Incidence and Risk Factors for Invasive Pneumococcal Disease in HIV-Infected and Non-HIV-Infected...

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© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].

Incidence and Risk Factors for Invasive Pneumococcal Disease in HIV-infected and non-HIV infected Individuals Before and After the Introduction of Combination Antiretroviral Therapy: Persisting High Risk among HIV-infected Injecting Drug Users Zitta Barrella Harboe1,2, Mette Vang Larsen3, Steen Ladelund3, Gitte Kronborg3,4, Helle Bossen Konradsen2, Jan Gerstoft1, Carsten Schade Larsen5, Court Pedersen6, Gitte Pedersen7, Niels Obel1,4, Thomas Benfield3,4 1Department of Infectious Diseases, Righospitalet 2Department of Microbiology & Infection control, Meningtis and Respiratory Tract Infections, Statens Serum Institut 3Department of Infectious Diseases and Clinical Research Center, Copenhagen University Hospital, Hvidovre 4Faculty of Health and Medical Sciences, University of Copenhagen 5Department of Infectious Diseases, Aarhus University Hospital 6Department of Infectious Diseases, Odense University Hospital 7Department of Infectious Diseases, Aalborg University Hospital Corresponding Author: Zitta Barrella Harboe, M.D, Ph.D. Meningtis and Respiratory Tract Infections, Department of Microbiology & Infection control, Statens Serum Institut, Artillerivej 5, DK-2300 S Copehangen, Denmark, Tel: +45- 3268 3268, Email: [email protected] Summary HIV-infected adults have a substantially high risk of IPD compared to those without HIV-infection. The risk was reduced among HIV-infected individuals who were on antiretroviral treatment and who had favorable markers of immunosuppression, but not for HIV-infected IDUs.

Clinical Infectious Diseases Advance Access published July 17, 2014 by guest on M

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ABSTRACT Background: Invasive pneumococcal disease (IPD) is an important cause of morbidity among HIV-infected individuals. We described incidence and risk factors for IPD in HIV-infected and uninfected individuals. Methods: Nationwide population-based cohort study of HIV-infected adults treated at all Danish HIV-treatment centers during 1995-2012. Nineteen population-matched controls per HIV-infected individual were retrieved. The risk of IPD (RR, [95% CI]) was assessed using Poisson regression. Results: The incidence of IPD was 304.7 cases/100,000 PYFU in HIV-infected and 12.8/100,000 PYFU in HIV-uninfected individuals. After adjusting for confounders, HIV-infection (RR 24.4 [23.7-25.1]), male sex (RR 1.20 [1.16-1.24]), increasing age (per year) (RR 1.03 [1.03-1.04]) and calendar period (pre-cART [RR 2.80 [2.70-2.91] compared to late cART) were significantly associated with an increased risk of IPD. Among HIV-infected individuals, male sex (RR 1.57 [1.49-1.66]), smoking (RR 1.34 [1.26-1.42]), and intravenous drug use (RR 2.51 [2.26-2.67]) were associated with an increased risk of IPD. Detectable viral loads (RR 1.88 [1.79-1.98]) and a relative fall in CD4 T-cell counts were also associated with an increased risk (≥500 to 350-<500 CD4 T-cells/µl RR 1.29 [1.21-1.37], and <100 cells/µl RR 7.4 [6.87-8.02]). The risk of IPD declined over time though this was not the case for IDUs where the risk remained unchanged. Conclusions: The incidence of IPD in HIV-infected individuals remained significantly higher than the incidence observed in non-HIV-infected, in spite of the widespread use of cART. IDUs have a persisting high risk of IPD. IDU, smoking, the receipt of cART are suitable targets for preventive measures in the future.

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INTRODUCTION Streptococcus pneumoniae is an important cause of severe bacterial disease in HIV and HIV-

uninfected individuals [1-4]. Incidence rates of invasive pneumococcal disease (IPD) have been

reported to be up to 100 times higher among HIV-infected patients compared to the background

population, and recurrences are common[5-8].

