July 16, 2010

Novel microfluidic HIV test is quick and cheap

Credit: Gulnaz Stybayeva, UC Davis

Contact: Holly Ober
hjober@ucdavis.edu
University of California - Davis - Health System

Microfluidic device uses antibodies to 'capture' white blood cells called T cells affected by HIV

UC Davis biomedical engineer Prof. Alexander Revzin has developed a "lab on a chip" device for HIV testing. Revzin's microfluidic device uses antibodies to "capture" white blood cells called T cells that are affected by HIV. In addition to physically binding these cells the test detects the types and levels of inflammatory proteins (cytokines) released by the cells.

Revzin's team collaborated with UCLA electrical engineer Prof. Aydogan Ozcan to integrate an antibody microarray with a lensfree holographic imaging device that takes only seconds to count the number of captured cells and amount of secreted cytokine molecules. The test returns results six to twelve times faster than traditional approaches and tests six parameters simultaneously, based on a small blood sample. The Revzin team published the results of their experiments in the May 2010 issue of Analytical Chemistry.

With further refinements, the test will have wide potential use for multi-parametric blood analysis performed at the point of care in the developing world and resource-poor areas. Its affordability will also make it an attractive option in wealthier areas. Revzin has filed for a patent and is looking for ways to bring his test into clinical use.

"In addition to HIV testing and monitoring, this device will be useful for blood transfusions, where the safety of blood is frequently in question," Revzin says.

The most accurate and effective way to diagnose and monitor HIV infection involves counting two types of T-cells, calculating the ratio between the two types of T-cells, and measuring cytokines. Scientists do this using a method called flow cytometry that requires an expensive machine and several highly trained specialists. Healthcare workers and AIDS activists in the developing world have called for less expensive, more easily performed tests.

"While the point of care field focuses on detection of single parameter (e.g. CD4 counts), we believe that the simplicity of the test need not compromise information content. So, we set out to develop a test that could be simple and inexpensive but would provide several parameters based on a single injection of a small blood volume," explains Revzin.

The HIV test addresses two distinct challenges of blood analysis: 1) capturing the desired cell type from blood, which contains multiple cell types, and 2) connecting the desired blood cell type with secreted cytokines. The test consists of polymer film imprinted with an array of miniature spots. Each spot contains antibodies specific to the two kinds of T-cells (CD4 and CD8) and three types of cytokines printed in the same array. When the blood flowed across the antibody spots, T cells stopped and stuck on the spots.

Each T-cell type was captured next to antibody spots specific for the cytokines they might produce. When antibodies activated the cells, spots adjacent to the cells captured the cytokines they secreted. This connected a specific T-cell subset to its secreted cytokines. The visible color intensity of antibody spots revealed differences in cytokine production by T-cells. Prof. Ozcan's lensfree on-chip imaging allowed the scientists to rapidly image and count T-cell arrays without the use of any lenses or mechanical scanning. Analysis of CD4 and CD8 T-cell numbers, the CD4/CD8 ratio and three secreted cytokines took only seconds.

In the future, Prof. Revzin envisions adding microarrays to the test that can detect proteins from the HIV and hepatitis C viruses.

Lensfree Holographic Imaging of Antibody Microarrays for High-Throughput Detection of Leukocyte Numbers and Function Gulnaz Stybayeva, Onur Mudanyali, Sungkyu Seo, Jaime Silangcruz, Monica Macal, Erlan Ramanculov, Satya Dandekar, Anthony Erlinger, Aydogan Ozcan, and Alexander Revzin Analytical Chemistry, Vol. 82, No. 9, May 1, 2010 3736�.

Source

Vaccination as a Tool for Cancer Prevention

Eric H. Raabe, MD, PhD; Julia M. Kim, MD, MPH; Miriam Alexander, MD, MPH
Authors and Disclosures
Posted: 07/15/2010

Abstract
 
Infectious agents, such as viruses and bacteria, are the causes of several common cancers. Infection with the bacterium Helicobacter pylori predisposes to gastric cancer. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with liver cancer, and Epstein-Barr virus (EBV) is associated with lymphoma and nasopharyngeal cancer. Human papillomavirus (HPV) is a major cause of cervical, anal, penile, and oropharyngeal cancer. Together, infection-associated tumors make up nearly 20% of all cases of cancer worldwide, causing more than 2 million malignancies per year. Most of these cases occur in developing countries. Under normal circumstances, immune surveillance helps to keep many of these virus-associated cancers in check, but in immunocompromised persons, such as those with late-stage HIV infection, the incidence and aggressiveness of these cancers increase. HBV and HPV vaccines are effective and in use, and vaccines against other cancer-causing agents are in development. Because many virus-associated cancers occur in the developing world (such as EBV-associated Burkitt's lymphoma in Africa and HBV-associated hepatocellular carcinoma [HCC] in Asia), the development and deployment of vaccines to prevent infection with HPV, HBV, HCV, and EBV can serve as effective preventative tools to reduce the burden of cancer morbidity and mortality worldwide.

Introduction: Cancer-Causing Infections

In the developing world, cancer is estimated to afflict 10 million people per year. Worldwide efforts to prevent cancer have generally focused on behavioral changes, such as smoking cessation. Because infectious agents cause some of the more common human cancers, understanding the role of the immune system is necessary to maximize cancer prevention strategies. The immune system has an endogenous role in preventing some cancers and can be stimulated with vaccines to prevent infection with cancer-causing viruses.

One of the paradoxes of cancer biology is that a lack of immune surveillance (such as in HIV-infected individuals or immunosuppressed organ transplant recipients) can lead to cancer, and chronic inflammation due to persistent infection can also do so. Chronic inflammation as a result of HBV or HCV infection leads to HCC, usually after the patient progresses to cirrhosis. In gastric cancer, nearly 60% of all cases in developed countries and 75% of cases in developing countries are attributable to chronic infection with H pylori.[1] It is likely that chronic inflammation due to H pylori leads to intestinal metaplasia of the gastric epithelium and eventually to gastric cancer.[2] Long-term infection with HPV and EBV leads to transfer of oncogenes present in the viral genome to human cells, thereby promoting cancer development.

