Hepatitis C Virus Postexposure Prophylaxis in the Healthcare Worker: Why Direct-Acting Antivirals Don't Change a Thing
Hepatitis C Virus Postexposure Prophylaxis in the Healthcare Worker: Why Direct-Acting Antivirals Don't Change a Thing
VIRAL HEPATITIS: Camilla S. Graham 1
Section Editor 1
0 Emory University School of Medicine , Atlanta , Georgia
1 Received 10 May 2016; accepted 5 August 2016; published online 28 September 2016
2 Duke University School of Medicine , Durham, North Carolina
3 Duke Clinical Research Institute
4 Johns Hopkins School of Medicine , Baltimore, Maryland
Currently, 380 000-400 000 occupational exposures to blood-borne pathogens occur annually in the United States. The management for occupational HIV or hepatitis B virus exposures includes postexposure prophylaxis (PEP) when necessary; however, PEP is not recommended for hepatitis C virus (HCV) exposures. Recent approval of HCV direct-acting antivirals (DAAs) has renewed discussions as to whether these therapies could be used to prevent infection after exposure. There are no published studies addressing this question, but the prescribing of DAAs for PEP has been reported. We will discuss the differences in transmission of the 3 most common blood-borne pathogens, the natural history of early HCV infection, and the scientific rationale for PEP. In particular, we will discuss how the low feasibility of conducting an adequately powered clinical trial of DAA use for PEP and the low costeffectiveness of such an intervention is not supportive of targeting limited resources for such use.
OCCUPATIONAL TRANSMISSION OF HCV
The occupational transmission of HCV is well documented,
although the variation in reported rates is wide (0%–10%)
[7–18] (Table 1). The majority of reports support a low
estimated transmission rate, and pooled longitudinal data following
parenteral exposure to blood from HCV-infected source
patients reported an estimated incidence of 1.9% per exposure
. This is compared to a 0.32% risk (approximately 1
infection for every 325 documented exposures) and 19%–37% risk
(approximately 1 infection for every 3–5 documented exposures
among HCWs without protective immunity from HBV
vaccination) per percutaneous exposure to blood from HIV-infected
and HBV-infected source patients, respectively [20–23].
These data conform to the conceptual model that
transmission risk is directly proportional to the infectivity of the body
fluid and the susceptibility of the tissue exposed . The
infectivity of the body fluid is assumed to correlate with both the
concentration of viral particles in the body fluid and the volume
of inoculation. Supporting this model is the observation that
transmission is high with hollow-bore needlesticks that can
transfer a larger inoculum and greatest with deep penetration
of a scalpel into muscle [18, 22].
While HCV RNA has been detected in other body fluids
including saliva, semen, and vaginal secretions, HCV RNA levels
are consistently higher in serum [25–27]. Existing data suggest
that a higher level of HCV RNA in serum correlates to higher
risk of transmission [22, 28–30]. Chimpanzee challenge studies
have suggested that there is an infectious titer (chimpanzee
infective dose) required to transmit infection, and that this level of
inoculum is different in other animal models (humanized liver–
mouse models) . Whereas these studies have unequivocally
established the infectivity of blood, it is possible that RNA
detected in other body fluids might not correspond as directly
with infectious virions.
Table 1. Selected Studies of Hepatitis C Virus Infection Following Occupational Exposure
Sodeyama et al, 1993 
Chung et al, 2003 
De Carli et al, 2003 
Tomkins et al, 2012 
Retrospective, needlestick injury, anti-HCV confirmation of source
Retrospective, needlestick injury, only analyzed source exposures with detectable
Retrospective, needlestick injury, only analyzed source exposures with detectable
Retrospective, needlestick injury, anti-HCV confirmation of source
Prospective, needlestick injury, anti-HCV confirmation of source
Prospective, needlestick injury
Retrospective, multiple injury types (87.7% needlestick or suture/surgical)
Prospective, needlestick injury, all source patients with detectable HCV RNA
Prospective, all injuries included, only analyzed source exposures with detectable
Retrospective, needlestick injury, anti-HCV confirmation of source
Prospective, needlestick, anti-HCV confirmation of source
Retrospective, all injuries included, anti-HCV confirmation of source
Abbreviations: HCV, hepatitis C virus; RNA, ribonucleic acid.
