Managing Occupational Risks for Hepatitis C Transmission in the Health
Clinical Microbiology Reviews, July 2003, p. 546-568, Vol. 16, No. 3
0893-8512/03/$08.00+0 DOI: 10.1128/CMR.16.3.546-568.2003
David K. Henderson
Warren G. Magnuson Clinical Center, National Institutes of Health, U.S.
Department of Health and Human Services, Bethesda, Maryland 20892
Hepatitis C virus (HCV) infection is a significant contemporary health
problem in the United States and elsewhere. Because it is primarily
transmitted via blood, hepatitis C infection presents risks for both
nosocomial transmission to patients and occupational spread to health
care workers. Recent insights into the pathogenesis, immunopathogenesis,
natural history, and treatment of infection caused by this unique
flavivirus provide a rationale for the use of new strategies for
managing occupational hepatitis C infections when they occur. This
article reviews this developing information. Recently published data
demonstrate success rates in the treatment of "acute hepatitis C
syndrome" that approach 100\%, and although these studies are not
directly applicable to all occupational infections, they may provide
important clues to optimal management strategies. In addition, the
article delineates approaches to the prevention of occupational
exposures and also addresses the difficult issue of managing HCV-infected
health care providers. The article summarizes currently available data
about the nosocomial epidemiology of HCV infection and the magnitude of
risk and discusses several alternatives for managing exposure and
infection. No evidence supports the use of immediate postexposure
prophylaxis with immunoglobulin, immunomodulators, or antiviral agents.
Based on the very limited data available, the watchful waiting and
preemptive therapy strategies described in detail in this article
represent reasonable interim approaches to the complex problem of
managing occupational HCV infections, at least until more definitive
data are obtained.
Hepatitis C infection is a significant problem for medicine and society,
both in the United States and throughout the world. The past 15 years
have seen the characterization of hepatitis C virus (HCV) as the major
cause of non-A, non-B hepatitis, development of effective screening
tests for HCV antibody to improve the safety of the blood supply,
delineation of the community and nosocomial epidemiology of HCV
infection, development of a clear understanding about the prevalence and
the factors that influence the prevalence of HCV infection in society,
development of a substantial body of information about the natural
history of HCV infection, host immunological responses to exposure and
infection, and immunopathogenesis of syndromes associated with acute and
chronic infection, and substantial progress in the development of
therapeutic interventions to modify or cure HCV infection.
As our understanding of the epidemiology, routes of transmission, and
prevalence of HCV infection in society have developed, we have also come
to understand that this blood-borne virus represents a substantial risk
to health care workers from occupational exposure to blood and other
body fluids containing the virus in the workplace.
The purpose of this article is to review the information obtained in the
past decade about the epidemiology, nosocomial epidemiology, natural
history, immunopathogenesis, and occupational risks associated with
managing HCV in the health care workplace. In addition, the article
delineates approaches to preventing occupational and iatrogenic exposure
and infection with this blood-borne flavivirus.
EPIDEMIOLOGY AND ROUTES OF TRANSMISSION
In the Community
HCV has become a major cause of blood-borne viral infection in the
United States and in the world and is a major cause of chronic liver
disease worldwide. Alter and coworkers from the Centers for Disease
Control and Prevention assert that hepatitis C infection is the most
common chronic blood-borne infection in the United States (14). These
investigators determined the seroprevalence of HCV infection among
participants in the National Health and Nutrition Examination Survey,
conducted in the United States from 1988 to 1994 (232), to be 1.8% and
estimated that between 3.1 million and 4.8 million people in the United
States are HCV infected (15). Armstrong and coworkers used the same data
to model HCV infection in the United States over time to estimate the
seroprevalence of HCV infection in various groups of the U.S.
population. The seroprevalence, stratified by decade of birth, ranged in
this study from 1.1% to 4.1% (19). HCV infection was also found to be
inversely associated with socioeconomic status in these studies.
Among blood donors in the United States, the prevalence of HCV infection
(as determined by screening tests for anti-HCV antibodies) is
approximately 0.5% for first-time donors and 0.003% for returning donors
(42). Note that the prevalence among blood donors is significantly lower
than for the population at large, suggesting efficacy of donor
self-deferral practices in U.S. blood banks (42).
Hepatitis C is primarily a blood-borne or parenterally transmitted
infection. Vehicles and routes of parenteral transmission include
contaminated blood and blood products, needle sharing, contaminated
instruments (e.g., in hemodialysis, reuse of contaminated medical
devices, tattooing devices, acupuncture needles, razors, and manicure
devices), and occupational and nosocomial exposures (e.g., needle stick
injuries) (discussed below).
The epidemiology of HCV infection in the community in the Western world
has changed dramatically over the past two decades, primarily as a
result of the identification of non-A, non-B hepatitis as the major
cause of transfusion-associated hepatitis (109), identification of the
hepatitis C virus as the major cause of non-A, non-B hepatitis (67),
cloning and specific identification of the HCV genome as the agent
responsible for the overwhelming majority of cases of posttransfusion
hepatitis (64-66), the development of screening tests for blood and
blood products for transfusion to eliminate hepatitis C virus from the
blood supply (13, 169, 184), and the development of PCR technology that
can accurately detect the hepatitis C virus genome in the circulation of
infected individuals (122, 374), which permits genotyping and sequencing
of the genome to identify discrete strains of virus (315, 323).
Prior to these events, injection drug use and transfusion were the most
common routes of transmission for HCV infection in the West. In the
1980s, the risk for hepatitis C infection associated with transfusion
was nearly 20% per unit transfused (89). By the year 2002, as a result
of both self-deferral and aggressive screening of the blood supply, the
risk has dropped to less than 0.03% per unit transfused (172).
HCV infection was far and away the major cause of posttransfusion
hepatitis in the 1980s and 1990s, accounting for more than 85% of cases
of posttransfusion hepatitis (11). The risk for infection following
transfusion of a unit of blood contaminated with HCV is greater than 90%
(356). Whereas needle sharing has consistently been among the most
important risk factors for HCV transmission, once the blood supply could
be effectively screened for hepatitis C virus, the most important
behavioral risk factor for the transmission of HCV in developed
countries of the West unquestionably became needle sharing and equipment
sharing in the process of injection drug use, accounting for up to 60%
of infections (14). Other routes of transmission are less clear. Alter
and colleagues argue that sexual transmission accounts for as much as
20% of HCV infections overall; however, many authorities believe that
sexual transmission is relatively uncommon (12, 167, 219, 235, 321, 336,
Investigators have detected HCV nucleic acid in semen (113, 202),
menstrual blood, and other body fluids. One piece of evidence that
indirectly supports sexual transmission comes from studies of family
contacts of HCV-infected individuals. In the overwhelming majority of
such studies, only sexual partners of the infected individuals appear to
be at substantially increased risk for infection, and in some of the
studies, this risk increases with the length of time of potential
exposure (4, 167, 168, 250, 340). Conversely, I note that common risk
factors for infection that may have produced infection in both sexual
partners were not excluded in the majority of these studies. Further
evidence for sexual transmission comes from genotyping and genetic
sequencing of strains from sexual partners. These studies demonstrate a
very high degree of relatedness of the HCV genomes in a fraction, but
certainly not in all, of the strains identified from sexual partners (3,
62, 225, 340).
Despite these pieces of information, the evidence for sexual
transmission is often indirect, and a variety of other known risk
factors for transmission (e.g., needle sharing) often cannot be
excluded. Furthmore, studies of sexual partners of individuals who
acquired HCV infection as a result of receiving contaminated blood or
blood products often demonstrate extremely low rates of transmission to
spouses or steady sexual partners (39, 129).
Data concerning other routes of transmission are even more speculative.
Routes of infection that have been incriminated in some studies include
intranasal cocaine use (12, 72), body piercing (12), tattooing (63, 135,
179, 329), acupuncture (166, 308, 311, 327), shaving in community
barbershops (217, 350), manicuring and other procedures in commercial
beauty shops (217), and even iatrogenic transmission in hospitals, as
well as physicians' and dentists' offices. According to Alter, despite
anecdotal cases (discussed below) documenting iatrogenic and nosocomial
transmission, case-control studies have as yet failed to demonstrate
health care procedures as a clear risk for HCV infection in the
developed world (14).
Only a relatively small fraction of HCV infections are symptomatic. Most
infected individuals remain asymptomatic and, presumably, undiagnosed.
Based on available data, the majority of individuals who acquire HCV
infection (perhaps as many as 70 to 85%) develop chronic infection and
are therefore at risk for the sequelae of this infection. One published
estimate suggests that HCV is responsible for 8,000 to 10,000 deaths
annually in the United States (15). Hepatitis C is already the most
commonly implicated precipitating factor (responsible for more than 30%
of cases) for liver transplantation in the United States (42).
In the Hospital
Patient-to-provider transmission. Since hepatitis C is a blood-borne
infection and is transmitted efficiently by transfusion and by needle
sharing, it stands to reason that an occupational risk for transmission
of HCV in the health care setting might exist, including transmission
from infected patients to staff, from patient to patient, and from
infected providers to patients. Evidence that direct, percutaneous
exposure to blood represents the primary route of transmission for HCV
from patients to providers comes from case reports of occupational
infection in the literature (46, 210, 223, 230, 237, 238, 282, 297, 300,
325, 330, 349, 351). So-called "inapparent parenteral inoculation" (60)
and "inapparent parenteral transmission" likely account for the largest
fraction of the remaining cases. Two case reports document transmission
of HCV as a result of a splashes of blood from infected patients onto
health care workers' mucous membranes (284, 293).
