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Between March 2000 and July 2001, at least 99 persons acquired a hepatitis C virus genotype 3a (HCV-3a) infection in an oncology clinic. This nosocomial HCV outbreak provided an opportunity to examine the subsequent clinical course in a well-defined cohort. This was a retrospective/prospective observational study of the short-term significant health outcomes of a large, single-source, patient-to-patient HCV-3a outbreak. Outbreak patients or their legal representatives consenting to study were enrolled between September 2002 and December 2007. We measured history and physical examinations, medical records, HCV serology, HCV RNA and genotype, liver enzymes, histology, response to antiviral therapy, and liver-related morbidity and mortality. Sixty-four of the 99 known HCV-3a outbreak patients participated. During a 6-year period, six patients developed life-threatening complications from liver disease, three died, one received a liver transplant, and two were stable after esophageal variceal banding or diuretic therapy of ascites. Thirty-three patients underwent antiviral therapy, with 28 achieving a sustained viral remission. One patient acquired HCV-3a infection sexually from an outbreak patient and was successfully treated. Eleven study patients died of malignancy, including two that had achieved a sustained viral remission after antiviral therapy. Conclusion: Our patient cohort had a nosocomial source and an oncologic or hematologic comorbidity. Compared with previous HCV outcome studies, a patient-to-patient HCV outbreak in an oncology clinic exhibited significant morbidity and mortality. Attention is needed to the public health risk of nosocomial HCV transmission, emphasizing infection control, early diagnosis, and therapy. (HEPATOLOGY 2009.)
Hepatitis C is predominantly acquired through percutaneous exposure to blood.1 The natural history of hepatitis C virus (HCV) infection is poorly understood, and the cofactors that predict significant outcomes are still being determined. Retrospective natural history studies of HCV infection are hampered by a lengthy course with a large variance in information regarding the confounding factors that may modify it. A retrospective/prospective study is the favored approach, but it is rarely possible.2 Presently, therapy of a finite duration would usually follow shortly after recognition of HCV infection; treatment of acute HCV has been shown to be highly effective and a significant rate of a durable remission is achievable in chronic infection.3
In September 2002, four chronic HCV-3a infections were identified in patients who had in common treatment at a Nebraska hematology/oncology clinic. Shortly thereafter, reporting of a suspected outbreak to the Nebraska Department of Health and Human Services occurred along with the discovery of other clinic patients that also had an HCV-3a infection without risk factors. Subsequent screening of 81% of the total clinic patient population revealed that between March 2000 and July 2001, at least 99 patients acquired HCV-3a through the flushing of their intravenous access with HCV-contaminated saline.4 The source patient with a previously acquired HCV-3a infection entered the clinic in March 2000. New infections ceased in July 2001 with the implementation of infection control measures and termination of a clinic employee.
Because of the paucity of symptoms and signs of HCV infection, an outbreak may go unrecognized for years.5–7 Despite the atypical acquisition within a patient care environment, a nosocomial outbreak may provide an opportunity to study the natural history by the ability to identify date of transmission, appearance of chronicity, progression of liver injury, and clinical sequelae. The Nebraska nosocomial HCV-3a cohort represents one of the largest patient-to-patient outbreaks of HCV. With the hypothesis that HCV infection in adult cancer patients may be associated with a significant increase in morbid health outcomes, the aim of the present study was to perform a retrospective/prospective observation of the ensuing liver injury, treatment response, morbidity, and mortality.
ALT, alanine aminotransferase; HCV, hepatitis C virus; HCV-3a, hepatitis C virus genotype 3a; SVR, sustained viral response.
Patients and Methods
Patient Recruitment and Selection.
The names of the 99 individuals who acquired hepatitis C infection who were identified by the two screenings of at-risk clinic patients were never made public by either the Nebraska Department of Health and Human Services or the Centers for Disease Control and Prevention. As the primary providers of viral hepatitis treatment to Nebraskans, and due to our proximal relationship to the affected community, the University of Nebraska Hepatitis Clinic Director and Staff attempted to contact the entire Nebraska HCV-3a outbreak cohort through public awareness of our study and a town hall meeting, presentations to and formal correspondence with primary care physicians, and newspaper articles. We invited all outbreak patients, those already referred to our clinics, and those previously notified by the State of their infection, but unknown to us, to participate. We proposed a retrospective/prospective study of the significant health outcomes and response to antiviral therapy of this large HCV-3a outbreak in an oncology clinic. Institutional review board approval was obtained.