ACUTE HCV INFECTION AND SPONTANEOUS
Clinical Presentation and Diagnosis
Following an occupational exposure, a minority (estimated
1.9%) of HCWs will develop acute HCV infection . Initial
infection with HCV is characterized by detection of HCV
RNA in the blood (8–10 days following exposure) followed by
a rapid increase in serum liver enzymes (alanine
aminotransferase [ALT] and aspartate aminotransferase [AST]), which occurs
during the plateau phase of infection (days 40–60) [33, 34]
(Figure 1). A majority of acutely infected patients are
asymptomatic, and for the 15%–30% of patients experiencing
Figure 1. Laboratory presentation of acute hepatitis C infection. Hepatitis C virus
(HCV) ribonucleic acid (RNA) (open and closed triangles) and alanine
aminotransferase (ALT) (open and closed circles) over time with infection in months. Reprinted
from “Spontaneous Clearance of Primary Acute Hepatitis C Virus Infection
Correlated with High Initial Viral RNA Level and Rapid HVR1 Evolution” by L. Liu, 2012,
Hepatology, 55(6):1684–91. Copyright 2012 by John Wiley & Sons Ltd. Reprinted with
symptoms, the presentation can be mild and consistent with a
nonspecific viral syndrome . Approximately 25% of patients
will go on to spontaneously clear the viral infection, defined as
persistent undetectable levels of HCV RNA (below the lower
limit of quantification, target not detected) in the blood, while
the majority will develop viral persistence and chronic infection
. For the exposed HCW, the most reliable early marker of
infection is the HCV RNA in the blood, which should be
detectable by day 14 postexposure (Table 2).
Multiple factors have been reported as predictive of
spontaneous clearance including female sex, lack of HIV infection,
positive hepatitis B surface antigen status, host genetic factors
including the IL28B genotype, and early favorable HCV RNA
kinetics [37–42]. There are limited long-term natural history
follow-up studies of acute HCV infection, which report
variability in the timing of natural clearance of the virus [41, 43–45].
While it is accepted that the majority of patients will
spontaneously clear the infection in the first 24 weeks, there can be
significant variability in HCV RNA in the early stages of infection
with interposed detectable and undetectable levels [41, 45, 46].
Thus, confirmation of HCV RNA clearance is recommended, a
minimum of 6 months apart.
The pathogenesis of acute infection is poorly understood
because of the absence of small animal models and due to the
asymptomatic nature of the infection. To this end, much of
our knowledge of the initial phase of infection is derived from
the chimpanzee model, which is no longer used. We do not
know what occurs at the site of inoculation or in the first 72
hours of exposure; most studies of early infection have
investigated the innate immune response in the host and the early
viral kinetics. The timing of hepatocyte entry and extent of
Table 2. Testing for Hepatitis C Virus Infection Following Exposure
Timing After Exposure
Source patient Immediate
Healthcare worker (if source
patient has evidence of
If HCV EIA positive: Yes
If HCV EIA negative: Recommend
only if source is at risk for
If HCV EIA positive: Yes
Although HCV RNA testing is not routinely recommended, it may be
useful in immunocompromised source patients who may have
Yes Healthcare worker does not require follow-up if source patient is
HCV negative; however, baseline testing of HCW is prudent.
Consider If earlier diagnosis of HCV infection is desired, testing for HCV RNA
may be performed to help guide treatment decision making. Due
to the intermittent nature of HCV viremia in acute HCV infection,
RNA testing should not be the sole screening test.
Yes HCV antibody testing 4–6 mo postexposure is considered the
optimal means of detecting infection, although seronegative
infections have been reported.
entry are unknown. The early innate response is attenuated by
countermeasures from HCV including expression of NS3/4A
that appears to diminish downstream signaling .
One of the hallmarks of acute HCV infection is the delayed
adaptive immune response, which is not detectable until weeks
5–9 after infection . Defective T- and B-cell priming has
been proposed as the mechanism for this delay, although how
or why this occurs is poorly understood. What we do know is
that clearance of HCV is strongly associated with CD4+ T-cell
responses, and reduced breadth and strength of the specific
CD4+ T-cell response results in persistence of HCV infection
[48–50]. In fact, a recent study in HCWs reports that subclinical
transmission, determined by proliferative T-cell responses
targeting nonstructural HCV proteins, is common despite
undetectable systemic viremia and lack of serologic evidence
of infection . Neutralizing antibodies generally are produced
too late to play a critical role in viral clearance .
SCIENTIFIC RATIONALE FOR POSTEXPOSURE
The rationale for PEP chemoprophylaxis is based on several core
principles: (1) the pathogenesis and time course of early infection;
(2) the biological plausibility that infection could be prevented with
antiviral drugs; (3) evidence of antiviral efficacy of the drugs being
used for PEP; and (4) the risk to the HCWs from exposure to PEP
. The impact of the failure to prevent the development of a
chronic infection also drives the clinical need for exploring PEP
for infectious pathogens. For example, in the case of HBV and
HIV, there is no cure for chronic infection and the long-term
impact of infection may be substantial; on the other hand, chronic
HCV infection is curable in the vast majority of patients. As
such, the impact on the HCW of the failure to prevent chronic
infection is less for HCV compared with HIV or HBV infection.
