August 9, 2010

Gut doi:10.1136/gut.2010.207423

Robert J Fontana 1, Jules L Dienstag 2, Herbert L Bonkovsky 3, Richard K Sterling 4, Deepa Naishadham 5, Zachary D Goodman 6, Anna S F Lok 1, Elizabeth C Wright 7, Grace L Su 1, the HALT-C Trial Group

+ Author Affiliations

1 Department of Internal Medicine, University of Michigan Medical School, Michigan, USA
2 Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
3 Departments of Medicine and Molecular & Structural Biology and The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Connecticut, USA
4 Hepatology Section, Virginia Commonwealth University Medical Center, Virginia, USA
5 New England Research Institutes, Massachusetts, USA
6 Armed Forces Institute of Pathology, Division of Hepatic Pathology and Veterans Administration Special Reference Laboratory for Pathology, Washington, USA
7 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Maryland, USA

Correspondence to
Robert J Fontana, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, Ann Arbor, Michigan, USA; rfontana@med.umich.edu

Revised 17 May 2010
Accepted 18 May 2010
Published Online First 30 July 2010

 Abstract

Objectives The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC).

Methods 462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ≥2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child–Turcotte–Pugh) score to ≥7.

Results Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663).

Conclusion Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.

Trial Registration Number NCT00006164.

Source
Gut doi:10.1136/gut.2009.199356

Jeffrey Wilkinson 1, Marek Radkowski 2, Jennifer M Eschbacher 1, Tomasz Laskus 1,2

+ Author Affiliations

1 Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
2 Institute of Infectious Diseases, Medical University of Warsaw, Warsaw, Poland

Correspondence to
Tomasz Laskus, Medical University of Warsaw, Pawinskiego 7C 02-106 Warsaw, Poland; immunopa@amwaw.edu.pl

Revised 23 April 2010
Accepted 27 April 2010
Published Online First 30 July 2010

Abstract

Objectives Hepatitis C virus (HCV) infection is commonly associated with cognitive dysfunction. Viral sequences and proteins were previously found in brain macrophage/microglia cells. The aim of the current study was to determine whether HCV infection affects the expression of key cytokines and chemokines in these cells.

Methods Autopsy brain tissue from 15 patients was studied; 7 patients were HCV positive and 8 were HCV negative. Cryostat sections of frontal cortex and subcortical white matter were stained with monoclonal antibodies specific for microglia/macrophages (anti-CD68) and separated by laser capture microscopy. Transcripts representing 25 various cytokines and chemokines were measured by real-time quantitative PCR.

Results Compared with HCV-negative controls, HCV-positive patients demonstrated significantly higher levels of proinflammatory cytokines interleukin 1α (IL-1α), IL-1β, tumour necrosis factor α (TNFα), IL-12 and IL-18. HCV infection was also associated with increased transcription of chemokines IL-8, IL-16 and interferon-inducible protein 10 (IP-10). Type 1 interferon (IFN) activation was suggested by increased concentrations of IFNβ and myxovirus resistance protein A (MxA) transcripts. Similar results were obtained when CD68-positive/HCV-positive cells were compared with CD68-positive/HCV-negative cells in each of the 7 HCV-infected patients.

Conclusion Evidence was found for activation of brain macrophages/microglia cells in autopsy brain tissue from HCV-positive patients. These findings could relate to the common presence of neurocognitive dysfunction among patients with chronic hepatitis C.

Source

The Rules...The dos and don'ts when someone you know is diagnosed.

BY LESLIE STARSONECK

The dos and don'ts when someone you know is diagnosed.

People want to know the rules about what to do or say when a friend or family member is diagnosed with cancer. Here are my experiences and suggestions.

> “My aunt had cancer”: When I was first diagnosed and sharing the news with friends and family, I didn’t want to hear about other people who had cancer. It made me feel like I needed to be empathetic to that person—who was usually a stranger—or sympathetic to the person telling me, at a time when I had trouble mustering much energy beyond saying what was happening to me. I also quickly learned that these disclosures rarely had any value to me medically because of how very different each person is in terms of the stage, biology, and treatment for the disease.

> Ask: Ask whether the person facing cancer is comfortable sharing the details of their prognosis and treatment. If the patient tells you, it may give you an idea of how you can help. On the other hand, if you ask and get only vague details, you should accept this as a request for privacy and not ask others to provide this information.

> Respond: Even if you’re at a loss for words, say something when a person tells you about his or her diagnosis. Say that you’re at a loss for words or don’t know what to say, but don’t remain silent or ignore the elephant in the room by talking about everything else. This says to the patient, “You shouldn’t have told me this because I can’t handle it.”

> Help: Ask the patient if they want your help, and be specific about how you can help. This goes for little things, such as doing the laundry, and big things, such as publicly honoring them at a race or fundraiser.

> Don’t forget the caregiver: Whether it’s helping with some of the caregiver’s responsibilities (for example, running errands), delivering leisure items for them to use during “downtime,” or getting them out of the house, make sure to ask permission to help in specific ways. Then make sure to follow through.

> It’s OK to say or do the wrong thing: Remember that what you do or say to the patient doesn’t have to be perfect. The most important thing is that it’s genuine and based on care and concern. It’s so much better to say or do the wrong thing than to not say or do anything at all.