Harnessing the immune system to prevent or clear cancer is a major goal of cancer research. Vaccination campaigns have been enormously successful in reducing the global burden of infectious diseases. A worldwide infrastructure exists for the manufacture, distribution, and administration of vaccines in urban, suburban, and rural areas. The use of vaccines to prevent cancer caused by chronic infection with oncogenic agents has had a substantial benefit in the developed world and could have a major effect on cancer incidence in the developing world. This article will review the most common infection-related cancers and the role of vaccines for cancer prevention worldwide.

HPV and Cancers of the Anogenital Tract and Oropharynx

HPVs are commonly spread through sexual contact. These viruses are the cause of genital warts, and subtypes 16, 18, 31, 33, and 35 are the major subtypes that cause cervical, anal, and head and neck cancer.[3] HPV infection is associated with 100% of cases of cervical cancer. The incidence of infection with HPV is far higher than the incidence of cancer, because the immune system clears most infections.[4] However, more than 500,000 new cases of cervical cancer are estimated to occur worldwide in 2010.[3] Routine Papanicolaou smears can monitor for early signs of cervical cancer, but many at-risk women in the United States and elsewhere do not receive appropriate gynecologic care.[5] These women are more likely to be from nonwhite, lower-income, and immigrant groups, and they are more likely to develop and die of cervical cancer.[5]

During the past 30 years, the incidence of aggressive serotype HPV-associated squamous-cell carcinoma of the anus has increased. This increase largely began in men who have sex with men, but increases in women have also been observed.[3] HPV is also associated with cancer of the vagina, vulva, and penis, although these are much less common than cervical cancer.

Squamous-cell carcinoma of the oropharynx and head and neck is associated with tobacco and alcohol use, but HPV serotypes 16 and 18 are commonly observed in a subset of persons with this cancer.[3] Of interest, the percentage of HPV-positive oral cancers is reported to be increasing in several countries.[6] This increase is attributed to changing sexual practices, suggesting that HPV-associated oral cancer, like HPV-associated anal and cervical cancer, can be considered a sexually transmitted infection.[6]

Hepatitis B and C Viruses and HCC

Chronic HBV infection is highly prevalent throughout the developing world, particularly in Asia and Africa, where some countries have a prevalence rate as high as 12% of the total population. It is estimated to cause more than 1 million annual deaths worldwide, with one third of these deaths caused by HCC and the remainder by cirrhosis.[1] Chronic HBV infection confers a 20 times increased risk for HCC. HBV vaccination is now included in the standard childhood vaccination series in the United States, but immigrant and older populations can have high HBV carrier rates.[7] Intrapartum transmission is a major cause of transmission of HBV to children. To prevent HBV infection, hepatitis B immune globulin, along with hepatitis B vaccine, must be given to neonates of HBV-positive mothers (see "Key Recommendations for Healthcare Providers to Prevent Cancers Caused by Infectious Disease").

HCV infection is another a major cause of HCC. Whereas the carrier rate of HCV in the United States was estimated at 1.6% in 2002, in Africa the prevalence ranged from more than 8% in Northern Africa to less than 2% in Southern Africa.[1] Vaccines for HCV are in development, but for patients who have already contracted HCV, a regimen involving 6 months of pegylated interferon alpha and ribavirin can lead to eradication in up 60% to 80% of patients.[8] Active surveillance for HCV and aggressive attempts at eradication can therefore reduce the subsequent risk for cancer in populations at risk.

EBV-Associated Cancers

EBV is the primary cause of infectious mononucleosis, a typically benign disease of adolescence and young adulthood. However, the virus is also a causative agent in many aggressive neoplasms, including 20% of cases of Hodgkin's lymphoma (one of the most common lymphomas of adolescence), nasopharyngeal carcinoma, and a subtype of Burkitt's lymphoma.[1] Nasopharyngeal cancer affects approximately 80,000 people each year, predominantly in less developed countries. Most of these cases are attributable to EBV infection.[1] Although this cancer is curable with intensive chemotherapy and radiation therapy, most of the people affected by this cancer do not have access to these treatments.

More than 28,000 worldwide cases of Hodgkin's lymphoma are attributed to EBV infection.[1] Like nasopharyngeal cancer, Hodgkin's lymphoma is highly treatable. More than half of Hodgkin's lymphoma cases occur in less developed countries, however, and curative treatment is often not available. The iconic image of a sub-Saharan African child with a very large facial or neck mass is an easily recognizable sign of endemic Burkitt's lymphoma caused by EBV infection. As many as 6800 cases of Burkitt's lymphoma caused by EBV occur every year, with more than 90% of these infections occurring in less developed countries.[1] EBV-associated non-Hodgkin's lymphoma is particularly common in patients with advanced HIV infection. An estimated 68,000 cases of EBV-associated non-Hodgkin's lymphoma occur annually, and two thirds occur in developing countries.[1]

H Pylori-Associated Gastric Cancer and Mucosa-Associated Lymphoid Tissue Lymphoma

The causative infectious agent for peptic ulcer disease, H pylori, is also a known cancer-causing agent. Chronic infection with this pathogen predisposes to stomach cancer and to gut mucosa-associated lymphoid tissue (MALT) lymphoma.[4] Gastric cancer accounts for nearly 10% of all cases of cancer worldwide, and the causative agent in more than 60% of these cases is estimated to be H pylori (other risk factors include diet and excessive alcohol intake). In 2002, it was estimated that H pylori caused as many as 600,000 cases of gastric cancer per year worldwide.[1] Eradication of H pylori can be accomplished with antibiotic therapy; however, the very high burden of infection in many countries (for example, in sub-Saharan Africa, more than 75% of adults are infected with H pylori) and the relative ease of reinfection make treatment of asymptomatic carriers unfeasible.[2] Because the infection first occurs in young children, H pylori seems to be an amenable target for vaccine development to prevent colonization and subsequent stomach cancer and gut-associated MALT lymphoma. Until a vaccine becomes available, healthcare providers should screen for dyspepsia and peptic ulcer disease and offer H pylori testing to affected patients. Healthcare providers should administer drug therapy for eradication of H pylori in those who are symptomatic and H pylori-positive.