Whereas blood is the major reservoir for occupational infection, other
body substances may present some (albeit likely substantially reduced)
risks for HCV infection, particularly if the health care worker is
exposed by the parenteral route or inadvertently receives a large
inoculum. HCV RNA has been detected in several other body fluids from
infected patients, including saliva (202, 372), menstrual fluid (313),
semen (113, 199, 202), urine (202), spinal fluid (189), and ascites
(202). Although HCV has been transmitted by a punch (2) and after human
bites (92, 110), the most common circumstance resulting in occupational
infection is percutaneous exposure, and the most frequent type of
exposure resulting in HCV transmission is a needle stick with a
hollow-bore, injection-style needle contaminated with blood from an
infected patient. Transmission of HCV resulting from exposures to body
fluids other than blood has not yet been documented, presumably because
viral titers in these fluids are substantially lower than in blood. HCV
environmental contamination has been suggested to play a role in some
settings (i.e., specifically in the hemodialysis environment) (1, 8, 78,
198, 366) (see discussion below); however, transmission of a specific
strain of HCV as a result of environmental contamination has not, to my
knowledge, been documented.
Patient-to-patient transmission. Whereas a risk for occupational
transmission from infected patients to health care workers providing
care for them has been identified for several years, we have only
recently begun to appreciate the risks for nosocomial and iatrogenic
infection in certain patient populations. Transmission of HCV in the
hemodialysis setting deserves special emphasis. The prevalence of HCV
infection among hemodialysis populations varies from 4% to more than 70%
in some countries (366). In the United States, in a survey of dialysis
centers conducted in 2000, antibody directed against HCV was found in
1.7% of hemodialysis center staff and in 8.4% of patients at these
centers (346). Although chronic, end-stage renal failure patients do
receive transfusions of blood and blood products, an increasing number
of instances of nosocomial, patient-to-patient spread of infection as
well as outbreaks of infection not linked to transfusion have been
reported (1, 9, 56, 78, 88, 99, 100, 131, 136, 159, 160, 170, 198, 213,
238, 248, 316, 326, 333).
Spread in these units has been suggested (but not definitively proved)
to be due to environmental contamination (1, 7, 8, 78, 198, 366),
contaminated dialysis machines (21, 78, 198), inadequate infection
control procedures in the dialysis unit (1, 56, 78, 88, 159, 198, 345),
dialyzing infected and noninfected patients in the same area (56, 88,
160, 248, 333), and understaffing of the dialysis unit (248). Numerous
cases of patient-to-patient HCV transmission have been linked to breaks
in infection control technique (discussed in more detail below). Several
instances of patient-to-patient HCV transmission have been reported from
Europe in the recent past (40, 81, 186, 200, 211, 247, 292, 299, 312,
365). In addition, patient-to-patient transmission in health care
settings, primarily related to faulty injection practices, appears to be
a reasonably important mode of HCV transmission in developing countries
(23, 117, 134, 156, 173, 216, 227, 273, 371).
In addition to clusters of HCV infections in the hemodialysis setting,
cases and outbreaks of hepatitis C infection have been linked to a
variety of medical procedures and interventions, including the use of
spring-loaded finger stick devices (81, 247), gynecological and
gynecologic endocrinologic procedures (200, 211, 263, 287),
contamination of multidose vials (182, 186, 211, 312, 348, 365),
contaminated intravenous administration devices (299), orthopedic
procedures (286), cardiothoracic surgery (41, 90, 97),
anesthesiologist's and anesthesia assistant's interventions (71, 143,
285), endoscopy (228), colonoscopy (40), administration of contaminated
immunoglobulin preparations (61, 93, 171, 191, 192, 288, 317), organ
transplantation (367), and outbreaks that were clearly nosocomial yet
for which no etiology could be determined (178, 188, 290). Some, if not
most, of these instances of HCV transmission most likely represent
cross-contamination, due, at least in part, to inadequate infection
control procedures or inadequate disinfection of devices or objects (40,
81, 143, 186, 200, 211, 228, 247, 292, 299, 312, 348, 365); others
appear to be direct, provider-to-patient transmission (discussed in
Provider-to-patient transmission. To date, iatrogenic transmission of
HCV from HCV-infected providers to their patients has been uncommon.
Nonetheless, the last several years have seen reports of individual
cases of provider-to-patient HCV transmission as well as both small and
large clusters of HCV infections. The first suggestion of iatrogenic
infection was reported from England in 1995 (261). At the time of the
initial publication, infection from a surgeon to his patients was
strongly suspected but not definitively proven. A patient who developed
acute hepatitis C infection following cardiovascular surgery (without
other risk factors) was found to have been operated on by a health care
worker who was positive for antibody to HCV. During the time that the
this case was being investigated, the first report of documented
iatrogenic transmission in surgery was reported from Spain (97). In a
look-back study, these investigators identified 6 of 222 patients who
had been operated on by an HCV-infected surgeon who acquired HCV
infection. In five of the six cases, the HCV strain isolated from the
patient was closely related to the strain carried by the surgeon (97).
All of the patients who became infected with the surgeon's strain had
undergone valve replacement surgery (97).
As a result of completion of the detailed evaluation of the initial
English case discussed above (261), Duckworth and colleagues reported
that 1 out of 278 patients identified in a look-back study of patients
who had had surgical procedures performed by an HCV-infected junior
surgeon developed HCV infection with a strain identical to the
surgeon's. The patient who developed HCV infection had undergone
coronary artery bypass surgery, during which the infected surgeon was
the first assistant (90). In the fall of 1999, a third case of
surgeon-to-patient transmission was reported (263). Other than the fact
that the surgeon involved was an English gynecologist and the patient
who became infected had undergone a gynecological procedure, few details
of this third case are available (263, 264). An extensive look-back
study (including patients from as far back as 1978) was conducted on
patients who had had procedures performed by this surgeon. More than
4,500 patients from 11 different hospitals in England and Wales in which
this surgeon had performed procedures were tested. Eight of these 4,500
individuals were discovered to have HCV infection caused by the same
strain of HCV as the surgeon's (264, 265). Although these cases occurred
some time ago, the specific details of these investigations are still
unavailable in the medical literature. Most of the information gleaned
about these events was published in the lay press.
More recently, Ross and coworkers reported the results of a look-back
study of the surgical patients of an HCV-infected orthopedic surgeon
(286). These investigators evaluated 207 of the 229 patients who had
undergone orthopedic operations in which an HCV-infected orthopedic
surgeon had actively participated. Three of the 207 were found to be HCV
infected (as determined by a positive HCV antibody test), and one of the
three was found to harbor an HCV isolate that was nearly identical to
the orthopedist's. The patient had undergone a total hip arthroplasty
with trochanteric osteotomy (286).
The same investigators also conducted a look-back study of individuals
who had been patients of an HCV-infected German
obstetrician-gynecologist for the preceding 7 years. The
obstetrician-gynecologist had been shown to transmit HCV infections to a
patient on whom he had performed a caesarian section (287). The
investigators were able to screen nearly 80% of the physician's 2,907
patients and did not identify any additional cases of transmission
(287). Cody and coworkers recently documented transmission of HCV
infection from an anesthesiologist who had acute HCV infection to a
patient for whom the physician had provided anesthesia services during a
thoracotomy. None of 348 patients for whom this physician had provided
anesthesia services were infected.
Two additional look-back studies involving the potential for health care
worker-to-patient transmission of hepatitis C are in progress in the
United Kingdom (264, 265). In the first of these studies, in which
approximately 1,900 patients were potentially exposed to an HCV-infected
surgeon, three infections were directly linked to the infected provider
(41, 265). In the second study, nearly 750 patients of an HCV-infected
provider were contacted. In that investigation, only one infection has
thus far been linked directly to the infected provider (265). Finally,
the Public Health Laboratory Service in the United Kingdom recently
reported initiating an additional look-back study in southern England
and sent letters to 228 patients of an HCV-infected practitioner
offering follow-up testing, again after an index case was identified as
being linked to the practitioner following an exposure-prone procedure
The United Kingdom experience is distinctive in that the rate of HCV
transmission from providers to patients seems to be higher in the United
Kingdom look-back studies than in the other studies published to date.
Summarizing the experience from the investigations and look-back studies
in the United Kingdom (and excluding index cases for these
investigations), 9 of 7,656 (0.12%) patients evaluated became infected
with HCV strains identical to their practitioners'. The transmission
rate in the United Kingdom studies, if one includes the index cases, is
0.18%. Experience in the other published look-back studies is
substantially different. In four such studies, again excluding the index
cases, no additional cases were found to have acquired iatrogenic HCV
infection among more than 3,000 individuals tested. The transmission
rate in these four studies, if one includes the index cases, is similar
to that in the United Kingdom studies (0.13%). At least to date, the
data available preclude any assessment of factors associated with risk
for transmission in the health care setting. Nonetheless, the fact that
two gynecologists, three cardiac or thoracic surgeons, and an orthopedic
surgeon were involved in these instances of provider-to-patient
transmission suggests that factors similar to those identified for
hepatitis B transmission (149) are likely operative. The large studies
and the recently reported experiences from the United Kingdom clearly
interject a substantial dose of concern about the potential for
iatrogenic spread of this blood-borne pathogen.
