Scandinavian Journal of Infectious Diseases
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Need for improvements in the surveillance and management of chronic viral hepatitis in HIV patients followed in a Danish outpatient clinic Karen Lise Dahl Andersen, Carsten Schade Larsen, Mikkel Steen Petersen & Peter Derek Christian Leutscher To cite this article: Karen Lise Dahl Andersen, Carsten Schade Larsen, Mikkel Steen Petersen & Peter Derek Christian Leutscher (2014) Need for improvements in the surveillance and management of chronic viral hepatitis in HIV patients followed in a Danish outpatient clinic, Scandinavian Journal of Infectious Diseases, 46:8, 578-584 To link to this article: http://dx.doi.org/10.3109/00365548.2014.918648
Published online: 16 Jun 2014.
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Date: 16 November 2015, At: 03:59
Scandinavian Journal of Infectious Diseases, 2014; 46: 578–584
ORIGINAL ARTICLE
Need for improvements in the surveillance and management of chronic viral hepatitis in HIV patients followed in a Danish outpatient clinic
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KAREN LISE DAHL ANDERSEN1, CARSTEN SCHADE LARSEN1, MIKKEL STEEN PETERSEN2 & PETER DEREK CHRISTIAN LEUTSCHER1 From the 1Department of Infectious Diseases, and 2Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
Abstract Objectives: The aim of this study was to assess hepatitis B virus (HBV) and hepatitis C virus (HCV) surveillance and management in HIV patients currently followed in an outpatient clinic at a Danish University Hospital. Methods: Patient data, including demographic characteristics, clinical findings, and hepatitis serology, were reviewed at baseline. Patients with incomplete or non-updated serology within the last 2 y were retested in the next 6 months, and the results were reviewed again at follow-up. Results: At baseline, 84% and 74% of the 574 HIV patients were found to have incomplete and/or non-updated HBV and HCV serology, respectively. At follow-up, updated HBV serology was achieved in 535 (93%) patients; 15 (3%) patients were found to have a chronic active infection and 156 (27%) had a resolved infection, whereas 65 (11%) were vaccinated against HBV and 299 (52%) were non-immune. No patients were found to have developed chronic HBV infection following HIV diagnosis (equal to 3649 patient-y). Updated HCV serology revealed that 25 (4%) had a chronic active HCV infection and 15 (3%) had a resolved HCV infection. The anti-HCV incidence rate was 0.27/100 patient-y. A liver pathology assessment had not been performed within the last 2 y in 80% of the HBV and 32% of the HCV co-infected patients. Conclusions: Hepatitis screening and assessment had been inadequately performed. New cases of chronic hepatitis seem to occur infrequently. However, a more proactive hepatitis surveillance and management strategy integrated into the overall HIV health care program is warranted.
Keywords: HIV, viral hepatitis, screening, seroprevalence, vaccination
Introduction The prevalence of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) in Northern Europe is low in the general population. In Denmark, the prevalence of HIV among adults has been estimated to be less than 0.1%, and of HBV and HCV to be less than 0.2% [1]. However, 6% of HIV patients have been found to be co-infected with HBV [2] and 13% with HCV [3]. International guidelines recommend HBV and HCV serology testing at the time of HIV diagnosis [4,5]. The results should be followed up with HBV
vaccination of non-immunized HIV patients and HCV control screening of HCV antibody (antiHCV)-negative subjects. In addition, HIV patients should be proactively treated for chronic active HBV and HCV infection aimed at viral suppression and eradication, respectively. Chronic hepatitis is at risk of being neglected in the HIV clinic, as shown in a recently published study from the USA on hepatitis screening and vaccination of HIV-infected men who have sex with men (MSM), in which a low adherence to the existing international hepatitis guidelines was observed [6].
Correspondence: K. L. Dahl Andersen, Department of Infectious Diseases, Aarhus University Hospital, Brendstrupgårdsvej 100, 8200 Aarhus N, Denmark. Tel: ⫹ 45 7845 2844. Fax: ⫹ 45 7845 2848. E-mail: [email protected] (Received 7 November 2013 ; accepted 22 April 2014 ) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.918648
HBV/HCV screening and vaccination in HIV patients The main objective of this study was to evaluate the practice and outcome of viral hepatitis management, including screening, vaccination, and liver pathology assessment among HIV patients followed in a Danish University Hospital outpatient clinic.
Methods
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Patients and study design At baseline in April 2012, historical HBV and HCV serology results were reviewed for all actively followed adult HIV patients in the outpatient clinic at Aarhus University Hospital. If the most recent serology result was dated prior to 1 January 2011, a new hepatitis serology test was performed at the next scheduled visit in the clinic. The goal was to obtain an updated (⬍ 2 y) hepatitis serology status for all patients followed at the clinic. At the time of follow-up in January 2013, all serology test results were reviewed again. When assessing hepatitis screening practices over the last 12 y among newly diagnosed HIV patients, hepatitis serology results were considered valid for analysis if testing had been performed within ⫾ 180 days of the HIV diagnosis. Hepatitis test Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis C virus antibody (anti-HCV) were assessed by use of a standard assay (Architect; Abbott Diagnostics). If anti-HCV was positive, HCV RNA (Procleix; Novartis) was measured quantitatively. HBV infection/immunization and HCV infection were defined according to serology test results in the following categories: chronic HBV infection (positive HBsAg of more than 6 months duration); resolved HBV infection (negative HBsAg, negative/positive anti-HBs, and positive anti-HBc); HBV immunization (positive anti-HBs and negative anti-HBc); non-immune HBV (negative HBsAg, anti-HBs, and anti-HBc) [7]; chronic HCV infection (positive antiHCV and positive HCV RNA); resolved HCV infection (positive anti-HCV and negative HCV RNA); and no previous HCV infection (negative antiHCV).