> It doesn’t end with recovery from surgery: Having the many phases of the journey acknowledged by others was important for me—fear of recurrence, the inevitable adjustments to medication, or the new way my body looks and feels—as opposed to treating cancer as a series of discrete events.

> Keep in touch: Show the patient that you recognize that cancer—whatever its particular path—is a journey.

> Set realistic expectations: This rule is for patients who, like me, may have learned that family and friends don’t suddenly change their personalities because you have cancer. There may be instances where people step up who you thought wouldn’t, or people you thought you could rely on who you can’t. But for the most part, how someone responds will be in keeping with how he or she has always been.

Breast cancer survivor Leslie Starsoneck lives in Raleigh, North Carolina.

Source
August 2010

The Future of HIV

The U.S. HIV epidemic has claimed more than 575,000 lives, and 56,300 Americans were newly infected with HIV in 2006. HIV prevention efforts to date have helped hundreds of thousands of people avoid infection, but have not reached enough of those currently at risk of acquiring or transmitting HIV with highly effective interventions to turn the course of the epidemic.

To help set U.S. HIV prevention goals, determine prevention program needs, and project future healthcare costs, the Centers for Disease Control and Prevention and Johns Hopkins University conducted an analysis [1] that projects what the HIV epidemic in the United States might look like in 10 years under different scenarios.

The CDC/Johns Hopkins study reveals that maintaining status quo HIV prevention efforts could put the nation on a dangerous trajectory, resulting in substantial increases in HIV and related costs to the U.S. healthcare system.

Unprecedented Challenges in HIV Prevention

Nearly 30 years into the HIV epidemic, HIV continues to take a heavy toll in the United States. More than 1.1 million people are currently living with HIV, nearly 18,000 people with AIDS still die each year, and lifetime medical care for those who become infected with HIV each year is estimated to cost $20 billion. Gay and bisexual men of all races, African-Americans, Latinos, and injection drug users are most affected.

In the fight against HIV, the nation is facing unprecedented challenges:

  • Impact of economic crisis: The current economic crisis has severely impacted state and local governments and community-based organizations, with $170 million in cuts to state HIV/AIDS prevention and care programs in fiscal year 2009 alone [2]. These cuts mean that essential HIV prevention services will reach fewer of those at risk of HIV infection. In addition, waiting lists for the federal AIDS Drug Assistance Program (ADAP), which provides HIV treatment to low-income individuals, are at record highs.
  • Increasing HIV prevalence: It is anticipated that the number of people living with HIV will continue to increase over time, due to the remarkable benefits of life-prolonging HIV treatments. As more people live with HIV, opportunities for transmission increase, as does the need for prevention services and medical care.
  • Complacency: Despite the severe impact of HIV in the United States, studies show that many Americans — even those at greatest risk of infection — have grown complacent about HIV [3,4]. This is a major concern since lack of awareness about HIV can contribute to increased risk behaviors, and reduce community and governmental mobilization.
Study Examined Five Scenarios

The CDC/Johns Hopkins study examined five scenarios: three scenarios examined likely outcomes of status quo HIV prevention efforts (“base-case scenarios”), and two scenarios investigated the impact of a significant expansion of HIV prevention efforts (“intensified intervention scenarios”).

As indicated in the graphs on the following page, the study found that rapid scale up of HIV prevention efforts could substantially reduce the number of HIV infections and the number of people living with HIV over the next 10 years, compared to the base-case scenarios.



Status Quo in HIV Prevention Could Translate into a Worsening U.S. HIV Epidemic

Researchers examined three “base-case scenarios” that assumed different epidemiologic trends and a continuation of current federal HIV prevention funding levels. Each scenario estimated the impact on future HIV incidence and prevalence (see box on this page for definitions) over the next 10 years. The study found that continuing current trends could increase the number of people living with HIV by as much as 38 percent, and would cost the U.S. healthcare system an additional $128 billion to $237 billion in medical care costs for those who become infected.

Stable HIV incidence: One scenario assumed that the number of annual new HIV infections would remain constant over the next 10 years at 55,400, which the study projected would increase national HIV prevalence by 29 percent (from 1.107 million to 1.427 million people living with HIV). This scenario is plausible given continued high HIV incidence among men who have sex with men — who make up the majority of individuals infected with HIV — and declining incidence among other risk groups. To hold HIV incidence stable in the face of increasing prevalence means that the HIV transmission rate would have to substantially decline.

Definitions

HIV prevalence: The number of people living with HIV — with or without a diagnosis of AIDS — at a point in time. CDC estimates that there were more than 1.1 million people living with HIV in the United States at the end of 2006.

HIV incidence: The number of people who become newly infected with HIV each year. CDC estimates that there were 56,300 new HIV infections in 2006. (The analysis described here draws on historical trends that indicate that 55,400 annual new infections occurred in the United States each year between 2003 and 2006.)

HIV transmission rate: Indicates the estimated number of new HIV infections transmitted per year per person living with HIV. CDC estimates that there were 5 transmissions for every 100 individuals living with HIV in the United States in 2006.

Continued decline in national HIV transmission rate: The most optimistic base-case scenario assumed a continuation of the downward trend in the nation’s HIV transmission rate observed in recent years (2000–2006), such that the HIV transmission rate would decline in 10 years from 5.0 to 3.1 new HIV infections per 100 persons living with HIV. Under this scenario, the study projected that HIV prevalence would increase by 24 percent (from 1.107 million to 1.373 million people living with HIV) and that HIV incidence would decline by 24 percent (from 55,400 to 42,300 annual new HIV infections). For this scenario to be realized, it would be necessary to discover and achieve enough new efficiencies in HIV prevention efforts to offset substantial cuts to HIV prevention budgets at state and local levels.

