Identification of chronic hepatitis B and hepatitis C co-infection in British Columbia from 1991 to 2007.

Fang, Lily ; Yu, Amanda ; Buxton, Jane A. 等

Globally, viral hepatitis accounts for a considerable burden of morbidity and mortality. Hepatitis B (HBV) and hepatitis C (HCV) are the most common causes of chronic liver disease in different regions (1) and the majority of cirrhosis and hepatocellular carcinoma has been attributed to either virus. (2) In 2002, 103,000 and 53,000 deaths worldwide were estimated to be directly caused by HBV and HCV, respectively. (3) There are an estimated 500,000 to 600,000 people in Canada infected with either HBV or HCV. (4) Among individuals acutely infected with HBV, the risk of chronic HBV infection varies inversely with age; the risk among HBV-infected infants is 90% compared to 1-5% in adults. (5) Among HCV-infected persons, 60-85% will develop chronic HCV infection. (6) Because HBV and HCV share common risk factors and routes of transmission, (1,7) co-infection is not uncommon. (8) Co-infection with two or more hepatitis viruses is associated with poorer outcomes and accelerated progression of liver disease. (1,7-9)

Although the burden of illness associated with HBV/HCV co-infection is substantial, few studies have detailed its epidemiology and none have described it in the general Canadian population.

This study identifies chronic HBV/HCV co-infection among all HBV and HCV reported cases in British Columbia (BC) since 1991, probably the largest cohort from North America. In Canada, including BC, most HBV infections are identified in immigrants from endemic countries. (10) Also, Vancouver continues to have the largest injection drug use problem among Canadian jurisdictions. (11) We determine HBV/HCV co-infections identified between 1991 and October 2007 and examine the order of virus identification, demographic characteristics at the time of co-infection identification, and observe temporal trends.

METHODS

Data source

All laboratories in BC routinely send HBV and HCV reports to the appropriate regional health authorities (HAs). Newly identified cases of HBV and HCV, who are BC residents and have not been reported elsewhere in Canada, are entered into the BC integrated Public Health Information System (iPHIS). Cases of chronic HBV and HCV reported 1991 to October 2007 were extracted from iPHIS.

Case identification and data management

Nominal data and Personal Health Number (PHN) from iPHIS were used to link reported cases of HBV and HCV to establish co-infection. For individuals entered into iPHIS with HBV or HCV more than once, the date of the first entry was used as the date of virus identification. Date of co-infection was the date when the second hepatitis virus was identified; if both HBV and HCV diagnoses were reported within 14 days, diagnoses were considered concurrent to account for laboratory testing and reporting delays. We included chronic HBV infection where the hepatitis B surface antigen (HBsAg) is present for over six months and undetermined where acute HBV infection was not identified through clinical history or laboratory tests. Cases reported as acute HBV only (i.e., not reentered later as chronic HBV) were excluded because most acutely infected adults do not develop chronic HBV. Once data linkage was performed using a computer algorithm, personal identifiers (first and last name and PHN) were deleted and anonymized data were analyzed. Data were cleaned of cases with probable data entry errors. BC guidelines recommend that testing of high-risk infants is performed 1-6 months after completion of HBV vaccine series (given at 0, 1 and 6 months); therefore HBV infections identified within seven months of birth were excluded. Babies at risk for maternal transmission of HCV should not be tested before six weeks of age; therefore cases identified within six weeks of birth were removed. To avoid bias to the sequence of virus identification, HBV and HCV diagnoses pre-1991 were excluded.

The study received ethical approval from the Behavioural Research Ethics Board at the University of British Columbia.

