Hepatitis  C  Update

Author:Craig V. Towers, M.D.
Patricia D. Hastings, RN, BSN, MSN

Objectives:  Upon the completion of this CNE article, the reader will be able to:

1.         Discuss the potential clinical impact of Hepatitis C infections and how patients are diagnosed and followed-up.

2.         Describe the different ways in which the Hepatitis C virus can be transmitted between adults and to children through perinatal transmission and breastfeeding.

3.         Discuss the potential treatment options for Hepatitis C infected individuals, the limitations of treatment, and the potential for an effective future vaccine or immunoglobulin.

Background and Healthcare Impact:

            Many different viruses can lead to injury of liver cells producing hepatitis.  Some of these are considered primary hepatitis viruses whereas others may produce hepatitis as part of their overall infection.  For the primary hepatitis viruses, for years only two were distinctly known and were called Hepatitis A and Hepatitis B.   Everything else was labeled non-A non-B hepatitis.  In 1989, Choo and Kuo identified an RNA viral strand that was felt to be the cause of non-A non-B hepatitis.  This RNA virus was soon labeled Hepatitis C (HCV).  Since the discovery of the Hepatitis C virus, several distinct genetic variants have been identified based on different nucleic acid sequences. 

At the present time, 6 major genotypes exist and each of these have four to six subtypes, which are labeled progressively “a”, “b”, “c”, etc.  Some studies have reported genotypes 7 through 11, but most authorities list these as primarily variants of genotypes 3 and 6.  The most common genotypes in the United States, Western Europe, and Japan are 1a, 1b, 2, 3a, and 4.  The hepatitis C virus has been classified as a separate genus to the flavivirus family.  This RNA virus is approximately 9379 to 9481 nucleotides long and is 30 to 38 nanometers in diameter.

As more information is obtained on the Hepatitis C virus, the potential clinical impact of this disease is becoming apparent.  Research shows that the majority of post-transfusion hepatitis is caused by Hepatitis C.  The Centers for Disease Control estimates that 170,000 new cases occur per year in the United States alone.  Based on information presented at the 1999 Consensus Conference on Hepatitis C, it is estimated that there are 170 to 200 million carriers worldwide, with 4 million in the United States.  Of acute infections, only 20% have symptoms (meaning 80% or 4 out of 5 have no symptoms and do not realize they were infected).  Once infected, 85% become chronic carriers and again they are usually asymptomatic.  Of these chronically infected HCV carriers, 75% will have elevated liver function tests, which means that 25% have normal tests but are still carriers.    Chronic hepatitis C is slowly progressive and it is estimated that 10% to 30% progress to cirrhosis after 20 years.  Of those with cirrhosis, the risk of developing hepatocellular carcinoma is 2% to 5% per year.  Therefore, the potential impact on healthcare in the United States and worldwide is enormous. 

Furthermore, another difficulty that occurs in evaluating patients infected with this virus is that a viral marker antigen that denotes infectivity has not be identified.  If one looks at hepatitis B, the presence of the hepatitis B surface antigen (HBsAg) denotes the possibility that a person is infectious.  A similar antigen marker for hepatitis C does not exist at the present time.  Therefore, research on the full ramifications of this virus is still limited to antibody studies and nucleic acid probes. 

Diagnosis:

Attempts at culturing the virus have unfortunately not been successful.  Therefore, the diagnosis of an HCV infection primarily relies upon the detection of antibodies to the virus or identifying the nucleic acid of the virus by PCR testing (polymerase chain reaction).  The laboratory work up primarily involves an ELISA screening test (enzyme linked immunosorbent assay) that looks for the presence of antibody to the virus.  Currently, most labs now use a third generation anti-HCV ELISA test called an ELISA-3.  This ELISA test, however, can have a very high incidence of false positive results especially if used in a low risk population.  Therefore, a positive ELISA test is usually confirmed by a more specific test called a RIBA (recombinant immunoblot assay).  The RIBA test is also currently a third generation test called RIBA-3.  This test is an evaluation of a group of antibodies to hepatitis C viral antigens that come from more than one region of the virus.  The mean period of time from an HCV infection to the development of an anti-HCV antibody response is 12 weeks but can take up to 6 months in some cases.  Therefore, during an acute episode of hepatitis, the ELISA and RIBA anti-HCV antibody tests may be negative.  Therefore, in evaluating a patient for acute hepatitis, the HCV RNA-PCR test should be ordered.

If an individual tests positive for HCV by ELISA and is confirmed by RIBA, they should have liver function tests performed along with HCV-RNA testing.  If the liver function tests are normal and the RNA probe is negative, many authorities recommend that these tests be repeated in 6 to 12 months.  If still negative, the individual is probably not a chronic carrier.  If the testing is positive, someone with experience in treating HCV infected individuals should follow the person.  These patients need to be continuously followed to determine if and when a liver biopsy and or treatment should be considered.