Stable HIV transmission rate: The most pessimistic base-case scenario projected the impact of a static HIV transmission rate (at the current CDC estimate of 5.0 new HIV infections transmitted annually per 100 persons living with HIV). It found that both HIV prevalence and incidence would increase by 38 percent (from 1.107 million to 1.530 million people living with HIV, and from 55,400 to 76,600 annual new HIV infections). Recent cuts to state and local HIV prevention budgets may make it difficult to make further progress in reducing HIV transmission.

Rapid Scale Up of HIV Prevention Efforts Could Save the Most Lives and Money

The study found that a rapid expansion of HIV prevention efforts could most effectively reduce the number of new HIV infections in the United States, and save the U.S. healthcare system up to 25 times the amount that would need to be invested in prevention.

Based on expert recommendations provided to Congress in 2008 [5,6], the researchers examined two “intensified intervention scenarios” that assumed a significant increase in the federal investment in HIV prevention in order to achieve a 50 percent reduction in the national HIV transmission rate (from 5.0 to 2.5 new infections per 100 persons living with HIV). One scenario examined the prevention interventions and resources that would be needed to cut the HIV transmission rate in half in five years; the other scenario investigated the interventions and resources that would be needed to cut the transmission rate in half in 10 years. Both scenarios placed considerable emphasis on expanding access to HIV testing and behavioral interventions for people living with HIV and those at very high risk of contracting HIV, though they made different assumptions about other HIV prevention efforts that would be required (e.g., local capacity building, HIV surveillance, research, and evaluation).

The study found that the greatest gains could be achieved by scaling up prevention in five years:

  • Expanding HIV prevention in 5 years: The study found that intensifying national HIV prevention efforts over a five-year timeframe and maintaining them for the subsequent five years could reduce annual HIV incidence by 46 percent (from 55,400 to 30,200 new infections) — saving as many as an additional 306,000 people from becoming infected over the next 10 years — compared to maintaining current prevention efforts. HIV prevalence in this scenario would increase by only 13 percent (from 1.107 million to 1.247 million people living with HIV) — the smallest increase of any scenario included in the analysis. This rapid scale up would also save 25 times the amount that would need to be invested: expanding HIV prevention in five years would require an additional investment of $4.5 billion over 10 years, and would save up to $104 billion in avoided lifetime medical costs.
  • Expanding HIV prevention in 10 years: The study shows that expanding HIV prevention over a 10-year timeframe could reduce national HIV incidence by 40 percent (from 55,400 to 33,300 new infections) — preventing as many as an additional 215,000 new infections. In this scenario, HIV prevalence would increase by 20 percent (from 1.107 million to 1.329 million people living with HIV) — lower than any of the “base-case scenarios.” This expansion of HIV prevention would require an additional investment of $10.1 billion over 10 years, and would save as much as $66 billion in averted lifetime medical costs. 
Rapidly expanding HIV prevention would not be easy, but it is achievable. It is estimated that HIV prevention efforts in the United States to date have averted more than 350,000 HIV infections and saved more than $125 billion in medical costs.

The release of the National HIV/AIDS Strategy in July, 2010 gives the HIV prevention community an opportunity to redefine our nation’s approach to HIV prevention and calls for shared responsibility to end the U.S. epidemic. Modeling studies, such as this one, can help guide appropriate actions as we collectively move forward to implement the National HIV/AIDS Strategy. It is clear that progress will require us to direct available resources to the populations and geographic areas with the most urgent needs. Additionally, we must expand HIV prevention efforts for individuals at the highest risk of HIV transmission and infection; ensure a focus on community-level interventions that address underlying HIV risk factors in hardest-hit areas; and work to ensure basic, fundamental HIV knowledge among all Americans.

References
  1. Hall HI, Green TA, Wolitski RJ, et al. Estimated future HIV prevalence, incidence, and potential infections averted in the United States: a multiple scenario analysis. J Acquir Immune Defic Syndr 2010 July 30; volume published ahead of print.
  2. National Alliance of State and Territorial AIDS Directors. Support FY2011 HIV prevention funding.
  3. Kaiser Family Foundation. 2009 survey of Americans on HIV/AIDS: summary of findings on the domestic epidemic. April 2009.
  4. MacKellar DA, Valleroy LA, Secura GM, et al. Perceptions of lifetime risk and actual risk for acquiring HIV among young men who have sex with men. AIDS Behav 2007 Mar; 11 (2) 263-270.
  5. Holtgrave DR. Written testimony on HIV/AIDS incidence and prevention for the U.S. House of Representatives Committee on Oversight and Government Reform. September 16, 2008.
  6. CDC. HIV/AIDS in the United States: a look back and a look forward. Statement of Julie L. Gerberding before the U.S. House of Representatives Committee on Oversight and Government Reform. September 16, 2008.
Last Modified: August 9, 2010
Last Reviewed: August 9, 2010

Content Source:
Divisions of HIV/AIDS Prevention
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Source

Learn More About Stem Cell Research and Treatment

Monday August 9, 2010  

This is a great initiative. The International Society for Stem Cell Research has recently started a a the ISSCR Task Force on Unproven Stem Cell Treatments to investigate individual clinics that claim to be providing stem cell treatments and cures. Called "A Closer Look at Stem Cell Treatments," their website gives people the opportunity to submit the name of clinics for review. From what I understand, the Society is not going to look at patient outcome data, but really wants to make sure that patients' rights are protected and that the clinics are being supervised by regulatory bodies in their countries or regions.
 