Patients were evaluated for the study if (1) as at-risk clinic patients they had been previously invited by the State to participate in either of two HCV screenings—the first with only HCV antibody testing, the second including both antibody and HCV RNA testing; and (2) the screening tests revealed HCV antibody and/or HCV RNA. The State-directed screening used enzyme immunoassay for HCV antibody (HCV EIA 2.0; Abbott Pharmaceuticals, Des Plaines, IL) and HCV RNA testing (COBAS Amplicor HCV 2.0; Roche Molecular Diagnostic Systems, Branchburg, NJ. and Associated Regional University Pathologist Laboratories, Salt Lake City, UT).
Between September 2002 and December 2007, following referral to our university-based clinics and/or medical record review, we enrolled 64 individual cases, alive or deceased, of the 99 patients identified by the State with an HCV-3a infection acquired at the Fremont Area Medical Center. The following data were obtained from our study patients' medical records: demographics; oncologic or hematologic diagnosis; dates of radiation, surgery, and chemotherapy; clinic records, including physician notes, intravenous access, and laboratory; risk factors and exposures; physical examinations; HCV antibody; HCV-3a genotype; serum HCV RNA level; serum aminotransferases (alanine aminotransferase, aspartate aminotransferase); bilirubin; antiviral therapy; and use of growth factors. Informed consent was obtained for all patients that presented to the clinic. The medical records of deceased individuals were reviewed by request and with permission of an attorney and/or legal representative. Once enrolled, patients were interviewed and examined at 4- to 6-month intervals; interviews and examinations were performed more frequently for those undergoing antiviral therapy or as needed for management of significant clinical health outcomes (such as liver disease). The measured health outcomes were the histologic appearance of liver fibrosis, the response to antiviral therapy, and complications indicating significant portal hypertension or hepatic dysfunction (jaundice, ascites, variceal bleeding, coagulopathy, encephalopathy, and liver transplantation).
Liver Biopsy and Antiviral Therapy.
As part of their initial evaluation, all HCV-3a study patients were offered a percutaneous liver biopsy, if one had not been performed in the previous 2 years, and no contraindications existed. No patients enrolled post mortem through a legal representative had a liver biopsy available for our review. Antiviral therapy consisted of a combination of weekly subcutaneous pegylated interferon alfa-2a (Peg Intron [1.5 μg/kg]; Schering-Plough Pharmaceuticals, Kenilworth, NJ) or pegylated interferon alfa-2b (Pegasys [180 μg]; Roche Pharmaceuticals, Nutley, NJ) and daily oral ribavirin (800 mg) for 24 weeks.8 In the case of leukopenia, absolute neutrophil count <400 cells/mm3, or anemia, hemoglobin less than 10 g/dL, occurred during antiviral therapy, filgastim (Neupogen [480 μg]; Amgen, Thousand Oaks, CA) or epoetin (Procrit [40,000 U]; Ortho Biotech, Bridgewater, NJ), respectively, would be recommended for administration weekly for a 4-week period. Repeated dosing of growth factors depended on serial testing. A sustained viral response (SVR) was defined by an undetectable HCV RNA level (HCV RNA Analyte Specific Reagent; Abbott Laboratories) at 6 months following completion of treatment.3
The demographics of the 64 HCV-3a study patients are depicted in Table 1. The study patients acquired an HCV-3a infection 26–50 months (estimated mean, 41 months) prior to our initial evaluation. Their average age at our meeting, or review of their medical data, was 59.1 years (range, 21–86 years). Our study group was younger (mean age, 59 versus 66 years) and had slightly fewer malignant diagnoses than that in the overall outbreak cohort (93% versus 96%).4 They were all Caucasian (Dodge County, Nebraska is 95.9% White according to the 2000 United States Census), and 56% were female. The primary diagnosis associated with their medical care in the oncology clinic was a solid tumor (75%), hematologic malignancy or disease (18%), or other (7%). Those patients with a history of malignancy had received a broad spectrum of radiation and/or chemotherapy treatment regimens. No patient had a past history of intravenous drug abuse.
Table 1. Demographics of the HCV-3a Outbreak Study: Patients, Treatment, and Outcomes
HCV Antibody, HCV RNA, Genotype, and Alanine Aminotransferase.