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and InfCare HIV databases (Health Solutions AB, Stockholm); the InfCare HIV database has been implemented as a clinical decision support tool and as an instrument for quality assurance among HIV patients at Aarhus University Hospital. Patient demographic data were analysed according to HBV/HCV immune status by use of the Chi-square test (all data other than age) and the Wilcoxon signed rank test. p-Values of ⬍ 0.05 were considered significant. HIV patients with an HBV/HCV chronic infection and resolved infection were tested against HBV/HCV non-immune HIV patients. If there were more than 2 variables, each variable was tested against all others. Stata Intercooled version 12 was used for the data analysis.
Results Socio-demographic characteristics The study population consisted of 574 HIV patients: 388 (68%) men and 186 (32%) women (Table I). Median age was 48 y (interquartile range (IQR) 40–55 y). Men were significantly older than women: 49 y (IQR 42–57) vs 43 y (IQR 38–49) (p ⬍ 0.05). A majority of patients were registered as Caucasian (72%), followed by African (20%) and Asian (5%). Most HIV patients originated from Denmark (n ⫽ 391; 68%). Two-thirds of the 183 HIV patients who did not originate from Denmark were female. MSM and heterosexual men accounted for the largest transmission risk group (both 37%), followed by women (24%) and intravenous (IV) drug users (3%). Table I. Baseline characteristics of the study population. Characteristics
N ⫽ 574
Data handling and analysis
Age, y, median (IQR) Sex, n (%) Male Female Ethnicity, n (%) Caucasian African Asian Other Country of origin, n (%) Denmark Other HIV risk/transmission group, n (%) MSM Heterosexual men Women IV drug users Other
48 (40–55)
Clinical history and serology data were extracted in January 2013 from the real-time InfCare Hepatitis
IQR, interquartile range; MSM, men who have sex with men; IV, intravenous.
388 (68) 186 (32) 411 115 31 17
(72) (20) (5) (3)
391 (68) 183 (32) 213 114 138 15 94
(37) (20) (24) (3) (16)
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K. L. D. Andersen et al. Table II. Distribution of HBV serology categories at baseline and follow-up among HIV patients (N ⫽ 574).
Chronic active infection Resolved infection Non-immune Immunized Incomplete or non-updated HBV serology
HBsAg
Anti-HBc
Anti-HBs
⫹ ⫺ ⫺ ⫺
⫹ ⫹ ⫺ ⫺
⫺ ⫹/⫺ ⫺ ⫹
Baseline, n (%) 9 29 51 4 481
(2) (5) (9) (1) (84)
Follow-up, n (%) 15 156 299 65 39
(3) (27) (52) (11) (7)
HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBc, hepatitis B core antibody; antiHBs, hepatitis B surface antibody.
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Baseline At baseline, 481 (84%) HIV patients were found with incomplete and/or non-updated (ⱖ 2 y) HBV serology (Table II). Of the remaining 93 (16%) patients with serology that was considered valid for serology interpretation, 15 (16%) were found with chronic infection, 29 (31%) with resolved infection, 4 (4%) patients were immunized by vaccination, and 51 (55%) were non-immune to HBV. Non-updated HCV serology was observed in 423 (74%) HIV patients (Table III). Among the 151 (26%) patients with serology valid for interpretation, 125 (83%) were anti-HCV-negative, 18 (12%) had a chronic infection, and 8 (5%) had a resolved infection.
Follow-up Updated HBV serology status was achieved in 535 (93%) patients. Fifteen (3%) HIV patients were found with a chronic active HBV infection and 156 (27%) patients were found with serology indicating resolved infection, making a total of 171 (30%) patients with a history of HBV infection (Table IV). Additionally, 65 patients (11%) were found to have positive anti-HBs and negative anti-HBc and were therefore considered immunized against HBV infection. Apart from 39 (7%) patients with incomplete or non-updated HBV serology, the remaining 299 patients (52%) were considered non-immune.
A total of 539 (94%) patients had been tested for HBsAg on at least 2 occasions during the last 12 y. None of these patients had a negative first HBsAg test and were later found to be positive. Hence, no new cases of chronic active HBV infection had been documented among the HIV patients followed during an accumulated observation time period of 3649 patient-y, equal to an HBsAg (⬎ 6 months) incidence rate of ⬍ 0.01/100 patient-y. When comparing the group of patients with chronic or resolved HBV infection to the group of non-immune patients, several associated demographic characteristics were identified (Table IV). A significantly higher proportion of patients with chronic or resolved infection were of African or Asian origin compared to Caucasian: 37% versus 17% (p ⬍ 0.001). When comparing HIV risk transmission profiles, the proportion of heterosexual men with serological evidence of current or past infection was significantly lower in comparison to the other risk groups: 17% vs 33% (MSM), 26% (women), and 53% (IV drug users) (p ⬍ 0.01) Updated HCV serology status was achieved in 540 (94%) patients. Twenty-five (4%) HIV patients had a chronic active HCV infection and 15 (3%) had a resolved infection, giving a total anti-HCV prevalence of 7% (n ⫽ 40) (Table V). None of the patients with chronic active HCV infection was found to be HBsAg-positive. A total of 527 (92%) patients had been tested for anti-HCV on at least 2 occasions after the time of the HIV diagnosis. Nine (2%) of these
Table III. Distribution of HCV serology categories at baseline and follow-up among HIV patients (N ⫽ 574).
Chronic infection Resolved infection Non-immune Incomplete or non-updated HCV serology
Anti-HCV
HCV RNA
⫹ ⫹ ⫺
⫹ ⫺
HCV, hepatitis C virus; anti-HCV, hepatitis C virus antibody.
Baseline, n (%) 18 8 125 423
(3) (1) (22) (74)
Follow-up, n (%) 25 15 500 34
(4) (3) (87) (6)
HBV/HCV screening and vaccination in HIV patients
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Table IV. Characteristics of HIV patients in accordance with HBV status. The group of patients with chronic or resolved infection were tested against the group of non-immune patients.