The widespread use of combination antiretroviral therapy (cART) during the last decades has

changed the epidemiology of IPD in HIV-infected patients. Several studies have reported a

decreased incidence of IPD after the implementation of cART that is presumed to be related to

immune reconstitution [7, 9-11]. We have previously shown that the risk of pneumonia in HIV-

infected individuals decreased significantly after the introduction of cART [12] but that the overall

incidence of pneumonia remained significantly higher than in a HIV-uninfected matched

population. In the US, the incidence of IPD in HIV-infected patients continued to be 35-fold higher

than in the general population after the introduction of cART [11]. Other studies have indicated that

the incidence of IPD has remained quite unchanged after the introduction of cART [1, 13, 14].

Clinical presentation, risk factors and outcomes after IPD differ between HIV-infected and HIV-

uninfected individuals. Ethnicity, income level, injecting drug use (IDU), alcohol abuse, smoking,

prior hospitalization, comorbidity, hepatitis C co-infection, low CD4 T-cell counts, and high HIV-

RNA viral load (VL) have all been associated with an increased risk of IPD [1, 7, 10, 15], while the

use of cART and a conjugate pneumococcal vaccine have been associated with protection [2, 10,

15, 16]. In particular, IDUs are at higher risk of recurrent bacterial infections, including pneumonia

[17, 18]. Several of these factors have also been associated with higher risk of IPD in the general

population [10, 19]. A large, multicenter, observational study on risk factors and outcomes after



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pneumococcal pneumonia in HIV-infected and HIV-uninfected patients found an increased 14-days

mortality in HIV-infected patients after adjustment for age and severity of disease [4]. Another

study indicated that HIV-infected patients without comorbidities have a lower mortality than HIV-

uninfected patients with higher levels of comorbidity [20].

In Denmark, the incidence of IPD had steadily increased in the general population since the late

1980s, mainly due to an increment in the number of cases diagnosed with pneumococcal bacteremia

[21]. More recently, the epidemiology of IPD has dramatically changed after the introduction of

pneumococcal conjugate vaccination in 2007 in the national childhood immunization program [22].

The total incidence of IPD has declined in approximately 20%, mainly due to a 70% reduction in

IPD in children younger than 2 years, but also a 20% reduction in adults older than 65 years was

seen [23]. It is not known whether these changes similarly have affected HIV-infected individuals

since the incidence of IPD has not yet been assessed nor has the effect on the risk of IPD after the

widespread implementation of cART.

The aim of this study was to examine changes in the incidence of IPD in a nationwide cohort of

HIV-infected individuals after the implementation of cART in Denmark, and compare these with

the incidence of IPD observed in a population of matched controls. We also assessed risk factors

associated with the occurrence of IPD and mortality related to it.

MATERIAL AND METHODS

Study Design and Setting: Nationwide population-based cohort study of HIV-1-infected and HIV-

uninfected individuals in Denmark from January 1, 1995 to December 31, 2010. The estimated

prevalence of HIV among adults in Denmark, a country with a population of 5.4 million, is ~0.09%



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[24]. Treatment for HIV-infection is provided at only eight specialized HIV-centers. The Danish

health care system provides free, tax-supported medical care for all residents, including

antiretroviral treatment for HIV-infection.

The study was based on the linkage of national laboratory surveillance data on IPD, the Danish HIV

Cohort Study (DHCS), and the Danish Civil Registration System (CRS). The linkage between data

sources was done by using the unique ten-digit identification number provided to all residents in

Denmark. We identified 19 control-individuals from the background population per HIV-infected

individual included in DHCS. Population controls were not registered in the DHCS and then

assumed to be HIV-uninfected individuals [25], so an individual known to be HIV-infected could

not be a selected as a control. Controls were matched to the corresponding HIV-infected individual

on the day the patient received the HIV-diagnose according to date of birth and sex. Death was

considered to be related to IPD when the date of death was registered within 30-days after the

clinical sample was obtained from the patient.

The study was approved by the Danish Data Protection Agency (record. nr. 2007-41-0229 and

2007-41-1196).