Our ability to rationalize the role of PEP in the first few days of
infection is limited by the lack of understanding of the
pathogenesis of early HCV infection. To use HIV as a correlate, primate
models of simian immunodeficiency virus (SIV) infection
suggest that systemic infection does not occur until postexposure
day 3–5; thus, it is theoretically possible to prevent or inhibit
systemic infection by blocking viral replication in the initial
target cells or lymph nodes . This was followed by primate
studies confirming that a 4-week regimen with tenofovir
administered 48 hours before, 4 hours after, or 24 hours after
intravenous inoculation of SIV prevented infection [54–56]. We lack
such a detailed understanding of the kinetics of acute HCV
infection. Viruses would be expected to pass through the liver
within hours of reaching the blood. There they attach to and
enter susceptible hepatocytes through a series of at least 5
distinct molecular encounters . Within the cell the positive
strand is released and associated with a ribosome, and a single
large polyprotein is made and initially cleaved using host
enzymes (Figure 2). The virus-encoded proteins then complete
replication including production of a negative strand that is
repeatedly copied as new virions are produced in the cytoplasm.
There is no known nuclear phase nor any permanent archive
of HCV infection which has to be sustained by ongoing
Biologic Plausibility of Prevention
Based on what we know about the early phase of HCV infection,
what mechanism would be most crucial to prevent infection?
Presumably, prevention of infection would require blocking of
early de novo infection of susceptible cells or spread of the
infection to the critical number of hepatocytes required to achieve
persistence. However, currently approved DAAs target
postentry processes and would not be predicted to prevent initial
hepatocyte entry. Necessary steps of protease cleavage, replication
complex assembly, and reproduction of the positive strand
would be inhibited by approved medications (Figure 2). Thus,
the key factors may be how many cells harbor the positive
strand genome and the relative stability of the RNAs. Since a
small number of “founder viruses” initially establish infection
 and viremia isn't detectable for more than a week, it is
also possible PEP might prevent the early amplification and
spread of infection. However, there is no in vivo information
to answer how long the downstream processes would need to
be inhibited before those RNAs lost the ability to initiate
infection. To date, there are no proof-of-principle studies
investigating the efficacy of PEP using direct-acting antivirals (DAAs),
although there was a registered study assessing the safety and
tolerability of telaprevir (NS3/4A protease inhibitor) dosed
750 mg 3 times daily for 4 weeks for occupational PEP for
HCV (Clinical Trials.gov identifier NCT01766115). That
study has since been withdrawn.
Antiviral Efficacy of DAAs
US Food and Drug Administration (FDA)–approved DAAs
target the NS3/4A protease, the NS5B polymerase, and the NS5A
protein (Figure 2). The most recently approved DAAs exhibit
picomolar antiviral potency in vitro, and when used in
combination have shown high efficacy for the treatment of chronic
HCV infection [58–66] (Supplementary Table 1). When used
as monotherapy in persons with established high-level
infection, failure rates are high, and for DAA with low barriers to
resistance (NS3/4A protease inhibitors and NS5A inhibitors),
the rapid selection of resistance mutations is universal at the
time of on-treatment failure . Similar to HIV, the expected
approach to PEP in HCV involves combination therapy of
multiple mechanistic targets, which is the same as the approach
to the treatment of chronic HCV infection. Also like HIV, the
longer the delay to delivering medications, the more similar
PEP is to treatment of chronic infection (vs preexposure
Risk and Benefit of HCW Exposure to PEP
The final consideration influencing the rationalization for PEP
is the risk and benefit of PEP to the exposed HCW, and to
extend this out to the population level, the cost of PEP. It is
unclear what length of treatment would be required for HCV
PEP; the use of 4 weeks of PEP for systemic HIV infection
was based on animal model data suggesting that 4 weeks was
superior to 3 or 10 days . We do not have such data in
HCV, although the ability to cure select patients with chronic
infection in as little as 6 weeks with potent all-oral DAA
combinations suggests that such a shortened course for prevention
may be reasonable for early viral eradication . While all
antivirals have been associated with adverse effects, interferon-free
regimens for HCV are much better tolerated and side effects are
unlikely to be a significant limitation to the implementation of
HCV PEP. Thus, while there is minimal perceived risk of HCV
PEP to the individual, there is also not a clear benefit as early
HCV infection can be eradicated with FDA-approved, highly
effective DAA regimens. Furthermore, the implementation of
HCV PEP carries significant financial implications.
