The unequivocal demonstration of a nosocomial transmission of the hepatitis C virus (HCV)123 to hemodialyzed (HD) patients has initiated a debate on the preventive measures to be taken in HD units4.
Following the successful experience of segregation of hepatitis B virus (HBV) (+) patients, which led to a drastic fall of HBV transmission before the vaccination era5, several authors have advocated the isolation of anti-HCV (+) patients in a separate HD room1,3,6789. In sharp contrast, other authors10111213 have stressed that nosocomial transmission probably resulted mainly from an inadequate application of the universal precautions delineated by the Centers for Disease Control (Atlanta, GA, USA)14, and concluded that prevention of HCV nosocomial transmission would be better achieved by strict adherence to the universal precautions by staff members, than by the cumbersome, not fully secure, segregation of patients.
We have taken advantage of an ongoing prospective Belgian multicenter study to evaluate the benefits of the latter policy in the absence of patient isolation. We demonstrate the full prevention of HCV transmission.
METHODS
Hemodialysis units
All 15 units involved in the initial 18-month phase of the study10 accepted to participate for two further 18-month periods, for a total follow-up of 54 months. A single small unit was closed as of September 1993, and most of its patients were transferred to another participating unit. None of the units isolated anti-HCV (+) patients. As the results of the initial 18 month survey strongly suggested nosocomial transmission of HCV10, staff meetings were held in participating units in order to explain the universal precautions14 and identify potential breaks in their implementation.
Patients
All patients given chronic hemodialysis either in hospital-based or in low-care facilities were included. They were tested for anti-HCV antibodies every 18 months from May 1991 to November 1995. Patients on home HD or peritoneal dialysis were not included.
No patient was an intravenous drug abuser or had antibodies against the human immunodeficiency virus.
Virologic tests
Screening
Screening was performed by second generation enzyme-linked immunosorbent assay (ELISA 2; Ortho Diagnostic Systems, Raritan, NJ, USA) in May 1991 and November 1992, and by the more sensitive15,16 third generation ELISA (ELISA 3; Ortho) in May 1994 and November 1995.
In order to facilitate comparisons between the three consecutive 18-month periods, only patients tested at these 18 month intervals were included. Thus, in contrast with our initial 18 month study10 in which patients were tested (and included) every six months, patients tested only in November 1991 and/or May 1992 were not included.
Confirmation
ELISA 2 positive patients were tested by the second-generation recombinant immunoblot assay (RIBA 2; Ortho). ELISA 3 positive patients were tested by the third generation RIBA15 and/or the reverse transcriptase nested polymerase chain-reaction (RT-PCR) for the detection of HCV-RNA17. The detection of antibodies against at least one HCV antigen or of HCV-RNA was considered as confirmatory. In order to differentiate true seroconversion from an apparent seroconversion resulting from the higher sensitivity of ELISA 3, the ELISA 2 (-) sera of patients who became subsequently ELISA 3 (+) were retested by the ELISA 3.
Genotyping of HCV strains
All genotyping of the HCV strains was performed by Inno-Lipa II18.
Hemodialysis practices
Blood transfusions administered throughout the study were recorded for each patient as previously described10. Each unit was asked to fill in a form detailing HD practices such as the frequency of disinfection of HD monitors and the existence of a program of dialyzer reuse, during each 18-month period, and to state the actual proportion of patients concerned.
Statistics
Standard statistical tests were performed as indicated. P values < 0.05 were considered as significant.
RESULTS
Patient characteristics
A total of 963 patients (545 males) were included. At the time of inclusion, they had a median age of 60 years (range, 12 to 88 years old) and had been on HD for a median of 11 months (range, < 1 to 257 months).
Follow-up of the included patients
Four hundred and eighty-eight patients were tested more than once and were included in both the longitudinal and prevalence studies. The other 475 were added to the prevalence study only, as they were tested only once as a result of death (N = 170), renal transplantation (N = 85), transfer to CAPD (N = 4) or to non-participating HD units (N = 16), recovery of renal function (N = 3) or inclusion in November 1995 (N = 197).
