of fatigue and other constitutional symptoms in treatment-relapse patients. Previously untreated patients experienced a low incidence of adverse events, despite combination therapy with RBV, and this suggested a possible experience effect from previous treatment in the treatment-relapse patients. The majority of significant aminotransferase elevations occurred in patients with high PEG-IFN-λ exposure values, which were well above the mean for the individual cohorts. Dose reductions were not allowed in the current study. However, because the aminotransferase elevations were reversible and may be related to high exposure, it may be possible in future studies to manage these effects with dose reductions.

Pharmacokinetic data suggest that the relationship between dose and exposure may be linear and that body weight is not an important determinant of exposure. Future studies will explore fixed microgram doses of PEG-IFN-λ; this is expected to be less complicated for self-administration than weight-based dosing. In addition, the use of a ready-to-use formulation in future studies may also reduce the interpatient variability in PEG-IFN-λ exposure estimates.

Only one patient developed a neutralizing antibody to PEG-IFN-λ during the study. Because the antibody was not observed until day 59, 4 weeks after the last dose of PEG-IFN-λ, no conclusions can be drawn regarding a potential effect on the PEG-IFN-λ serum concentration or antiviral activity. The incidence of neutralizing antibody formation with PEG-IFN-α is approximately 2% to 3%, although direct comparisons between different products may not be valid because the observed incidence of antibody positivity is highly dependent on the sensitivity of the assay.5, 6

These safety and tolerability results observed with the 4-week PEG-IFN-λ treatment compare favorably with the results of published studies of 48-week PEG-IFN-α therapy, in which up to 67% of patients have experienced fatigue, 62% have experienced headache, 56% have experienced myalgia, 48% have experienced rigors, 46% have experienced fever, 43% have experienced nausea, and 40% have experienced insomnia.3, 28 Although direct comparisons with the safety of PEG-IFN-α therapy are not possible because of the 4-week treatment duration in the current study, the incidence of constitutional side effects observed with PEG-IFN-λ therapy appears to be lower. The myelosuppression associated with IFN-α treatment is related to its binding to leukocytes.29 Although adverse hematologic events may appear after 4 weeks of therapy, the absence of IFN-λ binding to leukocytes may explain why such adverse effects have not yet been observed with PEG-IFN-λ therapy.

Key limitations in the current study include the lack of a direct comparison between PEG-IFN-λ and PEG-IFN-α, and this restricts any conclusions regarding the relative effects of one agent with respect to the other. Because the current study encompassed only 4 weeks of dosing, the long-term effects of PEG-IFN-λ could not be determined. The open-label design of the study may have influenced adverse event reporting. Lastly, the study included only patients with genotype 1 HCV infection, and it is not known if these results will translate to patients with other genotypes. Future studies will explore these questions.

The findings from this study offer evidence that PEG-IFN-λ, given QW for 4 weeks, exhibits potent antiviral effects against HCV with the potential for an improved tolerability profile with respect to that traditionally observed for PEG-IFN-α. These results are being tested in larger randomized controlled trials enrolling treatment-naive patients.

Source
SUMMARY: HIV positive people with normal levels of the liver enzyme alanine aminotransferase (ALT) who received hepatitis C therapy using pegylated interferon plus ribavirin responded as well as individuals with elevated ALT, according to findings presented at the XVIII International AIDS Conference (AIDS 2010) last month in Vienna.

By Liz Highleyman

A majority of people with chronic hepatitis C virus (HCV) infection will not progress to advanced liver disease such as cirrhosis or hepatocellular carcinoma, but a larger proportion will develop some degree of liver fibrosis, and research indicates that progression is more likely among HIV/HCV coinfected individuals than among those with HCV alone.


People with signs of liver disease progression are typically advised to receive treatment. Liver biopsy is the "gold standard" for determining extent of liver damage, but elevated ALT -- a sign of liver inflammation -- is also often considered an indicator of active disease progression and need for treatment.

At last month's conference, Miguel Angel von Wichmann de Miguel from Hospital de Donostia in San Miguel, Spain, and colleagues presented data from an analysis of hepatitis C treatment in HIV/HCV coinfected patients with persistently normal ALT, a group that has been less extensively studied.

This single-arm, open-label, Phase 4 (post-market) study included 68 coinfected participants at multiple centers in Spain. Just over half (35 people, or 52%) were classified as "case" patients with normal ALT (at least 5 normal measurements over a 24-month period), with the rest (33 people, or 49%) designated "control" patients with elevated ALT (that is, the type of patients usually treated and studied).

