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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”


The Hepatitis Report:

A Critical Review of the Research and

Treatment of Hepatitis C Virus (Hepatitis C Virus) and

Hepatitis & HIV Coinfection

by Michael Marco and Jeffrey Schouten, M.D.

   Credits & Acknowledgments

 Michael Marco is Director of Treatment Action Group's (TAG) Infections and Oncology Project, the author of  TAG's The OI Report, The KS Project Report, The Lymphoma Project Report, and editor of TAG's The   Wasting Report. He is a member of the NIH Office Of AIDS Research's Therapeutics Research Working   Group, the National Cancer Institute's AIDS Malignancies Working Group and AIDS Malignancies  Consortium, the USPHS/IDSA Prevention of Opportunistic Infections Working Group and a consultant to the   FDA's Oncologic Drug Advisory Committee. mikemarco@aol.com   Jeffrey Schouten, M.D., Attorney at Law, Clinical Assistant Professor of Surgery, University of Washington  (UW) is an HIV primary care provider at UW's Harborview Medical Center and Vice-Chair of Washington's  Governor's Advisory Council on HIV/AIDS. He is also a member of the Adult AIDS Clinical Trials Group's   (AACTG) Community Constituency Group, Executive Committee and Scientific Agenda Steering Committee.  Additionally, he is a member of the NCI's AIDS Malignancy Consortium, the Conference on Retroviruses and Opportunistic Infections Planning Committee, and Publications Editor for the Seattle Treatment Education

   Project (STEP).

   The Treatment Action Group (TAG) fights to find a cure for AIDS and to ensure that all people living with HIV receive the necessary treatment, care, and information they need to save their lives. TAG focuses on the AIDS research effort, both public and private, the drug development process, and our nation's health care delivery systems. We meet with researchers, industry, and government officials, and resort when necessary to acts of civil disobedience, or to acts of Congress. We strive to develop the scientific and political expertise needed to transform policy. TAG is committed to working for and with all communities affected by HIV.

   Acknowledgments. First thanks go to the board, staff, consultants, volunteers, and donors of TAG. Special thanks go out to Robert Huff for line-editing of the report, to Andrea Dailey for her forceful and exacting copy-edits, and to board member Lynda Dee of AIDS Action Baltimore, whose generous gift enabled us to print this report. Tremendous thanks goes out to my chief clinical editor, Marion Peters, for her many hours of editing, mentoring, laughter and writing the Foreword. Likewise, thanks to Thierry Poynard for his keen insight and generosity in writing The Clinician's View. Thanks to Jay Hoofnagle, Leonard Seeff, Teresa Wright and Douglas Dieterich for helpful instruction and going out of their way to assist me in my research. I must thank the many others who allowed me to interview them or made contributions to this project, including: Yves Benhamou, Clifford Brass, Megan Briggs, Massimo Colombo, Lawrence "Bopper" Deyton, Lorna Dove,  Juan Esteban, Judith Fradkin, Jaime Guardia, Roy "Trip" Gulick, Bart Henderson, Joseph Hoffmann, Leslye  Johnson, Michael Joyner, Christine Katlama, Brian Klein, David Kleiner, Thomas Kresina, Jay Lalezari,  James Learned, Alexandra Levine, Karen Lindsay, Anna Lok, Jules Levin, Patrick Marcellin, Henry Masur, Cindy Mays, Donny Moss, Alison Murray, Chris Papas, Billy Pick, Robert Purcell, Stephen Rossi, Mark Sulkowski, Norah Terrault, David Thomas, Richard Whitley, and Kevin Young. Finally, thanks go out to David Berry, Todd Goodale, Kurt Fulton, Mark Harrington, Rick Leeds, Donna Masini, and Jeffrey Rindler for their support, guidance and fellowship.

  If you would like more information about TAG, contact us at:

Treatment Action Group

350 Seventh Ave., Ste. #1603

New York, New York 10036

(T) 212.972.9022 / (F) 212.971.9019

Internet: http://www.treatmentactiongroup.org

   First distribution: XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000.

                .....The disease generally progresses at a snail's pace, requiring the passage of 3 to 4  decades, in most instances, to reach recognizable serious endpoints. It therefore represents a daunting task for the clinical investigator, few of whom are willing to devote their research careers to this exhaustive form of investigation... –LB Seeff, Hepatology 1997; 26:21S-28S                                    

   Because of the ageing phenomena, all [natural history] studies which do not take into account both the age at infection and the duration of  infection are meaningless. –T Poynard, e-mail correspondence, 23 June 2000.

                The patient who has a liver disease wants (or needs) to know about the natural history of  the disorder so as to plan for the future. The patient should be informed regarding the likely consequences, important milestones, major complications, and available therapies, all given with a large measure of compassion and sensitivity. –WC Maddrey, AASLD, Postgraduate Course, 1999.

   Physicians and patients must carefully weigh the risks (which are clinically significant in the case of treatment with interferon alfa-2b and ribavirin),  the benefits (moderate in this instance), and the cost (substantial in this  instance) of any treatment option for a disease that has emerged as an important public health problem. –TJ Liang, N Engl J Med 1999; 340:1207.

This report is dedicated to the memory of

Michael Wright

(1953 - 1992)

&

Bill Thorne

(1963 - 1999)

         Foreword

         Introduction

         Epidemiology, Modes of Transmission, & Risk Factors for Hepatitis C Virus Infection Pathogenesis, Viral Dynamics, & Immunologic Response of Hepatitis C Virus Natural History, Clinical Manifestations, and Prognostic Indicators of Disease Progression & Survival of Hepatitis C Virus Infection Diagnosis of Hepatitis C Virus Infection Treatment of Hepatitis C Virus Infection: The Interferon Story Experimental Treatments & New Areas of Research for Hepatitis C Virus Infection  Hepatitis and HIV Coinfection  Current Opinions & Controversies in Hepatitis C Virus Infection Research & Policy Recommendations Clinician's Response

   Forward by Marion Peters, M.D.

   This TAG report on hepatitis C virus (Hepatitis C Virus) is comprehensive and will bring you completely up to date. It runs the gamut of Hepatitis C Virus infection with areas of interest for the clinician, allied health care worker and educated patient. It contains information about epidemiology, natural history, diagnosis, pathogenesis and treatment. It is certainly an enormous task to undertake but the authors have been largely very successful. Many of the chapters contain the earliest literature in the area and are current to last month's abstracts. It may be difficult for some of us to read an abstract with the same conviction of fact, as abstracts have not been peer reviewed rigorously, nor is all the data usually available at the time presentation. However, in a fast moving field such as Hepatitis C Virus, it allows the reader to know what is "hot" and where the field is heading. We are clearly told what data and trials are peer reviewed, which are confirmed by other investigators and which appear to be "outside the envelope" but interesting nonetheless. This report is generally superbly referenced and will be of great value to you.