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HBV status
Age, y, median (IQR) Sex, n (%) Male Female Ethnicity, n (%) Caucasian African Asian Other/unknown Country of origin, n (%) Denmark Other HIV risk/transmission group, n (%) MSM Heterosexual men Women IV drug users Other/unknown
Chronic or resolved infection (n ⫽ 171)
Non-immune (n ⫽ 299)
p-Value
Immunized (n ⫽ 65)
49 (43–56)
48 (40–55)
NSa
42 (35–51)
42 (35–49)
NSb
42 (12) 23 (12)
23 (6) 16 (9) 25 11 1 2
113 (33) 58 (31)
210 (62) 89 (48)
105 51 12 3
238 38 13 10
Incomplete or non-updated HBV serology (n ⫽ 39)
(58) (33) (42) (59)
⬍ 0.001b ⬍ 0.001b NSb NSb
43 15 5 2
99 (25) 72 (39)
234 (60) 65 (36)
⬍ 0.001b
36 (9) 29 (16)
22 (6) 17 (9)
71 19 36 8 37
111 76 72 2 38
NSb ⬍ 0.001b ⬍ 0.02b ⬍ 0.01b ⬍ 0.02b
23 (11) 15 (13) 21 (15) – 6 (6)
8 4 9 5 13
(26) (44) (39) (18)
(33) (17) (26) (53) (39)
(52) (67) (52) (13) (40)
(10) (23) (16) (12)
(6) (10) (3) (12)
(4) (4) (7) (33) (14)
HBV, hepatitis B virus; IQR, interquartile range; NS, not significant; MSM, men who have sex with men; IV, intravenous. aWilcoxon signed rank test. bChi-square test.
patients were found to have proof of anti-HCV seroconversion. The patients with a first negative anti-HCV were followed for an accumulated observation time period of 3371 patient-y, resulting in an HCV incidence of 0.27/100 patient-y. All 9 seroconverted patients were male; 5 were MSM,
2 were heterosexual, and 2 had an unknown history of HIV transmission. Among patients with known HCV serology (n ⫽ 540), MSM (4%) were found to be anti-HCVpositive in nearly the same proportion as heterosexual men and women (6% and 4%, respectively).
Table V. Characteristics of HIV patients in accordance with HCV status. The group of patients with positive anti-HCV were tested against the group of patients with negative anti-HCV. HCV status
Age, y, median (IQR) Sex, n (%) Male Female Ethnicity, n (%) Caucasian African Asian Other/unknown HIV risk/transmission group, n (%) MSM Heterosexual men Women IV drug users Other/unknown
Anti-HCV-positive (n ⫽ 40)
Anti-HCV-negative (n ⫽ 500)
p-Value
Incomplete or non-updated HCV serology (n ⫽ 34)
47 (41–49.5)
48 (40–55)
NSa
43.5 (36–49)
NSb
28 (7) 12 (6)
339 (87) 161 (87)
21 (5) 13 (7)
32 3 2 3
(8) (3) (6) (18)
356 104 28 12
(87) (90) (90) (71)
NSb ⬍ 0.05b NSb NSb
23 8 1 2
(6) (7) (3) (12)
8 7 5 7 13
(4) (6) (4) (47) (14)
199 103 125 2 71
(93) (90) (91) (13) (76)
⬍ 0.02b NSb ⬍ 0.02b ⬍ 0.001b ⬍ 0.01b
6 4 8 6 10
(3) (4) (6) (40) (11)
HCV, hepatitis C virus; anti-HCV, hepatitis C virus antibody; IQR, interquartile range; NS, not significant; MSM, men who have sex with men; IV, intravenous. aWilcoxon signed rank test. bChi-square test.
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Patients with IV drug use were found to have the highest prevalence of positive anti-HCV (47%).
The percentage of newly diagnosed HIV patients tested for HBsAg increased from 25% in the period from 2000 to 2001 to 88% in the period from 2010 to 2011 (Figure 1). During the same period, a similar rise was observed in anti-HBs and anti-HBc test performance, from 33% to 60% and from 18% to 82%, respectively. For anti-HCV screening, 43% of newly diagnosed HIV patients were tested in the period from 2000 to 2001 in comparison with 88% in the period from 2010 to 2011. Liver pathology assessment Recent (⬍ 2 y) liver assessment by liver biopsy and/ or transient elastography (TE) had been performed in 3 (20%) patients, and 1 had been found to have cirrhosis. Hence, the current level of liver pathology was not known in 12 (80%) of the 15 HBV co-infected patients. Of the 25 patients with chronic active HCV infection, recent (⬍ 2 y) liver pathology assessment by liver biopsy and/or TE had been performed in 17 (68%) patients, and 2 (12%) had been found to have cirrhosis. Hence, the current level of liver pathology was not known in 8 (32%) of the 25 HCV co-infected patients. Discussion This study has shown that HIV patients in this population were not screened for viral hepatitis in 100% % of HIV patients serologytested
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Screening for HBV and HCV infection at the time of HIV diagnosis
accordance with the existing international guidelines, which recommend that patients are screened for HBV and HCV at the time of HIV diagnosis [8]. It is also recommended that HCV screening should be performed on an annual basis among HIV patients [8]. We observed that an HCV test had not been performed or the latest test result was dated more than 2 y ago in 74% of the HIV patients in our clinic. Defaults in correctly performed surveillance of viral hepatitis among HIV patients may lead to delays in HBV and/or HCV diagnosis and subsequently in the treatment of eligible patients, leading to the risk of a liver pathology developing, and therefore an increased risk of liver-associated morbidity and mortality [9]. The low performance of HBV and HCV screening practice can partly be explained by the fact that the national HIV and viral hepatitis guidelines in Denmark have not been aligned with international guidelines. Before March 2013, the Danish guidelines did not recommend HBV and HCV screening of HIV patients on a routine basis [10]. However, the guidelines have now been updated to match the international recommendations and recommend that HIV patients be screened for viral hepatitis at diagnosis and non-immune patients be vaccinated against HBV [11]. Although the screening rate in general had improved over the years even before implementation of the new guidelines by the National Board of Health, the most recent data from this study revealed that HBsAg and anti-HCV tests had not been carried out in 1 out of 9 newly diagnosed HIV patients. From that perspective, there is still need for further improvement aimed at higher HBV and HCV screening coverage rates. The problem with the remaining subgroup of patients not being screened in a timely
90% 80% 70% 60%
Full HBV
50%
HBsAg
40%
Anti-HBc
30%
Anti-HBs Anti-HCV
20% 10% 0% 2000-2001 2002-2003 2004-2005 2006-2007 2008-2009 2010-2011 Year of HIV diagnosis
Figure 1. Proportion of HIV patients tested for HBsAg, anti-HBc, anti-HBs, and anti-HCV at the time of HIV diagnosis according to the year of diagnosis.