About three-quarters were men, the median age was 43 years, most (74%) had hard-to-treat HCV genotypes 1 or 4, and just over half had high baseline HCV viral load (? 800,000 IU/mL). Almost all (89%) were on antiretroviral therapy (ART) with undetectable HIV viral load and the median CD4 cell count was 461 cells/mm3.

All participants received 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin for 48 weeks, with a 24-week post-treatment follow-up period to assess sustained virological response (SVR), or continued undetectable HCV RNA.

The AIDS 2010 report included results at week 4 (rapid virological response, or RVR) and week 12 (early virological response, or EVR); follow-up is continuing to determine SVR rates.

Results 
  • 35% of patients in the normal ALT group achieved RVR, or undetectable HCV RNA at week 4 of therapy, compared with 33% in the elevated ALT group, not a significant difference (P = 0.99).
  • EVR rates, or at least a 2-log reduction in HCV RNA by week 12, diverged a bit more -- 80% in the normal ALT and 96% in the elevated ALT group -- but the difference did not reach statistical significance (P = 0.10).
  • Rates of complete EVR, or undetectable HCV RNA at week 12, were 52% and 68%, respectively, also not a significant difference.
  • ALT levels decreased in both groups, but remained lower in the initially normal ALT group.
  • There were no significant differences between the 2 groups with regard to safety profiles.
  • 46% of patients in the normal ALT group and 45% in the elevated ALT group experienced adverse events.
  • Only 1 patient in each group required blood cell growth factors to manage anemia or neutropenia.
  • More patients in the normal ALT group compared with the elevated ALT group (19% vs 40%, respectively) received interferon or ribavirin dose adjustments or discontinued treatment due to adverse events, but again this did not reach statistical significance (P = 0.25).
Based on these findings, the researchers concluded, "Response to peginterferon alfa-2a plus ribavirin in HIV/HCV coinfected patients with persistently normal ALT levels is comparable to those with elevated ALT levels."

Investigator affiliations: Hospital de Donostia, San Sebastian, Spain; Hospital Universitario de Bellvitge, Barcelona, Spain; Hospital La Paz, Madrid, Spain; Hospital de Cruces, Bilbao, Spain; Hospital La Princesa, Madrid, Spain; Consorci Sanitari de Terrasa, Terrasa, Spain; Hospital Clinic de Barcelona, Barcelona, Spain; Hospital General Universitario de Alicante, Alicante, Spain; Hospital Santa Creu i Sant Pau, Barcelona, Spain; Hospital Joan XXIII, Tarragona, Spain.

8/10/10

Reference

MA von Wichmann de Miguel, M Santin, J Gonzalez, and others (CONTRA). Phase IV, open label study to evaluate peginterferon alpha-2a plus ribavirin for treatment of chronic hepatitis C in HIV-infected patients with persistently normal alanine aminotransferase. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. (Abstract).
Laboratory Investigation advance online publication 9 August 2010; doi: 10.1038/labinvest.2010.147

Thiago de Almeida Pereira 1,6, Rafal P Witek 1, Wing-Kin Syn 1, Steve S Choi 1, Shelton Bradrick 2, Gamze F Karaca 1, Kolade M Agboola 1, Youngmi Jung 1, Alessia Omenetti 1, Cynthia A Moylan 1, Liu Yang 4, Martin E Fernandez-Zapico 4,5, Ravi Jhaveri 2,3, Vijay H Shah 4, Fausto E Pereira 6 and Anna M Diehl 1

1 Division of Gastroenterology, Duke University, Durham, NC, USA
2 Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA
3 Department of Pediatrics, Duke University, Durham, NC, USA
4 Division of Gastroenterology and Hepatology, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
5 Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
6 Núcleo de Doenças Infecciosas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES, Brazil

Correspondence: Dr AM Diehl, MD, Florence McAlister Professor and Chief, Division of Gastroenterology, Duke University, Snyderman Building (GSRB-1), 595 LaSalle Street, Suite 1073, Durham, NC 27710, USA. E-mail: diehl004@mc.duke.edu

Received 10 May 2010; Revised 6 July 2010; Accepted 7 July 2010; Published online 9 August 2010.

Abstract

Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer.

Keywords: fibrosis; Hedgehog pathway; hepatitis B; hepatitis C; liver progenitors; morphogens

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School teacher goes back to teaching after a liver transplant

Revathi Ramanan, TNN, Aug 11, 2010, 01.53am IST

Liver Transplant Survival : www.TransplantExperience.com
Understanding Liver Transplants Information for Patients

CHENNAI: "This is the longest that I have been away from school," said S Moorthy, a 55-year-old teacher who is all set to go back to teaching accountancy and auditing to Class XI students in his village after what he describes as a brief setback.'