Transmission of HCV:

The spread of Hepatitis C is by a percutaneous or permucosal pathway.  Therefore, the transmission between individuals primarily occurs in the following ways:

·        Through Blood or Blood Products

·        Through IV Drug Abuse

·        Sexually

·        Perinatal Transmission

The risk of HCV transmission between family members or sexual partners seems to be low but is not zero.  Even after 10 years of study, the extent of sexual transmission is still unclear.  For example, in a study by Nakashima et al, of over 1100 residents in an HCV endemic area of Japan, anti-HCV antibody was detected in 14% of the population.  However, the positive rate amongst sexually active spouses was only 7% with half of those tested showing different serotypes.  In a study by Bresters et al, all 50 heterosexual partners of HCV positive individuals were HCV-RNA and anti-HCV negative.  The median duration of sexual relations was 13 years.  Several other studies have also shown a low transmission rate by sexual activity (in the range of 1% to 5%).  However, transmission can occur and it appears to be more common in patients with a history of multiple sexual partners.  The sexual transmission rate to an uninfected person is also higher (up to 10%) if the positive partner was infected through recurrent sources (IV drug abuse or multiple sexual partners).

This low transmission rate through sexual activity may be due to a low detection rate of the Hepatitis C virus in human secretions (other than blood).  Therefore, the larger risk for HCV transmission in the population seems to stem from blood transmission such as transfusion with blood products, IV drug abuse, organ transplantation, or other external sources such as acupuncture, etc.  However, an important fact that should be understood regarding HCV transmission is that most population studies identify a number of individuals who have no other explainable mode of transmission except for sexual activity.  Therefore, the use of condoms is still recommended for sexual activity with an infected HCV partner and especially in a partner with an unknown history because transmission of HCV through sex does occur.

As stated above, the main area of concern when looking at the transmission of hepatitis C is its relation to post-transfusion hepatitis.  Most studies revealed that the majority of post-transfusion hepatitis was caused by HCV.  With the addition of anti-HCV testing of donated blood, the risk of developing post-transfusion hepatitis is now about 3 per 10,000 units transfused.  This testing of donated blood has markedly decreased the incidence of post-transfusion hepatitis in the United States.  The table shows the current risks of becoming infected through transfusion, per unit of blood transfused.

Table: Current estimated risks of transmitting infection per unit of blood transfused from Units that are negative in laboratory testing.

            Hepatitis B                  1 in 200,000 units transfused

            Hepatitis C                  1 in 3,000 units transfused

            HIV                             1 in 700,000 units transfused

            HTLV I / II                 1 in 50,000 units transfused

Immunoglobulins have been used in medicine for years to help prevent or reduce the risk of infections (for example serum immune globulin, hepatitis B immune globulin, varicella zoster immune globulin, etc.).  In addition, anti-D immune globulin (Rhogam) has nearly eliminated Rh sensitization in the United States.  The safety of these products over the years has been excellent despite the fact that these immune globulin products come from pooled plasma where some donors probably carry transmissible infections.  In the mid 1990’s, there were reports of Hepatitis C transmission following the administration of some brands of serum immune globulin.  The frequency of this occurrence is still low, however, this underscores the importance of having a clear indication for the use of these products.

Immune globulin production starts with a fractionation procedure that effectively removes most if not all potentially infectious agents.  However, due to these reported HCV transmissions, most products (especially those used in the United States) add other purification steps such as a solvent-detergent treatment or a low pH treatment and pepsin.  Therefore, Hepatitis C transmission with these products will hopefully be non-existent in the future.

Perinatal Transmission of HCV:

Vertical transmission from an infected mother to the infant does occur during pregnancy.  Over 50 studies have been published on the topic of perinatal transmission during the past 5 years and the data is still not completely clear.  When studies are combined, the rate of perinatal HCV transmission in pregnant patients who are anti-HCV antibody positive is about 5% (with a range of 0% to about 10%).  These variations in percent transmission may be due to differences in those who are viral RNA positive in the bloodstream at the time of delivery.  More recent data have determined that transmission primarily only occurs in patients who are HCV-RNA positive at the time of delivery (however, the laboratory that performs the PCR testing is important, because it is an extremely sensitive test).  In addition, in patients who are HCV infected and are also HIV positive, the rate of perinatal transmission increases to a range of 15% to 23%.

The HCV positive carrier rate in studies of pregnant populations from Japan to Europe to the United States ranges from 0.5% to 3% (meaning 1 in 33 to 1 in 200 pregnant women are HCV antibody positive).  It is important to understand that all babies born to women who are HCV-antibody positive are HCV-antibody positive at birth.  This does not mean they are infected.  The newborn’s positive antibody test is caused by the mother’s antibody that crossed the placenta.  Mother’s IgG antibodies can freely cross the placenta, but unfortunately they are not protective to the newborn.  Most of these newborns convert to negative by 12 months of age when the maternal antibody disappears from the baby’s bloodstream.  However, this maternal antibody can remain positive for up to 20 months following delivery in some uninfected children.