There is no available cost-effectiveness analysis for HCV PEP,
although given the high cost of DAA (on average 54 600–94 500
US dollars [USD] per 12-week course) and the large number of
patients needed to treat to abort 1 early infection, it is it unlikely
that an intervention that prevents such a rare event would
provide adequate value for money to be considered cost-effective by
commonly cited US willingness-to-pay thresholds. This is all
the truer in the setting of highly efficacious combination
DAA therapies for established infection. In the setting of
chronic HCV, infection cure rates exceed 95%, an outcome that
clearly differentiates HCV from the other occupational
bloodborne pathogens. Although HIV PEP has been reported to
be cost-effective in the occupational exposure setting, these
models correctly assume that the failure to prevent incurable
chronic HIV infection will necessitate lifelong antiretroviral
The low incidence rate of HCV transmission in the setting of
an occupational exposure also creates limitations in feasibility
of conducting a clinical trial to determine efficacy and
safety, which would be necessary before HCV PEP could be
recommended and implemented in the healthcare setting. For
sample size calculations in clinical trials, there is a standard
assumption of a desired power (usually 80%–90%) to detect a
significant difference at a prespecified level of significance,
usually 5% . Due to the low incidence rate of HCV
transmission (estimated 1.9%) in the setting of an occupational
exposure, the sample size of a clinical trial to assess the efficacy
would have to be large enough to detect a relatively small
difference between groups, even if it is highly efficacious.
For clinical trials with extremely low incidence rates, the
common assumptions used for sample size calculations are
not feasible. For example, assuming an incidence rate of 1.9%
for the control arm and the ability to show an incidence of
approximately 1% in the intervention arm, the fixed sample
size analysis ( power 90%, significance level 5%) suggests a
sample size of up to 6532 (3266 per group) subjects .
Assuming 18 200 USD per 4 weeks of DAA PEP for the
intervention arm, the cost of drug alone would be 59.4 million USD
—a cost unlikely to be offset by the early prevention of a
maximum of 62 cases of acute HCV. On the other hand, the cost for
the delivery of highly effective, all-oral DAA regimens to
persons who are acutely infected is anticipated to be approximately
63 000 USD for an 8-week course (ledipasvir/sofosbuvir) or
54 600 USD for a 12-week course (elbasvir/grazoprevir) or
approximately 3.39 million USD to treat the maximum of
62 persons with acute HCV infection following exposure.
In fact, recent studies of acute infection suggest that high
rates of eradication (83%–100%) with abbreviated treatment
length, including 6 weeks, may be possible depending on how
early the patient is in the acute course of infection [71, 72].
Importantly, both strategies—PEP and early treatment of
HCV infection—are expected to result in the absence of chronic
infection in the vast majority of exposed persons.
Chow et al have proposed a different method for sample size
calculations in the setting of extremely low incidence rates
of outcome of interest based on precision analysis . Using
the same theoretical clinical trial as described above, assuming
an incidence rate of 1.9% for the control arm and the ability to
show a 50% relative reduction to an incidence rate of 1% in the
intervention arm, the precision sample size analysis suggests
that a sample size of 1100 subjects per group (N = 2200)
would be needed to reach statistical significance. The power
for correctly detecting a difference of 1.0% would be 53.37%.
While this decreases the drug-related costs to 20 million USD,
the cost is still >5-fold higher than treating the few patients who
develop active infection.
To explore the costs associated with PEP in the healthcare
setting, we performed a simple decision analysis to examine
the relative costs of PEP after a needlestick exposure to
HCVpositive bodily fluids. Two strategies were compared (Figure 3):
(1) PEP with DAA daily for 4 weeks, vs (2) No PEP; treat only
patients who develop active infection HCV.
We assumed a baseline rate of postexposure HCV infection
of 1.9% and further assumed that PEP was 100% effective at
preventing infection. We assumed that everyone who developed
active infection was treated and that treatment was 98%
effective, with no deaths from therapy and no chronic infections
(treatment failure). The base-case assumed therapy for PEP
consisted of a combination DAA therapy with elbasvir/
grazoprevir given for 4 weeks, which is currently the least costly
available therapy. For patients who became infected, we
assumed treatment for acute infection with ledipasvir/sofosbuvir
for 8 weeks. Patients for whom acute therapy failed were given
NS5A-sparing therapy of simeprevir plus sofosbuvir plus
ribavirin for 24 weeks. While on any therapy, we assumed
that patients were seen by a physician with HCV viral RNA
testing at baseline, week 4, end of therapy (EOT), and EOT plus 12
weeks, and comprehensive metabolic panel performed at
Table 3. Cost Estimates for Decision Analysis
Abbreviations: AWP, average wholesale price; CMS, Center for Medicare and Medicaid
Services; HCV, hepatitis C virus; PEP, postexposure prophylaxis; RNA, ribonucleic acid;
WAC, wholesale acquisition cost.
a Based on generic cost.
b Cost of postexposure prophylaxis with elbasvir/grazoprevir for 4 weeks.
c Cost of treatment of acute infection with ledipasvir/sofosbuvir for 8 weeks.
baseline, week 4, and EOT. Cost estimates for these
interventions are shown in Table 3.