   The natural history chapter reminds us that not all patients inexorably deteriorate to end-stage liver disease, liver transplantation or death. It is clear that for the large number of years that we have been following patients, some clinicians see the slowest rates of progression whilst others see Hepatitis C Virus as "the evil empire". Patients need to know the facts, not colored by drug company hype, or physician preference and this report provides these facts. Only by knowing that not all patients progress, can individuals patients decide whether  treatment for them is now or in the future. The epidemiology, risk factors and modes of transmission are well outlined with perhaps an overabundance of information. You can skim it or dive in for the total immersion, whichever is your preference. This is an excellent chapter with clear tables, explaining the high rate of transmission in IVDU patients and the low sexual transmission rate.

   The diagnosis of Hepatitis C Virus is often complex with multiple tests and the confusion of liver biopsy evaluation. Once again the authors have used excellent available reviews and references to present readable current state-of-the-art information. The reader must be cautioned that this area is not well regulated and Hepatitis C Virus RNA tests are changing rapidly. In addition, when tests are performed in the hospital setting or the community, often a different laboratory is used at different times (the pressures of managed care). In these cases, one cannot extrapolate from one bDNA to another PCR or even from one PCR to another. Therefore, it is critical that patients and clinicians not put excessive weight on small (less than one log) changes. Hepatitis C Virus RNA will change little from patient to patient but a lot from test to test.

   The area of co-infection with HIV is the youngest in the field and is a moving target. Large cohort studies are lacking and treatment trials are small in number and patient size. This is an area that is receiving a large amount of attention; treatment trials are underway and more hepatologists are becoming involved working side-by-side with infectious disease specialists. The role of Hepatitis C Virus in response to HIV therapy is largely unknown. Viral dynamics of Hepatitis C Virus is in its infancy, compared to that of HIV. Markers of response to Hepatitis C Virus have included genotype, age of acquisition, gender, viral load and amount of fibrosis on liver biopsy. Early studies suggest that these may be superceded by viral dynamics: those with rapid response to interferon therapy are more likely to achieve a sustained response versus those who are slow responders. Only time will tell if this sweeping statement is correct.

   The chapters on experimental therapies and current treatment are excellent. Once again we are reminded that at best only half of Hepatitis C Virus patients respond to current therapies. But only half may need therapy in the long term. Unfortunately clinicians cannot determine which patients will progress to fibrosis and end-stage liver disease and so most patients are treated especially if they have some scarring without cirrhosis. This is an area that requires intensive research from clinical, epidemiological and immunological aspects. Interferon remains the mainstay of therapy with pegylated IFNs providing exciting new advances. By combining IFN to polyethylene glycol, IFN remains in the circulation longer and thus only weekly dosing is required. This results in ease of treatment as well as an apparent higher response rate, including a surprisingly high rate in cirrhotics (<10% in all studies before pegylated IFN). We may need to look carefully at these studies when they are published but early reports are very encouraging. Side effects are not much different from those of daily dose interferon although there may be some populations in whom dose finding is necessary before putting patients on long- acting weekly IFN. Newer therapies aimed at the virus itself have been slow in coming but are clearly the next line of drugs. In particular, ribozymes may be the next "breakthrough" in this area. Immunomodulators have been generally less promising with the exception of IL-10 as an anti-fibrotic.

   I would recommend this report highly to those who want to be fully informed about the area. Those who need full references; those who may not have the time or inclination to gather the oldest and the latest information; and those who need to delve more deeply into particular areas of this fascinating field will find this report useful. Many scientists and clinicians have worked with Michael Marco to address specific areas of their expertise. It is a testament to them and to Michael that he has produced this informative but easily readable document. Not all of the statements in this report have been validated. You will not agree with all of them. But you will be stimulated to learn more and to keep abreast of new developments after reading these all encompassing chapters. You may not concur with all of the TAG policy recommendations but you will be forced to re-evaluate and think about many important issues surrounding Hepatitis C Virus. Good luck and enjoy.

   Marion Peters is Professor of Medicine and Chief of Hepatology Research, at the University of California, San Francisco.  

Introduction

by Michael Marco

 

                Clearly the problem of Hepatitis C Virus will require a responsible partnership of public and private organizations....If we are to make progress against this perplexing epidemic, careful and disinterested voices must prevail1.

       Despite the wide publicity about hepatitis C in the media, and the numerous educational conferences and publications in the medical literature, and the dissemination of the NIH consensus statement on hepatitis C, there are significant deficits in the knowledge of primary care physicians regarding hepatitis C2.

   My appreciation of and desire to study hepatitis C virus (Hepatitis C Virus) research is something new. It started off as mere curiosity during my research of AIDS-related opportunistic infections (OIs) when I thought about adding a short chapter on Hepatitis C Virus to TAG's OI Report because it was well know that many individuals with HIV are also coinfected Hepatitis C Virus. Approximately two years later, it seems laughable that one could simply write a "short chapter" on Hepatitis C Virus. It has become apparent to me that there is a need for a thorough study, review, and critical analysis of Hepatitis C Virus research.

   Many AIDS treatment advocates have critically analyzed the numerous facets of HIV clinical and basic research with great aplomb. They have produced a wealth of patient-readable HIV treatment information so that people with HIV/AIDS can become experts in understanding their virus. In my two years of researching Hepatitis C Virus, I found that there were only a few Hepatitis C Virus treatment advocates, yet none had created one text that contained a complete overview of the virus, analyzed the research, and offered important and sound Hepatitis C Virus treatment information as well as policy recommendations to move the field of Hepatitis C Virus research forward. Since I have been well trained and mentored in researching and writing such documents on HIV-related complications, I felt I would initiate TAG's Hepatitis Project and write a report on Hepatitis C Virus, as well as on hepatitis and HIV coinfection. People with Hepatitis C Virus deserve the same tools as those with HIV so that they can become experts about their virus.

   I quickly realized that people with Hepatitis C Virus were not the only ones who needed to become experts. I found that many primary care physicians lack a complete breath of knowledge of the epidemiology and clinical management of Hepatitis C Virus. This was blatantly obvious in the 1999 Hepatology article, "Current Practice Patterns of Primary Care Physicians in the Management of Patients with Hepatitis C" by Shehab and colleagues from Anna Lok's group at the University of Michigan.2 In a survey of over 400 primary care physicians from the Detroit area, 20% and 8%, respectively, considered blood transfusion in 1994 and casual household contact as significant risk factors for Hepatitis C Virus; 43% overestimated the likelihood of a sustained response to a course of interferon therapy, while 29% had no idea what the sustained response rate was; 38% would not a refer an Hepatitis C Virus antibody-positive patient to a gastroenterologist even though they had no experience in treating Hepatitis C Virus patients on their own. Another study by Villano and colleagues from Johns Hopkins found that a majority of the intravenous-drug-using patients in their natural history cohort tested Hepatitis C Virus antibody-positive their first time on study yet were under the care of clinic or primary care physicians.3 This striking lack of awareness by health care providers about Hepatitis C Virus epidemiology, risk factors, and clinical management is unacceptable. Let us hope that this report gets into the hands of the physicians and patients who need it.