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HBV/HCV screening and vaccination in HIV patients manner in accordance with the HIV diagnosis has now been solved by introducing a new laboratory work ordering system in which viral hepatitis serology is included in the overall packet of blood analysis to be performed at the first outpatient visit. Moreover, surveillance of viral hepatitis screening performance and management of chronic active cases is now supported by the recent introduction of real-time patient databases (InfCare HIV). In total, 32% of the HIV patients were found with serological evidence of HBV infection, and in this group, 1 out of 10, which is equal to 3% of the overall population, was diagnosed with chronic active HBV infection. The highest HBV prevalence was observed among patients categorized as IV drug users, followed by MSM and women of non-Danish origin. In general, the population of non-Danish origin was observed with a significantly higher HBV prevalence of 39% vs 25% in patients of Danish origin, as the majority originate from high-endemic countries. These findings are in agreement with those of previous studies. Omland et al. [2] found that HBV was more prevalent among non-white HIV patients and Kellerman et al. [12] stratified on risk group and found that MSM and IV drug users had the highest prevalence of HBV co-infection. Observation suggests an overall low HBV transmission rate due to a low level of exposure and/or a high level of protection, either through safe sex practices or vaccination. However, the findings from this study suggest that a low HBV vaccination coverage rate exists in this study population. Based on the outcome of serology assessment at follow-up, half of the patients were considered to be non-immune to HBV. This observation, however, should be interpreted with caution because HIV patients, and in particular those with low CD4 counts, may fail to achieve anti-HBs seroconversion after completion of a normal HBV vaccination schedule. Studies have shown seroconversion rates as low as 40–45% [13,14]. For this reason, standard vaccination against HBV should initiate post-vaccination serology testing and if necessary an enhanced vaccination regime [15]. Initial seroconversion should likewise be followed up, as protective antibody levels can be lost [16]. The implication of no anti-HBs seroconversion or loss of antibodies is not completely understood; one may speculate that the vaccine is offering protection via the cellular immune response, which is not measured in routine laboratory testing. It is not possible to go through the medical records to check for vaccination status because HBV vaccination of HIV patients in Denmark is administered by the general practitioner without being registered systematically. We did not identify any patients with serological evidence of having developed chronic active HBV
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infection after diagnosis with HIV. This is a surprising finding, especially among HIV patients who are MSM, because HIV and HBV share the same route of transmission, and other HIV clinics have made this observation [17,18]. A different consideration in this regard is the current antiretroviral therapy offered to HIV patients. The regimens often consist of nucleos(t)ide analogues (NA) agents, such as tenofovir, emtricitabine, or lamivudine, which also have a therapeutic anti-HBV effect in co-infected patients, but presumptively also have a preventive effect in non-immune individuals exposed to HBV infection [19]. The overall anti-HCV prevalence was 7%, and 4% of patients had a chronic active infection. The highest prevalence was found among patients with a history of IV drug use. The HCV incidence rate was as low as 0.27 per 100 patient-y. However, there seems to have been an increase in new HCV cases in Europe and the USA, particularly among MSM [20,21]. For this reason, annual anti-HCV screening is justified to identify patients who should start anti-HCV treatment. We did not screen for HCV RNA in anti-HCV-negative patients, although studies have shown that certain risk groups have a prolonged time to seroconversion after HCV infection [22,23]. With this in mind, one could recommend screening of HIV patients with CD4 cell counts below 200 cells/mm3 or with high alanine aminotransferase (ALT), although the number of these patients in this HIV clinic is small. Three HIV patients (1 co-infected with HBV and 2 with HCV) were found with cirrhosis. However, not all of the co-infected HIV and hepatitis patients had undergone a liver examination by biopsy and/or had had TE performed within the last 2 y, and therefore, the number of patients with cirrhosis due to viral hepatitis may be higher. For this reason, increased clinical attention should be paid to closer control measures of liver pathology in HBV and/or HCV co-infected HIV patients. Although the prevalence and incidence of HBV and HCV were low in this HIV study population, it is still important to maintain a high level of alertness towards relevant control measures, including patient information, screening, and vaccination. Moreover, adherence to existing guidelines for the management of HIV patients with chronic viral hepatitis, including liver pathology assessments and the treatment of eligible patients, is equally important to reduce the risk of developing liver-associated morbidity and mortality. The introduction of a real-time database for clinical decision support and monitoring of quality assurance has made a major contribution to improving standards of health care for HIV and hepatitis patients.
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Acknowledgements
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We wish to express our gratitude to Mattias Rasmussen, Morten Flink, and Inge Arbs for their assistance in data processing in InfCare HIV.
[10] [11]
Declaration of interest: No commercial interests to declare.