Statistical analyses

Data linkages and analyses were performed using SAS9.1 (Cary, NC). To determine the identification rate of HBV/HCV co-infection in BC, 2007 Population Estimates and Projections (P.E.O.P.L.E.32) were obtained from BC Stats. The mean population estimate during the observation period was used to calculate the cumulative identification rate. Data were available until October 2007; no seasonal variation was identified, therefore the annual identification rate and cases of virus identification for 2007 were pro-rated for the complete year. The order of hepatitis virus identification was compared by sex and residence using chi-square and by co-infection age using ANOVA. Sex differences were tested for age at co-infection, age at first hepatitis virus identification, and time from first virus to co-infection identification using t-tests. A two-sided p-value <0.05 was considered statistically significant. The distribution of age at co-infection identification was tested for normality using normal probability plots.

RESULTS

Between 1991 and October 2007, 1,815 BC residents were identified with HBV/HCV co-infection; the cumulative co-infection identification rate was 45.9 per 100,000 persons. The mean age at co-infection diagnosis was 40.5 years (95% CI, 40.0-41.0, SD=10.3, range 3-85 years) and 71.6% of cases were male (Table 1). Two thirds of cases resided in Vancouver Coastal Health Authority (VCHA) or Fraser Health Authority (FHA) at the time of co-infection diagnosis, with 26.6% living in the Vancouver Health Service Delivery Area (HSDA) (Figure 1). In comparison, among 55,289 BC residents identified with HCV but not HBV, the mean age of diagnosis was 41.3 years (95% CI, 41.2-41.4, SD=12.3, range 0-97 years) and 65% were male. Among the 27,455 identified cases of HBV but not HCV, the mean age at identification was 39.2 years (95% CI, 39.0-39.3, SD=14.2, range 0-95 years) and 52.9% were male.

[FIGURE 1 OMITTED]

Of all persons identified with HCV infection, 3.1% were identified as co-infected with HBV, and 5.2% of all chronic HBV-infected were diagnosed with HCV. The geographic distribution of HBV/HCV co-infection was similar to that of HCV (Table 1). The annual population rate of HBV/HCV co-infection identification decreased from 5.3 in 1996 to 1.02 per 100,000 in 2007 (Figure 2).

Overall, age-specific HBV/HCV co-infection identification rate was highest among BC residents aged 30-49 years; however, since 2005, the identification rate among individuals aged 20-29, 30-39, and 40-49 years was similar. Ages at infection were normally distributed. Females were significantly younger when they were diagnosed with the first hepatitis virus, mean age 35.2 years (95% CI, 34.0-36.5, SD=11.1, range 2-77 years) compared with 37.9 years (95% CI, 37.039.7, SD=10.5, range 2-84 years) among males (p=0.0005), and women were slightly younger when co-infection was identified, mean age 39.7 years (95% CI, 38.6-40.7, SD=12.0, range 3-79 years) compared with males, 40.8 years (95% CI, 40.2-41.4, SD=10.4, range 4-85 years) (p=0.05). Reported co-infection rates varied between HAs (Figure 1) and within HAs (data not shown).

[FIGURE 3 OMITTED]

Half (49.9%) of HBV/HCV co-infection cases consisted of concurrent identification of both viruses (Table 2). The mean age at co-infection diagnosis did not differ by order of virus identification (p=0.72). For those 478 (26.3%) persons where HBV was identified first, the median time to HCV identification was 882.5 days overall (887.5 days for males, 854.0 days for females). Among the 432 (23.8%) individuals identified with HCV first, the median time to HBV identification was 773.0 days overall (879.5 days for males, 615.0 days for females). Until 2003, the majority of co-infections consisted of cases diagnosed with HBV and HCV simultaneously. Since 2003, the number of coinfected cases by order of hepatitis identification (HBV first/HCV first or concurrent) was similar (Figure 3). Males had a higher rate of co-infection than females for all orders of diagnosis.