Another question that has not been fully answered is whether the virus can cross the placenta and infect the child prior to delivery.  Most studies would suggest that this is not the case.  Delamare et al tested the amniotic fluid obtained by genetic amniocentesis in 16 HCV-RNA positive women and in 15, the HCV-RNA probe was negative by PCR.  The HCV-RNA was positive in one case at a very low level of 230 copies per ml of fluid.  However, the amniocentesis procedure went through the placenta in a mother whose viral load was 340,000 copies per ml.  This child and 9 others were tested at birth and all were negative for HCV-RNA.  Therefore, the one positive amniotic fluid was probably caused by maternal blood contamination of the specimen.  (Levels of HCV-RNA in the blood that are less than 10,000 copies per ml are considered low titers.  PCR testing is very sensitive and can detect as few as 10 to 20 copies of virus in one milliliter of fluid.  Therefore, a very tiny contamination can result in false positive results.)

The Delamare report and most other studies suggest that the majority of perinatal transmission (when it occurs) takes place around the time of delivery.  Because of this finding, the next question is whether the type of delivery affects this transmission rate.  The majority of studies on this topic have reported that the mode of delivery did not seem to affect the perinatal transmission rate.  However, it is important to note that nearly all of these studies did not separate the cesarean section group into elective cesarean prior to the onset of labor and those c-sections performed for obstetrical reasons after labor begins or membranes have been ruptured.  One recent study by Gibb et al reported on the perinatal transmission rate in 441 mother-child pairs from Ireland and England using an estimation statistical approach.  The perinatal transmission rate in 339 vaginal deliveries was estimated at 7.7% and the transmission rate in 54 non-elective c-sections was 5.9%.  However, the transmission rate in 31 elective c-sections was 0%.  Despite this finding, these percentages were not statistically different.  However, the 0% transmission rate in the 31 elective cesarean sections versus a 7.4% transmission rate in 393 combined vaginal deliveries and non-elective c-sections was significant at P = 0.04.  Therefore, further studies are needed that analyze whether there is a difference between elective cesarean delivery and routine obstetrical delivery.

The final issue regarding pregnant women infected with HCV and their newborns is breastfeeding.  No studies to date have ever proven transmission to a newborn through breastfeeding.  Several studies have tested breast milk for the presence of HCV-RNA and most have not detected the virus.  In a few studies, HCV-RNA was detected in breast milk, but at very low levels (of < 1000 copies per ml) and usually, this was only seen in colostrums.  Furthermore, it is uncertain whether the virus can withstand the elements of the intestinal tract.  According to the American College of Obstetricians and Gynecologists, breastfeeding is not contraindicated in women who are HCV positive.

Treatment of HCV:

At the present time, there is no available Hepatitis C immune globulin or vaccine that can be used in preventing this infection.  The current recommendations for treatment are still very complex.  Therapy is still limited to interferon (or its variation) along with ribavirin and is dependent upon the patient’s age, general state of health, risk of cirrhosis, likelihood of response, and life expectancy.  The majority of patients should have a liver biopsy before starting treatment, which also establishes the individual’s baseline liver status.  Only patients who are HCV-RNA positive should be treated (and usually ones with elevated liver function tests).  Patients who are active heavy alcohol users, active IV drug users, patients with decompensated cirrhosis, and patients with mild disease should probably not be treated.

Patients with genotype 1 are usually treated for up to 48 months versus 24 months with types 2, 3, and 4.  Current therapy is interferon alpha-2a with ribavirin (ribavirin by itself is not effective); however, two recent studies in the New England of Medicine reported a better response to a new agent called peginterferon alpha-2a.  Unfortunately, up to 50% of HCV infected people rebound after the treatment is completed and some individuals never respond at all.

No vaccine is currently available and many hurdles still exist in its development.  The first hurdle in this regard is testing.  The only way to test for the potential of infectivity is by PCR for the presence of HCV-RNA.  Secondly, the only species that can be infected are humans and chimpanzees, which limit animal testing.  The third issue is that the virus does not replicate in vitro and culturing of the virus is currently not available.  A fourth hurdle is that many of the HCV viral proteins have a high mutation rate (meaning they are not the same from genotype to genotype).  Finally, and possibly the most important, is that researchers currently have not identified an antibody that kills the virus (for example, anti-HBsAg antibody kills the hepatitis B virus).  The best hope for a vaccine might be one that prevents the development of the chronic carrier state.   