Human Herpesvirus 8: Kaposi's Sarcoma

Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi's sarcoma, a once-rare sarcoma of blood vessels. Before the AIDS epidemic, Kaposi's sarcoma was primarily known to affect Mediterranean or eastern European men or immunosuppressed patients, such as organ transplant recipients.[9] With the increasing worldwide prevalence of HIV infection, most cases of Kaposi's sarcoma are now associated with HIV or AIDS. In 2002, it was estimated that more than 60,000 cases of Kaposi's sarcoma occur yearly,[1] and it is the most common type of cancer reported in some African countries highly affected by HIV, such as Zimbabwe. The best treatment for Kaposi's sarcoma in HIV-infected patients is initiation of antiretroviral agents to reduce HIV viral load and allow restoration of immune system function. Sometimes this is sufficient to cause regression of the cancer. In other cases, the cancer continues to spread and combination chemotherapy is required.[9]

Role of Vaccines for Cancer Prevention in the United States

HBV vaccine. In 1991, the Centers for Disease Control and Prevention (CDC) recommended adoption of a comprehensive strategy for prevention of HBV infection, which included:

•Routine maternal prenatal testing for HBV;
•Immediate postpartum intervention to prevent maternal to child transmission;
•Universal vaccination of children for HBV;
•Vaccination of all adolescents who had not received HBV vaccine previously; and
•Vaccination of adults at risk for becoming infected with HBV.[10]

The childhood immunization schedule, a 3-vaccine series administered in the first year of life, confers long-term immunity to HBV. Infants born to HBV-positive mothers must receive both vaccination and hepatitis B immune globulin within the first 12 hours of life. This regimen is 85-95% effective in preventing transmission of HBV. Because children are at increased risk for becoming chronic carriers when infected with HBV, starting the vaccine at birth and completing the series during routine well-child visits during the first year of life decreases the risk for infection from HBV-positive household contacts. Analysis of immunization rates in newborns in the United States from 2003-2005 showed only a 50% vaccination rate, leaving many infants unprotected from HBV infection. Clearly, the United States needs to increase newborn vaccination rates for HBV.[11]

HPV vaccine. Two HPV vaccines are approved for use in the United States: Gardasil® (Merck & Co., Inc., Whitehouse Station, New Jersey) and Cervarix® (GlaxoSmithKline, Philadelphia, Pennsylvania). Gardasil® targets the serotypes of the virus most associated with cervical cancer (16, 18) and genital warts (8, 11). Cervarix® also targets serotypes 16 and 18 and uses a different adjuvant than Gardasil® to boost immune response. Both vaccines are equally effective at preventing HPV infection caused by the serotypes contained in the vaccines, and both will prevent development of high-grade cervical lesions caused by the corresponding serotypes. These vaccines are most effective when given to women and girls who have not been exposed to HPV.[12] However, in a mixed population of HPV-exposed and HPV-unexposed young women, compared with placebo, vaccination with Gardasil® led to a 60% reduction in genital warts and a nearly 20% reduction in the incidence of precancerous cervical lesions. A corresponding reduction in the number of women who required invasive surgical resection of their precancerous lesions suggests that even in older, HPV-exposed women, vaccination may be helpful in reducing cervical cancer rates.[13] The follow-up timeframe for these vaccines is still short, so it is not clear how long the protective effect will last.[12] Additional postapproval studies are ongoing to determine the duration of protection and to determine whether post exposure vaccination is warranted.

The availability of HPV vaccines against serotypes 16 and 18 gives healthcare providers the tools to prevent HPV infection and subsequent cervical cancer. The US Food and Drug Administration (FDA) approved Gardasil® for girls and young women from age 9 to 26 years and for boys and men in that same age group, on the basis of trials showing efficacy preventing cervical neoplasia and cancer in women and anogenital warts in both women and men.[14] The FDA approved Cervarix® for girls and women ages 10 to 25 years for prevention of cervical neoplasia and cancer.[12] These vaccines may also be effective in preventing cancer of the oropharynx and anus caused by HPV 16 and 18 in both men and women.[6,15]

Whereas HPV vaccines have been approved and are being administered in the United States, the uptake of the vaccines has been uneven. A backlash against HPV vaccination has occurred in some communities. Further interventions are required to improve vaccination among those most at risk for invasive cervical neoplasia.[5] Clinicians should offer HPV vaccination to all adolescent girls and young women who have not yet had their sexual debut, and they should consider giving the vaccine to young women after sexual debut, on the basis of the findings described above. These vaccines do not cover all of the subtypes of HPV that cause cervical cancer, and widespread vaccination does not replace the need for intermittent cervical cancer screening, although it is projected to reduce the number of invasive procedures.[12]

Cancer Prevention Outside of the United States

Role of vaccines. The use of vaccines and eradication treatments to prevent infection-caused cancer in the United States and other developed countries will continue to reduce mortality and morbidity from these diseases. However, the major burden of disease and corresponding mortality lie in the developing world.[4] Taken together, the number of infection-related cancers is estimated at nearly 2 million cases per year, accounting for almost 20% of all cancer cases.[1] Widespread application of vaccines for HBV and HPV could decrease the global burden of cancer by 900,000 cases per year, on the basis of 2002 estimates.[1]

The HPV vaccine is approved for use in more than 60 countries. Widespread vaccination for HPV coupled with limited cervical cancer screening can be considered cost-effective in developing countries if a vaccine can be delivered for approximately $1 per dose (in a 3-dose regimen).[16] The current course in the United States costs more than $300 USD. Improvements in HPV vaccines to make them more thermostable and efficacious, and less costly, will increase the feasibility of vaccinating adolescents in developing countries.[4]

Drug treatment of HCV and H pylori infections to prevent cancer. Development of new vaccines or widespread identification and eradication efforts could further reduce the global cancer burden by reducing the carriage rate of H pylori, leading to fewer cases of gastric cancer (now estimated to be more than 500,000 cases per year).[1,2] Eradication of HCV by use of ribavirin plus pegylated interferon, although expensive, could eliminate the nearly 200,000 cases per year of HCC that are attributed to HCV.[1] To eliminate HCV in less developed countries successfully and cost-effectively, either a vaccine against HCV or a less burdensome eradication regimen is needed.