DISCUSSION

Identification of HBV and HCV depends on testing for these viruses. Half (48.5%) of all HBV reported infections in BC are male compared to two thirds (65.3%) of HCV infections. Between 1991 and October 2007, 1,815 cases of HBV/HCV co-infection were identified. The rate of HBV/HCV co-infection identification peaked during 1996-1999, following the 1996 notification of persons who had received blood products between 1986 and 1990 advising them to undergo HCV testing. Newly-identified HCV infections may be persons infected decades ago and now experiencing symptoms of liver damage/cirrhosis, or persons tested due to risk factors. Since 2003, BC Centre for Disease Control (BCCDC), where the majority of HCV testing is performed, has automatically tested HCV-reactive sera for hepatitis A virus and HBV immune status to determine vaccination eligibility. If HBV immunity is not identified, the specimen is tested for current infection. Automatic testing may account for some simultaneous identification, but does not appear to have affected the trends in simultaneous HBV/HCV identification. We used reporting within 14 days to determine concurrent identification; as date of diagnosis is used, delays in reporting will not affect the classification of order.

In BC, women have routine prenatal HBsAg testing but not HCV serology. However, a greater proportion of women than men had HBV identification secondary to HCV, suggesting follow-up of persons infected with HCV should be improved to ensure appropriate testing. Only 3.1% of persons with HCV infection were identified as co-infected with HBV; however, this underestimates past HBV infection by testing with hepatitis B core antibody (anti-HBc) as the virus is cleared in the majority of non-infant HBV infections. A study among HCV-infected northern Albertans found 44.3% had serologic evidence of past infection. (12)

HBV vaccination programs in BC may have contributed to the decline in HBV/HCV co-infection. In 1992, universal HBV vaccination for grade six students and provincially-funded HBV vaccine for injection drug users (IDUs) were introduced; HCV-reactive BC residents became eligible for HBV vaccine in 1997. An HBV vaccination blitz in Vancouver's Downtown Eastside, an area home to many IDUs, (13) was undertaken in 2000. Most chronic HBV cases in BC are immigrants; therefore, vaccination will have more effect on acute cases, but chronic HBV prevalence may decrease as endemic countries implement infant immunization programs. A universal infant HBV immunization program was introduced in BC in 2001.

The higher HBV/HCV co-infection rate among males is not surprising as 65% of all HCV cases identified in BC are male. The Provincial Laboratory of Northern Alberta also found the majority of HCV-positive individuals were male, (12) despite the fact that females were more likely to get tested. (14) The majority of HCV cases diagnosed in Vancouver in 2005 and 2006 reported injection drug use, (15) which is the leading cause of HCV infection. (16,17)

Inmates of correctional facilities have a high prevalence of hepatitis. In Maryland correctional facilities, 56.1% of individuals positive for anti-HBs and anti-HBc were HCV-positive, (18) and the prevalence of HCV among inmates in Ontario remand facilities is 22 times higher than that of the general population. (19) HA of residence (including a correctional facility) at time of testing is reported into iPHIS. Admission to a correctional facility provides an opportunity for HCV testing; therefore some HCV infections reported in FHA may reflect persons tested within correctional facilities located there.

There are several limitations of the data. With administrative data based upon laboratory diagnosis of a chronic sometimes asymptomatic infection, the time of infection and incidence or prevalence of HBV/HCV co-infection cannot be determined. Some persons identified as HCV-reactive may have cleared the virus; others were infected years prior to testing, while others may be recent sero-conversions. Although most HCV testing is performed at the BCCDC provincial laboratory, allowing quality control, HBV testing is performed at hospitals and private laboratories throughout the province. Access to laboratory results from the whole province, including previous negative results, would improve incidence and prevalence data. HCV became a reportable disease in BC in 1992, resulting in the underestimation of HBV/HCV co-infection values for 1991 and 1992. The identification rate of HBV/HCV co-infection is likely an underestimate, especially given the asymptomatic nature of the infection and the need to present for testing.

Despite limitations, the ability to estimate the current and projected burden of HBV/HCV co-infection in BC is valuable so that HBV and HCV prevention and care programs can be improved and evaluated. Although the number of co-infections identified in BC has been declining since 2001, more effort could be made to address individuals at risk for co-infection and at-risk persons should be tested for the second virus. Some cases of co-infection could be prevented through HBV vaccination; automatic testing of HCV-positive sera identifies individuals eligible for immunization. Harm reduction activities should be accessible for those with or at risk for infection with blood-borne pathogens.