   I also wrote the report in an attempt to quell the mass hysteria about Hepatitis C Virus created by major weekly news magazines as well as by the obnoxious "get tested, get treated" Hepatitis C Virus advertising campaign of a greedy pharmaceutical company. The push to immediately treat everyone who tests positive for Hepatitis C Virus made my blood boil, because that is often the same message given to those who initially test positive for HIV. For HIV, we have only clinical endpoint studies documenting a survival advantage to starting potent, combination antiretroviral therapy before a patient's CD4 count drops below 200 cell/m3, yet with both viruses, we still have not fully answered the question, When should one initiate antiviral therapy? (i.e., "When to start?").

   This Hepatitis C Virus report attempts to answer that question and documents what we know and what we don't know about the epidemiology, natural history, diagnosis, and treatment of Hepatitis C Virus. After an exhaustive analysis of peer-reviewed articles, over 40 researchers, clinicians, primary care physicians, government heath administrators, industry representatives, and patients with viral hepatitis were interviewed. Research and treatment policy recommendations have been issued and will need to be implemented in order to carefully find answers to the many basic and clinical science questions in Hepatitis C Virus research.

   This large report–which will grow still larger in version 2.0 to include an analysis of the research and treatment of hepatitis viruses A and B (HAV and HBV)–is a collaborative effort. Jeffrey Schouten was a great partner who worked with me over these two years, and he wrote selected Hepatitis C Virus chapters and the section on hepatitis and HIV coinfection. Expert hepatitis researchers, including Marion Peters, Thierry Poynard, Teresa Wright, Jay Hoofnagle, Leonard Seeff, and Douglas Dieterich went out of their way in varying capacities to help me, an AIDS treatment advocate they had never met.

   More collaborative and concentrated efforts on the part of industry, physicians, government, and the hepatitis community alike are needed if we are to effectively challenge, overcome, and cure Hepatitis C Virus.

   1 The Lancet. Making sense of hepatitis [editorial]. Lancet 352:1485, 1998.

   2 Shehab T, Sonnad SS, Jeffries M, et al. Current practice patters of primary care physicians in the management of patients with

   hepatitis C. Hepatology 30:794-800, 1999.

   3 Villano SA, Vlahov D, Nelson KE, et al. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 29:908-14, 1999.

   Epidemiology, Modes of Transmission, & Risk Factors for Hepatitis C Virus (Hepatitis C Virus) Infection by Michael Marco

        My opinion is that we just can't tell for sure about some of this because we are bad at measuring human behavior. ——Davis Thomas, e-mail correspondence

   Background

   During the 1970s and 1980s, no one knew what was causing hepatitis in certain individuals who had received blood transfusions. Screening tests for hepatitis A (HAV) and hepatitis B (HBV) in the mid-1970s revealed that about 25% of these cases of transfusion-associated hepatitis (TAH) were linked to hepatitis B but no hepatitis A. The remaining 75% of TAH cases, by default, were termed non-A-non-B hepatitis (NANBH) (H. Alter 1999). Ten to twenty percent of individuals who had received multiple blood transfusions (or used plasma products) developed NANBH, with a relative risk of 0.45% per unit transfused (Donahue 1992).

   Because primary infection was usually asymptomatic or, at worst, mild, clinicians did not initially consider NANBH to be a very serious disease. It was soon recognized, however, that the seemingly benign NANBH could develop into a chronic hepatitis with markedly elevated liver enzymes. Sometimes the hepatitis resulted in cirrhosis.

   According to the National Institutes of Health’s (NIH) Harvey Alter, attitudes to NANBH changed in the late 1980s:

        The NANBH agent remained a virologic enigma....until researchers at the Chiron Corporation used an ambitious molecular approach on large volumes of high-titer infectious chimpanzee plasma from the Centers for Disease Control and Prevention (CDC). They extracted RNA, cloned it into an expression vector, and screened the expressed product with presumed immune sera. A single positive clone was found in the millions screened, and, within a year, the entire genome was sequenced and the agent was identified as a novel flavivirus the hepatitis C virus (Hepatitis C Virus). (HJ Alter 1999).

   In 1988 Choo and colleagues characterized the hepatitis C virus (Hepatitis C Virus), and shortly thereafter, an antibody test was developed to detect infection (Choo 1989; Kuo 1989). When NIH researchers performed Hepatitis C Virus assays on archived blood samples, it was determined that 70% to 90% of NANBH cases were actually Hepatitis C Virus infections.

   Prevalence of Hepatitis C Virus Infection in the United States (U.S.)

   Hepatitis C Virus is considered the most common blood-borne infection and is one of the leading causes for liver transplantation among adults in the U.S. After the Hepatitis C Virus antibody test became available, epidemiology studies were performed to ascertain the incidence of the infection. The original studies, however, were considered flawed because they were conducted with first-time blood donors, individuals who had already been screened for risk factors such as infectious diseases.

   A recently published study by Miriam Alter and colleagues from the Centers for Disease Control and Prevention (CDC) reported that an estimated four million persons nationwide are Hepatitis C Virus- antibody-positive (ab+), indicating exposure to the virus. Roughly three-quarters of these have detectable Hepatitis C Virus RNA, indicating chronic infection (MJ Alter, 1999b). These data hail from the CDC’s third National Health and Nutrition Examination Study (NHANES III), conducted between 1988 and 1994, and involving a sample of almost 40,000 persons between the ages of 2 and 89 years.

   Out of this group, 21,241 individuals agreed to be both interviewed and tested for antibodies to Hepatitis C Virus; of these, 1.8% were found to be Hepatitis C Virus-antibody-positive. For the entire U.S., this corresponds to approximately 3.9 million residents infected with Hepatitis C Virus. Below is a breakdown of the prevalence of Hepatitis C Virus-antibody-positivity classified by race or ethnic group and gender.