Before anyone jumps to the conclusion that this organization is comprised of a bunch of nay-sayers or people who are against embryonic stem cell research and trying to shut down such efforts, let me reassure you that this group is interested in the integrity of stem cell science and medicine because they believe in it. These are people working in the field who want to keep stem cell science clean and free of scandal and charlatans. As their website states:

"The International Society for Stem Cell Research (ISSCR; http://www.isscr.org/) is an independent, nonprofit organization established to promote and foster the exchange and dissemination of information and ideas relating to stem cells, to encourage the general field of research involving stem cells and to promote professional and public education in all areas of stem cell research and application. Members are admitted on the basis of their professional credentials as scientists or clinicians working in the field of stem cell research."

The website also offers great resources for anyone interested in stem cell approaches, such as The Patient Handbook on Stem Cell Therapies and articles explaining the current state of stem cell research and treatment.

Source
Public release date: 8-Aug-2010

Contact: Eric Schoch
eschoch@iupui.edu
317-274-7722
Indiana University School of Medicine

INDIANAPOLIS — Adding a direct acting anti-viral drug to the standard treatment regimen for hepatitis C significantly increases the cure rate in the most difficult to treat patients, according to a research report published Monday in the online edition of the journal The Lancet.

The research team, led by Paul Kwo, M.D., of Indiana University School of Medicine, reported that adding the drug nearly doubled the treatment's effectiveness when given for 48 weeks in one treatment arm of the study.

An estimated 3.2 million Americans and 170 million people worldwide are infected with the hepatitis C virus, but many do not know it. In the United States, 70 percent of affected individuals are infected with genotype 1 hepatitis C, the most difficult to treat. Although there may be no symptoms for years, long-term infection can cause cirrhosis and the disease is a leading cause of liver cancer and liver transplantation. Hepatitis C infections occur mainly through transmission of infected blood, such as via injection drug use, and there is no vaccine.

Currently fewer than half of patients with genotype 1 hepatitis C are treated effectively by the standard combination of two drugs, peginterferon alfa-2b plus ribavirin, which is typically given for 48 weeks. The treatment can be difficult for some patients due to anemia and other side effects.

Adding the drug boceprevir increased the cure rate to as high as 75 percent in those who received 48 weeks of the three-drug combination therapy, compared to 38 percent of those in the control group, who received the standard two-drug treatment for 48 weeks, said Dr. Kwo, associate professor of medicine at the IU School of Medicine. The two-year phase 2 trial was conducted at 67 sites with 520 patients in the U.S., Canada and Europe.

In the boceprevir study, known as the SPRINT-1 trial, researchers tested several different options to evaluate the effectiveness of the combination therapy:

•To test whether the addition of boceprevir could make it possible to shorten treatment times, some patients were randomly selected to receive the three-drug combination for 28 weeks, some for 48 weeks.

•Researchers also investigated whether a 4 week lead-in with the standard two-drug combination prior to the addition of boceprevir to the treatment regime could improve sustained virologic response rates. The goal was to see if allowing the interferon and ribavirin to reach steady state levels -- which would activate the immune system and reduce virus levels -- before adding boceprevir would improve the response rates as well as reduce the virus' ability to develop resistance to boceprevir, said Kwo.

•In another arm of the trial, researchers tested whether a lower dose of ribavirin could reduce the anemia side effects while still treating the virus effectively.
 
"Both 28- and 48-week boceprevir regimens significantly increased sustained virologic response rates – which is the best definition of a cure we have – compared to the 48 week control," said Dr. Kwo. "The 48-week treatment arm with 4 weeks of peg interferon lead-in and 44 weeks of peg interferon, ribavirin, and boceprevir led to the largest improvement over the control group ever reported. That's very impressive."
 
Boceprevir, a product of Merck & Co., is an HCV protease inhibitor – a compound designed to block a function key to viral reproduction in the cell. Boceprevir directly targets the hepatitis C virus, Kwo noted, while peginterferon and ribavirin are less specific, acting more generally to stimulate the body's virus-fighting immune system.

The best results were reported for the 103 patients who were treated for four weeks with the standard two drug regiment, followed by 44 weeks of the three-drug regimen including boceprevir: 75 percent of these patients tested negative for evidence of the virus six months after the end of treatment. Results for the other treatment arms were:

•67 percent of those who received the three drug regimen for 48 weeks with no lead-in treatment tested negative for the virus (103 patients).

•56 percent of those who received the two-drug lead-in for four weeks, followed by 24 weeks of the three drug treatment tested negative for the virus (103 patients).

•54 percent of those who received the three-drug treatment for 28 weeks with no lead-in tested negative for the virus (107 patients).

•38 percent of the control group, who received the standard two-drug treatment for 48 weeks tested negative for the virus (104 patients).