[12]
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ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Need for improvements in the surveillance and management of chronic viral hepatitis in HIV patients followed in a Danish outpatient clinic Karen Lise Dahl Andersen, Carsten Schade Larsen, Mikkel Steen Petersen & Peter Derek Christian Leutscher To cite this article: Karen Lise Dahl Andersen, Carsten Schade Larsen, Mikkel Steen Petersen & Peter Derek Christian Leutscher (2014) Need for improvements in the surveillance and management of chronic viral hepatitis in HIV patients followed in a Danish outpatient clinic, Scandinavian Journal of Infectious Diseases, 46:8, 578-584 To link to this article: http://dx.doi.org/10.3109/00365548.2014.918648
Published online: 16 Jun 2014.
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Date: 16 November 2015, At: 03:59
Scandinavian Journal of Infectious Diseases, 2014; 46: 578–584
ORIGINAL ARTICLE
Need for improvements in the surveillance and management of chronic viral hepatitis in HIV patients followed in a Danish outpatient clinic
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KAREN LISE DAHL ANDERSEN1, CARSTEN SCHADE LARSEN1, MIKKEL STEEN PETERSEN2 & PETER DEREK CHRISTIAN LEUTSCHER1 From the 1Department of Infectious Diseases, and 2Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
Abstract Objectives: The aim of this study was to assess hepatitis B virus (HBV) and hepatitis C virus (HCV) surveillance and management in HIV patients currently followed in an outpatient clinic at a Danish University Hospital. Methods: Patient data, including demographic characteristics, clinical findings, and hepatitis serology, were reviewed at baseline. Patients with incomplete or non-updated serology within the last 2 y were retested in the next 6 months, and the results were reviewed again at follow-up. Results: At baseline, 84% and 74% of the 574 HIV patients were found to have incomplete and/or non-updated HBV and HCV serology, respectively. At follow-up, updated HBV serology was achieved in 535 (93%) patients; 15 (3%) patients were found to have a chronic active infection and 156 (27%) had a resolved infection, whereas 65 (11%) were vaccinated against HBV and 299 (52%) were non-immune. No patients were found to have developed chronic HBV infection following HIV diagnosis (equal to 3649 patient-y). Updated HCV serology revealed that 25 (4%) had a chronic active HCV infection and 15 (3%) had a resolved HCV infection. The anti-HCV incidence rate was 0.27/100 patient-y. A liver pathology assessment had not been performed within the last 2 y in 80% of the HBV and 32% of the HCV co-infected patients. Conclusions: Hepatitis screening and assessment had been inadequately performed. New cases of chronic hepatitis seem to occur infrequently. However, a more proactive hepatitis surveillance and management strategy integrated into the overall HIV health care program is warranted.
Keywords: HIV, viral hepatitis, screening, seroprevalence, vaccination
Introduction The prevalence of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) in Northern Europe is low in the general population. In Denmark, the prevalence of HIV among adults has been estimated to be less than 0.1%, and of HBV and HCV to be less than 0.2% [1]. However, 6% of HIV patients have been found to be co-infected with HBV [2] and 13% with HCV [3]. International guidelines recommend HBV and HCV serology testing at the time of HIV diagnosis [4,5]. The results should be followed up with HBV
vaccination of non-immunized HIV patients and HCV control screening of HCV antibody (antiHCV)-negative subjects. In addition, HIV patients should be proactively treated for chronic active HBV and HCV infection aimed at viral suppression and eradication, respectively. Chronic hepatitis is at risk of being neglected in the HIV clinic, as shown in a recently published study from the USA on hepatitis screening and vaccination of HIV-infected men who have sex with men (MSM), in which a low adherence to the existing international hepatitis guidelines was observed [6].
Correspondence: K. L. Dahl Andersen, Department of Infectious Diseases, Aarhus University Hospital, Brendstrupgårdsvej 100, 8200 Aarhus N, Denmark. Tel: ⫹ 45 7845 2844. Fax: ⫹ 45 7845 2848. E-mail: [email protected] (Received 7 November 2013 ; accepted 22 April 2014 ) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.918648
HBV/HCV screening and vaccination in HIV patients The main objective of this study was to evaluate the practice and outcome of viral hepatitis management, including screening, vaccination, and liver pathology assessment among HIV patients followed in a Danish University Hospital outpatient clinic.
Methods
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Patients and study design At baseline in April 2012, historical HBV and HCV serology results were reviewed for all actively followed adult HIV patients in the outpatient clinic at Aarhus University Hospital. If the most recent serology result was dated prior to 1 January 2011, a new hepatitis serology test was performed at the next scheduled visit in the clinic. The goal was to obtain an updated (⬍ 2 y) hepatitis serology status for all patients followed at the clinic. At the time of follow-up in January 2013, all serology test results were reviewed again. When assessing hepatitis screening practices over the last 12 y among newly diagnosed HIV patients, hepatitis serology results were considered valid for analysis if testing had been performed within ⫾ 180 days of the HIV diagnosis. Hepatitis test Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis C virus antibody (anti-HCV) were assessed by use of a standard assay (Architect; Abbott Diagnostics). If anti-HCV was positive, HCV RNA (Procleix; Novartis) was measured quantitatively. HBV infection/immunization and HCV infection were defined according to serology test results in the following categories: chronic HBV infection (positive HBsAg of more than 6 months duration); resolved HBV infection (negative HBsAg, negative/positive anti-HBs, and positive anti-HBc); HBV immunization (positive anti-HBs and negative anti-HBc); non-immune HBV (negative HBsAg, anti-HBs, and anti-HBc) [7]; chronic HCV infection (positive antiHCV and positive HCV RNA); resolved HCV infection (positive anti-HCV and negative HCV RNA); and no previous HCV infection (negative antiHCV).