 

   Prevalence of Antibody to Hepatitis C Virus (Anti-Hepatitis C Virus) According to Race or Ethnic Group & Gender in NHANES III

Characteristic

No. Tested

Prevalence (%) of

Anti-Hepatitis C Virus+ (95% CI)

Estimated No. Infected Nationwide(95% CI)

 

All Subjects

21,241

1.8 (1.5-2.3)

3,875,000 (3,102,000-4,840,000)

Race/Ethnic Group

 

 

 

 

 

Non-Hispanic White

7,965

1.5 (1.1-2.0)

2,359,000 (1,774,000-3,137,000)

 

Non-Hispanic Black

6,119

3.2 (2.6--4.0)*

762,000 (609,000-953,000)

 

Mexican Americans

6,268

2.1 (1.7-2.6)

261,000 (210,000-323,000)

 

Other

889

2.9 (1.4-5.8)

493,000 (245,000-993,000)

Gender

Male

10,076

2.5 (2.0-3.2)**

2,586,000 (2,012,000-3,323,000)

 

Female

11,165

1.2 (0.9--1.6)

1,289,000 (967,000-1,717,000)

 

 

 

 

 

  • P<0.05 for comparison with non-Hispanic whites (MJ Alter 1999b)  
  • ** P<0.05

Hepatitis C Virus Prevalence in Blood Donors in Southern Europe

   Several large Hepatitis C Virus epidemiology studies have been published in Italy, France, and Spain. Below is a breakdown of anti-Hepatitis C Virus prevelance in selected studies that have been conducted since the early 1990s.

Hepatitis C Virus Incidence Rates in Six Large Southern European Cohorts

N =

Anti-Hepatitis C Virus +

Country (Study)

173,038

0.63%

France (Anuelles 1992)

60,960

0.69%

France (Aymard 1993)

30,231

1.2%

Spain (Esteban 1991)

46,741

1.12%

Spain (Salmeron 1996)

55,587

0.93%

Spain (Munoz-Gomez 1996)

6, 917

3.2%

Italy (Bellentani 1994)

 

Hepatitis C Virus Prevalence in Egypt

   With an estimated Hepatitis C Virus infection rate of 25%, Egypt has a higher incidence of Hepatitis C Virus infection than any other country in the world (Arthur 1997). The Nile Valley area has higher rates of infection compared to cities and desert areas. The Egyptian Hepatitis C Virus epidemic is a result of a widespread treatment campaign against schistosomiasis, an ancient parasitic disease. From the 1920s to the 1980s, the government administered parenteral antischistosomal therapy (usually 6-12 injections) with reusable syringes (Frank 2000). With course of injections taking two to four weeks, an individual infected early in treatment could then spread Hepatitis C Virus on a subsequent injection to others who used the same syringe.

   Modes of Transmission and Risk Groups

   Numerous epidemiology studies have documented that individuals from high-risk groups, including recipients of blood transfusions before 1991, hemophiliacs, intravenous drug users (IDUs), homosexuals, and alcohol abusers, have an exceedingly high prevalence of Hepatitis C Virus antibodies.

   Blood Transfusion Recipients and Hemophiliacs before 1992

   In the mid-1960s, the rate of post-transfusion hepatitis was greater than 20% (HJ Alter 1972). When donor blood in the U.S. began to be screened and excluded for antibodies to HAV, HBV, and HIV between 1985-1990, the rate of new Hepatitis C Virus infections declined by more than 50%, lowering the risk of Hepatitis C Virus seroconversion to 1.54% per transfusion patient or to 0.19% per unit transfused (Donahue 1992). In May 1990, a first-generation enzyme immunoassay EIA-1 was introduced to screen U.S. blood donors. It was soon replaced by the much more sensitive multiantigen test (EIA-2) in July 1992. The EIA-2 has dramatically reduced the risk of Hepatitis C Virus infection, lowering rates to 0.001% per unit transfused (Schreiber 1996). According to Harvey Alter:

        The impact of Hepatitis C Virus blood donor screening has been enormous. The single-antigen first-generation enzyme immunoassay (EIA-1) prevented 40,000 Hepatitis C Virus infections within the first year, and the second-generation assay (EIA-2) has actually reduced new transfusion-related Hepatitis C Virus infections to almost zero. (HJ Alter 1999) Before 1985, the rate of Hepatitis C Virus infection in hemophiliacs who received clotting factor concentrates prepared from plasma pools was at least 90% (CDC 1998). Factor VIII and Factor IX, which inactivated blood-borne viruses such as Hepatitis C Virus, were introduced in 1985 and 1987, respectively.

   Injection Drug Users

   The rate of Hepatitis C Virus infection among IDUs who share contaminated needles, syringes, or drug preparation equipment continues to remain high. In numerous studies conducted around the world, the incidence of Hepatitis C Virus among IDUs ranges from 70% to 92% (Esteban 1989; van den Hoek 1990; Donahue 1991; Zeldis 1992; Garfein 1996; Broers 1998; Hershow 1998; van Beek 1998).

Rates of Anti-Hepatitis C Virus+ from IDU Cohorts in Selected Cities

% Anti-Hepatitis C Virus+

 

City

Source

70%

Barcelona

Esteban 1989

74%

Amsterdam

van den Hoek 1990

85%

Baltimore

Donahue 1991

72%

San Francisco/Davis

Zeldis 1992

76.9%

Baltimore

Garfein 1996

91.6%

Geneva

Broers 1998

90% (women only)

Chicago

Hershow 1998

75.6% (age <20 years)

Sydney

van Beek 1998

   The risk of contracting Hepatitis C Virus from shared injection equipment is extraordinarily high-and not only for long-term IV drug users. A study by Garfein and colleagues at Johns Hopkins documented that the risk of acquiring Hepatitis C Virus infection was as high 65% for new injectors within 6 to 12 months after beginning injection drug use (Garfein 1996). The risk of acquiring Hepatitis C Virus is markedly higher than that of acquiring other viral infections such as HIV. The same study documented a rate of HIV infection among IDUs during this brief window of only 14%.

   With regard to non-injectable drug use, intranasal cocaine use was reportedly associated with Hepatitis C Virus infection in a study conducted by Conry-Cantilena from Harvey Alter's group at the NIH (Conry-Cantilena 1996). Finding a highly significant correlation in a multivariate analysis, the author theorized that if the device shared for snorting cocaine (a straw) was contaminated with blood, it could convey virus to denuded nasal mucosa, allowing Hepatitis C Virus to enter the bloodstream. This possible mode of transmission-referred to by some as the "bloody straw" theory-was highly debated, and in 1998, the CDC listed intranasal cocaine users in the category of "Persons for whom routine hepatitis C (Hepatitis C Virus) testing is of uncertain need" (CDC 1998).

   It appears that this finding by Corny-Cantilena and colleagues may have been a fluke, or merely that intranasal cocaine use is a surrogate for other behavior which could foster Hepatitis C Virus transmission. More recently Murphy and colleagues, of the NHLBI Retrovirus Epidemiology Donor Study (REDS), published a study reporting that, in a multivariate logistic regression model, intranasal cocaine use (or use of any other powered drug) was not a risk factor for Hepatitis C Virus (Murphy 2000).