Patients receiving the low-dose of ribavirin did not fare as well – just 36 percent were virus-free after 48 weeks of treatment.

"Based on this phase 2 study, it appears that if this drug receives final approval approximately two-thirds of patients will be able to be treated successfully with 28 weeks of treatment and one-third will need 48 weeks of treatment, though this will require confirmation from the phase 3 trials, from which preliminary results were recently released," said Dr. Kwo.

###

The research was funded by Schering Corp. a division of Merck & Co., which provided assistance with the trial, data collection and analysis, and the manuscript.

Source
The Lancet, Early Online Publication, 9 August 2010
doi:10.1016/S0140-6736(10)60934-8
Cite or Link Using DOI

Dr Paul Y Kwo MD a , 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.

To read this article in full you will need to login or make a payment

Source


Adding Boceprevir to Standard Hepatitis C Treatment Could Double Response Rate

NEW YORK -- August 9, 2010 -- Fewer than half of patients given the standard hepatitis C virus (HCV) treatment for genotype 1 hepatitis C infection for 48 weeks achieve sustained virological response (SVR). But adding boceprevir to peginterferon and ribavirin can result in a near-doubling of the response rate, according to a study published early online and appearing in an upcoming edition of The Lancet.

Genotype 1 HCV remains the most difficult to treat with this standard regimen of pegylated interferon and ribavirin. In this 2-part study, Paul Y Kwo, MD, Indiana University School of Medicine, Indianapolis, Indiana, and colleagues aimed to establish the safety and efficacy of boceprevir when added to peginterferon and ribavirin, and to assess the possibility of using a lower dose of ribavirin.

In part 1 of the phase 2 trial, undertaken in 67 sites in the US, Canada, and Europe, 520 treatment-naive patients with genotype 1 HCV were randomly assigned to receive peginterferon alfa-2b 1.5 mcg/kg plus ribavirin 800 to 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 TID for 24 weeks (PR4/PRB24; n = 103) or 44 weeks (PR4/PRB44; n = 103); or peginterferon alfa-2b, ribavirin, and boceprevir TID for 28 weeks (PRB28; n = 107) or 48 weeks (PRB48; n = 103).

In part two, 75 patients were randomly assigned to receive either PRB48 (n = 16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir TID for 48 weeks (low-dose PRB48; n = 59).

The primary endpoint was SVR 24 weeks after treatment.

The researchers found that patients in all 4 boceprevir groups had higher rates of SVR than did the control group (58/107 [54%] for PRB28; 58/103 [56%] for PR4/PRB24; 69/103 [67%] for PRB48; and 77/103 [75%] for PR4/PRB44; vs 39/104 [38%] for PR48 control).

Low-dose ribavirin markedly reduced the effectiveness of the 3-drug combination.

Boceprevir-based groups had higher rates of anaemia (55% vs 34%) and distortion of their sense of taste (27% vs 9%) than did the control group.

"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," the authors wrote.

"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," they continued. "We also recorded increased response rates in difficult-to-treat groups, including black participants and those with cirrhosis."

In a linked commentary, Laura Milazzo, MD, and Spinello Antinori, MD, University of Milan, Milan, Italy, said: "The emergence of drug-resistant virus needs to be addressed...The lesson learned from anti-HIV therapy indicates that complete viral suppression is required to prevent drug resistance. Hence new strategies must be established to explore the combinations of new drugs, improve adherence to treatment, improve pharmacokinetics (for example by boosting the new protease inhibitors with ritonavir to achieve higher plasma concentrations of active drug and to limit the pill burden), and develop resistance testing."

SOURCE: The Lancet

Source

Recent Releases In Global Health

Article Date: 09 Aug 2010 - 1:00 PDT

Lancet Comment Calls For More Research Into Alcohol Use, HIV

According to a Lancet Comment, "alcohol remains conspicuously absent from the larger field of research and programming in HIV and substance use. ... Patterns of hazardous alcohol consumption prevail in countries with the most severe HIV epidemics, notably eastern and southern Africa." In addition, "hazardous drinking patterns also dominate in the concentrated epidemics of eastern Europe and Asia, where alcohol use by injecting drug users and other marginalised groups might be an additional barrier to effective efforts to prevent HIV infection." The comment notes that both men and women are harmed by excessive alcohol use and calls for more research "focused on reducing alcohol-related sexual-risk behaviour, [which] might offer valuable lessons for the wider field of HIV and substance-use research" (Fritz et. al, 8/7).

Lancet Comment Says HIV Treatment Needs Continued Scale-Up

Keying off a Lancet study on how prognostic modeling might help guide antiretroviral therapy in sub-Saharan Africa, the authors of a Lancet Comment write about the "enormous" challenge of treating all HIV-positive patients in need of drugs and the importance of gaining efficiencies in overall health care in developing countries. "There is a growing pessimism among donors about how to deal with the difficulty of HIV treatment in resource-poor settings. There is a move towards control of other diseases with less expensive therapies that are time-restricted and strengthening of health systems instead of provision of antiretrovirals. Funding for HIV treatment should again be put on the international agenda otherwise the efforts of the past will have been in vain," the authors write (Koole/Colebunders, 8/7).