Data sources and Definitions

National laboratory surveillance data on IPD: The characteristics and completeness of the

national surveillance system for IPD have previously been described and centralized at the National

Neisseria and Streptococcus Reference Laboratory (NSR), Statens Serum Institut (SSI) [26, 27].All

isolates are routinely serotyped as previously described [28, 29].



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We included cases of IPD defined as the isolation of S. pneumoniae from a patients’ cerebrospinal

fluid (CSF), blood or both. When both CSF and blood isolates were received simultaneously, the

case was categorized as meningitis. Recurrences were defined as new episodes of IPD occurring at

least 30-days after the first IPD episode.

In October 2007, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the

Danish childhood immunization program in a 2+1 schedule, but in April 2010, PCV13 gradually

started to replace PCV7 [30, 31].

The Danish HIV Cohort Study (DHCS): The cohort includes all HIV-infected individuals

followed at Danish HIV-treatment centers after January 1, 1995 [24, 32]. HIV-infected individuals

are followed on an outpatient basis at intended intervals of 12-24 weeks. Baseline characteristics

and HIV-related parameters are registered at inclusion in DHCS and updated annually. HIV-related

parameters include, among others, the route of infection, information on cART, development of

opportunistic infections and other AIDS-defining illnesses, and laboratory values including CD4 T-

cell counts and VL.The completeness and reliability of DHCS has been estimated to be as high as

99% for patients diagnosed with HIV-infection, when comparing it to other national hospital

databases [25]. Only HIV-1-infected individuals aged 16 years or older and living in Denmark were

included in the study.

The Danish Civil Registration System (CRS): National register that contains information on birth,

emigration, address, and vital status of all residents in Denmark [33]. Every person in the CRS is

identified by a unique 10-digit personal number, assigned at birth or immigration.



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Statistical analysis: Median and inter quartile ranges (IQR) were determined for age, duration of

HIV-infection and CD4 T-cell counts. Intergroup baseline characteristics were compared using the

chi square-test for dichotomous variables and Wilcoxon two-sample test for continuous variables.

Two-tailed p-values <0.05 were considered statistically significant. The person-years at risk were

counted from the day HIV-infected patients entered DHCS (earliest 1 January 1995, or a later date

of HIV-diagnose or immigration, whichever was last) to the date of IPD, emigration, death, or 31

December 2012, which ever was first.

Incidence rates of IPD were calculated as events per 100,000 person-years of follow-up (PYFU). In

order to investigate the effect of the introduction of cART, we studied three clinically relevant

periods that corresponded to the use of increasingly effective antiretroviral therapy: 1995 to 1996

(pre-cART), 1997 to 1999 (early-cART), and 2000 to 2012 (late-cART). Incidence rates were

compared by estimating incidence rate ratios (IRR) with 95% confidence intervals (95% CI).

We used a Poisson regression model to assess risk factors for the occurrence of IPD, both in the

total study population and for HIV-infected individuals only. Estimates are presented as relative risk

(RR) with 95% CIs. To account for changes over time in age, CD4 T-cell counts and different time

period of initiation of cART, we adjusted for these variables as time-dependent covariates by the

method described by Rostgaard [34]. For the total study population, the variables entered into the

model were HIV-infection (yes vs. no), age, and time period (pre-, early- and late-cART). For HIV-

infected individuals the variables entered into the model were: ethnicity (Caucasian vs. non-

Caucasian), sex (female vs. men), age (per-year increment), smoking (current or previous vs.

never), HIV transmission group, (IDUs, heterosexuals, and others vs. men who have sex with men



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(MSM)), and time period (pre-cART, early-cART and late-cART). Latest CD4 T-cell count before

IPD, latest VL measurement (undetectable <500 copies/mL vs. detectable ≥500 copies/mL), and

being on cART before IPD (cART vs. none) were included in the model as a time-dependent

variable.

SAS statistical software version 9.1 (SAS Institute Inc, Cary, NC, USA) was used for analysis.