Three weeks ago, Moorthy, who hails from Mathur village in Krishnagiri district, became the eighth person to successfully undergo a free liver transplant at Stanley Medical College and Hospital after he was diagnosed with liver cirrhosis caused by the Hepatitis C virus.

Moorthy who came to Chennai in June was told by doctors that a liver transplant was his only hope of survival. With liver transplants costing anything upwards of 30 lakh, it was impossible for Moorthy, a government school teacher, to afford one. He listed himself for transplant at a liver clinic without much hope.

Moorthy's case was given priority because he had a high MELD (Model for End-Stage Liver Disease) score and luckily for him he found a matching donor at Stanley Medical College which performed the complicated transplant operation free of cost. "Just because a person is poor he shouldn't be denied the right to live. We hope to do many more such liver transplants free of cost for the poor and needy," said Dr R Surendran, director of the hospital's institute of surgical gastroenterology.

Tamil Nadu leads the states with 100 liver transplants since October 2008. The month of July was the busiest with 15 liver transplantations in a month. "Liver transplant is the most complicated transplant and the operation takes around 14-18 hours. The liver has approximately 3,6000 functions, so we have to be very careful and continuously monitor the vital stats of the patient," Dr Surendran said.

Moorthy, who has been working as a school teacher at Government Boys Higher Secondary School at Mathur for the past 29 years, cannot wait to get back to teaching though all his three children are well settled. "Teaching is my life and I hope to teach for at least four more years," he said.

His students, he said, miss him and call him frequently to inquire about his health and want him back as soon as he is fit. "It is only because of the doctors at Stanley and God's grace that I could get a liver transplant and am fit enough to go back to my students," said Moorthy.

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Top Ten Things to Know About Stem Cell Treatments

Many clinics that are offering stem cell treatments make claims about what stem cells can and cannot do that are not supported by our understanding of science. The information on this page corrects some of the misinformation that is being widely circulated.

1. There are different types of stem cells—each with their own purpose.

There are many different types of stem cells that come from different places in the body or are formed at different times in our lives. These include embryonic stem cells that exist only at the earliest stages of development and various types of ‘tissue-specific’ or ‘adult’ stem cells that appear during fetal development and remain in our bodies throughout life.

Our bodies use different types of tissue-specific stem cells to fit a particular purpose. Tissue-specific stem cells are limited in their potential and largely make the cell types found in the tissue from which they are derived. For example, the blood-forming stem cells (or hematopoietic stem cells) in the bone marrow regenerate the blood, while neural stem cells in the brain make brain cells. A neural stem cell won’t spontaneously make a blood cell and likewise a hematopoietic stem cell won’t spontaneously make a brain cell. Thus, it is unlikely that a single cell type could be used to treat a multitude of unrelated diseases that involve different tissues or organs. Be wary of clinics that offer treatments with stem cells that originate from a part of the body that is different from the part being treated.

Read more about different Types of Stem Cells

2. A single stem cell treatment will not work on a multitude of unrelated diseases or conditions.

As described above, each type of stem cell fulfills a specific function in the body and cannot be expected to make cell types from other tissues. Thus, it is unlikely that a single type of stem cell treatment can treat multiple unrelated conditions, such as diabetes and Parkinson’s disease. The underlying causes are very different and different cell types would need to be replaced to treat each condition. It is critical that the cell type used as a treatment be appropriate to the specific disease or condition.

Embryonic stem cells may one day be used to generate treatments for a range of human diseases. However, embryonic stem cells themselves cannot directly be used for therapies as they would likely cause tumors and are unlikely to become the cells needed to regenerate a tissue on their own. They would first need to be coaxed to develop into specialized cell types before transplantation. A major warning sign that a clinic may not be credible is when treatments are offered for a wide variety of conditions but rely on a single cell type.

3. Currently, there are very few widely accepted stem cell therapies.

The range of diseases where stem cell treatments have been shown to be beneficial in responsibly conducted clinical trials is still extremely restricted. The best defined and most extensively used is blood stem cell transplantation to treat diseases and conditions of the blood and immune system, or to restore the blood system after treatments for specific cancers. Some bone, skin and corneal diseases or injuries can be treated with grafting of tissue that depends upon stem cells from these organs. These therapies are also generally accepted as safe and effective by the medical community.