In summary, HCV has rapidly become a difficult and confusing topic with many questions still unanswered.  However, the future impact of this virus on society and healthcare is massive.  Therefore, further research is needed along with increasing public awareness of this infection.  Hopefully, the future will bring an effective immune globulin and vaccine for prevention and research will identify a better mechanism to follow potential infectivity.

References or Suggested Reading:

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2.         Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:362-4.

3.         Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic Non-A, Non-B hepatitis. N Engl J Med 1989;321:1494-1500.

4.         Aach RD, Stevens CE, Hollinger B, et al. Hepatitis C virus infection in post-transfusion hepatitis. N Engl J Med 1991;325:1325-9.

5.         Consensus Statement – EASL International Consensus Conference on Hepatitis C.  J Hepatol  1999;31(suppl):3-8.

6.         Marcellin P.  Hepatitis C: the clinical spectrum of the disease.  J Hepatol  1999;31(suppl):9-16.

7.         Simmonds P.  Viral heterogeneity of the hepatitis C virus.  J Hepatol   1999;31(suppl):54-60.

8.         Nakashima K, Ikematsu H, Hayashi J, et al. Intrafamilial transmission of hepatitis C virus among the population of an endemic area of Japan. JAMA 1995;274:1459-61.

9.         Bresters D, Mauser-Bunschoten EP, Reesink HW, et al. Sexual transmission of hepatitis C virus. Lancet 1993;342:210-11.

10.       Osmond DH, Padian NS, Sheppard HW, et al. Risk factors for hepatitis C virus seropositivity in heterosexual couples. JAMA 1993;269:361-65.

11.       Brettler DB, Mannucci PM, Gringeri A, et al. The low risk of hepatitis C virus transmission among sexual partners of hepatitis C-infected hemophilic males: an international, multicenter study. Blood 1992;80:540-43.

12.       Hsu HH, Wright TL, Luba D, et al. Failure to detect hepatitis C virus genome in human secretions with the polymerase chain reaction. Hepatology 1991;14:763-67.

13.       Terada S, Kawanishi K, Katayam K. Minimal hepatitis C infectivity in semen. Ann Intern Med 1992;117:171-72.

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15.       Wejstal R.  Sexual transmission of hepatitis C virus.  J Hepatol 1999;31(suppl):92-5.

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20.       Giovannini M, Tagger A, Ribero ML, et al. Maternal-infant transmission of hepatitis C virus and HIV infections: a possible interaction. Lancet 1990;335:1166.

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25.       Delamare C, Carbonne B, Heim N, et al.  Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: a prospective study.  J Hepatol 1999;31:416-20.

26.       Gibb DM, Goodall RL, Dunn DT, et al.  Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission.  Lancet 2000;356:904-7.

27.       Breastfeeding and the risk of Hepatitis C virus transmission.  ACOG Committee Opinion #220 August 1999.

28.       Polywka S, Schroter M, Feucht HH, et al. Low risk of vertical transmission of hepatitis C by breast milk.  Clin Infect Dis  1999;29:1327-9.

29.       Garland SM, Tabrizi S, Robinson P, et al. Hepatitis C – role of perinatal transmission.  Aust N Z J Obstet Gynaecol  1998;38:424-7.

30.       Davis GL, Balart LA, Schiff e R, Lindsay K, et al. Treatment of chronic hepatitis C with recombinant interferon alfa: a multicenter randomized, controlled trial. N Engl J Med 1989;321:1501-6.

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35.       Heathcote EJ, Shiffman ML, Cooksley GE, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.  N Engl J Med 2000;343:1673-80.

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37.       Abrignani S, Houghton M, Hsu HH.  Perspectives for a vaccine against hepatitis C virus.  J Hepatol  1999;31(suppl):259-63.

About the Authors:

Dr. Towers is currently on a sabbatical writing a series of books that deal with the safety of over-the-counter drugs, herbal medications, and natural remedies used during pregnancy.  The first is in print entitled “I’m Pregnant & I Have a Cold – Are Over-the-Counter Drugs Safe to Use?” published by RBC Press, Inc.

Before his sabbatical, Dr. Towers was an Associate Professor in the Department of Obstetrics and Gynecology at the University of California, Irvine.  He also was the Director of Perinatal Medicine at Long Beach Memorial Women’s Hospital in Long Beach California.  He has practiced clinically in the states of Kansas, California, and Wisconsin.  Dr. Towers has multiple publications in peer review medical journals and he has given lectures on a wide variety of obstetrical and medical topics nationwide.

Patricia D. Hastings has been a registered nurse involved in clinical practice for more than 20 years.  She currently is the Clinical Director of Obstetrics and Women’s Services at John C. Lincoln-North Mountain Hospital in Phoenix, Arizona.   She is a member of AWHONN and the ANA, and is participating in the Advanced Practice Chapter of the Arizona Nurses Association.