RESULTS

Baseline Characteristics: 5362 HIV-infected individuals fulfilled inclusion criteria for the study,

and were individually matched to 101.869 controls. Of these, 137 HIV-infected patients and 136

controls experienced an episode of IPD (Table 1). The mean of CD4 T-cell counts/VL

measurements available per patient was 30 (IQR 13-47) and the mean time between the last

measurement before the event was 4 months (IQR 22 days-3.4 years). HIV-infected individuals

were younger at the time of IPD, and had fewer episodes of meningitis. HIV-infected individuals

with IPD were more often males, IDUs, and had a lower nadir CD4 T-cell count compared to HIV-

infected individuals without IPD (Table 2). Just over half of HIV-infected patients were on cART at

the time of IPD.

Incidence of IPD: The incidence in HIV-infected and uninfected individuals declined significantly

between pre-cART and early/late-cART periods (Table 3).

No IPD recurrences were observed among controls. In contrast, 13 out of 137 HIV-infected patients

had a at new IPD episode (range 1-3). Five of the recurrences were due to a PCV13-serotype, six of



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them were among IDUs, seven patients had CD4 T-cell counts <350 cells/µl and five had detectable

VL.

Factors associated with IPD: After adjusting for confounders (sex, age and calendar period) we

found that HIV-infected individuals had an overall 24-fold increased relative risk of IPD compared

to HIV-uninfected individuals from the background population (Table 4). In addition to this, male

sex, age, and the earliest calendar period were independently associated to an increased risk of IPD

in the total population.

Among HIV-infected individuals, we found that the risk of IPD was independently associated with

sex, smoking, HIV exposure group, treatment, lower CD4 T-cell counts, detectable VL and earlier

calendar periods (Table 4). The risk of IPD fell over time, being 22% higher in the pre-cART period

compared with the years 2000-2012, though this was not the case for IDUs (Figure 1).

Case fatality rate after IPD: The crude mortality proportion in HIV-uninfected individuals was

higher than among the HIV-infected individuals (14 vs. 6.5%, p=0.04). Controls tended to be older

and had more often pneumococcal meningitis than HIV-infected patients (Table 1). In the adjusted

analysis, age at IPD (increase per year: RR 1.05 [1.02–1.09]) was the only independent factor

associated with death, while sex (male RR 5.52 [0.7–43.1]), focus (meningitis vs. bacteremia: RR

2.67 [0.73–9.76]) and HIV-infection per se (RR 1.01[0.38–2.63]) did not reach statistical

significance.

Serotype distribution of pneumococcal isolates causing IPD: The serotype coverage of

pneumococcal conjugates vaccines differed slightly for HIV-infected and uninfected individuals.



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The overall coverage was ~30% for PCV7, 60% for PCV13, and 80% for PPV23 (Figure 2). The

higher serotype coverage of PCV7 in HIV-infected individuals was statistically significant

(p=0.02), and due to a higher prevalence of paediatric pneumococcal serotypes in this population.

DISCUSSION

In this nationwide population-based cohort study covering an 18-year period, we found that the

excess risk of IPD among HIV-infected individuals remained high compared to the risk of IPD

among HIV-uninfected individuals. Although the risk of IPD declined after the introduction of

cART, HIV-infection was associated with a 20-fold higher risk of IPD in the latest decade.

Remarkably, the risk of IPD in HIV-infected IDUs was unchanged over time and 300-fold higher

than in the background population.

In our cohort, the incidence of IPD was similar to that described in other studies on HIV-infected

populations [2, 7, 11, 13]. In the US, the availability of cART has significantly reduced the burden

of IPD in AIDS patients by approximately 50%, but the remaining risk of IPD was still ~35-fold

higher than in the general population [11]. Several factors, including secular trends of

pneumococcal disease; changes in blood culturing methods or clinical assessment protocols of HIV-

patients [13]; and changes in host related risk factors, such as an increasing proportion of HIV-

patients with comorbidities and IDUs [1, 13, 20] can at least partially explain this finding. A

limited effect of cART in reestablishing efficient antibody responses and preventing pneumococcal

disease has also been suggested [13, 35, 36].