Acknowledgements: We thank Sunny Mak for his assistance.

Received: January 8, 2009

Accepted: June 24, 2009

REFERENCES

(1.) Chuang CS, Tung SY, Lee IL, Shen CH, Wei KL, Chang TS, Wu CS. Clinical features and outcome of chronic viral hepatitis with acute exacerbation in patients with concurrent infections of hepatitis B and C virus. Dig Dis Sci 2008;53(2):511-16.

(2.) Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45(4):529-38.

(3.) World Health Organization. The World Health Report 2003: Shaping the future. Geneva, Switzerland: WHO, 2003.

(4.) Sherman M, Shafran S, Burak K, Doucette K, Wong W, Girgrah N, et al. Management of chronic hepatitis B: Consensus guidelines. Can J Gastroenterol 2007;21 Suppl C:5C-24C.

(5.) Heymann DL (Ed.). Control of Communicable Diseases Manual, 18th ed. Baltimore, MD: United Book Press, Inc., 2004.

(6.) NIH consensus statement on management of hepatitis C: 2002. NIH Consens State Sci Statements 2002;19(3):1-46.

(7.) Koff RS. Risks associated with hepatitis A and hepatitis B in patients with hepatitis C. J Clin Gastroenterol 2001;33(1):20-26.

(8.) Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, Bost-Bezeaux F, et al. Characteristics of patients with dual infection by hepatitis B and C viruses. J Hepatol 1998;28(1):27-33.

(9.) Sagnelli E, Coppola N, Scolastico C, Mogavero AR, Filippini P, Piccinino F. HCV genotype and "silent" HBV coinfection: Two main risk factors for a more severe liver disease. J Med Virol 2001;64(3):350-55.

(10.) Zhang J, Zou S, Giulivi A. Epidemiology of hepatitis B in Canada. Can J Infect Dis 2001;12(6):345-50.

(11.) Dell CA, Garabedian K. Canadian Community Epidemiology Network on Drug Use (CCENDU): 2002 National Report: Drug trends and the CCENDU network. 2003;93.

(12.) Kiefer LA, Honish A, Predy G, Talbot JA. The seroprevalence of hepatitis A and B in people testing positive for hepatitis C. CMAJ 2000;162(2):207-8.

(13.) Weatherill SA, Buxton JA, Daly PC. Immunization programs in nontraditional settings. Can J Public Health 2004;95(2):133-37.

(14.) Jayaraman GC, Lee B, Singh AE, Preiksaitis JK. Trends in testing behaviours for hepatitis C virus infection and associated determinants: Results from population-based laboratory surveillance in Alberta, Canada (1998-2001). J Viral Hepat 2007;14(4):249-54.

(15.) Buxton J, Mehrabadi A, Preston E, Tu A. Vancouver drug use epidemiology: Site report for the Canadian Community Epidemiology Network on Drug Use. 2007;80.

(16.) Gully PR, Tepper ML. Hepatitis C. CMAJ 1997;156(10):1427-30.

(17.) Patrick DM, Tyndall MW, Cornelisse PG, Li K, Sherlock CH, Rekart ML, et al. Incidence of hepatitis C virus infection among injection drug users during an outbreak of HIV infection. CMAJ 2001;165(7):889-95.

(18.) Solomon L, Flynn C, Muck K, Vertefeuille J. Prevalence of HIV, syphilis, hepatitis B, and hepatitis C among entrants to Maryland correctional facilities. J Urban Health 2004;81(1):25-37.

(19.) Calzavara L, Ramuscak N, Burchell AN, Swantee C, Myers T, Ford P, et al. Prevalence of HIV and hepatitis C virus infections among inmates of Ontario remand facilities. CMAJ 2007;177(3):257-61.