Burden of HIV as a cancer predisposition syndrome. The growing HIV epidemic is adding to the already substantial burden of cancer in lower-income countries (and in affected populations in the United States). Chronic HIV infection should be considered a cancer predisposition syndrome. Loss of immune surveillance as a result of HIV infection can lead, in HPV infection, to a rapid progression of precancerous lesions to cancer, and to increases in de novo cancer, particularly in HHV-8 and EBV-infected individuals.[1,17] Restoration of immune function as evidenced by normalizing CD4 helper T-cell numbers after initiation of highly active antiretroviral therapy (HAART) can lead to stabilization or regression of cancer. However, in lower-income countries, initiation of HAART continues to encounter multiple barriers (lack of healthcare providers, lack of drug distribution infrastructure, and cultural barriers to testing and starting treatment).[18] Although initial trials of an HIV-prevention vaccine have not succeeded, additional trials of new strategies for an HIV vaccine are ongoing and under development.

Role of vaccines in immunocompromised hosts. For patients who are already HIV-infected, the ability to respond to an antiviral vaccine, such as the HBV vaccine, may be severely attenuated, depending on their CD4 count.[19] Vaccination before HIV infection (such as in an HIV-negative child) may prevent subsequent infection with the target of the vaccine, even if the patient has become HIV-positive. Much depends on the degree of destruction of the immune system and the extent to which the immune system is reconstituted after starting antiretroviral therapy.

Future Directions

The current availability of vaccines against HPV and HBV cancer-causing viruses could prevent nearly 1,000,000 annual cases of cancer throughout the world.[1] Barriers to widespread vaccination include expense, lack of sufficient healthcare personnel, problems with drug delivery and storage, and opposition of the local population. HPV and EBV vaccines are being deployed and improved, and an effort to develop vaccines against HCV and EBV continues. These new vaccines, along with those currently in use, have the promise of substantially reducing global morbidity and mortality from cancer.[4] Finally, advances in immunobiology will further our understanding of the pathogenesis of cancer and may enable the development of vaccines to prevent other cancers not caused by infectious agents.[20]

Key Recommendations for Healthcare Providers to Prevent Cancers Caused by Infectious Disease

1. Hepatitis B: Test for HBV in members of at-risk groups and offer vaccination to all adolescent and adult patients who are HBV negative. Begin HBV vaccinations in all neonates starting before discharge from the hospital and continuing through well-baby checks during the first year of life, according to Advisory Committee on Immunization Practices (ACIP) guidelines.[10] Consider treatment of HBV-positive patients to reduce the risk for progression to cirrhosis and HCC, according to National Institutes of Health Consensus Conference guidelines.[21]

2. H pylori: Screen for dyspepsia and peptic ulcer disease and offer H pylori testing to affected patients. Administer drug therapy for eradication of H pylori in those who are symptomatic and positive for H pylori, according to American College of Gastroenterology guidelines.[22]

3. HIV: Offer HIV testing to at-risk patients. In some areas with increasing prevalence of HIV, this would be considered all patients aged 13-64 years, according to CDC guidelines.[23] In HIV-positive individuals, screen for HBV, HCV, and HPV, because HIV-positive patients are at increased risk for cancer caused by infectious agents .

4. HPV: Offer screening Papanicolaou smears for all women according to American Congress of Obstetricians and Gynecologists guidelines.[24] Offer vaccination against HPV to adolescent girls and women up to age 26 years, according to ACIP guidelines.[14]

5. Hepatitis C: Offer testing for HCV in all at-risk patients and offer eradication of HCV in patients who test positive, according to the National Institutes of Health Consensus Conference Statement on Hepatitis C.[8]

References

1.Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030-3044. Abstract

2.Del Giudice G, Malfertheiner P, Rappuoli R. Development of vaccines against Helicobacter pylori. Expert Rev Vaccines. 2009;8:1037-1049. Abstract

3.Parkin DM, Bray F. Chapter 2: the burden of HPV-related cancers. Vaccine. 2006;24 Suppl 3:S3/11-25.

4.Frazer IH, Lowy DR, Schiller JT. Prevention of cancer through immunization: prospects and challenges for the 21st century. Eur J Immunol. 2007;37 Suppl 1:S148-155. Abstract

5.Downs LS Jr, Scarinci I, Einstein MH, Collins Y, Flowers L. Overcoming the barriers to HPV vaccination in high-risk populations in the US. Gynecol Oncol. 2010;117:486-490. Abstract

6.Hong AM, Grulich AE, Jones D, et al. Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. Vaccine. 2010;28:3269-3272. Abstract

7.Mast EE, Weinbaum CM, Fiore AE, et al; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33.

8.Recommendations from the National Institutes of Health consensus development conference statement: management of hepatitis C: 2002. Hepatology. 2002;36:1039.

9.Arav-Boger R. Treatment for Kaposi sarcoma herpesvirus: great challenges with promising accomplishments. Virus Genes. 2009;38:195-203. Abstract

10.Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep.1991;40(RR-13):1-25.

11.Newborn hepatitis B vaccination coverage among children born January 2003-June 2005 -- United States. MMWR Morb Mortal Wkly Rep 2008;57:825-828.

12.Harper DM. Currently approved prophylactic HPV vaccines. Expert Rev Vaccines. 2009;8:1663-1679. Abstract

13.Muñoz N, Kjaer SK, Sigurdsson K, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 2010;102:325-339. Abstract

14.Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Advisory Committee on Immunization Practices (ACIP). Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2):1-24.

15.Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer. 2008;113(10 Suppl):3036-3046.

16.Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries -- key challenges and issues. N Engl J Med. 2007;356:1908-1910. Abstract

17.Krishnan A, Levine AM. Malignancies in women with HIV infection. Womens Health (Lond Engl). 2008;4:357-368. Abstract

18.Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300:555-570. Abstract

19.Kim HN, Harrington RD, Crane HM, Dhanireddy S, Dellit TH, Spach DH. Hepatitis B vaccination in HIV-infected adults: current evidence, recommendations and practical considerations. Int J STD AIDS. 2009;20:595-600. Abstract

20.Disis ML. The ultimate in cancer chemoprevention: cancer vaccines. Cancer Prev Res (Phila Pa). 2010;3:406-409. Abstract

21.Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health consensus development conference statement: management of hepatitis B. Hepatology. 2009;49(5 Suppl):S4-S12.