Ross and colleagues reported a cluster of cases of HCV infection linked
to an anesthesia assistant (285). In this unusual case, the anesthesia
assistant acquired acute HCV infection as a result of an occupational
exposure to a patient in the operating room (presumably as a result of
contaminating an open wound on his right-hand third finger). The
assistant may have represented an increased risk for transmission
because he was working while developing acute HCV infection. In the
course of 3 weeks, during which his finger lesion was purportedly still
weeping, he infected five patients (285). Interestingly, the assistant
did not wear gloves, and the authors argued that this cluster would
likely have been prevented entirely by the use of universal standard
In one highly unusual case, a child acquired HCV infection from his
mother as a result of her providing health care (54). The child was a
hemophiliac and required frequent clotting factor concentrate infusions.
The child's mother provided this care; however, she did not wear gloves.
The mother, who was chronically infected with HCV, recalled several
instances in which she stuck her own finger with the needle for the
infusion, with blood visible several times. She could not recall if she
continued to use the same needle for the infusion, but it seems likely
that she did (54). Sequence analysis demonstrated that the mother's and
child's HCV isolates were identical.
A cluster of cases of iatrogenic HCV infection have also been identified
that were linked to a health care worker's injecting drugs intended for
patients into himself and then reusing the needle to inject his
patients. In this outbreak, an anesthesiologist infected 171 patients
with a hepatitis C strain that was identical to the strain he carried
Clearly, without meticulous attention to infection control and
disinfection and sterilization procedures, the risk for transmission of
blood-borne pathogens in the health care setting is magnified. In some
countries where HCV infection is endemic in the general population,
hospitalization and invasive procedures do appear to be significant risk
factors for HCV infection in some epidemiological studies (87, 218, 327,
To be able to manage any disease state effectively, a practitioner must
first have a clear understanding of the etiology, pathogenesis, and
natural history of the condition. Whereas we learned about the etiology
of hepatitis C in 1989 (65), and, in the past 12 to 13 years, a great
deal of progress has been made in attempting to understand the
pathogenesis and immunopathogenesis of infection caused by this
flavivirus, the natural history of the disease caused by the hepatitis C
virus still remains a matter of some controversy.
To understanding the natural history of the disease produced by this
interesting pathogen, one needs several key pieces of data (302). To
characterize the natural history of any disease, the investigator must
first be able to determine the precise time of onset of the disease.
Additionally, the investigator must have a clear appreciation for the
signs, symptoms, and morbidity that the disease produces; a dependable
marker or markers for the disease; accurate measures of disease
progression; and reliable measures of disease status in order to chart
the course of a chronic disease. Furthmore, one must be able to follow
the disease in its isolated state, uninfluenced by comorbidities,
therapeutic interventions, and other external factors in order to
identify morbidity and mortality events directly associated with the
The controversy regarding the natural history of hepatitis C infection
arises from the fact that many, if not most, of the conditions outlined
above cannot be met. The fact that 13 years after identification of the
etiologic agent the natural history of the disease remains remarkably
clouded relates directly to the complexity of hepatitis C infection.
More than three-fourths of hepatitis C infections do not cause jaundice
and are asymptomatic or at least so mild clinically that they are not
detectable as significant clinical illnesses (353). The significance of
asymptomatic HCV viremia in the absence of transaminase elevation is
still not fully understood (69, 266, 305). Acute, symptomatic hepatitis
C infection is a relatively uncommon presentation (unlike hepatitis B
virus infection). More than 70 to 85% of individuals who are detected as
being infected through the use of antibody screening progress to develop
chronic infection. What remains unclear, however, is what fraction of
patients exposed to and subsequently infected with the hepatitis C virus
ultimately progress to serious liver disease, cirrhosis, and/or
hepatocellular carcinoma. Further muddying this circumstance is the fact
that recent information suggests that a population of patients may be
exposed to the hepatitis C virus, clear the infection through natural or
cellular immune mechanisms, never develop productive hepatitis C
infection, and never make an antibody response against the virus (332).
These individuals would be missed entirely by either anti-HCV antibody
detection or PCR for HCV RNA. Interestingly, such individuals often do
have immunological memory, as manifested by robust, persistent T-cell
cytotoxicity responses directed against HCV-associated epitopes.
We now appreciate that the scope of the natural history of hepatitis C
infection encompasses a spectrum of virus-host interactions that range
from immediate viral clearance without stimulating humoral immunity;
acute subclinical infection that resolves spontaneously; acute clinical
infection that resolves spontaneously; subacute or acute infection that
either resolves spontaneously or leads to chronic viremia without
defined histologic or biochemical evidence of hepatic disease;
persistent but stable hepatitis without progression; and progressive
disease that leads to acute or chronic liver failure, cirrhosis (which
may range from relatively stable over time to rapidly progressive), and
hepatocellular carcinoma. What remains elusive, even 13 years after the
discovery of the hepatitis C virus, is the frequency of these various
outcomes and the factors that influence them.
Some factors have been associated with either favorable or untoward
outcomes of HCV infection; however, these findings are not always
consistently identified from study to study. One recent study, for
example, found that the following factors were associated with virus
clearance: nonblack race, not coinfected with human immunodeficiency
virus (HIV), age less than 45 years, and the presence of ongoing
infection with hepatitis B virus (337). Factors found in other studies
that were not validated in the study of Thomas and coworkers cited above
include the extent of weekly alcohol use and the frequency of injection
drug use (337).
Conversely, when factors associated with the worst outcome, end-stage
liver disease, were assessed in the same study, the following factors
were identified as associated with this adverse outcome: age greater
than 38 years, increasing time from first use of injected drugs, more
frequent use of injecting drugs, consumption of more than 260 g of
ethanol per week, and male gender. No association was found with HIV
coinfection, black race, chronic carriage of hepatitis B virus, and HCV
viral load or viral burden, as determined by quantitative PCR (337).
Other investigators have suggested that alcohol consumption may be the
or, at least, a primary determinant of fibrosis and cirrhosis as an
outcome of HCV infection (254, 296, 352).
Other factors that have been associated with adverse outcomes of
hepatitis C infection in some studies include the patients' major
histocompatibility complex (MHC) class II alleles (20, 24, 76, 103, 215,
344); the viral HCV genotype in many (91, 157, 190, 239, 256, 257, 271,
314) but not all (283, 301, 368) studies; viral burden in some (130) but
not all (102, 157, 337) studies; smoking (245, 296, 357); and
coinfection with other blood-borne pathogens (2, 33, 111, 120, 269, 282,
Several studies have identified HIV coinfection as predisposing to a
more rapid progression of hepatitis C infection (summarized in reference
204). Several studies have suggested that the course of hepatitis C
infection is accelerated and that the disease may produce more severe
hepatic damage in HIV-coinfected patients (10, 30, 196, 204, 254, 319,
324, 337-340). These studies also demonstrate that patients infected
with both viruses generally have higher circulating HCV viral burdens
than do patients who are not HIV infected. Some of the health care
workers who have become infected with both viruses following
occupational exposures have had unusual courses, including rapid
progression of illness and delayed seroconversion (55, 282).
IMMUNITY AND IMMUNOPATHOGENESIS
The role that the host immune system plays, both in the defense against
HCV infection and in the pathogenesis of HCV-associated disease states,
has been a subject of intense interest and controversy over the past
several years. This issue has been reviewed in detail (and,
interestingly, from several various perspectives) in the past 5 years
(83, 95, 118, 233, 279). The relative importance of the natural, humoral,
and cellular limbs of the immune system has been the focus of much
investigation during the past decade. Suffice it to say, as discussed
above, that both direct and indirect evidence suggests that a variety of
factors, some related to genetics, some related to host defense, some
related to environmental factors, and some related to the virus, have
been shown to influence outcome in this often persistent flavivirus
A substantial body of evidence points to immune participation in the
pathogenesis of HCV-associated illness. Both autoimmunity (274)
(including a suggestion of autoimmune hepatitis) (233) and essential
mixed cryoglobulinemia (243) are features frequently associated with HCV
infection. Similarly, investigators have documented that cellular
immunity plays a significant role in the pathology of HCV infection.
Direct cell-mediated (CD8+) cytotoxicity likely represents an important
mechanism for the killing of HCV-infected hepatic cells (233). In
addition, some investigators have postulated that CD4+ cells may also
contribute to the pathogenesis of infection (180). In fact, a host of
presumably immunologically mediated extrahepatic manifestations have
been documented as being associated with hepatitis C infection,
including porphyria cutanea tarda, lichen planus, vitiligo,
cryoglobulinemia, membranoproliferative glomerulonephritis,
lymphoproliferative disorders (including non-Hodgkin's lymphoma), a
Sjogren-like syndrome, ischemic retinopathy, systemic vasculitis, and
autoimmune thrombocytopenia (summarized in references 96, 220, 229, 243,
251, 375, and 379).
With respect to the beneficial aspects of the host immunological
responses, clearance of HCV infection is accomplished through balanced
coordination of aggressive, effective, persistent cellular and humoral
immune responses (176). Diminished effectiveness of cell-mediated
cytotoxicity (165), inadequate CD4+ helper T-cell responses (126), and
decreased efficacy of B cells, which have been demonstrated in animal
models of other viral infections (253, 341, 342), have all been
associated with long-term viral persistence. A brief discussion of the
relative contributions of humoral and cellular immunity to host defense
In the 15% of individuals who, when infected, spontaneously clear
hepatitis C infection, recovery is frequently associated with (but not
necessarily causally related to) the development of specific antibodies
directed against HCV. The fact that HCV infection persists in the face
of the antibody response indicates that, in the chronically infected
patients, antibody is insufficient to clear the infection. Individuals
who develop chronic infection also develop HCV-specific humoral
responses, though these responses are not adequate to clear infection.