Incidence of seroconversion for hepatitis C virus
During the three consecutive 18-month periods, the yearly seroconversion rate dropped from 1.41% (5 of 236 patients at risk) to 0.56% (2 of 238 patients at risk) and 0% (0 of 269 patients at risk) (
2 for trend, P = 0.014).
The five seroconversions observed during the initial 18 months were detected in three unrelated HD units: unit A, N = 2; unit B, N = 2; unit C, N = 1. The subsequent two seroconversions were detected in two unrelated HD units: unit A and unit D. The genotypes of HCV strains of patients with seroconversion from units A and B were 1b, 4 and 4 c/d one each (unit A) and 1b for both patients (unit B).
Prevalence of anti-hepatitis C virus positive patients
Anti-HCV antibodies persisted in all patients throughout the follow-up period, for a total follow-up of 169 patient-years. The prevalence of confirmed anti-HCV (+) patients dropped from 13.5% (54 of 399) in May 1991 to 11.8% (51 of 433) in November 1992, 12.7% (61 of 481) in May 1994 and 9.4% (48 of 510) in November 1995. This drop in prevalence between May 1991 and November 1995 barely reached significance (2, P = 0.0507).
Evolution of hemodialysis practices
During the three consecutive 18-month periods, no significant change was observed in the percentage of patients with dialyzer reuse (37, 37 and 35% respectively; 2 for trend, NS) and in that of patients whose HD monitors were disinfected after each session (25, 28 and 31%, respectively; 2 for trend, NS). The same was true when only the percentage of involved units was considered (Table 1; 2 for trend, NS).
Table 1 - Incidence of seroconversion and evolution of hemodialysis (HD) practices over three consecutive 18 month periods.
Full table (22K)Blood transfusions
The number of blood transfusions administered to patients at risk of seroconversion did not change during the three consecutive periods: 1.4 
3.7 (SD) unit/18 months/patient, 1.7 4.3 and 1.3 3.8, respectively (Mann-Whitney U-test, NS; Table 1). Of note, three of the seven patients with seroconversion (2 of 5 and 1 of 2 during the first and second 18-month studies, respectively) had not been transfused during the preceding 18 months.
DISCUSSION
In our multicenter study, the incidence of seroconversion for HCV in HD patients fell progressively to zero over a 54 month period. This observation is even more impressive as ELISA tests were more sensitive in the last two periods than in the first one. Admittedly, rare new HCV infection(s) might have been missed by the ELISA tests, as recently reported in abstract form19. Still, in the few cases of unexplained alanine aminotransferase increase, which were tested by PCR, HCV-RNA was not detected (data not shown).
Possible explanations for our results should be discussed. Better prevention of transfusional HCV transmission is not a likely explanation as the average transfusional load did not change over the three periods. Admittedly, the testing of blood donors improved substantially over the 54 months, the first generation tests being replaced by the more sensitive second and, eventually, third generation tests. The risk of transfusional transmission of HCV has clearly decreased with recent screening tests20,21. However, three of the seven detected seroconversions occurred in non-transfused patients; furthermore, our initial study strongly pointed to nosocomial HCV infection in some of our patients10.
Changes in dialyzer reuse are also unlikely to have contributed to the fall of the incidence of HCV seroconversion. Dialyzer reuse was not a risk factor for seroconversion over the initial 18-month period10. Furthermore, in contrast to the progressive fall in the incidence of seroconversion over the entire 54 months, the overall reuse policy did not change, as illustrated by the stability of the % of patients with reuse. Interestingly, most units with reuse do not use a separate room for the reuse of dialyzers in HCV (+) patients (data not shown), a finding in contrast with the recent suggestion that the absence of this precaution may be a risk factor for seroconversion22.