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and InfCare HIV databases (Health Solutions AB, Stockholm); the InfCare HIV database has been implemented as a clinical decision support tool and as an instrument for quality assurance among HIV patients at Aarhus University Hospital. Patient demographic data were analysed according to HBV/HCV immune status by use of the Chi-square test (all data other than age) and the Wilcoxon signed rank test. p-Values of ⬍ 0.05 were considered significant. HIV patients with an HBV/HCV chronic infection and resolved infection were tested against HBV/HCV non-immune HIV patients. If there were more than 2 variables, each variable was tested against all others. Stata Intercooled version 12 was used for the data analysis.
Results Socio-demographic characteristics The study population consisted of 574 HIV patients: 388 (68%) men and 186 (32%) women (Table I). Median age was 48 y (interquartile range (IQR) 40–55 y). Men were significantly older than women: 49 y (IQR 42–57) vs 43 y (IQR 38–49) (p ⬍ 0.05). A majority of patients were registered as Caucasian (72%), followed by African (20%) and Asian (5%). Most HIV patients originated from Denmark (n ⫽ 391; 68%). Two-thirds of the 183 HIV patients who did not originate from Denmark were female. MSM and heterosexual men accounted for the largest transmission risk group (both 37%), followed by women (24%) and intravenous (IV) drug users (3%). Table I. Baseline characteristics of the study population. Characteristics
N ⫽ 574
Data handling and analysis
Age, y, median (IQR) Sex, n (%) Male Female Ethnicity, n (%) Caucasian African Asian Other Country of origin, n (%) Denmark Other HIV risk/transmission group, n (%) MSM Heterosexual men Women IV drug users Other
48 (40–55)
Clinical history and serology data were extracted in January 2013 from the real-time InfCare Hepatitis
IQR, interquartile range; MSM, men who have sex with men; IV, intravenous.
388 (68) 186 (32) 411 115 31 17
(72) (20) (5) (3)
391 (68) 183 (32) 213 114 138 15 94
(37) (20) (24) (3) (16)
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K. L. D. Andersen et al. Table II. Distribution of HBV serology categories at baseline and follow-up among HIV patients (N ⫽ 574).
Chronic active infection Resolved infection Non-immune Immunized Incomplete or non-updated HBV serology
HBsAg
Anti-HBc
Anti-HBs
⫹ ⫺ ⫺ ⫺
⫹ ⫹ ⫺ ⫺
⫺ ⫹/⫺ ⫺ ⫹
Baseline, n (%) 9 29 51 4 481
(2) (5) (9) (1) (84)
Follow-up, n (%) 15 156 299 65 39
(3) (27) (52) (11) (7)
HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBc, hepatitis B core antibody; antiHBs, hepatitis B surface antibody.
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Baseline At baseline, 481 (84%) HIV patients were found with incomplete and/or non-updated (ⱖ 2 y) HBV serology (Table II). Of the remaining 93 (16%) patients with serology that was considered valid for serology interpretation, 15 (16%) were found with chronic infection, 29 (31%) with resolved infection, 4 (4%) patients were immunized by vaccination, and 51 (55%) were non-immune to HBV. Non-updated HCV serology was observed in 423 (74%) HIV patients (Table III). Among the 151 (26%) patients with serology valid for interpretation, 125 (83%) were anti-HCV-negative, 18 (12%) had a chronic infection, and 8 (5%) had a resolved infection.
Follow-up Updated HBV serology status was achieved in 535 (93%) patients. Fifteen (3%) HIV patients were found with a chronic active HBV infection and 156 (27%) patients were found with serology indicating resolved infection, making a total of 171 (30%) patients with a history of HBV infection (Table IV). Additionally, 65 patients (11%) were found to have positive anti-HBs and negative anti-HBc and were therefore considered immunized against HBV infection. Apart from 39 (7%) patients with incomplete or non-updated HBV serology, the remaining 299 patients (52%) were considered non-immune.
A total of 539 (94%) patients had been tested for HBsAg on at least 2 occasions during the last 12 y. None of these patients had a negative first HBsAg test and were later found to be positive. Hence, no new cases of chronic active HBV infection had been documented among the HIV patients followed during an accumulated observation time period of 3649 patient-y, equal to an HBsAg (⬎ 6 months) incidence rate of ⬍ 0.01/100 patient-y. When comparing the group of patients with chronic or resolved HBV infection to the group of non-immune patients, several associated demographic characteristics were identified (Table IV). A significantly higher proportion of patients with chronic or resolved infection were of African or Asian origin compared to Caucasian: 37% versus 17% (p ⬍ 0.001). When comparing HIV risk transmission profiles, the proportion of heterosexual men with serological evidence of current or past infection was significantly lower in comparison to the other risk groups: 17% vs 33% (MSM), 26% (women), and 53% (IV drug users) (p ⬍ 0.01) Updated HCV serology status was achieved in 540 (94%) patients. Twenty-five (4%) HIV patients had a chronic active HCV infection and 15 (3%) had a resolved infection, giving a total anti-HCV prevalence of 7% (n ⫽ 40) (Table V). None of the patients with chronic active HCV infection was found to be HBsAg-positive. A total of 527 (92%) patients had been tested for anti-HCV on at least 2 occasions after the time of the HIV diagnosis. Nine (2%) of these
Table III. Distribution of HCV serology categories at baseline and follow-up among HIV patients (N ⫽ 574).
Chronic infection Resolved infection Non-immune Incomplete or non-updated HCV serology
Anti-HCV
HCV RNA
⫹ ⫹ ⫺
⫹ ⫺
HCV, hepatitis C virus; anti-HCV, hepatitis C virus antibody.
Baseline, n (%) 18 8 125 423
(3) (1) (22) (74)
Follow-up, n (%) 25 15 500 34
(4) (3) (87) (6)
HBV/HCV screening and vaccination in HIV patients
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Table IV. Characteristics of HIV patients in accordance with HBV status. The group of patients with chronic or resolved infection were tested against the group of non-immune patients.