22.Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-1825. Abstract

23.Branson BM, Handsfield HH, Lampe MA, et al; Centers for Disease Control and Prevention (CDC). Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17.

24.American College of Obstetricians and Gynecologists. ACOG Practice Bulletin number 109, December 2009: Cervical cytology screening. Obstet Gynecol. 2009; 114:1409-1420. Abstract

Source
SUMMARY: Hepatitis C virus (HCV) can survive and remain infectious in a liquid environment for up to 5 months at cool temperatures, according to a German study described in the June 15, 2010 Journal of Infectious Diseases. Various alcohols and antiseptics reduced HCV RNA to undetectable levels, but the antiviral effect diminished when hand disinfectants were diluted.

By Liz Highleyman

Sandra Ciesek and colleagues looked at the infectivity, environmental stability, and susceptibility to chemical disinfectants of HCV grown in laboratory cell cultures.

Until recently, HCV could not be grown in laboratory cultures, so the antiviral activity of disinfectants against HCV was estimated based on studies using the structurally similar bovine viral diarrhea virus, the investigators noted as background. But the recent development of an HCV infection model system has allowed direct assessment.

The study authors analyzed HCV RNA levels using quantitative real-time polymerase chain reaction (PCR). Genome stability was determined by introducing recovered viral RNA into Huh7.5 cells.

Results 
  • HCV infectivity in a liquid environment was detectable for up to 5 months at lower temperatures.
  • Different alcohols and commercially available antiseptics reduced HCV to undetectable levels.
  • Diluting hand disinfectants reduced their virucidal activity. 
The results, they suggested, "should be useful in defining rigorous disinfection protocols to prevent nosocomial transmission of HCV" in healthcare settings.

Investigator affiliations: Division of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Joint venture between Hannover Medical School and the Helmholtz Centre for Infection Research; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Medical Microbiology, University Hospital Essen, Essen, Germany; MikroLab, Bremen, Germany.

7/16/10

Reference

S Ciesek, M Friesland, J Steinmann, and others. How stable is the hepatitis C virus (HCV)? Environmental stability of HCV and its susceptibility to chemical biocides. Journal of Infectious Diseases 201(12): 1859-1866 (Abstract). June 15, 2010.

Source

Future Directions for NIAID’s HIV Vaccine Clinical Research

Research
July 16, 2010

By Carl W. Dieffenbach, Ph.D., Director of NIAID’s Division of AIDS, and Margaret I. Johnston, Ph.D., Director of the Vaccine Research Program in NIAID’s Division of AIDS

The development of a safe and effective preventive vaccine for HIV remains one of NIAID’s highest priorities. As we look to the future, we are also seeking to expand the capability of our HIV vaccine clinical research infrastructure to contribute to the development of vaccines for other infectious diseases of public health significance that impact people who are infected with HIV and those who are at risk for HIV infection.

HIV vaccine development has presented significant challenges for the scientific community. However, in late 2009, we obtained the first clinical evidence that a safe and effective HIV vaccine may indeed be possible. The RV144 Thai trial showed that an experimental “prime-boost” vaccine regimen was safe and 31 percent effective in preventing HIV infection. This information brought renewed hope and optimism to researchers and the HIV/AIDS community. Most recently, the identification by NIAID-led scientists of two new broadly neutralizing human antibodies that can prevent more than 90 percent of known HIV strains from infecting human cells will certainly help to advance HIV vaccine design. As we chart a path forward, we must keep our eye on the goal of developing a safe and effective vaccine that prevents HIV acquisition. To achieve this goal, we are following a two-pronged approach for an HIV vaccine.

The first approach grew out of the 2008 NIAID HIV vaccine summit and consists of a strengthened commitment to basic vaccine discovery for HIV. For example, investigators are actively evaluating the earliest steps during HIV infection and how a vaccine may influence the course of infection. Studies in non-human primates are addressing questions that cannot be addressed in humans. This has resulted in a proliferation of new ideas and concepts to pursue, and we must continue to encourage “out of the box” thinking and approaches to HIV prevention. As these lines of thinking and research progress, we hope that some ideas will mature into novel vaccine concepts worthy of further evaluation. Clearly, an important component of the research endeavor is the eventual evaluation of the most promising new concepts for safety and activity in humans, which includes testing candidate HIV vaccines with acquisition of infection as a clinical trial endpoint.

Second, we need to follow up on the results of the RV144 trial to determine if the results can be extended and improved through clinical trials in higher risk populations and where different strains of HIV circulate. If a measurable sign of how vaccinated study participants were protected — what is known as a “correlate of protection” — is identified through the ongoing studies using RV144 specimens, there will be a relatively straightforward path to the improvement of vaccine design. Absent a correlate, different prime-boost strategies can be evaluated for safety and activity in “proof of concept” trials to yield additional information about what immune responses may or may not correlate with efficacy. One strategy currently under consideration is to use an adaptive trial design so that the vaccine candidates that fail early would be eliminated, resulting in a more streamlined development path. In order for these clinical trials to be performed in an expeditious manner, they will need to be conducted at sites where volunteers at high risk for HIV infection can be rapidly recruited. In addition, clinical trials that enroll volunteers with different routes of potential HIV exposure will need to be developed.

There are a number of other infectious diseases that burden populations impacted by HIV. These include, but are not limited to, tuberculosis, hepatitis C infection, and malaria. Like HIV/AIDS, finding preventive vaccines for these diseases has proven elusive as well. By integrating efforts, the best minds in infectious diseases, vaccine discovery and development can work together, so that the research processes and discoveries for each disease can inform vaccine development for other diseases. Furthermore, integration of efforts to evaluate vaccines against these diseases of public health importance would lead to a more efficient and effective use of clinical laboratory expertise and clinical trial site capacity. Our goal is to have the restructured NIAID HIV clinical trial networks make significant contributions to the development of new preventive vaccines for HIV and other diseases of critical public health importance, including those that impact the most vulnerable populations around the world (e.g., young children and pregnant women). Developing effective preventive vaccines for these diseases will greatly improve the health and well-being of people living in areas with high rates of HIV.