With respect to HCV infection, humoral immunity can assist in the direct
neutralization of cell-free virions but can only play an extremely
limited role in eradicating HCV inside cells.
Immunocompetent patients who acquire HCV infection commonly produce a
variety of antibodies directed against both structural and nonstructural
regions of the virus. The antienvelope portion of the antibody response
decreases gradually over time. In chronic infection, the host's humoral
immunological response places substantial pressure on the virus,
resulting in the emergence of generations of quasispecies (104-107).
Some investigators have suggested that a brisk antibody response
directed against the hypervariable region of the HCV envelope protein
may be an important component of viral clearance mechanisms affecting
recovery (208, 376-378). Ray and coworkers found that quasispecies
complexity was increased and that selective pressure was decreased in
five patients who had chronic infection manifested by persistent viremia
Farci and coworkers provided convincing evidence that the ultimate
outcome of hepatitis C infection (especially as regards viral clearance
and recovery versus viral persistence) may be determined early in the
course of primary infection by the rate at which diverse viral forms
emerge (106). The emergence of increasing (as opposed to decreasing)
numbers of quasispecies, presumably permitting the virus to escape host
immunity, both humoral and cellular, predicts chronic infection (106).
In this study, acute infection that progressed to chronicity was
directly associated with the development of increasing viral diversity
within the first 4 months of infection (106). The authors argue that
monitoring viral diversity during the early evolution of infection may
permit accurate prediction of outcome (106).
Not all studies have corroborated the finding that the immunological
pressure may produce "escape" quasispecies. Working with a chimpanzee
model of HCV infection, Bassett and coworkers found that viral clearance
was not associated with an antienvelope antibody response (25). In fact,
in this animal model, antibody directed against the major variable
envelope protein was identified only in animals that had persistent
viremia. Taken together, these results suggest that, at least in the
chimpanzee model, factors other than immunological pressure resulting in
escape quasispecies may contribute to the maintenance of chronic
infection. Other studies in patients (albeit with relatively small
populations) (48, 207, 209, 212) concluded that the evolution of HCV
quasispecies is not simply a matter of immunological pressure.
Current evidence suggests that both CD4+ and CD8+ T lymphocytes play
significant roles in host defense against hepatitis C infection. Studies
in animal models and limited human studies of hepatitis C infection
demonstrate that brisk T-helper and T-cytotoxic responses are both
associated with resolution of HCV infection (59, 74, 83-85, 94, 126,
278-281, 360). Both helper and cytotoxicity responses are robust when
infection resolves spontaneously; furthermore, these cellular responses
appear to correspond in time with the resolution of infection (195),
although one recent primate study did not demonstrate a clear
correlation between cellular responses and viral clearance (343). As
noted above, when the host possesses certain HLA genes, spontaneous
resolution of infection occurs more commonly (20, 24, 76, 103, 215,
344). Keeping in mind that spontaneous resolution is the exception
rather than the rule for HCV infection, science needs to understand why
these responses fail in the majority of instances. Some investigators
have suggested that individuals who develop chronic viremia or infection
produce modest, if any, CD4+ T-cell responses (126, 139, 332). Whether
persistent infection produces or is a direct result of abnormal
attenuation of T-cell responses is unclear at this time (231), though
one argument that the virus is responsible for downregulation of the
CD4+ responses comes from the fact that these responses develop (or
redevelop) following interferon therapy (75).
Similarly, CD8+, suppressor, and cytotoxic responses in acute HCV
infection are also incompletely characterized. Reasonably brisk
cytotoxic responses have been documented among patients who develop
chronic HCV infection (193, 335). Possible explanations for why these
responses are inadequate to clear the infection include the possibility
that the responses are downregulated as a result of the HCV viremia
(126, 193, 194) and that the magnitude of the response is inadequate or
that the overall quality of the immunological response may be too
narrow, or not be directed specifically against key protein or peptide
antigens. Other investigators have incriminated an inadequate CD8
response as a major contributor to viral persistence and chronic
infection (132, 362).
Takaki and colleagues studied a cohort of women who had been
inadvertently exposed to a single HCV strain of known sequence in a
point source epidemic and found that, despite documented exposure,
circulating HCV-specific antibodies were undetectable in many patients
20 years after recovery (332). Conversely, these investigators found
that the same individuals who lacked anti-HCV antibodies had detectable
levels of helper and cytotoxic T-cell responses directed against HCV
antigens. These authors argue that the these HCV-specific cellular
immune responses serve as more reliable biomarkers for previous HCV
exposure or infection than do tests for specific anti-HCV antibody
(332). They also emphasize that because anti-HCV antibodies are not
detectable in a substantial fraction of exposed or previously infected
individuals and because the current screening tests for exposure are
based entirely on detecting anti-HCV antibodies, the true incidence of
self-limited HCV infection may be considerably underestimated (332).
In summary, although the precise mechanics of the successful
immunological response to HCV have not been delineated, and despite the
fact that the relative importance of humoral, cellular, and natural
immunity in host defense against HCV remains a matter of substantial
controversy, one can mount a reasonable argument that both cellular and
humoral immune responses play important roles in determining the
outcomes of HCV infection. As yet, we do not understand either why some
individuals develop balanced, aggressive, persistent responses that are
effective in clearing the virus and others do not, or why some
individuals develop a persistently bland, slow, or nonprogressive
infection and others develop aggressive fibrosis and cirrhosis.
RISKS FOR HEALTH CARE WORKERS
Prevalence of HCV Infection
Studies of the prevalence of HCV infection in health care workers have
generally demonstrated that health care workers are at only minimally
increased risk for HCV infection compared with the population at large
(summarized in reference 181). Interpreting the results of these studies
is complex because of all of the potentially confounding variables that
may influence such studies, e.g., geographical differences in prevalence
(361), genetics, socioeconomic factors, race, and environmental factors,
most of which were not investigated in these studies. In addition,
appropriate control groups are not always included, and many of the
studies (because of the convenience of the data) inappropriately employ
blood donors as controls. As a group, blood donors are probably not the
best controls, since individuals who are at risk for blood-borne
infection or have a history of hepatitis have been specifically excluded
(310). Factors that have been associated with increasing HCV prevalence
in at least one study include increasing seroprevalence with increasing
age, increasing seroprevalence with increasing number of years in a
health care occupation, history of transfusion of blood or blood
products, and having sustained needle stick injuries (summarized in
Several case reports describing instances of well-documented
occupational HCV infection have been published since serological and
molecular testing for HCV has been developed (46, 210, 223, 230, 237,
238, 282, 284, 293, 297, 299, 300, 325, 330, 349, 351). I would stress
that the nosocomial epidemiology of occupational HCV infection remains
somewhat unclear. The overwhelming majority of infections are associated
with parenteral exposures (46, 210, 223, 230, 237, 238, 282, 297, 299,
300, 325, 330, 349, 351), although two of the anecdotal reports describe
infection associated with mucosal splashes (284, 293). Delineating
additional factors associated with occupational risk has been difficult
for a variety of reasons, the most problematic of which is the fact that
our current understanding of the pathogenesis, host response, and other
early events in HCV infection is not precise. Factors that have been
shown to influence risk for other blood-borne pathogen infections, such
as the presence of visible blood on the injuring device, the depth of
the injury, the device inserted into a vascular channel, and viral titer
in the source patient (45), have not yet been linked to HCV exposures
and infection. Nonetheless, it seems entirely reasonable and logical to
assume that factors that relate directly to inoculum size are very
likely to operate in HCV infection as they do in HIV and hepatitis B
virus infection in this setting.
Investigators in four studies have attempted to determine the number of
incident HCV infections among cohorts of previously uninfected health
care workers (73, 86, 123, 187). Taken together, these studies clearly
document some risk for HCV infection, though clearly not of the same
magnitude as for hepatitis B infection and slightly higher than for HIV
infection (123). Cooper and coworkers retrospectively evaluated 960
dental health care workers over a 2-year period and found an incidence
of 0.15 HCV infections per 100 person-years of follow-up (73). Lanphear
and colleagues evaluated hospital staff over a 10-year period and found
six incident cases of non-A, non-B hepatitis, four of which could be
serologically proven to be HCV infection, an incidence of 21 cases per
100,000 health care workers per year (187). This incidence in this
health care worker cohort was approximately three times higher than that
for non-health care workers. DiNardo et al. evaluated 765 hospital
workers over a 6-year period and found one incident infection, an annual
incidence of 0.02% (86). Gerberding evaluated a population of health
care workers working at a large public hospital in San Francisco for 8
years and identified one incident infection (123). From these data, the
investigators calculated an incidence density of 0.08 per 100
person-years (123). Together, these cohort studies demonstrate a small
but measurably increased risk for health care providers to acquire HCV
infection as a result of occupational exposure.