The prevention of HCV transmission through contaminated HD monitors is also unlikely to account for the decreasing incidence of seroconversion. Indeed, no new case of HCV transmission occurred despite an unchanged (and poor) disinfection policy of monitors: over the 54 months, over 70% of the patients were dialyzed in units whose monitors were not disinfected after each session. This observation argues against a significant role of monitors in HCV transmission at all!
The role of infected staff members as a significant source of HCV infection for patients appears also unlikely. Indeed, the number of HCV (+) nurses working in participating units decreased only slightly from six23 to five (unpublished data) over the last three years. In contrast, the incidence of HCV transmission dropped markedly. The recent demonstration of HCV transmission from a surgeon to five of his patients24 thus remains unusual.
It might be argued that the trend towards a lower prevalence of anti-HCV (+) patients was the factor that reduced the risk of nosocomial transmission, and hence decreased the incidence of seroconversion. This hypothesis does not account for our observations as the prevalence of anti-HCV (+) at the onset of the last 18 month period was 12.7%, similar to that at the onset of the study (13.5%).
In the absence of a more convincing explanation, we propose that the suppression of HCV transmission resulted from the improved enforcement of universal precautions. Although adherence to universal precautions was not quantitated in this long-term multicentric study, it is noteworthy that the decrease in HCV transmission coincided with the efforts to fully describe the universal precautions to staff members as well as patients, and improve their actual implementation in the participating units. A special emphasis was laid upon hand washing, the use of gloves and the avoidance of sharing of articles between patients. Our results support the CDC statement that universal precautions should prevent HCV transmission in HD patients12, especially as the infectivity of HCV is much lower than that of HBV. They are also in line with the experience reported in abstract form by the E. Rist Medical Center in Paris, where a 0% incidence has been maintained over several years despite a high HCV prevalence and the absence of isolation25.
The alternative policy to the strict implementation of universal precautions is the isolation of anti-HCV (+) HD patients in a separate room or on separate monitors. In 1993, these respective policies were adopted by 18 and 37% of HD units from the European Dialysis and Transplant Association Registry26. These percentages have increased more recently in Spain and Portugal22,27.
The effectiveness of isolation in separate rooms remains to be demonstrated. In Portugal, units isolating anti-HCV (+) patients reported a rather high (3.2%) yearly incidence of seroconversion in 1991 to 1993 (prevalence around 25%)22. The safety of isolating anti-HCV (+) HD patients also remains unproved. Indeed, as pointed out elsewhere11, isolation entails the risk of less than adequate implementation of universal precautions, with an attendant higher risk of cross-infection by multiple HCV strains and/or other viruses. In this regard preliminary results suggest that the incidence of infection by the recently discovered hepatitis G virus (HGV) also fell to zero in our unit in parallel with that of HCV. Finally, isolation entails a substantial cost, especially in units with HBsAg (+) patients, in which up to four wards (to accommodate the B+C+, B+C-, B-C+, B-C- patients) may be required.
The dedication of separate monitors for HCV (+) patients has been advocated as an alternative. Two small single center studies have recently reported a low (but not 0%) incidence of seroconversion for HCV28,29 with this policy. The risks of cross-infection are not avoided by this policy, and its large scale effectiveness remains to be demonstrated. As the role of the monitors in HCV transmission appears limited, the degree of effectiveness of this policy is likely to depend mainly on the associated improved application of universal precautions, the segregation acting mainly as a reminder of the risk of viral transmission.
Nosocomial transmission of HCV has recently been demonstrated both in a hematology ward30 and in renal transplant recipients31. On the basis of our observations it may be proposed that in these other, less exposed settings, prevention should also rely mainly on an enforced adherence to universal precautions.
In conclusion, we report the full prevention of HCV transmission to HD patients by implementing universal precautions, rather than isolation of anti-HCV (+) patients.
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Acknowledgments
This study was presented at a Mini Symposium at the XXIXth American Society of Nephrology meeting (New Orleans, 1996). The authors gratefully acknowledge the invaluable help of the nurses of all participating units, and Ortho Diagnostics Systems for the gift of ELISA tests.