We welcome your thoughts and feedback with regard to this topic. In our next blog post, we will shift the discussion toward the leadership structure for a revamped NIAID HIV clinical trial network system..

If you enjoyed this post, please consider leaving a comment or subscribing to the feed to have future articles delivered to your feed reader or email.

Source
SUMMARY: Immunosuppressive chemotherapy drugs can potentially cause the immune system to lose control over hepatitis B virus, but HBV screening is not required for all patients about to start cancer treatment, according to a controversial provisional clinical opinion from the American Society of Clinical Oncology (ASCO) published in the July 1, 2010 Journal of Clinical Oncology. Clinicians may, however, test individuals at risk for infection or known to have been exposed to HBV.

By Liz Highleyman

The immune system is able to naturally suppress HBV in many people with normal immune and others are apparently cured with successful antiviral treatment. But a low level of virus can remain in the body and become active -- or reactivate -- if the immune system is weakened, for example due to HIV infection or use of immunosuppressive drugs to treat cancer.

The U.S. Centers for Disease Control and Prevention (CDC) in 2008 recommended routine hepatitis B screening-- that is, testing for hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti-HBc), and hepatitis B surface antibodies (anti-HBs) -- for "persons receiving cytotoxic or immunosuppressive therapy" such as chemotherapy for malignancies.

The ASCO opinion takes a less aggressive approach due to lack of data showing benefits of routine testing.

"The evidence is insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in individuals with cancer who are about to receive cytotoxic or immunosuppressive therapy or who are already receiving therapy," the opinion states.

"Individuals with cancer who undergo certain cytotoxic or immunosuppressive therapies and have HBV infection or prior exposure to HBV may be at elevated risk of liver failure from HBV reactivation," the statement continues. "As such, HBV screening requires clinical judgment. Physicians may consider screening patients belonging to groups at heightened risk for chronic HBV infection or if highly immunosuppressive therapy is planned."

Highly immunosuppressive treatments include bone marrow stem cell transplants and chemotherapy regimens that include rituximab (Rituxan).

If screening is deemed appropriate for an individual patient, the opinion recommends testing for HBsAg as a serologic marker for HBV infection. "In some populations, testing for anti-HBc should also be considered," according to the statement. However, "[t]here is no evidence to support serologic testing for anti-HBs in this context."

When evidence of chronic HBV infection is detected, "antiviral therapy before and throughout the course of chemotherapy may be considered to reduce the risk of HBV reactivation, although evidence from controlled trials of this approach is limited," the opinion adds. But "[s]creening and/or treating HBV infection should not delay the initiation of chemotherapy."

The ASCO opinion is subject to controversy. In addition to the CDC, the American Association for the Study of Liver Diseases (AASLD) and Memorial Sloan-Kettering Cancer Center also recommend routine HBV screening before immunosuppressive chemotherapy.

A retrospective review from Memorial Sloan Kettering Cancer Center, presented by Emmy Ludwig at the 2010 ASCO annual meeting last month, found 23 documented cases of HBV reactivation in cancer patients on immunosuppressive therapy in the prior 3 years at that center, resulting in 19 hospitalizations, 4 deaths, 4 clinically significant delays in cancer treatment, and 1 liver transplant. But in the nearly 1 year since HBV screening was implemented, with entecavir (Baraclude) treatment for those who test positive, there have been no cases of reactivation.

7/13/10

References

AS Artz, MR Somerfield, J Feld, and others. American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. Journal of Clinical Oncology 28(19): 3199-3202 (Abstract). July 1, 2010.

RB Mendelsohn, S Nagula, Y Taur, E Ludwig, and others. Reactivation of chronic hepatitis B virus in cancer patients receiving immunosuppression: The case for screening. American Society of Clinical Oncology Annual Meeting. Chicago, June 4-8, 2010. Abstract 9088.

Other Source

Zosia Chustecka. Screening Cancer Patients for Hepatitis B: Should it Be Routine? Medscape (http://www.medscape.com/). June 24, 2010.

Source

Congressmen Request $50 Million Funding for HCV

We need several hundred million to address HCV in the USA and we need a National HCV Testing Day, but below is a letter to Congress' Labor/HHS Committee for $50Mill from 4 Congressmen.

You can help in the effort to secure funding for HCV by contacting your Congressional Representative & ask them to support this request:

The Honorable David Obey
Chair
Subcommittee on Labor-HHS-Education
House Appropriations Committee
2358 Rayburn House Office Building
Washington, DC 20515

The Honorable Todd Tiahrt
Ranking Member
Subcommittee on Labor-HHS-Education
House Appropriations Committee
2358 Rayburn House Office Building
Washington, DC 20 515

NVHR.org

July 15, 2010
Re: FY 2011 Viral Hepatitis Funding

Dear Chairman Obey and Ranking Member Tiahrt:

On behalf of the 140 community based organizations that are represen ted by the National Viral Hepatitis Roundtable (NVHR) I am writing respectfully to request that you provide funding for the Division of Viral Hepatitis (DVH) of the Centers for Disease Control and Prevention in the amount of $50 million.

In accordance with the request made to you yesterday by the Honorable Members of Congress, Mr. Cao, Mr. Cassidy, Mr. Johnson, and Mr. Towns, we believe that the Affordable Care Act's Prevention and Public Health Fund provides the opportunity to address the critically underfunded viral hepatitis epidemic in the United States. As the Members noted, with the impending plan for viral hepatitis being developed in the Department of Health and Human Services, under the direction of Assistant Secretary of Health, Dr. Howard Koh, the time to fund viral hepatitis prevention is now.

In the United States, up to 1.4 million people have chronic hepatitis B virus (HBV) infections and up to 3.9 million are infected with chronic hepat itis C virus (HCV). Three to five times as many people are living wi th chronic viral hepatitis infections than with HIV infection, and mortality rates from hepatitis associated liver disease and liver cancer equal those of HIV, yet DVH received only $19.3 million in FY 2010. This is only 2% of funding that HIV/AIDS receives.

A report released in January by the Institute of Medicine (IOM) cites the dearth of federal resources to address viral hepatitis. This is causing many Americans to go unaware that they are infected with hepatitis B or hepatitis C until their disease has progressed to significant liver damage or liver cancer. Further, not knowing one's status, can lead to virus transmission to others.