   Occupational (Needlestick) Exposure

   The prevalence of Hepatitis C Virus infection in health care workers, including orthopedic, general, and oral surgeons averages 1-2% (Thomas 1993, 1996). The serocoversion rate after an unintentional needlestick injury from an Hepatitis C Virus-positive source is ~1.8% (MJ Alter 1994; Puro 1995). It appears that the seroconversion rate with solid needles is lower compared to needlesticks with hollow cannula devices (Puro 1995).

   Percutaneous Exposure in Other Settings

   While apparently rare, Hepatitis C Virus transmission has been associated with commercial barbering, tattooing, ear piercing, and religious scarification (Tumminelli 1995; Abildgaard 1991; Thompson 1996; Conry-Cantilena 1996; Murphy 2000). Tumminelli and colleagues found that 38% of Sicilian barbers studied had antibodies to hepatitis C and suggested that shaving was a potential route of transmission. In the REDS study, Murphy and colleagues determined that religious scarification, sharing toothbrush and/or razor, having been tattooed,

   and having been pierced (body or ear) were all risk factors for Hepatitis C Virus seropositivity after controlling for IVDU (OR = 3.8; 1.6; 3.9; and 2.7, respectively).

   Perinatal Transmission

   Most U.S. and international studies have reported the incidence of anti-Hepatitis C Virus positivity in pregnant women to be between 0.7% and 4.4% (Marcellin1993; Marranconi 1994; Leikin 1994; Hillemanns 1998; Resti 1998; Conte 2000). One recent perinatal transmission study from the metropolitan New York City area documented an ominous 41% anti-Hepatitis C Virus incidence rate in a cohort of pregnant women—79% of whom were past or present IDUs (Granovsky 1998). The rate of Hepatitis C Virus RNA detectability in several international cohorts of anti-Hepatitis C Virus-positive women ranges from 65% to 72% (Resti 1998; Granovsky 1998; Conte 2000).

   Reported rates of mother-to-infant Hepatitis C Virus transmission have ranged from 0% to 36% in numerous studies, with higher rates occurring when mothers are HIV-positive (Ohto 1994; Zanetti 1995; Sabatino 1996; Tovo 1997; Granovsky 1998; Resti 1998; Thomas 1998b; Conte 2000). When these data are analyzed together, the average rate of vertical Hepatitis C Virus transmission appears to be approximately 5%. Studies have demonstrated that rates of vertical transmission are dependent upon five factors: 1) presence or absence of Hepatitis C Virus RNA in the mother; 2) high or low Hepatitis C Virus viral load; 3) HIV status of the mother; 4) vaginal vs. caesarean delivery; and 5) breast vs. bottle feeding.

   The only consistent factor found in studies is that vertical transmission does not occur if the mother is Hepatitis C Virus RNA-negative at time of birth. In 20 perinatal Hepatitis C Virus transmission studies analyzed by Dore and colleagues, none of the 735 aggregate HCVab+ but Hepatitis C Virus RNA-negative women gave birth to an Hepatitis C Virus-infected infant (Dore 1997). Some studies have documented a decreased incidence of vertical transmission from mothers with low Hepatitis C Virus viral load (Hepatitis C Virus RNA levels differ among studies). Other studies, however, have not found this correlation to be significant.

Mother’s Hepatitis C Virus RNA Level and Its Correlation with Transmission of Hepatitis C Virus to Her Newborn: Conflicting Results

Hepatitis C Virus RNA in transmitting mothers (copies/mL)

Hepatitis C Virus RNA in non-transmitting mothers (copies/mL)

P

Study

1,000,000

15,000

<0.001

Ohto 1994

>2,000,000

<1,000,000

<0.001

Lin 1994

~1,000,000

~670,000

NS

Zanetti 1995

2,000,000

350,000

<0.001

Thomas1998b

380,000

240,000

NS

Resti 1998

>1,000,000

<1,000,000

0.02

Mast 1999

2,150,306

2,038,375

NS

Conte 2000

   There is considerable controversy as to whether the rate of Hepatitis C Virus vertical transmission is higher when the mother is also HIV-positive. Many studies have been conducted solely in coinfected pregnant women and others in Hepatitis C Virus-positve women with and without HIV. One of the most provocative findings comes from Zanetti and colleagues, a 1995 Italian study which included 116 Hepatitis C Virus-positive women—22 of whom were coinfected with HIV. Of the 22 coinfected women, 18 had detectable Hepatitis C Virus RNA. None of the infants born to 92 HIV-negative women acquired Hepatitis C Virus, but 8 of the 22 (36%) infants born to coinfected mothers acquired Hepatitis C Virus.

   While the eight mothers who transmitted Hepatitis C Virus had detectable Hepatitis C Virus RNA, there was no significant difference in Hepatitis C Virus RNA levels between them and the other ten coinfected Hepatitis C Virus RNA-positive women (Zanetti 1995).

   Another Italian study of 245 infants found the incidence of Hepatitis C Virus vertical transmission higher in coinfected mothers. Overall, 28 (11.4%) of the 245 infants acquired Hepatitis C Virus: 3 of 80 (3.7%) whose mothers had Hepatitis C Virus infection alone vs. 25 of 165 (15.1%) whose mothers were coinfected (P<0.01) (Tovo 1997).

   In a study of solely coinfected mothers, Thomas and colleagues found that the risk of Hepatitis C Virus infection was .2-fold greater if the infant also acquired HIV compared to HIV-uninfected infants (17.1% of 41 vs. 5.4% of 112, P=0.04). All Hepatitis C Virus transmissions were from mothers with Hepatitis C Virus RNA viral loads over 2,000,000 copies/mL (Thomas 1998b).

   A mother's co-infection was found not to be a significant risk factor for transmitting Hepatitis C Virus in a New York multicenter study conducted by Granovsky and colleagues (Granovsky 1998). Five of 73 (7%) coinfected mothers transmitted Hepatitis C Virus to their infants compared to 2 of 49 Hepatitis C Virus+/HIV- mothers (P=0.7). There was also no significant difference in Hepatitis C Virus viral load levels between transmitting and non-transmitting mothers. Lastly, an interesting finding about HIV and it's possible enhancement of Hepatitis C Virus transmission comes from the largest

 


   Hepatitis C Virus vertical transmission study yet conducted. In a cohort of 370 anti-Hepatitis C Virus-positive women, 15 (4.0%) were coinfected with HIV but did not transmit Hepatitis C Virus to their infants. All of the coinfected women were receiving HIV antiretroviral therapy during their pregnancy, and investigators believe that reducing HIV-related immunosuppression may have affected Hepatitis C Virus titers and the consequent likelihood of Hepatitis C Virus transmission (Conte 2000).