From the previous screening tests performed by the State of at-risk individuals, 18% of the total viremic cohort had undetectable HCV antibody >1 year following infection.4, 9 Eleven of our 64 HCV-3a study patients had undetectable HCV antibody at their initial study screening, but four of these patients developed detectable antibody while being observed approximately 40, 42, 44, and 52 months, respectively, following acute infection. Seven study patients never developed HCV antibody during our observation, regardless of their antiviral therapy or response to antiviral treatment. The antibody-negative, HCV-3a–viremic patients had a broad spectrum of ages, malignancies, and chemotherapy regimens (Table 2).
Table 2. Diagnosis and Treatment History of HCV Antibody–Undetectable Patients
All study patients had HCV RNA, and the 62 study patients that had HCV genotype testing had HCV-3a. The medical records of two study patients enrolled following their death from malignancy revealed the presence of HCV antibody, HCV RNA, no risk factors, but no genotype analysis. In 59 patients with a quantitative determination of HCV RNA, the median viral level was 6.94 × 105 IU/mL (range, 7.96 × 103 to 5.98 × 106 IU/mL). One patient had very low viral loads of 2.0 × 104 IU/mL and 9.24 × 103 IU/mL at screening and 1 year later, respectively, and has had undetectable viremia (< 50 IU/mL) annually for the following 3 years without antiviral therapy. This patient had an absent HCV antibody at screening, but had detectable antibody when tested 1 year later. This patient is the only study patient that exhibited evidence of a spontaneous clearance of infection during observation, nearly 4 years after acquisition.
In our study group, the mean alanine aminotransferase (ALT) level was 105 ± 78.7 (range, 18–331 U/mL). At initial evaluation, only 16 patients (25%) had ALT levels within the normal range (15–50 U/mL) for the Nebraska Medical Center laboratory. The previously published epidemiologic analysis of the outbreak reported that a new elevation of ALT was identified in only 56 of the 99 total cohort.4 At entry, all of the HCV-3a outbreak study patients had total bilirubin levels within the normal range (0.2–1.3 mg/dL).
Within 12 months of enrollment, we ultimately performed a percutaneous liver biopsy in 40 HCV-3a patients and received liver pathologic specimens from an additional two patients. Thus, 42 of 64 (66%) patients had liver histology obtained an estimated 26–42 months following the date of HCV acquisition. Liver specimens were reviewed by a hepatic pathologist (J. G.) (Fig. 1) and characterized according to the METAVIR classification of inflammation and fibrosis, as well as to the degree of steatosis (absent to severe).10, 11
In Fig. 1A, the METAVIR inflammation score is depicted for 42 HCV-3a patients. At a mean of 31 months following acute infection, a mild degree of inflammation was found with 37 of 42 patients showing liver histology of METAVIR grade 1 inflammation or less. Likewise, absent to mild degrees of steatosis (29/42 [69%]) predominated the liver histology specimens in patients undergoing liver biopsy approximately 3 years following infection (Fig. 1B). Differing from that found for inflammation and steatosis, a broad spectrum of fibrosis stages were observed (Fig. 1C). Of the 42 patients, 22 (52%) exhibited an advanced stage of fibrosis (stage 2 or greater) in their liver histology, with nearly 25% of the total group that underwent biopsy showing bridging fibrosis or cirrhosis (stages 3–4).
A discussion was held with 57 HCV-3a outbreak study patients regarding antiviral therapy (Fig. 2). Self-administration, duration, risks, benefits, side effects, likelihood of response, the prognosis of their comorbidity, and, when available, liver histology were discussed. Liver histology was available in 29 patients prior to therapy. Twenty-four patients declined antiviral therapy. No patient initiated antiviral therapy sooner than an estimated 27 months following acute HCV-3a infection. Thirty-three HCV-3a patients ages 21–74 years (mean, 51 years) opted for therapy; 32 received both pegylated interferon plus ribavirin, and one received just pegylated interferon, with 28 (84%) achieving an SVR (Table 1, Fig. 2). Twenty-eight patients completed a 24-week course of combination therapy, with 26 of these patients successfully achieving a SVR. The patient treated with pegylated interferon alone also achieved an SVR. One patient had an SVR with only 13 weeks of combination therapy, ceasing antiviral medications following the appearance of a severe ribavirin-associated rash. One 63-year-old woman who had been deemed a treatment failure due to onset of anemia during an earlier course of antiviral therapy prior to our evaluation successfully achieved an SVR when retreated in our study. Sixteen of 32 patients (50%) treated with combination therapy required growth factor support.