The results of our model showed that treating 100 exposed
patients with PEP would cost 1 857 272 USD vs 132 870 USD
in the no PEP strategy. In sensitivity analysis, we considered
a range of costs for treatment of acute HCV, but even at the
highest end of the range (94 500 USD for 12 weeks of therapy),
the PEP strategy was still more expensive by a factor of 9. Likewise,
we considered a range of probabilities for infection after exposure,
but even at a rate of 10%, the PEP strategy was still significantly
more expensive. To achieve cost savings for PEP, the cost of
medications would need to drop to 1329 USD per week. However, this
assumes that the cost of treatment for acute therapy does not
change; in a 2-way sensitivity analysis where the costs of therapy
decrease for both PEP and acute treatment, PEP remains the
more expensive option. We examined the cost of a shorter PEP
regimen and found that any regimen longer than 2 days would
still be more expensive than the no-PEP option.
We would also acknowledge the less tangible issues
surrounding an occupational exposure that carries the risk of a
blood-borne pathogen infection. There is a clear psychological
impact on not only the HCW but also their family and in
particular their sexual partners. Furthermore, the development of
an acute blood-borne infection can carry particular significance
for individuals who engage in work that potentially places
others at risk for acute infection (eg, surgeons). We did not
account for worry and anxiety in the model, in part because
it is difficult to project the differences in these emotions
between the PEP and no PEP groups and it was beyond the
scope of this article; however, it is unlikely to change the
outcome of the model. Here we focused on the HCW because we
have the most reliable data on the risk per exposure. However,
PEP and pre-exposure prevention of HCV infection are even
more important for groups with a higher risk of transmission,
including people with intravenous drug use and some
HIV-infected men who have sex with men. Additional work is needed
to address the role of DAA in HCV prevention in these groups.
Occupational transmission of HCV is uncommon, yet of the
3 most prevalent healthcare-related blood-borne pathogens, it
remains the only infection without available PEP and/or
preexposure vaccine. There are many arguments for why PEP in
HCV should not be recommended: (1) Risk of transmission
in HCW is very low; (2) for the rare HCWs who develop
acute infection, the eradication rate with highly efficacious
and safe DAA combination therapies is near 100%; and (3)
there is unlikely to be a scenario by which PEP is cost-effective
compared with early HCV treatment, with the exception of a
2-day course of PEP. Based on acute HCV infection models
using intravenously infected chimpanzees, there is little
plausibility that 2 days of DAA therapy would block the first phase of
viral replication. Thus, any studies of or recommendations for
PEP would have to acknowledge that this intervention is not
cost-effective. In addition, the clinical application of these
results would need to consider differences in efficacy across
genotypes and use a pan-genotypic regimen when feasible.
The lack of understanding of the appropriate length of therapy
for PEP and the lack of feasibility of conducting an adequately
powered clinical trial to assess efficacy further solidify this
argument. Instead, appropriate follow-up and postexposure
testing, reassurance, and early treatment of acquired HCV
infection with potent DAA combination therapies should be
Supplementary materials are available at http://academic.oup.com/cid.
Consisting of data provided by the author to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the author, so
questions or comments should be addressed to the author.
Financial support. This work was supported by the National Institute
of Allergy and Infectious Diseases (NIAID) (K23-AI096913-03 to S. N. and
K01-AI083782 to D. P. H.) and the National Institute on Drug Abuse (K24
DA034621-01 to M. S. S. and R37DA013806 to D. L. T.).
Potential conflicts of interest. S. N. has received research funding from
Vertex Pharmaceuticals, Merck, Gilead Sciences, Janssen Pharmaceuticals,
AbbVie, Bristol-Meyers Squibb (BMS), and Tacere, and has served as a
consultant and scientific advisor for Vertex Pharmaceuticals, Merck, Gilead
Sciences, Janssen Pharmaceuticals, AbbVie, and BMS. M. S. S. has received
research funding ( paid to Johns Hopkins University) from AbbVie, BMS,
Gilead Sciences, Janssen Pharmaceuticals, and Merck, and has served as a
consultant and scientific advisor to AbbVie, Cocrystal, Gilead Sciences,
Janssen Pharmaceuticals, Merck, and Trek. All authors have submitted
the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts
that the editors consider relevant to the content of the manuscript have been
1. Porta C , Handelman E , McGovern P. Needlestick injuries among health care workers: a literature review . AAOHN J 1999 ; 47 : 237 - 44 .
2. Panlilio AL , Orelien JG , Srivastava PU , Jagger J , Cohn RD , Cardo DM ; NaSH Surveillance Group; EPINet Data Sharing Network. Estimate of the annual number of percutaneous injuries among hospital-based healthcare workers in the United States , 1997 - 1998 . Infect Control Hosp Epidemiol 2004 ; 25 : 556 - 62 .
3. Deuffic-Burban S , Delarocque-Astagneau E , Abiteboul D , Bouvet E , Yazdanpanah Y. Blood-borne viruses in health care workers: prevention and management . J Clin Virol 2011 ; 52 : 4 - 10 .