   A handful of studies have documented modest increases in the rate of Hepatitis C Virus vertical transmission to infants delivered vaginally rather than by caesarean section (Tovo 1997; Granovsky 1998). However, larger studies with more patients have not observed any differences due to mode of delivery (Resti 1998; Mast 1999; Conte 2000). Hepatitis C Virus transmission through breast feeding has not been considered a route likely source of infection for infants (Kumar 1998). In the vast majority of studies that evaluated breast feeding in infants born to Hepatitis C Virus-positive women, no difference has been observed between bottle and breast feeding (Resti 1998; Tovo 1997; Mast 1999; Conte 2000). In fact, the CDC and the American Academy of Pediatrics do not feel that there is a risk from either breast feeding or vaginal delivery and have chosen not to recommend caesarean section or bottle feeding to Hepatitis C Virus-infected mothers without HIV (CDC 1998).

   Finally, no diagnostic screening criteria for perinatal Hepatitis C Virus infection currently exist. Many studies have theorized about the optimal time to determine the infection status of an infant because various patterns have been observed in both infected and uninfected infants of Hepatitis C Virus-positive mothers. For example, Conte and colleagues documented that the rate of Hepatitis C Virus-positivity at birth for 366 newborns was 100%, but decreased to 90%, 63%, 16%, and 9% after 4, 8, 12, and 18 months respectively (Conte 2000). Hepatitis C Virus RNA was detectable

   in 18 (4.9%) infants at birth, but 16 became negative by month four; and 6 infants who tested negative at birth became positive at month four. With similar findings from a recent CDC-sponsored study, Mast and colleagues concluded that "anti-Hepatitis C Virus testing may not be a reliable marker of perinatal Hepatitis C Virus infection until the infant is 2 years of age" (Mast 1999).

   There appear to be as many knowns as unknowns with regard to Hepatitis C Virus vertical transmission and the exact prognostic factors which lead to infection. According to Johns Hopkins' David Thomas:

   Without a randomized clinical trial, perinatal transmission cofactors will be difficult to evaluate conclusively. Even multiple consistent results from observational studies could be misleading....The most conclusive randomized trial would have to include more than 800 mother-infant pairs to detect a twofold increase in  transmission with 80% power. (Thomas 1998a)

   Sexual Transmission

   Is Hepatitis C Virus sexually transmissable? For the past 11 years, this question has been widely studied and heavily debated among researchers from Atlanta to Australia. Miriam Alter and colleagues in a 1989 JAMA paper reported the first study to suggest that heterosexual transmission may play an important role in the spread of NANB hepatitis (Alter 1989). In this study, of 140 patients with Hepatitis C Virus, 64 patients (46%) had no commonly recognized percutaneous risk factors; 7 (11%) had had multiple sexual partners and were believed to have contracted Hepatitis C Virus through sex. Since then, there have been at least 50 articles published (not to mention scads of letters to the editors) in major hepatology, virology, and HIV-related peer-reviewed medical journals which have looked at Hepatitis C Virus sexual transmission among the general population, hemophiliacs, heterosexuals, homosexuals, people with HIV and STDs, and sex workers.

   Heterosexuals in Long-term Monogamous Relationships

   Sexual transmission of Hepatitis C Virus between heterosexual couples in long-term monogamous relationships who have no identifiable percutaneous risk factors (or after stratifying for such factors) appears to be quite infrequent. Gordon and colleagues reported that 2 of 42 (4.8%) heterosexual adults who were in stable sexual relationships with an Hepatitis C Virus-infected partner developed Hepatitis C Virus (Gordon 1992). Since one of the individuals had a risk factor for Hepatitis C Virus, only 1 of 42 individuals (2.4%: 95% CI, 0.6-12.9%) was thought to have been infected through sex. Osmond and colleagues found the incidence of Hepatitis C Virus to be high in their cohort of 170 men and 170 women in sexual partnerships: 31 (18%) of the women and 56 (33%) of the 170 men tested anti-Hepatitis C Virus-positive (Osmond 1993b). Sexual transmission was not demonstrated because IV drug use, a history of a blood transfusion, or hemophilia treatment were associated with all but 2 of 87 Hepatitis C Virus infections.

   No Hepatitis C Virus transmissions were documented in a study of 94 husbands whose spouses all contracted Hepatitis C Virus from contaminated anti-D immunoglobulin (Meisel 1995) nor in an Australian study which tested 50 heterosexual partners of Hepatitis C Virus viremic individuals (Brester 1993). In Asian countries, however, higher rates of sexual transmission in married heterosexual couples have been reported, ranging from 8.8 to 28% (Chang 1994; Nakashima 1995; Chayama 1995).

   Two large studies looking at the sexual transmission among female sex partners of Hepatitis C Virus-infected hemophiliac males documented a low transmission rate. Eyster and colleagues and Brettler and colleagues found a sexual transmission rate of 2.6% and 2.7%, respectively (Eyster 1991; Brettler 1992).

   In an elegant, high-tech study, Zylberberg and colleagues conducted genotypic, sequence and phylogenetic analyses on 24 anti-Hepatitis C Virus-positive couples to ascertain if they harbored the same strain of virus (Zylberberg 1999). The mean duration of the partnership was 12 years (range 1 to 36). Serum Hepatitis C Virus RNA was detected in both partners in 18 (75%) of the couples and in only one partner in the other 6 (25%) couples. In the 18 couples who had detectable Hepatitis C Virus RNA in both spouses, 11 of 18 (61%) had the same genotype while 7 of 18 (39%) did not. Phylogenetic analysis was conducted in 7 of the 12 genetically concordant couples. In three couples, Hepatitis C Virus strains differed by 1 to 3 nucleotides with a sequence similarity of 98% (evolutionary distance 0.065) suggesting that these spouses were infected by a common source. The other four couples differed by 4 to 15 nucleotides (evolutionary distance 0.0129) and thus their strains were considered unrelated. Sexual transmission of Hepatitis C Virus was, however, ruled out in the three matched couples because all six spouses had at least one identifiable parental risk factor.