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HBV status
Age, y, median (IQR) Sex, n (%) Male Female Ethnicity, n (%) Caucasian African Asian Other/unknown Country of origin, n (%) Denmark Other HIV risk/transmission group, n (%) MSM Heterosexual men Women IV drug users Other/unknown
Chronic or resolved infection (n ⫽ 171)
Non-immune (n ⫽ 299)
p-Value
Immunized (n ⫽ 65)
49 (43–56)
48 (40–55)
NSa
42 (35–51)
42 (35–49)
NSb
42 (12) 23 (12)
23 (6) 16 (9) 25 11 1 2
113 (33) 58 (31)
210 (62) 89 (48)
105 51 12 3
238 38 13 10
Incomplete or non-updated HBV serology (n ⫽ 39)
(58) (33) (42) (59)
⬍ 0.001b ⬍ 0.001b NSb NSb
43 15 5 2
99 (25) 72 (39)
234 (60) 65 (36)
⬍ 0.001b
36 (9) 29 (16)
22 (6) 17 (9)
71 19 36 8 37
111 76 72 2 38
NSb ⬍ 0.001b ⬍ 0.02b ⬍ 0.01b ⬍ 0.02b
23 (11) 15 (13) 21 (15) – 6 (6)
8 4 9 5 13
(26) (44) (39) (18)
(33) (17) (26) (53) (39)
(52) (67) (52) (13) (40)
(10) (23) (16) (12)
(6) (10) (3) (12)
(4) (4) (7) (33) (14)
HBV, hepatitis B virus; IQR, interquartile range; NS, not significant; MSM, men who have sex with men; IV, intravenous. aWilcoxon signed rank test. bChi-square test.
patients were found to have proof of anti-HCV seroconversion. The patients with a first negative anti-HCV were followed for an accumulated observation time period of 3371 patient-y, resulting in an HCV incidence of 0.27/100 patient-y. All 9 seroconverted patients were male; 5 were MSM,
2 were heterosexual, and 2 had an unknown history of HIV transmission. Among patients with known HCV serology (n ⫽ 540), MSM (4%) were found to be anti-HCVpositive in nearly the same proportion as heterosexual men and women (6% and 4%, respectively).
Table V. Characteristics of HIV patients in accordance with HCV status. The group of patients with positive anti-HCV were tested against the group of patients with negative anti-HCV. HCV status
Age, y, median (IQR) Sex, n (%) Male Female Ethnicity, n (%) Caucasian African Asian Other/unknown HIV risk/transmission group, n (%) MSM Heterosexual men Women IV drug users Other/unknown
Anti-HCV-positive (n ⫽ 40)
Anti-HCV-negative (n ⫽ 500)
p-Value
Incomplete or non-updated HCV serology (n ⫽ 34)
47 (41–49.5)
48 (40–55)
NSa
43.5 (36–49)
NSb
28 (7) 12 (6)
339 (87) 161 (87)
21 (5) 13 (7)
32 3 2 3
(8) (3) (6) (18)
356 104 28 12
(87) (90) (90) (71)
NSb ⬍ 0.05b NSb NSb
23 8 1 2
(6) (7) (3) (12)
8 7 5 7 13
(4) (6) (4) (47) (14)
199 103 125 2 71
(93) (90) (91) (13) (76)
⬍ 0.02b NSb ⬍ 0.02b ⬍ 0.001b ⬍ 0.01b
6 4 8 6 10
(3) (4) (6) (40) (11)
HCV, hepatitis C virus; anti-HCV, hepatitis C virus antibody; IQR, interquartile range; NS, not significant; MSM, men who have sex with men; IV, intravenous. aWilcoxon signed rank test. bChi-square test.
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Patients with IV drug use were found to have the highest prevalence of positive anti-HCV (47%).
The percentage of newly diagnosed HIV patients tested for HBsAg increased from 25% in the period from 2000 to 2001 to 88% in the period from 2010 to 2011 (Figure 1). During the same period, a similar rise was observed in anti-HBs and anti-HBc test performance, from 33% to 60% and from 18% to 82%, respectively. For anti-HCV screening, 43% of newly diagnosed HIV patients were tested in the period from 2000 to 2001 in comparison with 88% in the period from 2010 to 2011. Liver pathology assessment Recent (⬍ 2 y) liver assessment by liver biopsy and/ or transient elastography (TE) had been performed in 3 (20%) patients, and 1 had been found to have cirrhosis. Hence, the current level of liver pathology was not known in 12 (80%) of the 15 HBV co-infected patients. Of the 25 patients with chronic active HCV infection, recent (⬍ 2 y) liver pathology assessment by liver biopsy and/or TE had been performed in 17 (68%) patients, and 2 (12%) had been found to have cirrhosis. Hence, the current level of liver pathology was not known in 8 (32%) of the 25 HCV co-infected patients. Discussion This study has shown that HIV patients in this population were not screened for viral hepatitis in 100% % of HIV patients serologytested
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Screening for HBV and HCV infection at the time of HIV diagnosis
accordance with the existing international guidelines, which recommend that patients are screened for HBV and HCV at the time of HIV diagnosis [8]. It is also recommended that HCV screening should be performed on an annual basis among HIV patients [8]. We observed that an HCV test had not been performed or the latest test result was dated more than 2 y ago in 74% of the HIV patients in our clinic. Defaults in correctly performed surveillance of viral hepatitis among HIV patients may lead to delays in HBV and/or HCV diagnosis and subsequently in the treatment of eligible patients, leading to the risk of a liver pathology developing, and therefore an increased risk of liver-associated morbidity and mortality [9]. The low performance of HBV and HCV screening practice can partly be explained by the fact that the national HIV and viral hepatitis guidelines in Denmark have not been aligned with international guidelines. Before March 2013, the Danish guidelines did not recommend HBV and HCV screening of HIV patients on a routine basis [10]. However, the guidelines have now been updated to match the international recommendations and recommend that HIV patients be screened for viral hepatitis at diagnosis and non-immune patients be vaccinated against HBV [11]. Although the screening rate in general had improved over the years even before implementation of the new guidelines by the National Board of Health, the most recent data from this study revealed that HBsAg and anti-HCV tests had not been carried out in 1 out of 9 newly diagnosed HIV patients. From that perspective, there is still need for further improvement aimed at higher HBV and HCV screening coverage rates. The problem with the remaining subgroup of patients not being screened in a timely
90% 80% 70% 60%
Full HBV
50%
HBsAg
40%
Anti-HBc
30%
Anti-HBs Anti-HCV
20% 10% 0% 2000-2001 2002-2003 2004-2005 2006-2007 2008-2009 2010-2011 Year of HIV diagnosis
Figure 1. Proportion of HIV patients tested for HBsAg, anti-HBc, anti-HBs, and anti-HCV at the time of HIV diagnosis according to the year of diagnosis.