4. Centers for Disease Control . Recommendations for prevention of HIV transmission in health-care settings . MMWR Morb Mortal Wkly Rep 1987 ; 36 (suppl 2): 1S - 18S .
5. Garner JS ; Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals . Infect Control Hosp Epidemiol 1996 ; 17 : 53 - 80 .
6. Beekmann SE , Henderson DK . Health care workers and hepatitis: risk for infection and management of exposures . Infect Dis Clin Pract 1992 ; 1 : 424 - 8 .
7. Hernandez ME , Bruguera M , Puyuelo T , et al. Risk of needle-stick injuries in the transmission of hepatitis C virus in hospital personnel . J Hepatol 1992 ; 16 : 56 - 8 .
8. Mitsui T , Iwano K , Masuko K , et al. Hepatitis C virus infection in medical personnel after needlestick accident . Hepatology 1992 ; 16 : 1109 - 14 .
9. Sodeyama T , Kiyosawa K , Urushihara A , et al. Detection of hepatitis C virus markers and hepatitis C virus genomic-RNA after needlestick accidents . Arch Intern Med 1993 ; 153 : 1565 - 72 .
10. Lanphear BP , Linnemann CC , Gannon CG , et al. Hepatitis C virus infection in healthcare workers: risk of exposure and infection . Infect Control Hosp Epidemiol 1994 ; 15 : 745 - 50 .
11. Puro V , Petrosillo N , Ippolito G ; Italian Study Group on Occupational Risk of HIV and Other Bloodborne Infections . Risk of hepatitis C seroconversion after occupational exposures in health care workers . Am J Infect Control 1995 ; 23 : 273 - 7 .
12. Arai Y , Noda K , Enomoto N , et al. A prospective study of hepatitis C virus infection after needlestick accidents . Liver 1996 ; 16 : 331 - 4 .
13. Takagi H , Uehara M , Kakizaki S , et al. Accidental transmission of HCV and treatment with interferon . J Gastroenterol Hepatol 1998 ; 13 : 238 - 43 .
14. Hasan F , Askar H , Al Khaliki J , et al. Lack of transmission of hepatitis C virus following needlestick accidents . Hepatogastroenterology 1999 ; 46 : 1678 - 81 .
15. Baldo V , Floreani A , Dal Vecchio L , et al. Occupational risk of blood-borne viruses in healthcare workers: a 5-year surveillance program . Infect Control Hosp Epidemiol 2002 ; 23 : 325 - 7 .
16. Chung H , Kudo M , Kumada T , et al. Risk of HCV transmission after needlestick injury, and the efficacy of short-duration interferon administration to prevent HCV transmission to medical personnel . J Gastroenterol 2003 ; 38 : 877 - 9 .
17. De Carli G , Puro V , Ippolito G ; Italian Study Group on Occupational Risk of HIV and Other Bloodborne Infections . Risk of hepatitis C virus transmission following percutaneous exposure in health care workers . Infection 2003 ; 31 : 22 - 7 .
18. Tomkins SE , Elford J , Nichols T , et al. Occupational transmission of hepatitis C in healthcare workers and factors associated with seroconversion: UK surveillance data . J Viral Hepat 2012 ; 19 : 199 - 204 .
19. Henderson DK . Managing occupational risks for hepatitis C transmission in the health care setting . Clin Microbiol Rev 2003 ; 16 : 546 - 68 .
20. Henderson DK . HIV in the healthcare setting . In: Mandell GL, Bennett JE , Dolin R, eds. Principles and practice of infectious diseases. 7th ed . New York, NY : Elsevier Churchill Livingstone, 2009 ; 3753 - 70 .
21. Seeff LB , Wright EC , Zimmerman HJ , et al. Type B hepatitis after needle-stick exposure: prevention with hepatitis B immune globulin: final report of the Veterans Administration Cooperative Study . Ann Intern Med 1978 ; 88 : 285 - 93 .
22. Yazdanpanah Y , De Carli G , Migueres B , et al. Risk factors for hepatitis C virus transmission to health care workers after occupational exposure: a European case-control study . Clin Infect Dis 2005 ; 41 : 1423 - 30 .
23. Ippolito G , Puro V , Petrosillo N , De Carli G , Micheloni G , Magliano E. Simultaneous infection with HIV and hepatitis C virus following occupational conjunctival blood exposure . JAMA 1998 ; 280 : 28 .
24. Sulkowski M , Ray SC , Thomas DL . Needlestick transmission of hepatitis C. JAMA 2002 ; 287 : 2406 - 13 .
25. Rey D , Fritsch S , Schmitt C , Meyer P , Lang JM , Stoll-Keller F. Quantitation of hepatitis C virus RNA in saliva and serum of patients coinfected with HCV and human immunodeficiency virus . J Med Virol 2001 ; 63 : 117 - 9 .