4. Just because people say stem cells helped them doesn’t mean they did.

There are three main reasons why a person might feel better that are unrelated to the actual stem cell treatment: the ‘placebo effect’, accompanying treatments, and natural fluctuations of the disease or condition. The intense desire or belief that a treatment will work can cause a person to feel like it has and to even experience positive physical changes, such as improved movement or less pain. This phenomenon is called the placebo effect. Even having a positive conversation with a doctor can cause a person to feel improvement. Likewise, other techniques offered along with stem cell treatment—such as changes to diet, relaxation, physical therapy, medication, etc.—may make a person feel better in a way that is unrelated to the stem cells. Also, the severity of symptoms of many conditions can change over time, resulting in either temporary improvement or decline, which can complicate the interpretation of the effectiveness of treatments. These factors are so widespread that without testing in a controlled clinical study, where a group that receives a treatment is carefully compared against a group that does not receive this treatment, it is very difficult to determine the real effect of any therapy. Be wary of clinics that measure or advertise their results primarily through patient testimonials.

5. A large part of why it takes time to develop new therapies is that science itself is a long and difficult process.

Science, in general, is a long and involved process. Understanding what goes wrong in disease or injury and how to fix it takes time. New ideas have to be tested first in a research laboratory, and many times the new ideas don’t work. Even once the basic science has been established, translating it into an effective medical treatment is a long and difficult process. Something that looks promising in cultured cells may fail as a therapy in an animal model and something that works in an animal model may fail when it is tried on humans. Once therapies are tested in humans, ensuring patient safety becomes a critical issue and this means starting with very few people until the safety and side effects are better understood.

If a treatment has not been carefully designed, well studied and gone through the necessary preclinical and clinical testing, it is unlikely to have the desired effect. Even more concerning is that it may prove to make the condition worse or have dangerous side effects.

See How Science Becomes Medicine

6. To be used in treatments, stem cells will have to be instructed to behave in specific ways.

Bone marrow transplantation is typically successful because we are asking the cells to do exactly what they were designed to do, make more blood. For other conditions, we may want the cells to behave in ways that are different from how they would ordinarily work in the body. One of the greatest barriers to the development of successful stem cell therapies is to get the cells to behave in the desired way. Also, once transplanted inside the body the cells need to integrate and function in concert with the body’s other cells. For example, to treat many neurological conditions the cells we implant will need to grow into specific types of neurons, and to work they will also have to know which other neurons to make connections with and how to make these connections. We are still learning about how to direct stem cells to become the right cell type, to grow only as much as we need them to, and the best ways to transplant them. Discovering how to do all this will take time. Be wary of claims that stem cells will somehow just know where to go and what to do to treat a specific condition.

7. Just because stem cells came from your body doesn’t mean they are safe.

Every medical procedure has risks. While you are unlikely to have an immune response to your own cells, the procedures used to acquire, grow and deliver them are potentially risky. As soon as the cells leave your body they may be subjected to a number of manipulations that could change the characteristics of the cells. If they are grown in culture (a process called expansion), the cells may lose the normal mechanisms that control growth or may lose the ability to specialize into the cell types you need. The cells may become contaminated with bacteria, viruses or other pathogens that could cause disease. The procedure to either remove or inject the cells also carries risk, from introducing an infection to damaging the tissue into which they are injected.

8. There is something to lose by trying an unproven treatment.

Some of the conditions that clinics claim are treatable with stem cells are considered incurable by other means. It is easy to understand why people might feel they have nothing to lose from trying something even if it is unproven. However, there are very real risks of developing complications, both immediate and long-term, while the chance of experiencing a benefit is likely very low. In one publicized case, a young boy developed brain tumors as a result of a stem cell treatment. Participating in an unproven treatment may make a person ineligible to participate in upcoming clinical trials (see also number 9). Where cost is high, there may be long-term financial implications for patients, their families and communities. If travel is involved there are additional considerations, not the least of which is being away from family and friends.

9. An experimental treatment offered for sale is not the same as a clinical trial.

The fact that a procedure is experimental does not automatically mean that it is part of a research study or clinical trial. A responsible clinical trial can be characterized by a number of key features. There is preclinical data supporting that the treatment being tested is likely to be safe and effective. Before starting, there is oversight by an independent group such as an Institutional Review Board or medical ethics committee that protect patients’ rights, and in many countries the trial is assessed and approved by a national regulatory agency, such as the European Medicines Agency (EMA) or the U.S. Food and Drug Administration (FDA). The study itself is designed to answer specific questions about a new treatment or a new way of using current treatments, often with a control group to which the group of people receiving the new treatment is compared. Typically, the cost of the new treatment and trial monitoring is defrayed by the company developing the treatment or by local or national government funding. Beware of expensive treatments that have not passed successfully through clinical trials.