   Sex Workers

   A small number of studies, mostly outside the U.S., have been conducted among sex workers to ascertain if they are at higher risk for Hepatitis C Virus transmission. Wu and colleagues studied 622 sex workers in Taiwan for anti-Hepatitis C Virus antibodies and risk factors of transmission (Wu 1993). Seventy- four (12%) of the women were anti-Hepatitis C Virus-positive and 60 (~10%) were Hepatitis C Virus RNA-positive. In a multivariate analysis, history of paid sex for longer than six months and blood transfusion were positively associated with anti-Hepatitis C Virus (P<0.001). Less than 20% of the Hepatitis C Virus-infected sex workers had undergone a blood transfusion. Lissen and colleagues tested 310 Spanish female sex workers and 88 of their clients for anti-Hepatitis C Virus (Lissen 1993). All denied prior transfusion of intravenous drug use. The prevalence of anti-Hepatitis C Virus by ELISA, confirmed by a RIBA-2, was 6.4% among the sex workers and 6.8% among the clients. In contrast to these two studies, a very low rate of Hepatitis C Virus positivity was reported in a study of Peruvian sex workers (Hymans 1993). Of 966 sex workers tested, only 7 (0.7%) had antibodies to Hepatitis C Virus.

   Homosexuals, People with HIV and STDs, and Sex Partners of IDUs

   The prevalence of Hepatitis C Virus appears to substantially higher in homosexuals (men who have sex with men [MSM]), and people with HIV and STDs than in the general population. Below is an analysis of 16 studies, most in high-risk populations, which document either sexual transmission or an infectious disease as a risk factor for Hepatitis C Virus.

Sexual Transmission or an Infectious Disease as a Risk Factor for Hepatitis C Virus

Risk Group

Country

N

N (%) Hepatitis C Virus+

Sexual and/or ID Risk Factor/s

(Multivariate Analysis) Controlling for or besides IV/BT Study

MSM

US

926

15 (1.6%)

HAV

Donahue 1991

STD Clinic (MSM & HET)

UK

MSM 275 HET 771

19 (6.9%)

8 (1.0%)

HIV+, HBV+, and lifetime number of STDs(MSM only) Tedder 1991

Female (F) sex partners of male (M) hemophiliacs

US

 

F 234

M 231

5 (2.6%)

Sex with an Hepatitis C Virus+/HIV+ M: 3% Hepatitis C Virus+ for sex with HIV+/Hepatitis C Virus+ M vs. 0% with HIV-/Hepatitis C Virus+ M Eyster 1991^

MSM

US

735

34 (4.6%)

> 50 sex partners/year > 25 oral receptive partners per year

Osmond 1993

MSM, prostitutes, & HET partners of an Hepatitis C Virus+ person

Spain

MSM 168

 HET 147

7 (4.2%)

11 (7.4%)

Sex with Hepatitis C Virus+/HIV+ (9.2% vs. 4.1% for HET sex with Hepatitis C Virus+/HIV+ vs. Hepatitis C Virus+ only)

Lissen 1993^

    Prostitutes Taiwan

622

74 (12%)

 

History of paid sex > 6 months

Wu 1993

STD Clinic (MSM & HET)

US

1,257

122 (9.7%)

M = >29 years & lack of condom use

F = > 29 years & >1 sex partner prior month

Thomas 1994

STD Clinic (MSM & HET)

US

1,039:

M 555 F 484

M 37 (7%)

F 19 (4%)

Age >28; >24 lifetime sex partners; HIV+; Trichomonas infection; cigarette smoking.

Omitting HIV+ showed MSM significant risk

(p = 0.012)

Thomas 1995

MSM

Australia

1,038

79 (7.6%)

HIV+

Bodsworth1996

Women with or at risk for HIV

US

296

 

123 (42%)

HIV+, sex with male IDU, history of gonorrhea, >35 years, not graduating high school

Hershow 1996

Volunteer blood donors

US (REDS)

862,398

3,126

(0.36%)

HTLV I or II, HBV or HIV (OR, 10.4)

Murphy 1996

Hepatitis C Virus+ blood donors & Hepatitis C Virus-controls

Canada

Hepatitis C Virus+ 267

Hepatitis C Virus- 1,068

N/A

Sex with an IDU (OR, 6.9)

Delage 1999

Hepatitis C Virus+ blood donors & Hepatitis C Virus- controls

US (REDS)

Hepatitis C Virus+ 2,316 Hepatitis C Virus- 2,316

N/A

Sex with an IDU (OR, 6.3)

Murphy 2000

MSM

Canada

120 HIV+ 112 HIV-

20 (8.6%):

HIV+ 14% HIV- 2.7% For the HIV+ men: Fisting (OR, 4.06)

Rimming (trend)

Craib 2000

 

 

 

 

 

 

 ^ = subset analysis; BT; blood transfusion; MSM = men having sex with men; HET = heterosexual; STD = sexual transmitted disease; ID = Infectious disease

   In recent NEJM letters to the editor, CDC's Miriam Alter and Edward Murphy and colleagues from the NHLBI REDS sparred over the plausibility of Hepatitis C Virus sexual transmission, citing selected studies to make their cases. Murphy started with, "[a] review of the literature suggests that sexual transmission of Hepatitis C Virus is inefficient at best," and Alter countered that "results of both incidence and prevalence studies [show] that high-risk sexual behavior accounts for 15 to 20 percent of Hepatitis C Virus infections in the United States." (Murphy 1999; MJ Alter 1999a).

 

   Both make statements that are far too general and more importantly do not acknowledge that sex is not a defined act; it means different things to different people, and sexual practices can and do differ widely from household to household. These limitations (i.e., lack of detailing sexual acts or high-risk behavior) are common in a majority of studies reviewed. While some studies document that sleeping with an HIV-positive or HBV-positive individual is a risk factor for transmission, we don't know what was done in bed (if it was in a bed) that created the extra risk. Too often, "high-risk sexual behavior" and "sexual promiscuity" are not defined, nor are we privy to whether condoms were used. Thus, it is the particular sexual act (e.g., insertive vaginal or anal intercourse, oral sex, anal fisting, etc.) that needs to be explored for its risk of Hepatitis C Virus transmission. Murphy's belief that sexual transmission is "inefficient at best" is surprising since it contradicts his 1996 JAMA and 2000 Hepatology papers on risk factors for Hepatitis C Virus transmission in the REDS cohort, which document that HIV and HBV, and sex with an IDU, respectively, are risk factors in multivariate analyses (Murphy 1996, 2000).

   Murphy's argument against sexual transmission-even in homosexuals-is weakly supported by a single review article, which fails to note that most studies rejecting the risk of sexual transmission were too small and underpowered to detect such risks (MacDonald 1996). According to Donahue and colleagues, who documented a 1.6% incidence rate of Hepatitis C Virus in a cohort of 926 homosexuals, "the small number of Hepatitis C Virus-seropositive subjects may have limited the power to identify risk factors for infection" (Donahue 1991).

   Likewise, Buchbinder aknowledged that the small sample size of her 1994 study (Buchbinder 1994) may have limited its power to find sexual transmission as a risk factor in the multivariate analysis, even though numerous sex acts were identified in the univariate analysis (Susan Buchbinder, personal communication, 2000).