The IOM identified hepatitis as an underappreciated health threat reflected by studies which show that 65 - 75% of persons living with chronic hepatitis are unaware of their infection and The report cited the lack of national coordination as hampering efforts to prevent and control these diseases and recommended increased commitments to surveillance, education, vaccination and screening, and health services to reduce viral hepatitis associated liver disease and cancer.

Undiagnosed infections drive up medical care costs due to disease complications and ongoing transmission. It is imperative that we make individuals aware of their infections to increase quality of life and decrease costs. The projected direct and indirect costs of this epidemic, if left unchecked, will be over $85 billion annually by 2024.

Thank you for considering this request.
Sincerely,

Martha Saly
Director
National Viral Hepatitis Roundtable

Click here to read Letter from Congress scroll to bottom of page.

Source


Desperate need for organ donors as liver transplant register soars

05 July 2010 @14:56:36

New figures show a staggering 17% increase on the liver transplant register in the past year, with 370 people now currently waiting for the organ. National liver charity, the British Liver Trust, has expressed its concern that, with rising rates of liver disease, there are not enough donors to meet the increasing demand.

Alison Rogers, Chief Executive of the British Liver Trust, says: “With only 100 extra liver transplants available in five years and more people being affected by liver disease each year, we are very concerned about the consequences.

“Currently two people a week die waiting for a liver transplant; this figure is set to increase further unless we see the upward mortality trend of liver disease fall. Increasing rates of liver disease are not just driving demand for transplants; they're driving demand for all liver services and pushing up NHS costs.”

Liver disease, when compared to the other five big causes of death, is the only one showing a steady increase year-on-year. In 2008, liver disease killed 16,087 people – a 4.5% increase from 2007. If these rates continue, deaths from liver disease are predicted to double in 20 years.

Alcoholic cirrhosis, already the leading cause of liver disease, has increased by a fifth in the last five years and resulted in 130 transplants last year alone. However there has also been at least a 10% rise in liver transplants since 2006 due to causes such as hepatitis C, liver cancer, hepatic artery thrombosis and polycystic disease.

Of particular concern is non-alcoholic fatty liver disease (NAFLD or fatty liver) – a liver condition closely related to obesity. It is set to become one of the leading causes of liver transplantation and has increased by 360% since 2008. These rates are expected to continue in line with rising rates of obesity throughout the country.

The Trust is currently feeding into the National Liver Strategy for Liver Disease and hopes to see long-term commitment to addressing the burden of liver disease from the Government. The majority of liver disease is preventable, yet 300 people each week die from the disease. There is certainly not a one-hit wonder approach to liver disease as it is a demographically diverse killer.

“Aside from improving treatment services and diagnosis rates for liver disease, there are a packet of measures that could help; excess alcohol consumption could be curbed through the introduction of a minimum price per unit; fatty liver needs better awareness and due recognition; people need to be tested for viral hepatitis and hepatitis B could be relatively easily addressed with a universal vaccination,” said Rogers.

In supporting National Transplant Week (4th - 10th July 2010) the British Liver Trust is promoting NHS Blood and Transplant's (NHSBT) campaign theme, 'Heart to Heart'. With three people dying every day whilst waiting for organs, NHSBT is calling on people to discuss the issues around organ donation and sign up to the NHS Organ Donor Register. For more information please visit www.organdonation.nhs.uk/transplantweek

The Trust is also promoting its resources on liver transplantation and has profiled a selection of inspirational real life liver transplantation stories featured on its website.

/home/the-liver/real-transplant-stories.aspx

ENDS
For further information please contact: Sarah Matthews
Phone: 01425 481 320
Out of hours: 07968 366 526
Email: sarah.matthews@britishlivertrust.org.uk  
Web: http://www.britishlivertrust.org.uk/
British Liver Trust, 2 Southampton Road, Ringwood, BH24 1HY

Editor’s Note:

1. NHS Blood and Transplant figures show that the number of people on the liver transplant register has increased by 17%. 374 people were registered at the end of May 2010, compared to 319 people listed at the same time in May 2009.

2. Alcohol-related liver transplants have increased by 20.4% since 2006 where there were 108 transplants compared to 130 reported in 2009/10.

3. In 2008, there were only five recorded liver transplants where fatty liver disease was the specified cause. However in 2009/10 this rose to 23.

4. Government mortality statistics for the UK indicate that deaths from liver disease continue to rise, increasing by 12% in the last three years, totalling 46,244 lives lost. In 2008, liver disease killed 16,087 people – a 4.5% increase from 2007. If these rates continue, deaths from liver disease are predicted to double in 20 years.

5. This graph overleaf, produced by the British Liver Trust, illustrates the true extent of liver disease in the UK. Liver disease, when compared to the other five big causes of death, is the only one showing a steady increase year-on-year:


6. The British Liver Trust is Britain’s only national liver disease charity for adults. We work to improve the lives of people suffering from liver disease with key roles in education, support and research. We rely on voluntary contributions from individuals and funding from companies and charitable trusts.

7. The Trust is working urgently to encourage prevention and investment in treatment and care for people with liver disease. Much of the increasing incidence of liver disease stems from lifestyle trends – relating to alcohol, obesity and viral hepatitis. However, liver disease has many other causes including genetics, abnormalities in the immune system and even the medicines we take. The Trust is working to raise awareness about the liver and combat the stigma associated with liver disease.

8. The Trust provides a comprehensive website www.britishlivertrust.org.uk, free medical helpline – 0800 652 7330, and distributes a wide range of information leaflets to individuals and healthcare professionals. In addition, the Trust is a contact point for support groups nationwide, as well as co-ordinating funding and providing support for research.

Source

Immune Cells Show Signs of Senescence after Liver Transplantation

SUMMARY: T-cells of patients who undergo liver transplantation have shorter telomeres and more markers of maturity, indicating senescence and reduced immune function, according to a U.K. study described in the May 2010 issue of Liver Transplantation. These findings suggest that transplant recipients may experience faster immune cell aging, which could help explain their increased rates of infections, cancer, and other conditions.
By Liz Highleyman

William Gelson from University of Cambridge and colleagues investigated whether liver transplant recipients demonstrate features of immune senescence, or reduced immune function due to immune cell exhaustion.