Responsibly-conducted clinical trials are critical to the development of new treatments as they allow us to learn whether these treatments are safe and effective. The ISSCR supports participation in responsible clinical trials after careful consideration of the issues highlighted on this site and in discussion with a trusted physician.

For more information on clinical trials work click here

10. Stem cell science is constantly moving forward.

Stem cell science is extraordinarily promising. There have been great advances in treating diseases and conditions of the blood system using blood-forming stem cells, and these show us just how powerful stem cell therapies can be. Scientists all over the world are researching ways to harness stem cells and use them to learn more about, to diagnose, and to treat various diseases and conditions. Every day scientists are working on new ways to shape and control different types of stem cells in ways that are bringing us closer to developing new treatments. Many potential treatments are currently being tested in animal models and some have already been brought to clinical trials. In February 2010 the British company ReNeuron announced it had been approved to conduct a Phase I clinical trial of a neural stem cell treatment for stroke. The first embryonic stem cell-based treatment for acute spinal cord injury is currently under review by the U.S. Food and Drug Administration (FDA) and will hopefully move into clinical trials soon. Although it is sometimes hard to see, stem cell science is moving forward. We are tremendously optimistic that stem cell therapies will someday be available to treat a wide range of human diseases and conditions.

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By RedChip Staff · Tuesday, August 10th, 2010

Developed by Aethlon Medical, Inc. (OTCBB: AEMD), the Hemopurifier® is a filtration device designed to improve the ability of the immune system to fight infections by isolating exosomes secreted by tumors so that they can be permanently removed from the circulatory system before they reach blood cells.

For years, researchers have struggled to find cures and formulate vaccinations against deadly viruses such as the Human Immunodeficiency Virus (HIV), AIDS, and Hepatitis C. In the top 5 causes of death worldwide, cancer is listed as #3 while the HIV/AIDS virusfollowed at #4. The World Health Organization estimates that as of 2008, 33.4 million people worldwide were living with HIV, and in 2008 over 2 million deaths were attributed to AIDS globally. While the deaths of its victims are certainly the most tragic consequence of the virus, it also puts a heavy financial strain on affected households. A major study that appeared in the November 2006 issue of Medical Care says that the average lifetime cost of HIV treatment is $618,900. This forces many families to reduce their consumption of food, resulting in malnutrition for all members of the family which can lead to other health risks. In Matthew M. Kavanagh’s article, “Living with HIV, Dying of Tuberculosis”, he examines the effect of malnutrition and food insecurity in the global HIV/AIDS community. HIV/AIDS affected households have less capacity to produce or purchase foods and have higher medical costs. In addition, children often stop their schooling to work, or simply because the family affected by HIV can no longer afford the education. With the vast amount of people affected by deadly viruses like AIDS, it is pertinent that researchers develop a vaccine that prevents and treats infectious viruses as soon as possible. No such vaccine currently exists, but a number of approaches are currently in development.

The Hemopurifier® is one of the antiviral devices that researchers have been developing that can potentially decrease the presence of infectious viruses in the bloodstream dramatically. Developed by Aethlon Medical, Inc. (OTCBB: AEMD), the Hemopurifier® is a filtration device designed to improve the ability of the immune system to fight infections by isolating exosomes secreted by tumors so that they can be permanently removed from the circulatory system before they reach blood cells. Exosomes are secreted by solid tumors, lymphomas, and leukemia, and high exosome levels have been shown to induce what is known as “programmed cell death” and decreased immune system function in cancer patients. Research studies have verified that the Hemopurifier® can effectively and selectively capture immunosuppressive exosomes. At present, over 65 Hemopurifier® treatments (representing approximately 260 hours of treatment time) have been conducted in multi-site studies at the Apollo Hospital, Fortis Hospital, and Sigma New-Life Hospital in India. The studies enrolled end-stage renal disease (ESRD) patients infected with either HCV or HIV. In addition to establishing treatment safety, robust viral load reductions have been reported in both Hepatitis-C virus (HCV) and HIV infected individuals. According to a statement by the Company, “The ability to preserve immune cells by inhibiting the immunosuppressive activity of exosomes is an unmet medical need that would likely improve patient responsiveness to chemotherapy and other cancer treatment strategies.” Aethlon’s Hemopurifer® may be the first step towards a permanent solution to the infectious virus endemic.

Disclosure: The subject security is a client of RedChip Companies, Inc. RedChip Companies, Inc., employees and affiliates may have positions and affect transactions in the securities or options of the issuers mentioned herein. For full financial disclosures for all RedChip clients, please visit http://www.redchip.com/disclosures.asp?src=rcv.

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