Hepatitis C Virus: Emergence of a Silent Pathogen

Hepatitis C is a relatively common bloodborne disease with risk considerations for health professionals, parenteral drug users, and other at-risk people. Medical and dental professionals have had to familiarize themselves with the rapidly emerging information about this form of hepatitis in order to treat infected patients and protect themselves, their co-workers and others from exposure. This article summarizes the current status of scientific and clinical evidence with regard to hepatitis C.

Health care infectious-disease concerns about viral hepatitis prior to 1989 primarily focused on hepatitis B and its etiologic agent, hepatitis B virus (HBV). The documented occupational risks for HBV had been well-studied and described during the previous two decades with regard to viral characterization, transmission mechanisms, carrier risks following infection, infection control precautions designed to minimize viral cross-infection, and the effectiveness of an HBV component vaccine to stimulate protective host immunity. Viral hepatitis challenges continue to be defined; and, during the past 10 years, the following scenario has subsequently become a reality for a number of blood transfusion recipients, health care professionals, and others:

Since the discovery of hepatitis C virus in 1988,¹ variations of the above story have frequently been repeated; and hepatitis C is now regarded as a relatively common bloodborne disease with risk considerations for health professionals, parenteral drug users, and other at-risk people.

The amount of information published in the scientific and clinical literature is extensive; and knowledge continues to evolve in areas such as characterization and genetic mapping of the HCV virion, epidemiologic features of disease, modes of viral transmission, progression of acute and chronic infections, serologic diagnostic assays, risk factors, treatment approaches for HCV-infected patients, and infection control measures for health care facilities and patients’ homes. Medical and dental professionals alike have had to familiarize themselves with the rapidly emerging information about hepatitis C in order to treat infected patients and protect themselves, their co-workers, and other patients from exposure. The following discussion summarizes the status of scientific and clinical evidence by using representative questions asked by health care workers.

Early case investigations of post-transfusion hepatitis in the 1950s suggested a possible infectious etiology for the condition. This finding led to the practice of screening potential blood donors for blood or liver abnormalities in an effort to reduce the incidence of post-transfusion hepatitis.^2-4 Later discoveries of hepatitis A virus (HAV) and hepatitis B virus as organisms responsible for two forms of viral hepatitis were facilitated by major scientific advances in serology and tissue culture technologies and provided the tools for further viral investigations.^5-9 As more cases of hepatitis A and hepatitis B were diagnosed in the 1970s, clinicians noted that sera from a number of patients presenting with hepatitis signs and symptoms were negative for HAV and HBV immunological markers. Subsequent reports described another form of post-transfusion and percutaneous injury hepatitis that could not be attributed to any microorganism. Since diagnosis of this condition was based on abnormal liver function and the exclusion of positive markers for known hepatitis viruses, the term non-A, non-B (NANB) hepatitis was introduced.^10-15 Efforts to discover other microbial etiologies continue, and at least six viral agents have been found that cause the majority of cases of viral hepatitis (Table 1). Of these, HCV has emerged as an occupational concern for health care workers because of the risk of bloodborne transmission and the significant potential for chronic infection.

HCV is a single-stranded RNA virus classified in the Flaviviridae family; it was isolated and cloned using recombinant DNA technology.¹ Worldwide, six distinct HCV genotypes have been characterized. In the United States, approximately 70 percent of the individuals with chronic HCV infection have been shown to harbor genotype 1. More recent studies investigating viral structures from clinical isolates have shown that there is also an extensive diversity in HCV genomes. Thus, different HCV strains, termed "quasispecies," can have substantial variations in genome sequencing, with resultant high rates of virion amino acid variability.^16-17 This heterogeneity occurs as result of viral RNA mutations that occur during viral replication. It is thought that the consequence of this genetic diversity in clinical infections is to allow the virus to escape protective host immune responses, with the most common result being a high rate of chronic infection¹⁸ (Table 2).

How is HCV transmitted, and what is the status of serologic testing?