As noted above, in the National Health and Nutrition Examination Survey,
Alter and coworkers did not identify an association between a health
care occupation and HCV infection (15). In fact, in this study, in the
three ethnic groups studied and in the total population surveyed, the
prevalence of HCV was actually lower among those who had ever worked in
a health care setting compared with those who had not (15). These data
were not corrected for either socioeconomic status or other potentially
confounding risk factors. Nonetheless, whatever contribution to risk is
made by working in health care occupations is dwarfed by these other
factors. Conversely, in an Italian population-based survey for acute
viral hepatitis (a suboptimal marker for HCV infection that would tend
to underestimate risk because of the infrequency with which HCV
infection presents as acute hepatitis), health care workers were nearly
three times as likely to acquire acute hepatitis C as were members of
the general population (322). When the study was repeated 3 years later,
health care workers were only 1.7 times more likely to have acute HCV-induced
Several studies have attempted to assess the magnitude of risk for
infection associated with parenteral (and in some cases mucosal)
occupational exposures to HCV in the health care setting (18, 22, 86,
116, 137, 140, 147, 152, 174, 187, 222, 223, 244, 249, 267, 268, 270,
277, 309, 318, 320, 380; G. Ippolito, V. Puro, and G. De Carli, 10th
Int. Conf. AIDS, 1994, abstract 271 B/D; A. Veeder, K. Stellrecht, A.
Steinmann, K. Putnam, W. Caldwell, and R. Venezia, Eighth Annu. Meet.
Soc. Health Care Epidemiol. Am., 1998, abstr. 31). Whereas most of the
studies employed anti-HCV antibody as the primary detection system for
HCV infection, seven of the studies used PCR technology to attempt to
detect HCV RNA as a marker of infection among individuals who had been
parenterally exposed to blood from patients known to harbor HCV (18, 22,
137, 140, 222, 223, 320; Veeder et al., abstr. 31).
Table 1 lists the published longitudinal studies of health care workers'
occupational risk for HCV infection following parenteral exposure to
blood from individuals known to be infected with HCV. Transmission rates
in these studies range from 0% (9 of the 25 studies) to 22.2%. The
reasons for the substantial variation in transmission rates include
different infection detection systems with different sensitivities, the
possibility that different exposures may pose different levels of risk,
geographic differences and, likely, genetic differences in the
populations being studied, substantial differences in sample sizes, the
potential for variable infectivity of source patients (i.e., viral
burdens), different viral genotypes, the presence of other cofactors
(e.g., HIV infection) in source patients, and a veritable host of other
potentially confounding risk factors and variables. Additional
limitations of the studies that have employed HCV RNA-PCR testing
include not knowing what fraction of individuals who are exposed to HCV
may have intermittent PCR spikes, with or without developing productive
HCV infection, and the fact that nucleic acid-based tests may also be
technically difficult to perform reproducibly and may be falsely
positive or negative if samples are not handled or processed
appropriately. Nucleic acid contamination is a major problem in many
laboratories that conduct these tests. Nonetheless, if one ignores the
limitations of the data, the differences in study design, and the
substantial differences in testing methods employed and combines the
data from all of the studies, the average infection risk following
parenteral exposure is 1.9%. This risk places HCV occupational risk
squarely between the risk for transmission of hepatitis B virus (about
30% per parenteral exposure to blood from an e antigen-positive patient)
(306, 364) and that for HIV (approximately 0.3% per parenteral exposure)
TABLE 1. Longitudinal and prospective studies of risk for infection with
hepatitis C virus following parenteral occupational exposure to blood
from infected patients
No. of paren- teral HCV exposures
No. of HCV infections
Of subjects infected
EIA-1, RIBA-1, PCR
Ippolito et al.c
RIA-1, PHA-2, PCR
EIA-2, PCR, sequencing
EIA-1, EIA-2, PCR
Veeder et al.e
EIA-3, RIBA-2, PCR
Recent data (discussed above) from studies of the immunology and
immunopathogenesis of HCV infection suggest that none of these
techniques may provide a true denominator of who has been "exposed" to
HCV. One anecdotal case report documents HCV RNA circulation in an
individual who never made anti-HCV antibody despite the development of
HCV infection with circulating viral burdens of 106, 106, and 103
copies/ml at 2, 3, and 4 weeks, respectively (224). Additionally, some
studies have suggested that the most reliable marker of past exposure is
an assessment of specific cellular immunity directed against HCV (332)
(not used in any of these longitudinal studies); these investigators
suggest that both antibody tests and tests for circulating HCV RNA
underestimate the true number of exposures.
From these data, one can conclude that the risk associated with an
occupational exposure is likely to be less than the 1.9% summary risk
presented above. How much less than 1.9% is, at this time, uncertain. A
reasonable estimate, based on studies of exposed health care workers
combined with the studies of Takaki et al., is that between 1% and 2% of
those who are exposed develop markers of infection. As noted above, this
estimate places the occupational HCV risk directly between the risks for
occupational hepatitis B virus and HIV infections, approximately 10-fold
less than the hepatitis B virus risk, and approximately 10-fold higher
than the HIV risk.
Based on the data summarized above, the risks for occupational
transmission of hepatitis C are incompletely characterized. Whereas the
parenteral route of transmission of HCV is definitively established as
an important mode for both transfusion recipients and intravenous
substance users, transmission to health care providers as a result of
occupational parenteral exposure remains a relatively uncommon event.
PREVENTING OCCUPATIONAL TRANSMISSION
Lessons from Chronic HCV Infection
The treatment of chronic hepatitis C infection has met with increasing,
albeit modest, success over the past 15 years (34, 82, 155, 201). The
cornerstone of therapy was initially alpha interferon. Initial treatment
regimens with interferon alone resulted in response rates of from 20% to
35%; however, cures or sustained remissions occurred in less than 10 to
20% of patients (255, 334). Therapy has been particularly problematic
for patients infected with genotypes 1a and 1b. In the 1990s, the
nucleoside analog ribavirin was shown to decrease alanine
aminotransferase levels in patients and to improve the hepatic histology
with chronic HCV infection. A number of trials subsequently demonstrated
that combination therapy with interferon and ribavirin is superior to
interferon alone in terms of percent responding, percent with sustained
responses, and histological improvement in the liver (175). The
combination produced sustained responses in the range of 30 to 40% (47,
201), although not all studies have found a substantial benefit with the
The next significant advance in treatment was the modification of
interferon with polyethylene glycol to improve drug pharmacokinetics and
to provide long-term activity. Compared to interferon, so-called
pegylated interferon or peginterferon has similar activity and far
superior pharmacokinetics (359). Use of pegylated interferon in
combination with ribavirin has produced sustained response rates in some
studies that are greater than 50%, with some approaching 60% (77, 82,
119, 154, 206, 236).
Other candidate therapies that are currently in evaluation include
alternative interferons, amantadine, micophenolate, nucleoside analogs,
1 thymosin, Maxamine (histamine), HCV-specific protease, helicase and
polymerase inhibitors, antisense oligonucleotides, and interleukin-10
(158, 214). Whereas interferon has both immunomodulatory and direct
antiviral activity (234), and some antiviral agents specifically
directed against HCV are on the horizon, the majority of the agents
being evaluated are immunomodulators.
What lessons have been learned from the treatment of chronic HCV
infection? First, even with the current gold standard therapy, the
outcomes associated with therapy remain suboptimal and somewhat
discouraging. Second, the primary approach to therapy (i.e., the
interferons) has mainly been immunomodulatory, and such interventions
are not likely directly comparable in the postexposure management
setting to the use of antiviral compounds as postexposure prophylaxis
for occupational exposure to other blood-borne pathogens (e.g., HIV).
Third, the long courses of treatment required (i.e., 6 months to a year)
and substantial toxicities in therapy recipients are daunting.
Lessons from Acute HCV Infection
The experience of treating acute hepatitis C infection has been somewhat
more favorable (6, 44, 153, 161, 162, 354). In general, these studies
(although many of the studies have limitations in study design) have
shown higher resolution rates and lower rates of chronic infections
among patients who received treatment for their acute infections than is
the case with therapy for chronic infection (34, 82, 155, 201). These
data should be interpreted with caution in light of the fact that we do
not yet have a clear understanding of the early events in the
pathogenesis and host response to hepatitis C virus exposure and
infection (see discussion of immunopathogenesis, above).
Special mention should be made of the study recently published by
Jaeckel and coworkers (161). In this study, the authors treated 44
German patients who had acute hepatitis C with 5 million units (MU) of
interferon 2b daily for 4 weeks and then three times weekly for the
ensuing 20 weeks. Of the 44 patients studied, 9 acquired HCV infection
through needle sharing in intravenous substance use; 14 were health care
workers who acquired HCV infection as a direct result of an occupational
needle stick exposure; 7 acquired infection as a result of
patient-to-patient spread in a health care institution or as a result of
nosocomial spread of the virus; 10 were thought to have acquired
infection following sexual exposures; and four had acute infection, the
etiology of which could not be determined (161). The patients with acute
hepatitis received single-agent therapy with interferon 2b. At the
conclusion of treatment as well as after 6 months of follow-up, HCV RNA
was undetectable, and alanine aminotransferase levels were entirely
normal in 43 of 44 patients (98%) (161).
These results are strikingly different from (and strikingly better than)
those in published studies of even the best and most effective
treatments for chronic HCV infection (154). I would underscore that the
outcomes and therapeutic responses that result from treating patients
who present with acute hepatitis caused by hepatitis C are very likely
substantially different from those in studies describing the treatment
of patients who have asymptomatic HCV viremia, those who have an
indolent presentation of HCV infection, and those who present with
chronic, progressive infection. As noted above, the immunological
response to HCV is exceedingly complex, and it could be argued that
individuals who develop acute hepatitis at the time of infection may do
so because they are mounting a more robust immunological response.