26. Farias A , Re V , Mengarelli S , et al. Detection of hepatitis C virus (HCV) in body fluids from HCV monoinfected and HCV/HIV coinfected patients . Hepatogastroenterology 2010 ; 57 : 300 - 4 .
27. Savasi V , Parrilla B , Ratti M , Oneta M , Clerici M , Ferrazzi E. Hepatitis C virus RNA detection in different semen fractions of HCV/HIV-1 co-infected men by nested PCR . Eur J Obstet Gynecol Reprod Biol 2010 ; 151 : 52 - 5 .
28. Ohto H , Terazawa S , Nobuhiko S , et al. Transmission of hepatitis C virus from mothers to infants . N Engl J Med 1994 ; 330 : 744 - 50 .
29. Lin HH , Kao JH , Hsu HY , et al. Possible role of high-titer maternal viremia in perinatal transmission of hepatitis C virus . J Infect Dis 1994 ; 169 : 638 - 41 .
30. Thomas DL , Villano SA , Riester KA , et al. Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1-infected mothers . J Infect Dis 1998 ; 177 : 1480 - 8 .
31. Bukh J , Meuleman P , Tellier R , et al. Challenge pools of hepatitis C virus genotypes 1-6 prototype strains: replication fitness and pathogenicity in chimpanzees and human liver-chimeric mouse models . J Infect Dis 2010 ; 201 : 1381 - 9 .
32. Centers for Disease Control and Prevention . Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis . MMWR Morb Mortal Wkly Rep 2001 ; 50 (RR-11): 1 - 52 .
33. Cox AL , Netski DM , Mosbruger T , et al. Prospective evaluation of communityacquired acute-phase hepatitis C virus infection . Clin Infect Dis 2005 ; 40 : 951 - 8 .
34. Page-Shafer K , Pappalardo BL , Tobler LH , et al. Testing strategy to identify cases of acute hepatitis C virus (HCV) infection and to project HCV incidence rates . J Clin Microbiol 2008 ; 46 : 499 - 506 .
35. Orland JR , Wright TL , Cooper S. Acute hepatitis C. Hepatology 2001 ; 33 : 321 - 7 .
36. Micallef JM , Kaldor JM , Dore GJ . Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies . J Viral Hepat 2006 ; 13 : 34 - 41 .
37. Thomas DL , Astemborski J , Rai RM , et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors . JAMA 2000 ; 284 : 450 - 6 .
38. Soriano V , Mocroft A , Rockstroh J , et al. Spontaneous viral clearance, viral load, and genotype distribution of hepatitis C virus (HCV) in HIV-infected patients with anti-HCV antibodies in Europe . J Infect Dis 2008 ; 198 : 1337 - 44 .
39. Thomas DL , Thio CL , Martin MP , et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus . Nature 2009 ; 8 : 798 - 801 .
40. Gerlach JT , Diepolder HM , Zachoval R , et al. Acute hepatitis C: high rate of both spontaneous and treatment induced viral clearance . Gastroenterology 2003 ; 125 : 80 - 8 .
41. Mosley JW , Operskalski EA , Tobler LH , et al. The course of hepatitis C viremia in transfusion recipients prior to availability of antiviral therapy . J Viral Hepat 2008 ; 15 : 120 - 8 .
42. Vogel M , Dominguez S , Bhagani S , et al. Treatment of acute HCV infection in HIV-positive patients: experience from a multicenter European cohort . Antivir Ther 2010 ; 15 : 267 - 79 .
43. Larghi A , Zuin M , Crosignani A , et al. Outcome of an outbreak of acute hepatitis C among healthy volunteers participating in pharmacokinetics studies . Hepatology 2002 ; 36 : 993 - 1000 .
44. Spada E , Mele A , Berton A , et al. Multispecific T cell response and negative HCV RNA tests during acute HCV infection are early prognostic factors of spontaneous clearance . Gut 2004 ; 53 : 1673 - 81 .
45. Villano SA , Vlahov D , Nelson KE , Cohn S , Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection . Hepatology 1999 ; 29 : 908 - 14 .
46. Grebely J , Page K , Sacks-Davis R , et al. The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection . Hepatology 2014 ; 59 : 109 - 20 .
47. Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence . J Clin Invest 2009 ; 119 : 1745 - 54 .
48. Thimme R , Bukh J , Spangenberg HC , et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease . Proc Natl Acad Sci U S A 2002 ; 99 : 15661 - 8 .
49. Diepolder HM , Zachoval R , Hoffmann RM , et al. Possible mechanism involving T lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection . Lancet 1995 ; 346 : 1006 - 7 .
50. Missale G , Bertoni R , Lamonaca V , et al. Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response . J Clin Invest 1996 ; 98 : 706 - 14 .
51. Heller T , Werner JM , Rahman F , et al. Occupational exposure to hepatitis C virus: early T-cell responses in the absence of seroconversion in a longitudinal cohort study . J Infect Dis 2013 ; 208 : 1020 - 5 .