HCV infection most commonly occurs following parenteral exposure to contaminated blood or blood products. Statistics collected during the the 1970s and ’80s indicated that parenteral NANB hepatitis was responsible for nearly 90 percent of the reported U.S. transfusion-associated hepatitis cases.^19-20 In recent years, however, less than 5 percent of the reported cases have been traced to blood transfusions. The highest rates of HCV infection have been demonstrated in groups with large or repeated percutaneous exposures, such as parenteral drug users and patients with hemophilia.^21-22 Health care workers who have frequent contact with blood and personal contact with others who may be infected within households, have also been documented with an increased incidence for hepatitis C compared to the general population.²³ Sexual transmission^24-25 and perinatal passage from HCV-infected mothers to their offspring^26-27 can occur, although neither of these routes is thought to be an efficient mode of viral exposure. Table 2 lists groups described by the Centers for Disease Control and Prevention as being at increased risk for HCV infection.

Recombinant nucleic acid techniques were used to successfully clone the HCV genome. As a result, a sensitive serologic assay for anti-HCV immunoglobulins was developed. This first-generation radioimmunoassay was able to detect antibodies against viral c100-3 antigen.¹ Anti-HCV is found to develop in virtually all people infected with the virus and is associated with current or past HCV infection. It is important to note that the detection of anti-HCV in a person’s serum does not indicate whether the person has had hepatitis C and is immune or has become chronically infected (i.e., still capable of transmitting the virus). Anti-HCV can persist in blood for years but may become undetectable spontaneously or following regimens of antiviral interferon.^18,22,28-30 Although not absolute in being able to detect all HCV infections and eliminating the potential for false positive results, subsequent second- and third-generation assays have increased the sensitivity and specificity of tests (Table 3). Since techniques aimed at growing HCV in vitro are not yet available, detection of viral RNA in a person suspected of hepatitis C is currently used as a direct viral marker.³¹

Manifestations of HCV infection can be variable, exhibiting patterns similar to those observed for other hepatitis viruses. Briefly, affected persons may develop asymptomatic infections and appear healthy with normal liver function and no pathological sequelae, or they may develop acute and/or chronic disease manifestations. HCV infection often induces less hepatic inflammatory reactions than do hepatitis A or B, thereby manifesting milder symptoms. The most characteristic feature of acute hepatitis C is a fluctuating alanine aminotransferase pattern.²² The range of asymptomatic patients with acute hepatitis C is 60 percent to 70 percent, with 20 percent to 30 percent becoming jaundiced, and the remaining 10 percent to 20 percent manifesting only fatigue, anorexia, and abdominal pain.³² Since appearance of anti-HCV in a person’s serum may not occur for weeks to months after viral infection, patients can continue to be infectious for extended intervals prior to onset of symptoms and diagnosis.

Although HCV is similar to HBV infection in certain aspects, a major difference can be found between the carrier rate incidence for the two. While hepatitis B has a 5 percent to 10 percent chronic carrier risk of longer than six months, approximately 85 percent of individuals infected with HCV can become carriers, with persistent or occasional viremia.^33-35 This form of persistent HCV infection increases later risks for hepatic failure and hepatocellular carcinoma. Individuals with certain immune-compromised conditions have also been found to have higher hepatitis C morbidity. Such individuals include people who are HIV-infected or who are preparing to undergo kidney or liver transplantation. Transmission in these cases is most probably due to frequent parenteral exposure to HCV via blood transfusion or intravenous drug use. High-risk sexual activity may also be a factor.³⁶

In a similar manner as historically demonstrated for hepatitis B, accidental percutaneous injuries from contaminated sharps represent the major hepatitis C occupational risks for health care workers. Occupational risks for NANB hepatitis were described even before there was a description of HCV.^12,37-38 Later, occupational risk investigations published after the virus was cloned further documented instances of HCV transmission to health care workers after bloodborne percutaneous accidents.^39-45 Syringe needles contaminated with patient blood were involved in most clinical reports.

Few transmission studies have been performed investigating HCV risks in dental professionals. Klein and his colleagues reported a higher incidence of anti-HCV in a sample group of New York City area dentists (1.75 percent) compared with blood donor controls (0.14 percent). In one portion of the study, an observed higher incidence of anti-HCV markers in the sera of participant oral surgeons (9.3 percent) led to the suggestion that greater occupational risks occurred with increased exposure to blood.⁴⁰ Later data have not completely substantiated the earlier findings.^46-48 In fact, a recent review suggested that the prevalence of HCV among dentists, surgeons, and hospital-based health care workers is similar to the 1 percent to 2 percent figure reported for the general population.⁴⁹