Although many such patients may well clear their infections
spontaneously, having 98% of patients clear the infection is essentially
Whereas the authors refer to this collection of 44 patients as having
"acute hepatitis," the patients themselves represent a truly
nonhomogenous group, having substantial differences in severity of
presentation, route of exposure, source of infection, gender, and age.
The time from hepatitis C virus exposure to development of the first
symptoms of the acute hepatitis syndrome in this population ranged from
15 to 105 days (mean, 54 days), and the time from exposure and infection
until initiation of therapy ranged from 30 to 112 days (average, 89
days) (161). Nonetheless, a 98% success rate cannot be discounted.
Vogel and coworkers previously reported success in treating a similarly
nonhomogenous group of 24 individuals with acute HCV infection (355).
Twenty-two of the patients completed therapy, and 20 of those cleared
their infections and remained PCR negative for HCV for 6 months.
Eighteen of these patients remained PCR negative for more than 18 months
(355). In a smaller study, Pimstone and coworkers treated seven patients
with acute HCV infection with a regimen that included 5 MU of alpha
interferon for 12 weeks followed by 3 MU three times a week for the
remainder of a year. All seven were PCR negative for HCV RNA at 6 months
following the completion of treatment (252). A number of additional
single case reports or small studies also document the success of
treating acute hepatitis in health care workers who sustained an
occupational exposure and developed evidence of productive HCV infection
(98, 237, 241, 294, 331, 347, 358). These studies used different doses
of different interferon products; however, none of the subjects in these
studies progressed to chronic infection, unlike the case reported by
Nakano et al. (230). In the cases in which the disease did not progress
to chronic infection, the majority were treated between 5 and 25 weeks
following the exposure; the majority had acute hepatitis; and all had
PCR tests positive for HCV RNA (though the tests several were positive
at a very low level). In the case in which the disease did become
chronic, a short course of interferon was administered prophylactically
(i.e., in the immediate postexposure period, prior to the development of
either symptoms or viremia) (230) (discussed in more detail below).
What have we gleaned from the studies evaluating the treatment of acute
hepatitis C? First, even with the limitations of these studies, data are
accumulating that conclusively suggest that treatment of acute infection
may be advantageous. Second, some aspects of the experience with
treatment of acute infection may be directly relevant to the management
of health care workers who have sustained occupational exposures to HCV
(discussed in more detail below). In fact, in two of the three studies
cited above, 15 of the patients studied were health care workers who had
sustained occupational exposures and progressed to the development of
the acute hepatitis C syndrome. Third, the investigators were able to
achieve extremely high regimen adherence rates despite the rigorous
regimens outlined and their obvious toxicities. Despite the use of very
high doses of interferon in one of the studies (5 MU of alpha interferon
subcutaneously daily for 4 weeks and then the same dose administered
three times per week for another 20 weeks ), combining data from
all three studies, only 3 of 75 individuals (4%) failed to complete the
half-year to year-long regimens.
Management of Health Care Workers after Exposure
Immediate management and follow-up strategies. Administering first aid
to a person subjected to an occupational exposure makes implicit sense.
If the worker her- or himself has not already cleansed and
decontaminated the exposure site, the Occupational Medicine staff should
assist in this process as soon as possible after the exposure. To my
knowledge, however, no data have demonstrated any direct benefit from
first aid in terms of preventing occupational infections. Puncture
wounds and other open wounds should be washed with soap and water. Some
authorities have recommended that open wounds be flushed with sterile
saline or a disinfectant solution (125). For splash exposures involving
the mouth and nose, I recommend rinsing aggressively with water. Splash
exposures to the eye should be flushed with water or with irrigation
fluids designed for irrigating the eye.
Each institution should develop streamlined mechanisms that facilitate
both the reporting of occupational exposures and the provision of
follow-up care for workers sustaining exposures. Institutions should
publicize these procedures widely so that employees at all levels of the
organization are aware of the importance of immediately reporting such
exposures as well as the importance of follow-up. Underreporting of
occupational exposures to blood-borne pathogens remains a significant
problem in the health care workplace (28, 31, 138, 150, 205).
Irrespective of the source patient's underlying infection status,
protecting the medical privacy and confidentiality of both the source
patient and the exposed health care workers should be a major priority.
In our institution, we manage records of occupational exposures
separately from both employee health records and source patients'
As would be the case for an occupational exposure to any blood-borne
pathogen, baseline testing of the source patient (to make certain an
exposure has occurred) and baseline testing of the exposed health care
worker (to make certain that the individual is not already infected) are
Since not all exposures are directly linked to an obvious source
patient, it is important to emphasize that making the effort to identify
the source, whenever even remotely possible, is worth the effort. Source
patients should be evaluated clinically and epidemiologically for
evidence of infection with all relevant blood-borne pathogens (e.g.,
HIV, hepatitis B virus, and HCV), and the examining physician should
consider other potentially transmissible infectious diseases, based on
the source patient's clinical history and condition. When the source
patient cannot be identified, we attempt to make an epidemiological
assessment of the likelihood of exposure to blood-borne pathogens (147).
Employees sustaining a "source unknown" exposure should be managed on a
case-by-case basis but should, at a minimum, be offered follow-up to
assess whether a blood-borne pathogen has been transmitted.
Even when the source patient is hospitalized because of hepatitis C
infection, testing for other blood-borne pathogens (because of the
similarities in epidemiologies) is appropriate. I recommend baseline
testing of the source patient for hepatitis B surface antigen, hepatitis
C antibody, and HIV. Testing for hepatitis B surface antigen usually
does not require informed consent (125), nor does testing for antibody
to hepatitis C in most jurisdictions. In addition, I recommend that the
source patient be tested for antibody against HIV. In some states and
jurisdictions, this process requires informed consent. In those
instances, I recommend that the testing be discussed appropriately with
the source patient and that consent be obtained. Most source patients
agree to testing voluntarily. As noted above, every effort should be
made to preserve the medical privacy and confidentiality of both the
source patient and the health care worker. Where permitted by statute,
it may be possible for the managing physician to obtain consent for
serological testing from the source patient's immediate next of kin,
from the individual holding the source patient's durable power of
attorney, or from another individual who has been identified as legally
able to make the decision. This permission may allow source patient
assessment when testing would otherwise not be possible. Because there
are substantial differences in state and local regulations concerning
testing for blood-borne pathogen exposures, each institution should
create procedures that facilitate postexposure management and both
source and health care worker testing that are consonant with state and
local laws relevant to these blood-borne diseases.
Screening by antibody tests alone is subject to the limitations of these
tests. As noted above, none of the tests, even the current generations,
are capable of identifying 100% of those who have been infected
previously (332). In fact, Alter and coworkers suggest that as many as
10% of patients who harbor hepatitis C infection may not be detected by
currently available antibody tests (16). Furthermore, finding antibody
directed against HCV in the serum of the source patient for an
occupational exposure is not a totally accurate indicator of HCV
infectivity of the source patient. Some individuals with anti-HCV
antibodies have no or very low levels of circulating HCV, and some of
these individuals may have totally resolved HCV infection. Nonetheless,
in the acute setting of occupational exposure, sources found to be
positive by the antibody screening test should be assumed to be
Currently, the U.S. Public Health Service (55) recommend the following
approach for follow-up of health care workers who sustain parenteral or
mucosal occupational exposures to HCV: testing the source patient for
antibody directed against HCV; testing the exposed health care worker at
the time of exposure and at 6 months following the exposure for antibody
directed against HCV and for alanine aminotransferase levels; using
supplementary HCV antibody tests to confirm any positive results of HCV
antibody testing; not using postexposure prophylaxis with
immunoglobulin, antiviral agents, or immunomodulators; and educating the
exposed worker about the risk of infection, nosocomial epidemiology, and
secondary transmission as well as about strategies effective in
preventing transmission of blood-borne pathogens, including hepatitis C
virus in occupational settings (55).
At our institution, we monitor health care workers who have sustained
occupational exposures to HCV at 2-week intervals with an HCV RNA PCR
assay. In addition, anti-HCV antibody studies are performed at
three-month intervals or whenever HCV RNA is detected by PCR. If an
individual is found to be repeatedly positive by PCR, she or he is
referred to our hepatology service for follow-up and management. This
team is currently conducting a study of occupational infections and is
evaluating the watchful waiting strategy outlined below.
Unlike the case for hepatitis B infection, immunoglobulin prophylaxis is
of no value in managing occupational exposures to hepatitis C. Studies
conducted prior to the identification of hepatitis C as the cause of the
overwhelming majority of cases on so-called non-A, non-B hepatitis
suggested a possible benefit of immunoglobulin prophylaxis for the
prevention of this syndrome (177, 291, 307); however, since we have
become aware of HCV as a significant cause of posttransfusion hepatitis,
no study to date has demonstrated any benefit of immunoglobulin
prophylaxis. Although the Advisory Committee on Immunization Practices
from the Centers for Disease Control and Prevention previously
recommended (for parenteral occupational exposures to patients who had
non-A, non-B hepatitis) that "it may be reasonable to administer
immunoglobulin as soon as possible after exposure," currently the
committee actually recommends not administering immunoglobulin (53, 55).
Whereas the pooled "standard lot" immunoglobulin product once contained
antibody directed against hepatitis C virus (112), plasma donors are now
screened and eliminated from the donor pool if they are HCV positive.