Immune senescence is a normal process associated with aging, the study authors noted as background, but it may be accelerated in people who undergo liver transplants due to chronic hepatitis B or C, liver cancer, heavy alcohol use, or other causes of severe liver disease.

The researchers examined lymphocytes (a class of white blood cells including B-cells, T-cells, and natural killer cells) collected from 97 liver transplant recipients and 41 sex- and age-matched control subjects. The transplant patients had well-established grafts (donor livers) for at least 3 years.

Using flow cytometry, the investigators measured expression of a variety of T-cell markers that reflect activity and senescence, including killer cell lectin-like receptor subfamily G member 1, CD27, CD28, CD45RO, CD57, and CD127. Length of lymphocyte telomeres was assessed by flow-fluorescence in situ hybridization.

Telomeres are region of repeated DNA at the end of chromosomes. Lymphocytes have a finite lifespan. As a cell goes through the cycle of division and maturation, its telomeres become progressively shorter, until finally the cell "burns itself out" and can no longer divide to produce new cells, a state known as replicative senescence. Outside the transplant setting, the authors noted, immune cells with shortened telomeres have been linked to cardiovascular disease, blood malignancies, and infections.
Results
  • T-cell lymphocytes from liver transplant recipients expressed more phenotypic markers of maturity than cells from control subjects.
  • Lymphocyte telomeres were significantly shorter in transplant recipients compared with control subjects (115.12 vs 122.95 mfi, respectively; P = 0.004).
  • Telomere length differences between the transplant and control groups varied among types of T-cells (e.g., 9.93 mfi less for CD57 negative CD8 cells; 1.50 mfi less for CD45RO positive CD4 cells).
  • Telomere length was positively associated with markers of T-cell maturity and negatively associated with markers of immaturity.
  • Naive as well as experienced memory T-cells showed greater aging in transplant recipients.
  • Other factors independently associated with markers of lymphocyte maturity were older age and history of cytomegalovirus (CMV) infection.
  • Factors independently associated with shorter lymphocyte telomeres were older age, hepatocellular carcinoma (HCC) at the time of transplantation, and skin cancers developing after transplantation.
  • Transplant patients with normal liver biochemistry (e.g., normal ALT) had more immature CD8 T-cells.
Based on these findings, the researchers concluded, "lymphocytes from liver transplant recipients are older biologically than lymphocytes from age-matched and sex-matched controls."

"Hepatocellular carcinoma at transplantation, subsequent skin malignancy, and previous cytomegalovirus infection are associated with lymphocyte senescence in liver transplant recipients," they continued.

The study authors estimated that the difference in telomere length between transplant recipients and control subjects represented about 6 additional years of aging for patients with HCC and 4 additional years for those with post-transplant skin cancer. However, they found that the rate of aging did not appear to differ significantly in the transplant and control groups.

As to reasons for this association, "one possibility is that patients with more naive lymphocytes may respond to the complications of transplantation more effectively than those who have an exhausted immune system, or conversely that those patients with healthy grafts have had fewer complications and therefore have not worn out their immune system," they speculated.

These findings suggest that weakened immunity leading to infections and cancers in transplant patients may be attributable to aging and exhaustion of protective lymphocytes, as well as immunosuppressive drugs used to prevent organ rejection.

In an accompany editorial, Janet Lord from the University of Birmingham wrote, "If accelerated T-cell immunosenescence does indeed reflect chronic activation of the adaptive immune system, then shortened telomeres or increased markers of T-cell maturation may represent good indicators of patients likely to develop more postgraft complications. As graft recipients are now surviving much longer, we can anticipate that such prognostic indicators will be useful in the long-term management of these patients."

Department of Medicine, Centre for Applied Medical Statistics, and Department of Surgery, University of Cambridge, Cambridge, UK; Department of Immunology, University College London, London UK.

7/16/10

References

W Gelson, M Hoare, S Vowler, and others. Features of immune senescence in liver transplant recipients with established grafts. Liver Transplantation 16(5): 577-587 (Abstract). May 2010.

JM Lord. An aged T cell phenotype: A prognostic indicator in liver transplant recipients? (Editorial). Liver Transplantation 16(5): 548-549. May 2010.

Source
Authors: Park, S. K.; Cho, Y. K.; Park, J. H.; Kim, H. J.; Park, D. I.; Sohn, C. I.; Jeon, W. K.; Kim, B. I.
Source: Internal Medicine Journal, Volume 40, Number 7, July 2010 , pp. 503-511(9)
Publisher: Blackwell Publishing

Abstract:

Background:
Hepatitis C virus (HCV) infection is associated with a high prevalence of diabetes mellitus (DM). Insulin resistance (IR) is known to play a crucial role in the development of DM in chronic hepatitis C (CHC) patients. We prospectively investigated changes of insulin sensitivity in CHC patients during a 5-year period and analysed the factors significantly associated with IR.

Methods: 
Sixty-two CHC patients with normal insulin sensitivity (CHC group), and a healthy control group of 172 subjects matched by age, gender, body mass index and lifestyles were studied. We compared the initial baseline insulin sensitivity, metabolic parameters and incidence of IR at the end of the follow-up period between the two groups. The changes in insulin sensitivity, metabolic parameters and the development of IR were analysed as well as factors associated with the development of IR.

Results:
IR developed in 22.5% of 62 CHC patients and 5.2% of 172 normal individuals (P < 0.001). HCV infection per se and the genotype 1 were independent risk factors for the development of IR. The duration of infection ≥120 months, initial fasting glucose 90-100 mg/dL, fasting insulin ≥10 µIU/mL and the homeostasis model assessment (HOMA-IR) 2.3-2.7 were significantly associated with the development of IR in the CHC group.

Conclusion: 
HCV infection was an independent risk factor for the development of IR. All CHC patients, even those with normal insulin sensitivity, require careful monitoring for the development of IR.

Keywords: insulin resistance; HCV infection; HOMA-IR
Document Type: Research article
DOI: 10.1111/j.1445-5994.2009.02042.x

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