Based on this type of information, it appears that HCV is more difficult for health care workers to contract occupationally than HBV, yet HCV is a far more infectious bloodborne pathogen than HIV. Table 4 compares viral concentrations of HBV, HCV, and HIV in blood and calculates infection risks following worst-case scenario needlestick accidents.⁵⁰ HCV is present in concentrations ranging from a few virions to 100,000 or more particles per milliliter of infected blood. This range falls far below that typically found in sera from HBV-infected persons. This information should serve as reinforcement for the routine use of universal bloodborne precautions aimed at preventing HBV transmission in clinical settings. Those same precautions are appropriate for HCV infection control. Unfortunately, even though HCV is less transmissible than HBV, a person who is infected with HCV appears to have a greater chance of developing chronic hepatitis C and only a low chance of recovering with immunity. Despite apparent lower health care worker and patient risks from sharps, however, HCV infection carries with it the increased possibility of chronic liver disease. The progression from persistent viral infection to either hepatic cirrhosis in about 25 percent of infected persons or hepatocellular carcinoma in others present real challenges to infection control for health care providers.

As part of an effort to prevent occupational transmission of HCV infection, the CDC published prescribed guidelines for follow-up procedures subsequent to accidental health care worker exposures to blood.⁵¹ These procedures include:

* Baseline testing for anti-HCV immunoglobulins for both the person exposed and the source individual, with periodic follow-up testing for the exposed person;

* Confirmation of any positive serologic tests;

* Lack of proven effectiveness of prophylactic antisera; and

* Continued health care worker education about HCV risks and prevention measures. These guidelines were expanded in a more detailed 1998 CDC series of recommendations targeting prevention and infection control issues.⁵²

Antiviral chemotherapy with interferon has generally been recommended for individuals with chronic hepatitis C who are at the greatest risk for disease progression to cirrhosis.^53-54 The Food and Drug Administration approved a recombinant form of this antiviral agent for treatment of chronic hepatitis C in 1991.⁵⁵ Additional investigations attempted to further refine therapeutic dosages and time intervals for drug administration. For more detailed information, the reader is referred to the 1997 National Institutes of Health consensus statement.⁵³ In recent years, combining of chemotherapeutic agents has shown promising results. A combination of interferon and ribavirin is now FDA-approved for treatment of chronic hepatitis C patients who have relapsed following interferon regimens.⁵² Test groups of patients who received this drug combination showed a substantial increase in success rates (40 percent to 50 percent) compared with those receiving interferon alone (15 percent to 25 percent).^52,56-57

Patients are counseled prior to initiation of therapy, since both of these agents can cause mild to severe adverse effects. For example, interferon therapy has a number of potentially serious adverse effects associated with prolonged subcutaneous injection protocols, with the most common being flu-like symptoms in 60 percent to 80 percent of the trial recipients. Fortunately, evidence indicates that the side effects are in part dose-related and reversible after interferon therapy is stopped.^58-59 A serious problem associated with ribavirin use is the possible induction of hemolytic anemia, which can be life-threatening for some patients.⁵³

Summary

Hepatitis C was formerly called parenterally transmitted non-A, non-B (NANB) hepatitis. This infectious disease has epidemiological characteristics similar to hepatitis B, with infection from contaminated blood appearing to be a primary source of the virus. Although at one time, NANB hepatitis was responsible for 80 percent to 90 percent of the transfusion-associated hepatitis cases in the United States, injection drug abuse has become the major documented risk factor for HCV infection. Health care workers and their patients face hazards for HCV infection primarily through needlestick and other contaminated sharps accidents, although the risks are much lower than those historically documented for HBV infection. Current universal bloodborne precautions for infection control appear to be effective against occupational cross-infection in patient care settings. A summary of these and other important features is presented in Table 5. There are pressing issues that still need to be explored, however, including provision of routine anti-HCV testing of health care workers after possible exposure, improvements in chemotherapeutic treatment regimens, and management of health care workers who develop chronic hepatitis C following occupational exposures.

Author/

John A. Molinari, PhD, is professor and chairman of the Department of Biomedical Sciences at the University of Detroit Mercy School of Dentistry.

References/

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To request a printed copy of this article, please contact/ John A. Molinari, PhD, UDM School of Dentistry, 8200 W. Outer Drive, Detroit, MI 48219-0900.