Five patients that began antiviral treatment did not achieve a SVR. The two patients with a past history of bone marrow transplantation for their underlying malignancy failed combination antiviral therapy; neither patient was able to tolerate the treatment, regardless of growth factors. One treatment failure patient had evidence of cirrhotic portal hypertension prior to therapy and relapsed viremia after treatment cessation, eventually undergoing liver transplantation 18 months following therapy. Two viremic patients that never exhibited HCV antibody failed therapy: a 64-year-old woman with histologic stage 1 fibrosis and a 43-year-old man with chronic lymphocytic leukemia (in remission) and stage 1 liver fibrosis who relapsed after a 6-month course of therapy. The latter patient initiated antiviral therapy nearly 50 months following HCV acquisition.
Morbidity and Mortality.
At our initial evaluation, any past symptoms attributed to hepatitis or liver disease were distinctly unusual. Only two of the patients in our study group had been icteric within the 72 weeks prior. Flu-like symptoms and fatigue were associated by the patients with their past chemotherapy and could not be directly related to an acute hepatitis either through our interview or through a detailed medical records review. Only one patient had clinical symptoms (fever and malaise) coincident with a new ALT elevation occurring several weeks following exposure.
Six of the 64 (9%) study patients were found during our evaluation or observation to develop new evidence of significant liver disease (cirrhotic portal hypertension or coagulopathy). Two HCV-3a outbreak patients died from complications of liver disease at 25 and 39 months, respectively, following acute infection, prior to antiviral therapy, and following a liver transplant evaluation. One was a 59-year-old man who died unlisted for transplant because of ongoing alcohol use; the other was a 49-year-old woman who had been listed. Alcoholic liver disease and autoimmune hepatitis, respectively, were attributed as cofactors in their mortality. A 78-year-old woman with no evidence of preexisting liver disease who declined antiviral therapy underwent endoscopic treatment of bleeding esophageal varices approximately 45 months following acute infection. Six years after acute infection, a 76-year-old woman presented with new ascites and esophageal varices and is stable on nadolol and diuretics. A 48-year-old man underwent liver transplantation, as described above, and is alive and well at the time of this report. An additional patient died with progressive liver failure 40 months after HCV acquisition, without a liver transplant evaluation because of recurrent lymphoma, nearly 4 years following a pre-outbreak bone marrow transplant. Therefore, six patients had life-threatening complications attributed to liver disease; of these six patients, three died, one survived with liver transplantation, and two are undergoing surveillance of esophageal varices or diuretic therapy.
Ten patients had liver histology showing stage 3 or 4 fibrosis (bridging fibrosis or cirrhosis) on liver biopsy performed during the first year of their evaluation and observation period. Nine of these 10 patients were successfully treated with antiviral therapy and achieved an SVR. The other patient underwent a successful liver transplantation an estimated 60 months following HCV acquisition.
During the observation period, 11 of the 64 patients in the study cohort died of their underlying malignancy, including two successfully treated HCV patients that had achieved an SVR with antiviral therapy (Fig. 2). As many as 46 of the 99 (46%) total Nebraska outbreak patients were dead as a result of their underlying cancer at 6 years following HCV infection (Evelyn V. McKnight and Travis T. Bennington, personal commmunication).
There has been a confirmed hepatitis C infection attributed to sexual transmission of HCV-3a from an outbreak study patient. The outbreak patient has since successfully achieved an SVR following antiviral therapy, and the newly infected individual has recently undergone therapy, achieving an SVR as well.
This study, initiated within 2 years of the nonconcurrent nosocomial outbreak, details the short-term (6-year) outcomes of 64 patients with HCV-3a infection originating in an oncology clinic. Despite our public efforts to recruit patients, and primarily because of their cancer comorbidity, our study was only able to enroll 64 of the 99 patients in the cohort. However, our enrollment of 64 patients is significantly greater than the number in the published epidemiologic study in which only 56 of the 99 were reported.4 We report no data on the acquisition or liver disease outcomes of HCV-3a infection in 35 individuals who were unable to consent, declined participation, or suffered complications from their underlying malignancy. This patient-to-patient HCV outbreak is notable for its size, common source, genotype, aged population, cancer comorbidity, near universal acquisition of chronicity, number of patients with undetectable HCV antibody, advanced stage of liver fibrosis, and morbidity and mortality, regardless of response to antiviral therapy.