52. Wedemeyer H , He XS , Nascimbeni M , et al. Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection . J Immunol 2002 ; 169 : 3447 - 58 .
53. Spira AI , Marx PA , Patterson BK , et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques . J Exp Med 1996 ; 183 : 215 - 25 .
54. Tsai C-C , Follis KE , Sabo A , et al. Prevention of SIV infection in macaques by (R)- 9-(2phosphonylmethoxypropyl) adenine . Science 1995 ; 270 : 1197 - 9 .
55. Scheel TKH , Rice CM . Understanding the hepatitis C virus life cycle paves the way for highly effective therapies . Nat Med 2013 ; 19 : 837 - 49 .
56. Tsai C-C , Emau P , Follis KE , et al. Effectiveness of postinoculation (R)-9-(2phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment . J Virol 1998 ; 72 : 4265 - 73 .
57. Li H , Stoddard MB , Wang S , et al. Elucidation of hepatitis c virus transmission and early diversification by single genome sequencing . PLoS Pathogen 2012 ; 8 : e1002880 .
58. Poordad F , McCone J , Bacon BR , et al. Boceprevir for untreated chronic HCV genotype 1 infection . N Engl J Med 2011 ; 364 : 1195 - 206 .
59. Jacobson IM , McHutchison JG , Dusheiko G , et al. Telaprevir for previously untreated chronic hepatitis C infection . N Engl J Med 2011 ; 364 : 2405 - 16 .
60. Jacobson I , Dore G , Foster GR , et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomized, double-blind, placebo-controlled trial . Lancet 2014 ; 384 : 403 - 13 .
61. Lawitz E , Mangia A , Wyles D , et al. Sofosbuvir for previously untreated chronic hepatitis C infection . N Engl J Med 2013 ; 368 : 1878 - 87 .
62. Wyles DL , Ruane PJ , Sulkowski MS , et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1 . N Engl J Med 2015 ; 373 : 714 - 25 .
63. Afdhal N , Zeuzem S , Kwo P , et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection . N Engl J Med 2014 ; 370 : 1483 - 93 .
64. Feld JJ , Kowdley KV , Coakley E , et al. Treatment of HCV with ABT-450/rombitasvir and dasabuvir with ribavirin . N Engl J Med 2014 ; 370 : 1594 - 603 .
65. Zeuzem S , Ghalib R , Reddy KR , et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial . Ann Intern Med 2015 ; 163 : 1 - 13 .
66. Feld JJ , Jacobson IM , Hezode C , et al. Sofosbuvir and velpatasvir for HCV genotype 1 , 2, 4 , 5 , and 6 infection. N Engl J Med 2015 ; 373 : 2599 - 607 .
67. Jiang M , Mani N , Lin C , et al. In vitro phenotypic characterization of hepatitis C virus NS3 protease variants observed in clinical studies of telaprevir . Antimicrob Agents Chemother 2013 ; 57 : 6236 - 45 .
68. Kohli A , Kattakuzhy S , Sidharthan S , et al. Four-week direct-acting antiviral regimens in noncirrhotic patients with hepatitis C virus genotype 1 infection: an open-label, nonrandomized trial . Ann Intern Med 2015 ; 163 : 899 - 907 .
69. Pinkerton SD , Holtgrave DR , Pinkerton HJ . Cost-effectiveness of chemoprophylaxis after occupational exposure to HIV . Arch Intern Med 1997 ; 157 : 1972 - 80 .
70. Chow SC , Chiu ST . Sample size and data monitoring for clinical trials with extremely low incidence rates . Ther Innov Regul Sci 2013 ; 47 : 438 - 46 .
71. Rockstroh J , Bhagani S , Hyland RH , et al. Ledipasvir/sofosbuvir for 6 weeks in HIV-infected patients with acute HCV infection . In: Conference on Retroviruses and Opportunistic Infections (CROI) , Boston, MA, 22 - 25 February 2016 . Abstract 154LB .
72. Deterding K , Spinner C , Schott E , et al. Six weeks of sofosbuvir/ledipasvir (SOF/ LDV ) are sufficient to treat acute hepatitis C virus genotype 1 monoinfection: The HepNet Acute HCV IV Study . In: European Association for the Study of Liver Disease, Barcelona, Spain, 14 - 17 April 2016 .
73. Red Book. Ann Arbor, MI: Truven Health Analytics , 2014 .
74. Red Book. Ann Arbor, MI: Truven Health Analytics , 2010 .
75. Center for Medicare and Medicaid Services . Clinical laboratory fee schedule . Available at: http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ ClinicalLabFeeSched/clinlab.html. Accessed 17 December 2013 .
76. Center for Medicare and Medicaid Services . Physician fee schedule . Available at http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PFSlookup/ index.html. Accessed 17 December 2013 .