These immunoglobulin products no longer contain antibodies to HCV and
thus offer even less theoretical benefit (221). In addition, in one
series of experiments, neither anti-HCV-negative intravenous
immunoglobulin nor immunoglobulin that contained high-titered antibody
directed against hepatitis C administered 1 h after exposure to
HCV-containing blood prevented transmission of HCV infection in
chimpanzees (183). Finally, it should be noted that administration of
intravenous immunoglobulin preparations has been incriminated as
transmitting HCV in Spain, France, Italy, Scandinavia, the United
Kingdom, and the United States (32, 38, 43, 52, 61, 68, 93, 108, 114,
128, 141, 142, 163, 164, 197, 203, 226, 240, 272, 276, 288, 298, 369,
370, 373). Newer approaches, such as solvent or detergent treatment and
heating at low pH, have reduced the risk of HCV transmission from these
products (37, 58, 289), but the clusters of infection linked to
intravenous immunoglobulin treatment clearly underscore the lack of
value of immunoglobulin as postexposure prophylaxis.
Despite oblique inferences in the literature suggesting the use of
immunomodulating substances in the immediate postexposure prophylaxis
setting, for a variety of reasons, among them the toxicity associated
with the administration of immunomodulators, the long courses of
treatment needed, and a paucity of data suggesting their efficacy in the
setting of postexposure prophylaxis, to my knowledge no one has formally
recommended that individuals sustaining an occupational exposure to HCV
be "prophylactically" treated with immunomodulators (17). The one
instance reported in the literature in which this approach was tried
indicated that it was not successful in preventing infection (230).
Additionally, should an effective vaccine directed against HCV infection
be developed, its use would also likely become part of an effective
postexposure management program (i.e., analogous to the use of the
hepatitis B vaccine after occupational exposures to hepatitis B virus).
As yet, other than alpha interferon, no agents with clearly defined
antiviral activity (as opposed to immunomodulatory activity) are either
marketed or in late-stage development for the treatment, preemptive
therapy, or prophylaxis of hepatitis C. Agents with antiviral properties
(e.g., specific protease, helicase, and polymerase inhibitors) are in
development, as noted above. In the absence of data about the efficacy
of these and other compounds in the postexposure setting, no
recommendation can be made about their potential use for postexposure
prophylaxis. Should compounds that are relatively safe and have efficacy
against HCV be developed, this subject should clearly be revisited,
especially in light of the animal and human data developed over the past
decade demonstrating that antiviral compounds are likely effective in
preventing occupational infection with human immunodeficiency virus
(summarized in reference 144).
Preemptive Therapy versus Watchful Waiting
One postexposure strategy that has been advocated by some authorities
working in this field (and parenthetically, a strategy that is in
relatively widespread use in the United States ) involves the
periodic monitoring of health care workers who have experienced
occupational exposures by PCR for HCV RNA at approximately 2-week
intervals following the exposure and aggressive implementation of
interferon therapy if HCV infection is documented to have occurred, as
measured by repeated positive RNA assays for HCV in the serum of the
exposed health care provider (preemptive therapy of documented early HCV
infection). Schiff, in an editorial in Hepatology, first suggested this
strategy in 1992 (295). One can marshal a substantial intellectual
argument that this strategy is sensible, in that therapy would be
initiated at a time when one would likely be dealing with one or only a
limited number of HCV quasispecies and when nonspecific stimulation of
the cellular immune system might be of maximal benefit.
Other investigators have argued for a "watchful waiting" strategy.
Following this line of thinking, clinicians would monitor the exposed
health care worker biweekly by PCR and then monitor those who develop
viremia over time to see if chronic infection develops. One suggestion
has been to treat only individuals who remain positive for HCV RNA by
PCR and have elevated alanine aminotransferase levels 2 to 4 months into
the course of their infections (6, 154). Under this scenario,
individuals who spontaneously resolve their infections would be spared
the toxicities (and the expense) (154) of lengthy courses of interferon.
Nonetheless, in the most recent National Institutes of Health Consensus
Conference on the Management of Hepatitis C Infection (304), Alberti et
al. concluded that the currently available evidence base supports the
treatment of individuals who have acute hepatitis C (6). He points out,
however, that the current evidence does not permit clear identification
of which patients should be treated, when therapy should be initiated,
or what regimen should be chosen for treatment (6)
Despite the interesting and very encouraging data addressing the
efficacy of early pharmacological and immunomodulatory intervention to
treat acute HCV infection (summarized above), we do not have data, at
least as yet, definitively establishing the ability of this
interventional strategy to manage occupational exposures to HCV. Based
on our experience with HIV postexposure prophylaxis, such information
may be extremely difficult to obtain, both because of health care
workers' unwillingness to participate in placebo-controlled trials (S.
W. LaFon, B. D. Mooney, and J. P. McMullen, 30th Intersci. Conf.
Antimicrob. Agents Chemother., 1990) and because occupational HCV
transmission events are sufficiently rare and sufficiently complex to
require a very large population in both arms of a placebo-controlled
trial to achieve statistical significance (17, 145).
Several anecdotal reports have reported the success of the preemptive
therapy approach to the management of occupational HCV exposures (18,
237, 241, 331, 358). Unfortunately, as is the case with almost all
infectious diseases, not all of the case reports demonstrate success
(230). The case report describing failure of a postexposure interferon
intervention may be instructive nonetheless. In this case, an individual
sustained a deep needle stick exposure to blood from a patient known to
have chronic HCV infection. In an attempt to prevent transmission of
HCV, the individual was given true postexposure prophylaxis with alpha
interferon, 5 MU per day intramuscularly for 4 days, beginning the day
of the exposure (230). By 1 month following the exposure, the individual
had elevated aminotransferase levels and was positive for HCV RNA by PCR
(230). At 11 weeks following the exposure, the patient's anti-HCV
antibody test became positive, and at 6 months after the exposure, a
liver biopsy demonstrated chronic persistent hepatitis. The patient was
subsequently treated with a 6-month course of alpha interferon (total
dose, 720 MU) and became disease free and PCR negative for a year of
follow-up (230). In this case, postexposure prophylaxis with interferon
for 4 days was not successful, whereas the watchful waiting approach of
treating established infection for 6 months to 1 year resulted in a
favorable outcome. Conversely, in some of the cases described in the
literature, individuals who had reproducibly positive HCV RNA tests were
treated immediately (and successfully) upon identification of the
viremia, in some instances without the exposed individual's ever
seronconverting to HCV antibody positivity (224).
The lessons learned from the treatment of acute HCV infections (see
above) may be relevant to the use of preemptive therapy; however, the
data should be interpreted with caution for a variety of reasons. First,
as noted above, we do not yet have a clear understanding of the complex
early events in the pathogenesis of HCV infection that determine the
outcome of HCV infection. Specifically, we do not know what fraction of
individuals who are infected with the small inoculum on a needle will
mount a brisk cellular immune response, completely resolving the
infection without ever developing antibody against HCV-associated
antigens (5, 161, 224, 332). Investigators need to gain much more
insight into the early events in HCV infection in order for us to
understand the pathogenesis, immunopathogenesis, and appropriateness and
efficacy of immunomodulating interventions in the postexposure
management setting. Second, a substantial fraction of individuals who
are infected with HCV via transfusion spontaneously clear the infection
despite the arguably large inoculum of virus received. Seeff and
colleagues found that more than 20% of patients who acquired
transfusion-associated HCV infection cleared the infection spontaneously
(303). Administering interferon to all individuals detected as having
circulating HCV by PCR would unnecessarily expose the 20% of individuals
who will spontaneously clear the infection to the toxicities of the
agent with no potential benefit. For individuals who develop the acute
HCV hepatitis syndrome, as many as 50% (or perhaps even more) may
recover spontaneously (6, 127, 188, 242, 353).
Third, information about the treatment of acute hepatitis may only be
relevant to individuals who present with this relatively unusual form of
HCV infection. As noted above, individuals who develop acute hepatitis
have higher rates of spontaneous resolution of the infection, and these
individuals, as a group, make more robust humoral and cellular responses
to viral antigens. Fourth, available information on which a decision to
base therapy would rely is limited to the anecdotal evidence described
above and the studies of the therapy of acute infection (most of which
are un- or poorly controlled). Fifth, the use of immunomodulating agents
in the postexposure prophylaxis setting is substantially different from
the use of antiviral agents directed against specific viral targets
(compared with postexposure prophylaxis for HIV exposures, where
antiretrovirals are the mainstay of therapy). Sixth, some individuals
have suggested that administering interferon before the infection is
established, and therefore before the cellular immune response has begun
in earnest, might be ineffective (6, 29, 133, 246). In fact, in one
instance in which a short course of alpha interferon was administered
prophylactically (i.e., immediately after a needle stick injury), the
recipient went on to develop acute HCV infection (230).
Despite all these limitations, and despite the absence of U.S. Public
Health Service support for such an approach, a substantial proportion of
institutions in the United States have adopted either the preemptive
therapy or watchful waiting approach to the management of occupational
exposure to HCV (17). Both the preemptive therapy and watchful waiting
models represent entirely reasonable approaches to the management of
occupational HCV exposure based on the currently available information.
From my perspective, monitoring for viremia by PCR, monitoring hepatic
function by alanine aminotransferase levels, and then making the
decision whether to intervene from the clinical and chemical data
obtained represent a far superior approach to postexposure management
than the 3-month to 6-month antibody testing previously recommended for
follow-up of these exposures (29, 53, 55). As noted above, the watchful
waiting strategy is the approach to this problem that is currently taken
in my institution.