Gates Foundation To Transition Living Proof Project To ONE

The Bill & Melinda Gates Foundation "will transition 'The Living Proof Project: U.S. Investments in Global Health Are Working' to the global anti-poverty advocacy organization ONE," according to a foundation press release. The project is "a multimedia storytelling initiative to reach American audiences with positive stories about global health, emphasizing the progress, optimism, and opportunity that have been created with the help of U.S. investments," according to the release. Through its 2 million member network, ONE will "expand The Living Proof Project to reach new audiences in more countries around an expanded set of development issues, including agriculture and access to clean water" and feature the benefits of European investments abroad, the release notes (8/5).

Council On Foreign Relations Examines Politics of HIV Donor Support

An expert brief posted on the Council for Foreign Relation's website examines the "messy politics" of HIV donor support. Despite criticism, the author writes, the U.S. government is "by far the biggest supporter of both bilateral and multilateral HIV efforts," noting that when combined with private donations including the Gates Foundation, the U.S. accounts for 85 percent of global HIV/AIDS support. The author also observes the "essentially zeroed out" commitment from AIDS 2010's host Austria and notes that none of the Eastern European countries, including Russia, "even sent high-level delegations to the conference, though the region has the fastest-growing HIV epidemic." The author also describes the world's growing economies - China, Brazil and India - as "negligible donors." Additionally, the post examines President Obama's FY2011 foreign assistance budget request and how Congress has responded (Garrett, 8/4).

Blog: Innovation Needed To Address 'Grand Challenges' Of Development

A Huffington Post article stresses the importance of "the search for elusive solutions to development 'grand challenges'" as discussed at a recent USAID meeting with "leading scientists, inventors, engineers and technologists." For example, the authors write, one longstanding development challenge that could be addressed is "how to provide high-quality, affordable, primary health care in rural communities." The post cites examples of how USAID and the Obama Administration "understand the importance of science, technology and innovation for global development," including calls for better relationships between U.S. and foreign scientists and USAID's creation of a "center of excellence for science and technology" (Shah/Holdren, 8/4).

U.N. Examines MDG Priorities Ahead of 2015

"Even as we strive to achieve the [Millennium Development Goals] MDGs by 2015, the heightened attention and greater public and private investment in global health in recent years is paying dividends," UN Chronicle writes, citing reductions in child and maternal mortality, increased vaccination and the distribution of antiretroviral drugs. The author also writes that "many of the low-income countries are unlikely to achieve" the MDGs partly because of health worker shortages and "weak health care systems." The article also examines the need for collaboration among governments, academia and non-governmental agencies and concludes that a "balanced funding strategy for vaccine and drug development on one hand, and capacity building on the other, will determine how well and how fast we achieve the MDGs and address the other global health priorities for the twenty-first century" (Debas, 8/3).

Blog: Global Community Should Invest In Vaccines

"New vaccines can prevent a large proportion of deaths but the global community has not committed the resources necessary to bring the full range of vaccines to all children," write the authors of a blog on the "Huffington Post." The authors argue that reducing under-five child mortality by two-thirds by 2015, which is Millennium Development Goal (MDG) 4, "will not be possible without additional support for immunization. It would be a crime if this goal were missed simply for lack of adequate financial support." The authors outline possible reasons for the lack of investment in vaccines including: fewer passionate advocates for prevention, stress on the global economy, and donor and recipient fatigue. They call for a "balanced immunization investment strategy that reinforces routine immunization, achieves existing initiatives to eradicate polio and reduce measles deaths by 95 percent, and enables introduction of new vaccines" (Carter/Annan, 8/3).

Several Blogs, Publications Examine Obama Administration's MDG Plan Released Last Week
  • Details Needed On Obama's Plan To Meet MDGs: A post on the "One" blog reflects on President Barack Obama's plan to meet the Millennium Development Goals (MDGs), writing that it is a "first step toward providing leadership," but "a successful outcome ... will require some more details on how this plan will become a reality." The author writes that the U.S. should clarify how its strategies will "complement other countries' efforts to meet the MDGs and feed into the global plan," and provide further details on its effort to "expand development-related activities ... including a clear timeline, process, and metrics for success." The Administration also "needs to provide clarity" on how the plan will fit in to "ongoing efforts to reform U.S. development policy," the author writes (Thornton, 8/3).
  • USAID Administrator Discusses U.S. MDG Strategy With UN Dispatch: USAID Administrator Rajiv Shah discussed the Obama Administration's MDG strategy in an interview with UN Dispatch. "This document fully embraces the MDGs, our desire to build on past progress, and our analysis of where we are about 10 years in," Shah said. In order to find solutions "that scale," he continued, "we are going to have to do things differently ... we have huge opportunities to transition from more costly and ineffective strategies to things that are more highly scalable and lower cost." In the article, Shah also spoke about focusing on the "cross-cutting nature" of the MDGs, rather than treating them as separate goals, and the importance of empowering women and girls in development (Goldberg, 7/30).
  • USAID Deputy Chief Comments On U.S. MDG Plan: The Center for Global Policy's "Science Speaks" blog features an interview with Ben Hubbard, deputy chief of staff at USAID, commenting on the Obama Administration's MDGs strategy. Hubbard told the blog, that while the plan is "a U.S. strategy, we want this to help shape global strategy. It is important we don't want to take a siloed systems approach. An effective strategy needs to address multiple goals at the same time." He also discusses investing in research, a commitment to science and technology, and focusing investment where the U.S. "can really move the dial forward in some of these key sectors" (Donnelly, 7/30).
  • Blog: Obama Needs A Bigger Global Poverty Strategy: Analyzing the new MDGs plan, a post on the "One" blog asks "where's the bigger plan?" Acknowledging that the plan is a "great stepping stone," the author writes, "If the U.S. is committed to fighting global poverty, President Obama needs to deliver a global development strategy at the upcoming MDG Summit." The author also writes that she is "happy to report" the plan mentions a "development policy," which would unify "all of these piecemeal reform efforts." The post also cites a leaked White House document that describes the U.S.'s role as being one that helps "to create a world with more prosperous and democratic states, able to meet the needs of their people and to be our partners in addressing common threats, challenge and opportunities" (McConnell, 7/30).
  • Education Key To Achieving MDGs: The Obama administration's MDGs plan "represents a missed opportunity to deliver on Obama's commitment to invest $2 billion in a Global Fund for Education to achieve universal primary education," according to a post by the Brookings Institution. Success for most of the MDGs, the author writes, will be "nearly impossible without the achievement of universal primary education, MDG 2." The post examines the role education plays in each of the MDGs, including the reduction of child mortality by educating mothers, improving maternal health and combating HIV/AIDS, citing "research on the last decade of the AIDS epidemic" that indicates "increased schooling is lowering the rate of AIDS infections" (Gartner, 7/30)
Blog: 100 Reps. Sign Letter Asking President Obama To Make 3 Year, $6B Global Fund Commitment