Lily Fang, MHSc, [1,2] Amanda Yu, BSc, [1] Jane A. Buxton, MBBS, MHSc [1,3]

[1.] British Columbia Centre for Disease Control, Vancouver, BC

[2.] Department of Public Health Sciences, University of Toronto, Toronto, ON

[3.] School of Population and Public Health, University of British Columbia, Vancouver, BC

Correspondence: Dr. Jane A. Buxton, BC Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC V5Z 4R4, Tel: 604-660-8747, Fax: 604-660-0197, E-mail: jane.buxton@bccdc.ca

Table 1. Demographic Characteristics of
1,815 Chronic HBV-HCV Co-infected,
31,346 Chronic HBV Mono-infected and
56,546 Chronic HCV Mono-infected British
Columbia Residents between 1991 and
October 2007

                                       No. (%) of Cases

                          HBV/HCV
Characteristic          Co-infection     HBV Only        HCV Only

Sex                     1810           31,085          56,347
  Male                  1299 (71.6)    14,650 (52.9)   36,648 (65.0)
  Female                 511 (28.2)    16,434 (47.1)   19,693 (35.0)
  Transgender *            0  (0.0)         1  (0.0)        6  (0.0)
Age at time of          1774           27,455          55,289
  diagnosis (years)
  0-9                      2  (0.1)       187  (0.7)      242  (0.4)
  10-19                   20  (1.1)      1632  (5.9)      827  (1.5)
  20-29                  236 (13.3)      5332 (19.4)     7598 (13.7)
  30-39                  611 (34.4)      7605 (27.7)   16,275 (29.4)
  40-49                  592 (33.4)      6968 (25.4)   18,835 (34.1)
  50-59                  221 (12.5)      3174 (11.6)     7673 (13.9)
  60+                     92  (5.2)      2557  (9.3)     3839  (6.9)
Residence at time       1815           31,346          56,546
  of diagnosis
  Fraser Health          529 (29.2)      9792 (31.2)   18,099 (32.0)
    Authority
  Interior Health        223 (12.3)       535  (1.7)     8044 (14.2)
    Authority
  Northern Health        119  (6.6)       356  (1.1)     3490  (6.2)
    Authority
  Vancouver Coastal      643 (35.4)    19,572 (62.4)   15,971 (28.2)
    Health
    Authority ([dagger])
  Vancouver Island       301 (16.6)      1091  (3.5)   10,942 (19.4)
    Health Authority

* Sex at birth unknown
([dagger]) Includes City of Vancouver

Table 2. Demographic Characteristics of
HBV-HCV Co-infected British Columbia
Residents Identified between 1991 and
October 2007 by Order of Virus
Identification

Diagnosis Order         Number (%)         Median Time Interval
                         of Cases           between HBV and HCV
                                           Identification (Days)

HBV first               478 (26.3)                 882.5
HCV first               432 (23.8)                 773.0
HBV/HCV                 905 (49.9)                  N/A
  concurrently *

Diagnosis Order                                     Sex
                                             No. (%) of Cases

                           Male                   Female

HBV first               330 (69.3)              146 (30.7)
HCV first               267 (62.1)              163 (37.9)
HBV/HCV                 701 (77.7)              201 (22.3)
  concurrently *

* This includes HBV and HCV infections
diagnosed within 14 days.

Figure 2. Rate of HBV/HCV co-infection identification in
British Columbia stratified by sex

       1991  1992  1993  1994  1995  1996  1997  1998  1999  2000

Male   0.54  2.02  2.53  2.24  5.47  6.95  7.28  6.82  7.62  5.48
Female 0.06  1.21  0.78  0.65  1.74  3.6   2.17  3.05  2.82  2.41

Total   0.3  1.61  1.65  1.47  3.65  5.27  4.74  4.92  5.21  3.94

       2001  2002  2003  2004  2005  2006  2007

Male   4.64  3.43  3.11  2.21  2.23  2.15  1.39
Female 1.56  1.74  1.1   0.52  1.12  0.55  0.65

Total  3.11  2.58  2.09   1.36 1.67  1.35  1.02