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HBV/HCV screening and vaccination in HIV patients manner in accordance with the HIV diagnosis has now been solved by introducing a new laboratory work ordering system in which viral hepatitis serology is included in the overall packet of blood analysis to be performed at the first outpatient visit. Moreover, surveillance of viral hepatitis screening performance and management of chronic active cases is now supported by the recent introduction of real-time patient databases (InfCare HIV). In total, 32% of the HIV patients were found with serological evidence of HBV infection, and in this group, 1 out of 10, which is equal to 3% of the overall population, was diagnosed with chronic active HBV infection. The highest HBV prevalence was observed among patients categorized as IV drug users, followed by MSM and women of non-Danish origin. In general, the population of non-Danish origin was observed with a significantly higher HBV prevalence of 39% vs 25% in patients of Danish origin, as the majority originate from high-endemic countries. These findings are in agreement with those of previous studies. Omland et al. [2] found that HBV was more prevalent among non-white HIV patients and Kellerman et al. [12] stratified on risk group and found that MSM and IV drug users had the highest prevalence of HBV co-infection. Observation suggests an overall low HBV transmission rate due to a low level of exposure and/or a high level of protection, either through safe sex practices or vaccination. However, the findings from this study suggest that a low HBV vaccination coverage rate exists in this study population. Based on the outcome of serology assessment at follow-up, half of the patients were considered to be non-immune to HBV. This observation, however, should be interpreted with caution because HIV patients, and in particular those with low CD4 counts, may fail to achieve anti-HBs seroconversion after completion of a normal HBV vaccination schedule. Studies have shown seroconversion rates as low as 40–45% [13,14]. For this reason, standard vaccination against HBV should initiate post-vaccination serology testing and if necessary an enhanced vaccination regime [15]. Initial seroconversion should likewise be followed up, as protective antibody levels can be lost [16]. The implication of no anti-HBs seroconversion or loss of antibodies is not completely understood; one may speculate that the vaccine is offering protection via the cellular immune response, which is not measured in routine laboratory testing. It is not possible to go through the medical records to check for vaccination status because HBV vaccination of HIV patients in Denmark is administered by the general practitioner without being registered systematically. We did not identify any patients with serological evidence of having developed chronic active HBV
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infection after diagnosis with HIV. This is a surprising finding, especially among HIV patients who are MSM, because HIV and HBV share the same route of transmission, and other HIV clinics have made this observation [17,18]. A different consideration in this regard is the current antiretroviral therapy offered to HIV patients. The regimens often consist of nucleos(t)ide analogues (NA) agents, such as tenofovir, emtricitabine, or lamivudine, which also have a therapeutic anti-HBV effect in co-infected patients, but presumptively also have a preventive effect in non-immune individuals exposed to HBV infection [19]. The overall anti-HCV prevalence was 7%, and 4% of patients had a chronic active infection. The highest prevalence was found among patients with a history of IV drug use. The HCV incidence rate was as low as 0.27 per 100 patient-y. However, there seems to have been an increase in new HCV cases in Europe and the USA, particularly among MSM [20,21]. For this reason, annual anti-HCV screening is justified to identify patients who should start anti-HCV treatment. We did not screen for HCV RNA in anti-HCV-negative patients, although studies have shown that certain risk groups have a prolonged time to seroconversion after HCV infection [22,23]. With this in mind, one could recommend screening of HIV patients with CD4 cell counts below 200 cells/mm3 or with high alanine aminotransferase (ALT), although the number of these patients in this HIV clinic is small. Three HIV patients (1 co-infected with HBV and 2 with HCV) were found with cirrhosis. However, not all of the co-infected HIV and hepatitis patients had undergone a liver examination by biopsy and/or had had TE performed within the last 2 y, and therefore, the number of patients with cirrhosis due to viral hepatitis may be higher. For this reason, increased clinical attention should be paid to closer control measures of liver pathology in HBV and/or HCV co-infected HIV patients. Although the prevalence and incidence of HBV and HCV were low in this HIV study population, it is still important to maintain a high level of alertness towards relevant control measures, including patient information, screening, and vaccination. Moreover, adherence to existing guidelines for the management of HIV patients with chronic viral hepatitis, including liver pathology assessments and the treatment of eligible patients, is equally important to reduce the risk of developing liver-associated morbidity and mortality. The introduction of a real-time database for clinical decision support and monitoring of quality assurance has made a major contribution to improving standards of health care for HIV and hepatitis patients.
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Acknowledgements
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We wish to express our gratitude to Mattias Rasmussen, Morten Flink, and Inge Arbs for their assistance in data processing in InfCare HIV.
[10] [11]
Declaration of interest: No commercial interests to declare.
[12]
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