Last week, 100 members of the House of Representatives, led by Rep. Barbara Lee (D-Calif.), sent "a letter to President Obama encouraging him to make a three-year commitment of at least $6 billion to the Global Fund to fight AIDS, Tuberculosis and Malaria," according to the Center for Global Policy's "Science Speaks" blog. After attending AIDS 2010, Rep. Lee stated, "there's a lot of concern in the international community that we are not providing the necessary funding to meet our promises to combat this disease." The letter precedes a Global Fund "replenishment meeting" expected to take place in New York in October (Bryden, 8/2).

This week, Sen. Richard Lugar (R-Ind.) also sent a letter to President Obama, "expressing concern about funding being diverted [from HIV/AIDS programs] to other parts of the President's global health initiative," according to a post on his website (8/4).

Blog: Nine Empty Management Positions Hamper USAID

USAID Administrator Rajiv Shah "cannot captain his own ship without a crew," writes the author of a post on the Center for Global Development's "Rethinking U.S. Foreign Assistance Blog," noting that nine management positions must be filled before Shah will "have a full management team in place." Despite skilled leaders throughout the agency, the author writes, "having all remaining management seats empty eighteen months into the administration is unconscionable." Other "important decisions," like "whether USAID will lead the Feed the Future initiative may very well depend on whether Shah has staff in place," the author notes. The post also examines possible explanations for the unfilled positions, including Shah's attention to Haiti, good candidates who may be "worried about USAID's future and turning jobs down," and the difficulty of the White House vetting process (Staats, 8/2).

Health Affairs Examines Motivation of Ethiopian Doctors, Nurses To Work In Rural Areas

An article published in Health Affairs examines what would "best motivate doctors and nurses to work in rural areas of poor countries." After asking 861 Ethiopian health professionals hypothetical questions, researchers found that doctors value "higher wages and quality housing incentives," while nurses were more likely to move to a rural village after "improvements in the availability of medical equipment and supplies." The least attractive element for both doctors and nurses was time commitment, measured by "having to pay back an extra year of work in a remote location after receiving training," the study found (Hanson/Jack, August 2010).

Blog: Despite Warning, Aid Is 'Too Little and Too Slow' To Sahel Region

A post on The Hill's "Congress Blog" looks at the 10 million people across the Sahel region of Africa facing "devastating hunger." The author writes that "despite plenty of warnings of a looming crisis, aid has been too little and too slow to arrive," noting that the U.S. is leading the way in providing emergency food to the region with a $100 million contribution. However, "donors have so far only provided only 25 percent of what aid agencies estimate is needed." The post also states that the U.S.'s generosity is "undermined" by requirements that aid has to be given as food rather than cash and sent from the U.S. on American ships, citing a report to Congress which "estimated that for each dollar spent on food aid, less than 50 cents is actually spent on food." The author also writes that USAID is taking the "extraordinary step" of providing cash to enable local organizations to purchase food in the region" (Offenheiser, 7/30).

American Bar Association Journal Highlights HIV/AIDS And Human Rights

The latest issue of the American Bar Association's "Human Rights" magazine is dedicated to HIV/AIDS and the rule of law. In the issue, the editors "hope to shine a light on the human rights issues at home and around the globe that continue to fuel this epidemic," according to the magazine. The issue includes articles on the need for more "focused attention to human rights" to achieve universal access, sex trafficking and HIV/AIDS, a "deadly junction for women and girls," the role of faith-based organizations and how "culture, history and laws can combine to deny women and girls equal access to HIV prevention and care" (Spring 2010).

This information was reprinted from globalhealth.kff.org with kind permission from the Henry J. Kaiser Family Foundation. You can view the entire Kaiser Daily Global Health Policy Report, search the archives and sign up for email delivery at globalhealth.kff.org.

© Henry J. Kaiser Family Foundation. All rights reserved.