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HIV-infection is an important risk factor for IPD in our and other study populations [5, 37], and

also increasing age and being a male were identified as factors independently associated to IPD [19,

38]. Among HIV-infected patients, the risk of IPD was additionally associated to IDU, smoking,

lower CD4 T-cell counts and higher VL, in agreement with findings from other studies [1, 10, 15,

39]. The receipt of cART at the individual level was protective. The association of IDU and

smoking was not possible to address in the control population in this study.

We observed a lower mortality among patients with IPD among HIV-infected individuals compared

to the HIV-uninfected population. In our study, HIV-uninfected individuals were older at the time

of IPD and had a relatively higher proportion of pneumococcal meningitis (Table 1), all known risk

factors associated with mortality after IPD [19, 40]. A previous study from the US similarly found

that mortality after IPD in HIV-infected patients was approximately one-fifth of that of the HIV-

uninfected patients [20]. The investigators attributed the lower mortality to a younger age and less

comorbidity among IPD cases in HIV-infected patients. However, due to limitations in our study

design we were not able to verify the effect of comorbidity on mortality after IPD and further

studies are needed in order to clarify this hypothesis. Also, the number of deaths after IPD was

relatively small. HIV-infected individuals in ambulatory care may have earlier access to care by

specialized infectious disease physicians, and, thus, may have received adequate care at an earlier

time point.

The effectiveness of PPV23-vaccination on HIV-infected individuals receiving cART remains

controversial, and research on the impact of conjugate vaccines on IPD in HIV-infected patients is

still needed [3, 13, 35, 41]. A recent study from Malawi, showed that PCV7 was effective in

protecting HIV-infected individuals from recurrent IPD caused by PCV7-serotypes and 6A [16].



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The introduction of general conjugate pneumococcal vaccination in young children in the US has

reduced the incidence of IPD in non-vaccinated persons, including HIV-infected individuals,

through the vaccines’ indirect effect [42]. HIV-infected individuals have higher rates of carriage

and infections caused by the so-called pediatric pneumococcal serotypes (groups 6, 14, 19 and 23)

[2, 43-45]. We found a similar pneumococcal serotype distribution in our study, thus providing

preventive opportunities for using conjugate pneumococcal vaccines. However, we did not take into

account seasonal variations and epidemiological trends of pneumococcal serotypes over the study

period [21]. Studies exploring the immunogenicity of conjugate pneumococcal vaccines in HIV-

infected individuals receiving cART are important, since pneumococcal vaccination is the only

available tool for preventing pneumococcal disease. On the light of our results, IDUs might be an

important target group for pneumococcal immunization, since they had the highest susceptibility to

the disease over time in spite of the availability of treatment.

The present study has certain limitations. It cannot be discarded that the greater absolute disease

incidence and relative lower mortality after IPD in the HIV-infected population could be affected by

referral bias, since febrile HIV-infected individuals are more likely to have taken blood cultures and

in our setting are often seen in infectious disease outpatient clinics. Also, the RR estimates for

HIV-infected individuals might be overestimated, since rates were obtained by comparing

incidences of IPD in HIV-infected individuals vs. those observed in controls, in whom the incidence

of IPD is relatively low compared to the incidence in youngest children and the elderly [21].

However, it is possible that the true incidence of IPD was probably underestimated in both HIV-

infected and non-HIV-infected individuals, since only cases with positive CSF or blood cultures

were included in the study. However, cases of pneumococcal infection of other sterile sites such as

pleural, synovial or peritoneal are not ascertained systematically in Denmark, and to maintain a high



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order of specificity, we included only blood and CSF specimens. We were not able to retrieve

information regarding comorbidity; social factors like crowding, alcoholism, socio economic status

or pneumococcal vaccination status, all factors might influence the incidence of the IPD in the study

population. A sensitivity analysis to address the problem of potential residual confounding such as

comorbidity and the use of immunosuppressive therapy would be of great value in order to further

validate our findings and constitute a field for future analyses.