Standard Universal Precautions and Exposure Avoidance
No discussion of prevention would be complete without emphasizing
primary prevention activities in the health care setting. Perhaps the
best strategy to prevent occupational and nosocomial transmission of all
blood-borne pathogens is to prevent health care worker injuries and
occupational exposure to blood (124). To minimize the bidirectional risk
of blood-borne pathogen transmission, health care providers should
follow standard universal precautions (50, 51, 121). Effective use of
these precautions, which have been shown to be effective in reducing
occupational exposures to blood (26, 101), will substantially reduce
blood exposures and thus the risk for transmission of HCV in either
direction. Elements of these precautions (summarized in detail in
references 50, 51, and 121) include hand hygiene, use of protective
barriers (especially gloves), and attention to the appropriate use and
disposal of needles and other sharp objects. Numerous strategies have
been shown to be effective in reducing occupational injuries, including
educating staff about the occupational risks prevalent in the health
care workplace, modifying procedures and work practices that are
intrinsically risky, and monitoring adherence to standard universal
precautions (26). Institutions should also continually scan the health
care marketplace for devices and technological advancements that can be
used to reduce occupational risk. Furthmore, institutions should collect
data about all occupational exposures and use these data to reduce
exposures. Finally, the appropriate use of vaccines, (e.g., hepatitis B
vaccine) is also a key part of primary prevention.
Active Immunoprophylaxis and Vaccine Development
The hepatitis B vaccine significantly reduced the occupational risk of
transmission of this blood-borne pathogen in the health care setting.
Clearly, the development of a vaccine for hepatitis C virus infection
would represent a major advance and would have a similarly substantial
impact on occupational risk for HCV infection in health care.
Nonetheless, in 2002, there are still many barriers to the development
of an HCV vaccine (summarized in references 115 and 258). Among these
challenges are the heterogeneity of isolates, the virus's ability to
modify envelope (and other) proteins rapidly in the face of
immunological pressure, incomplete understanding of the pathogenesis and
immunopathogenesis of HCV infection, the likely need to develop a
vaccine that stimulates both humoral and cellular immunity against HCV,
and the inability to culture the virus (115). Although several
investigators are aggressively pursuing a variety of approaches to
vaccine construction, no clear candidate is even on the distant horizon.
MANAGING HCV-INFECTED PROVIDERS
Transmission of HCV from health care providers to patients has been
reported infrequently, although several instances of iatrogenic
transmission have been reported in the past few years, primarily in the
United Kingdom (discussed in detail above) (35, 36, 41, 71, 90, 97,
259-261, 263-265, 286). As is the case for health care worker who carry
other blood-borne pathogens, chronically HCV-infected workers are
unlikely to transmit infection during routine (i.e., noninvasive)
patient contact. In addition, the risk for provider-to-patient HCV
transmission during the performance of "invasive" procedures is very
small and is likely to be intermediate between the remote risk of HIV
transmission and the small but measurable risk of transmission of
hepatitis B (27). Based on the experience in the United States to date,
transmission from infected providers to their patients is likely to
occur very uncommonly, will likely be associated with clear instances of
exposure of patients to providers' blood, and will likely also be
associated with providers who have relatively higher circulating titers
of HCV RNA.
Because of an increasing number of instances in which
provider-to-patient transmission of HCV has been documented in the
United Kingdom, practice restrictions have now been implemented for
HCV-infected providers (79, 80, 151, 262); however, not all authorities
in the United Kingdom believe that these restrictions are warranted
(70). In the United States, neither the Public Health Service (49) nor
professional organizations have recommended restricting the practices of
health care workers who perform so-called invasive procedures (149).
Discounting the experience in the United Kingdom, such restrictions seem
unnecessary unless transmission has been definitively linked to an
individual provider. If the experience in the United Kingdom is
ultimately shown to represent the risks accurately and the risk of
iatrogenic transmission is substantially larger than it currently
appears to be in the United States, the issue of managing HCV-infected
providers will clearly need to be revisited by public health officials.
As is the case for all instances of managing providers infected with
blood-borne pathogens, each provider should be evaluated individually.
The existing public health guidelines for managing providers infected
with blood-borne pathogens were primarily designed to address the risks
of hepatitis B and HIV infection. Because so little was known about the
risks for HCV transmission at the time of their creation, little is said
about the management of HCV-infected providers (summarized in detail in
reference 147). These guidelines did, however, suggest that health care
providers who were high-titered carriers of hepatitis B virus or
infected with HIV notify "prospective patients of the health-care
worker's seropositivity before they undergo exposure-prone invasive
procedures" (49). The guidelines did not define "exposure-prone invasive
procedures"; rather, they summarized the characteristics of procedures
that might be considered exposure prone (49). Ultimately, after
considerable discussion in the health care community, each state was
encouraged to consider this problem independently, and many states
crafted guidelines, resulting in uneven guidelines for this circumstance
across the country.
The issue of blood-borne pathogen-infected providers is an extremely
difficult one, both for medicine and for society. The risk for
transmission of these pathogens to patients is miniscule; however, the
consequences of transmission may be substantial. To craft a sensible
approach to this problem, medicine needs more information than is
currently available, including better quantification of the magnitude of
risk for provider-to-patient transmission of these blood-borne
pathogens; factors that might be used as intervention or prevention
strategies that might lessen the risk for patient exposures and,
therefore, patient infections; a clearer understanding of the ethics of
this complex issue; and definitive understanding of the sociopolitical
and legal consequences of issuing either restrictive or nonrestrictive
guidelines (147). At the time this article is being written, none of
these questions can be answered definitively.
Perhaps most perplexing among these difficult questions are the ethical,
legal, and sociopolitical issues associated with managing HIV-infected
providers. Basically, we find ourselves in a circumstance in which the
rights of the practitioner (i.e., medical privacy, right to practice)
intersect directly with the rights of the patient (147). Arguments of
substance have been made on both sides of this issue, and society
continues to wrestle with this difficult problem (summarized in
Our society manages risk and even perceives risk in a less than even
manner and is willing to accept voluntary risks (some of which are not
truly voluntary) while eschewing so-called involuntary risks. For
example, some individuals elect to smoke, to drive automobiles, and to
consume alcohol. Some talk on cellular telephones while driving. These
voluntary risks are often accompanied by hidden involuntary risks. One
cannot determine, for example, how much alcohol the person driving on
the other side of the road or immediately behind you on the road has
consumed. Instances of transmission of blood-borne pathogens from
infected providers to their patients (despite their rarity) serve as
lightning rods in society. These cases receive wide publicity and often
provoke almost visceral responses among members of society at large.
I would be remiss in not mentioning a fundamental principle of health
care provision, primum non nocere, that is, that providers first do no
harm. A major difficulty for medicine and society is the need to place
the potential for harm associated with allowing an infected provider to
practice in the appropriate perspective. Virtually every aspect of
health care is associated with risks (some of them less well defined,
and likely substantially larger, than the provider-to-patient
transmission risk). Restricting the practices of infected providers
because of risks that society considers negligible in other
circumstances may have other significant adverse effects (147). This
extremely complex issue needs excellent public health and political
leadership for resolution. As additional information about these risks
and the factors that might influence or reduce them becomes available,
the public health leadership should revisit the issue. Leadership must
develop a balanced, science-based analysis of all these risks for
society and for political leaders (147).
In deciding about the management of infected providers, several
additional issues should be considered. First, provider-to-patient
transmission accounts for only a minimal part of the burden of illness
attributable to these viruses (124). Mandatory practice restrictions
could result in a disincentive to surgeons and others conducting
invasive procedures to treat infected patients (124). As noted above,
the most effective method for preventing transmission is preventing
parenteral exposure. Treatment of infection (e.g., antiretroviral
therapy for HIV and immunomodulator therapy for HCV) may also decrease
iatrogenic risks for transmission by lowering circulating viral burdens
(although this concept has not been definitively demonstrated in the
postexposure prophylaxis setting). One codicil should be inserted,
however, about therapy of blood-borne pathogen infections in health care
providers. The administration of these agents to health care providers
may result in toxicities that lead to impaired performance, at least
over the short run. This statement is particularly germane to long-term
interferon therapy for hepatitis C infection.
Finally, one should also consider the fact that many, if not all, of the
successful prevention strategies currently in place were not being used
at the time the risk estimates for iatrogenic transmission of hepatitis
B virus, HCV, and HIV were developed. Use of these prevention strategies
should substantially reduce the already extremely small risks for
provider-to-patient transmission of these blood-borne pathogens.
Information gleaned from the past 15 years' investigation of hepatitis C
has yielded a better understanding of the virology, natural history,
immunological responses, and therapy of acute and chronic hepatitis C
infections. These data are now being incorporated into management
strategies for health care workers who are occupationally exposed to
hepatitis C. Furthermore, the past 15 years have seen the accurate
characterization of the nosocomial epidemiology and the magnitude of
risk associated with occupational exposure to hepatitis C in the health
Because data demonstrating the efficacy of any intervention are not yet
available, no definitive recommendations can be made about the use of
immunomodulating therapy for health care workers who are exposed to
hepatitis C. Based on data gleaned from a variety of other relevant
settings, however, the preemptive therapy and watchful waiting
strategies outlined in this article represent reasonable interim
approaches to this complex problem, at least until more definitive data
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