   It is not surprising that the risk of Hepatitis C Virus sexual transmission appears greater for homosexuals than for heterosexuals. From HIV studies, we have excellent data documenting that the risk of transmitting HIV is greater for homosexuals than heterosexuals, for women from men than for men from women, and for anal than vaginal intercourse (Padian 1991; Kingsley 1990). Moreover, specific sex acts as well as the physical condition of an individual play major roles in establishing risk. For example, Moss and colleagues in 1987 documented that douching before anal sex (vs. not douching) was independently associated with HIV seropositivity (OR, 2.2-2.8) (Moss 1987). Chmiel and colleagues from the Multicenter AIDS Cohort Study (MACS) examined numerous types of sexual behavior between homosexual men and found that, aside from unprotected receptive anal intercourse, "the factor most strongly associated with prevalent HIV infection according to a multiple logistic regression model was rectal trauma, a composite variable which included receptive anal fisting, enemas before sex, reporting of blood around the rectum, and the observation of scarring, fissures or fistulas on rectal examination (OR, 7.7)." (Chmiel 1987)

   While such behaviors are physical symptoms are not universal among all homosexual men, if one partner with Hepatitis C Virus has penile sores or ulcers and the other partner has blood around the rectum, fistulas or fissures, it is plausible that there will be blood-to-blood contact and possible Hepatitis C Virus transmission. Documentation of specific risk factors like these is necessary in order to 1) elucidate various ways the virus might enter the body; and 2) define specific "high-risk behavior" so that individuals can be counseled about which sexual practices to lower the risk-no matter how small it might be-of contracting Hepatitis C Virus.

 

   The CDC states that "data indicate overall that sexual transmission of Hepatitis C Virus appears to occur, but that the virus is inefficiently spread through this manner." They do, however, call for further research into this controversial area: More data are needed to determine the risk for, and factors related to, transmission of Hepatitis C Virus between long-term steady partners as well among persons with high-risk sexual practices, including whether other STDs promote transmission of Hepatitis C Virus by influencing viral load or modifying mucosal barriers. (CDC 1998)

   After this call for more data, it is interesting to see that the CDC in its Recommendations for Prevention and Control of Hepatitis C Virus (Hepatitis C Virus) Infection places both "long-term steady partners of HIV-positive persons" and "persons with a history of multiple sex partners or sexually transmitted diseases" in the same category of "persons for whom routine Hepatitis C Virus testing is of uncertain need [emphasis added]" (CDC1998).

   The CDC and the Infectious Disease Society of America took a more proactive stance in 1999 calling for HIV-infected individuals to be screened for Hepatitis C Virus in its revised USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in People with Human Immunodeficiency Virus (CDC 1999). Acknowledging that many HIV-infected individuals are coinfected with Hepatitis C Virus, the guidelines give a nod to the safer-sex practice of condom use:

   Although the efficiency of sexual transmission of Hepatitis C Virus remains controversial, safer-sexual practices should be encouraged, and barrier precautions (e.g., latex condoms) are recommended to reduce the exposure of sexually transmitted diseases. (CDC 1999)

   Why did it take until 1999 for the CDC to issue such a recommendation? In 1993, University of California-San Francisco (UCSF) epidemiologist Dennis Osmond sounded a calm but serious warning, which appeared to fall on deaf ears:

        Despite the infrequency of Hepatitis C Virus sexual transmission, sexual behavior may still be an important mode of spread if the pool of asymptomatic but infectious carriers is large. Because Hepatitis C Virus infection becomes chronic in a high proportion of cases and subclinical hepatitis may be common, there is reason to believe that this carrier pool could be large, and even a low level of sexual transmission may result in a substantial attributable risk. (Osmond 1993a)

   A Warning for Veterans

   A fascinating study was recently presented which infers that the rate of Hepatitis C Virus infection in U.S. veterans is 10 times higher than in the general population, and that combat blood exposure is a highly significant risk factor for Hepatitis C Virus transmission. Briggs and colleagues from Teresa Wright's group at the San Francisco Veterans Affairs Medical Center (SFVAMC) conducted a study with 791 veterans undergoing routine outpatient phlebotomy at the SFVAMC (Briggs 1999). Participants had their blood screened for anti-Hepatitis C Virus positivity by EIA II, which was confirmed by Chiron bDNA. All were asked to answer a detailed questionnaire regarding sociodemographic characteristics and potential Hepatitis C Virus risk factors. Of the 791 participants (95% male), 150 (19%) and 110 (13.9%) were anti-Hepatitis C Virus-positive and Hepatitis C Virus RNA-positive, respectively. The multivariate analysis below documents four significant risk factors, including the surprising finding that those exposed to blood during combat were 2.5 times more likely to develop Hepatitis C Virus.

   Risk Factors for Hepatitis C Virus Infection in San Francisco Veterans: Multivariate Analysis

 

        

Risk Factor

Relative Risk

95% CI

P

IV drug use

24.74

8.17-74.86

<0.0001

Incarceration >48 hours

3.37

1.36-8.31

<0.0080

Blood transfusion <1992

2.23

0.90-5.53

<0.0820

Combat blood exposure

2.47

1.06-5.73

<0.0350 (Briggs 1999)

 

   Conclusion

   The discovery of the Hepatitis C Virus virus by molecular techniques and the development of an antibody assay in 1989 were the first steps in understanding and identifying the cause of liver disease in blood transfusion recipients. Since then, the sensitivity and specificity of the EIA has markedly improved, and the screening of blood donors has made the blood supply significantly safer (risk of 0.001% per unit transfused). In the U.S., approximately 2% of the population (four million people) are infected with Hepatitis C Virus, and Hepatitis C Virus appears to more common in Blacks and Hispanics. Internationally, the prevalence ranges from 0.1% to 5%, but in Egypt, it is estimated to be 25%. It is almost certain that blood-to-blood contact is the only way to transmit Hepatitis C Virus.

   Intravenous drug use (IVDU) remains the main mode of transmission, with rates of infection ranging from 75% to 92% in various cohorts. Those engaging in IVDU should be tested for Hepatitis C Virus and refrain from sharing syringes, cotton, and cooking equipment. The rate of perinatal transmission of Hepatitis C Virus is approximately 5%, and the CDC does not feel that there is a risk from either breast feeding or vaginal delivery. The risk of transmitting Hepatitis C Virus sexually is a controversial subject. In monogamous heterosexual couples, there appears to be little if no risk, yet in certain populations, including homosexuals and people with HIV or STDs, the risk appears to be 5–15%. Larger studies are needed to determine which sexual practices place individuals at increased risk of contracting Hepatitis C Virus. Until then, individuals with “multiple sexual partners” engaging in “high-risk” sexual behavior should always use condoms.

 

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