Source

Adverse Effects of HCV Therapy More Common in HIV-Infected Women

By Will Boggs, MD

NEW YORK (Reuters Health) Aug 05 - Women with HIV have higher rates of adverse events from treatment for hepatitis C virus (HCV) compared to men with HIV, researchers reported online July 8th in the Journal of Acquired Immune Deficiency Syndromes.

"Our study did not demonstrate that any particular side effect occurred more commonly in women than in men. Rather, physicians should be aware that HIV-infected women have a greater chance of developing side effects overall during interferon-based and ribavirin HCV therapy and that antiretroviral regimens during therapy may play a role in the development of these side effects," said lead author Dr. Debika Bhattacharya from the University of California, Los Angeles, in e-mail to Reuters Health.

The findings are from a meta-analysis of 3 trials involving 1376 subjects, including 288 women (21% women).

According to Dr. Bhattacharya and colleagues, adverse events requiring treatment discontinuation occurred in 24% of women vs 16% of men. Nearly two-thirds of women (61%) had adverse events requiring treatment modification, compared to less than half of men (48%).

Women on regimens containing non-nucleoside reverse transcription inhibitors were more likely to have adverse events requiring treatment discontinuation than antiretroviral therapy-na�ve women or women on other antiretroviral regimens. This association was not observed in men.

In contrast, antiretroviral therapy-na�ve women were more likely to have an adverse event requiring treatment modification. The opposite was true in men: those who had never taken antiretrovirals were less likely to have adverse events requiring treatment modification.

Women were 54% more likely than men to discontinue therapy and 43% more likely to require treatment modification as a result of adverse events.

Furthermore, the median time to an adverse event requiring treatment modification was 24 weeks in women vs 48 weeks in men.

There was no gender difference in the types of adverse events that occurred, however.

"This work highlights the importance of examining sex differences in the clinical outcomes of HCV therapy in HIV infection," Dr. Bhattacharya concluded. "These differences should be further investigated."

Also, the researchers say, HIV/HCV coinfection studies should consider the possibility that antiretroviral regimens might figure importantly in women's risks for adverse events during HCV therapy.

SOURCE: http://link.reuters.com/fuw53n

J Acquir Immune Defic Syndr 2010.

Source

Tattoos Increase Risk of Hepatitis C

By Michael Smith, North American Correspondent, MedPage Today
Published: August 09, 2010
Reviewed by Adam J. Carinci, MD; Instructor, Harvard Medical School.

The global fad for tatoos, particularly among young people, is growing -- and along with it the risk of acquiring hepatitis C, according to a multinational study.

A systematic review and meta-analysis of 124 published studies from 30 countries, found that people with tattoos were almost three times more likely to have hepatitis C as those without tattoos, according to Jane Buxton, MD, of the British Columbia Centre for Disease Control in Vancouver, and colleagues.

But in some subgroups -- particularly non-injection drug users -- the odds of having the virus were almost six-fold higher, Buxton and colleagues wrote online in the International Journal of Infectious Diseases.

In recent years, tattoos have become increasingly popular. An estimated 36% of Americans under 30 have the skin designs, the researchers wrote. In Canada, they added, around 8% of high school students have at least one tattoo and among those without a tattoo, 21% are eager to get one.

Since tattoo instruments come in contact with blood and bodily fluids, infection is possible if instruments are used on more than one person without being sterilized or without proper hygiene, the researchers noted. Additionally, tattoo dyes are not kept in sterile containers and may also transmit infections, they wrote

To help quantify the risks, the researchers reviewed and analyzed 124 studies from 30 countries -- including Canada, Iran, Italy, Brazil and the U.S. Of those, 83 cross-sectional, case-control, and cohort studies were included in the meta-analysis.

The pooled odds ratio for hepatitis C -- comparing those with and without tattoos -- was 2.74 (95% CI 2.38 to 3.15), they found.

However, in sub-group analyses, the risk could go much higher, they found. For example, in samples derived from non-injection drug users the OR was 5.74 (95% CI 1.98 to 16.66).

In other groups, the odds ratios were:

•3.73, for blood donors (95% CI 2.46 to 5.67).
•3.20, for samples from hospitals (95% CI 2.25 to 4.56).
•3.06, for injection drug users (95% CI 1.2 to 7.25).
•2.80, in high-risk populations, (95% CI 1.63 to 4.82).
•2.79, in community samples (95% CI 1.95 to 4.00).
•2.56, in prison samples (95% CI 1.97 to 3.32).

Some studies had wide confidence intervals, the researchers reported, but when those were discounted there was little change in the overall effect size.

One limitation of the analysis is the observational nature of the included studies, the researchers wrote. As well, they added, studies with a non-significant effect may not have been published, which would tend to increase the observed odds ratios.

What's needed, the researchers concluded, are infection-control guidelines for tattoo artists and clients, and enforcement through inspections, reporting of adverse events and record keeping. Also, they wrote, prevention programs should focus on young people -- those most likely to get tattoos -- and among prison inmates -- who live in environments with a higher prevalence of hepatitis C.

There was no external support for the study.
The authors said they had no conflict of interest in the tattoo industry.

Primary source: International Journal of Infectious Diseases
Source reference:
Jafari S et al. "Tattooing and the risk of transmission of hepatitis C: a systematic review and meta-analysis" Int J Infect Dis 2010; DOI: 10.1016/j.ijid.2010.03.019.

Source