Patient, virus, and social cofactors are known to influence the natural history of HCV and its response to therapy.3, 12 Although an infected individual's HCV genotype is thought to have little influence on the natural history, our study examined the outcome of a single genotype, HCV-3a, in patients with the presence of a significant comorbidity. Genotype 3a comprises less than 10% of all chronic HCV infections in the United States.13 In community-based studies comparing genotype to outcome, this small percentage is a consistent representation, with a significant majority (>70%) infected with genotype 1 typically at a young age.5, 14 Immunosuppression of the HCV patient (and, notably in one report, oncology patients infected with genotype 3) has been implicated as a cofactor that can lead to progression of liver injury.15, 16 Chemotherapy or bone marrow transplantation has been reported to accelerate liver injury in pediatric and adult HCV patients but the possible mechanisms—immunosuppression and/or idiosyncratic drug hepatotoxicity—are unclear.16, 17
Age of HCV acquisition >40 has also been shown to be the most aggressive cofactor that predicts rapid progression of liver fibrosis to cirrhosis.18–21
The mean age of our study cohort was approximately 55 years at acquisition of HCV-3a, and 93% were undergoing concurrent therapy for an underlying solid tumor or hematologic disease. When first evaluated, more than 95% of those individuals identified by State-directed screening with antibody and HCV RNA detection exhibited chronicity (that is, persisitent viremia). Remarkably, any clinical or biochemical evidence of acute hepatitis was distinctly unusual during the months prior to our evaluation. Portal hypertension was the most common presentation of patients with severe outcomes, with five patients developing ascites and/or esophageal variceal hemorrhage. Three study patients died of liver disease during the 72 months following acute infection, with preexisting but undiagnosed subtle liver disease the probable cofactor most responsible for their demise. One patient survived after undergoing a liver transplantation. The exceptionally high rates of chronic infection, antibody absence, and liver-related morbidity during a relatively short period of observation show the suspected effects of age and immunosuppression. Other risk factors for progressive liver fibrosis, particularly alcohol abuse, were rare in this cohort.
Corresponding to the risk of progressive fibrosis attributed to older age at infection and our observation of outcomes of significant morbidity and mortality, liver histology from 42 patients revealed an advanced stage of fibrosis within 48 months following infection. Genotype 3a infection is also associated with the histological steatosis in liver biopsy specimens obtained >20 years following acquisition of HCV.22 A mild degree of steatosis predominated the liver histology in our HCV-3a outbreak patients undergoing liver biopsy a mean of just 31 months following acute infection. Perhaps the appearance of hepatic steatosis during HCV-3a infection requires decades for metabolic factors to contribute.
Despite their age and comorbidity, antiviral therapy was successful in achieving an SVR in 84% of our study patients who elected treatment. Our observed SVR rate was similar to that reported by Hadziyannis et al.8 for younger patients with HCV-3a infection in a large, randomized trial. Patient preference, based on personal welfare, and concurrent cancer diagnosis led to no antiviral therapy in a significant number of patients. The effect of HCV and antiviral therapy on the clinical course of an individual's cancer or, conversely, the effect of chemotherapy on HCV infection and its treatment is unknown.
This patient-to-patient outbreak of viral hepatitis resulted from a failure of standard infection control practice and illustrates the continuing significant public health risk. Although our study group may not reflect, because of age and cancer comorbidity, the demographics of the prevalent HCV-infected person, the Nebraska outbreak and its outcomes demonstrate the risk to patients resulting from poor infection control. This HCV outbreak was emotionally and psychologically devastating to the affected patients and their families. The short-term significant health outcomes, focusing on the liver complications, are described by this study, but the effect on their quality of life and the long-term consequences will likely never be fully appreciated. As of May 2008, 89 outbreak-associated lawsuits had been completed, with out-of-court settlements reached in 88 of the 89 actions, and only one case had been ultimately litigated in a court trial.
The authors thank Evelyn V. McKnight and Travis T. Bennington for their support and communication.