In conclusion, the incidence of IPD in HIV-infected individuals remained significantly higher than

the incidence observed in HIV-uninfected individuals, in spite of the widespread use of cART in

Denmark. IDUs have a remarkably high risk of IPD that hasn’t declined over time, and remain an

obvious group for targeted immunization because pneumococcal vaccination. Injecting drug use,

smoking and the receipt of cART are suitable targets for preventive measures in the future.

NOTES

ACKNOWLEDGEMENTS The authors thank the staff at the participating clinical departments and the clinical microbiological laboratories for their contribution in collecting data for the DHCS. We also thank all departments of clinical microbiology across the country for submitting invasive pneumococcal isolates to the NSR at the Statens Serum Institut for national surveillance. Centers in The Danish HIV Cohort Study: Departments of Infectious Diseases at Copenhagen University Hospitals, Rigshospitalet (J Gerstoft, N Obel) and Hvidovre (G Kronborg), Odense University Hospital (C Pedersen), Aarhus University Hospitals, Skejby (CS Larsen) and Aalborg (G Pedersen), Herning Hospital (A L Laursen), Helsingør Hospital (L Nielsen) and Kolding Hospital (J Jensen). Author Contributions: TB and ZBH conceived and designed the study. GK, NO, JG, CS, GP, CP, ZBH collected and quality controlled the data. ZBH, MVL and SL analyzed the data. ZBH, MVL, TB, GK, NO interpreted the results of the study. ZBH wrote the first draft of the paper. ZBH, MVL, TB, NO, GK, CP contributed to the writing of the paper. ZBH had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.



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Financial support: This study was supported by Statens Serum Institut, since data on Invasive Pneumococcal Disease were collected routinely with surveillance purposes through funding allocated to national surveillance. The funding entity did not have any influence in the study design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, writing of the paper; approval or decision to submit it for publication. The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of Statens Serum Institut. Potential conflicts of interest: ZBH has received travel grants and consultant fees from Pfeizer and GSK. TB reports receiving travel grants, research grants, honoraria, and consultancy fees from Bristol-Myers-Squibb, Gilead, GlaxoSmithKline, and Jannsen Pharmaceuticals. HBK as received consultant fees from both Pfeizer and GSK and research grants from Pfeizer NO has received research funding from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Abbott, Boehringer Ingelheim, Janssen-Cilag and Swedish Orphan. JG reports receiving travel grants, research grants, honoraria, and consultancy fees from Bristol-Myers-Squibb, Gilead, ViiV, Abbvie, MSD, Medivir and Jannsen Pharmaceuticals. All other authors no conflicts of interest. Reference List (1) Barry PM, Zetola N, Keruly JC, Moore RD, Gebo KA, Lucas GM. Invasive pneumococcal

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FIGURE LEGENDS

Figure 1: Incidence of Invasive Pneumococcal Disease (IPD) per 100.000 person years of follow-up (PYFU) among HIV-infected patients by transmission groups, Denmark 1995-2012. IDU: injecting drug users, MSM: men who have sex with men. Periods: pre-HAART years 1995-1996, early HAART years 1997-1999, late-HAART years 2000-2012. Figure 2: Serotype distribution of pneumococcal isolates obtained from patients with invasive pneumococcal disease according to their HIV-status. Bars indicate the serotype coverage of three currently available pneumococcal vaccines. PCV-7: 7-valent pneumococcal conjugate vaccine (including serotypes 4, 6B, 9V, 14, 18C, 19F, 23F), PCV-13: 13-valent pneumococcal conjugate vaccine (including PCV7 serotypes plus serotypes 1, 3, 5, 6A, 19A), PPV-23: pneumococcal polysaccharide vaccine (including PCV13 serotypes but not 6A, plus serotypes 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F), only-PPV23 serotypes: non PCV13 serotypes included in PPV23. *Indicates that differences among HIV-infected and non-infected are statistically significant.



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Table 1: Characteristics of HIV-infected individuals and matched population controls, Denmark 1995-2012

Values are median and IQR unless otherwise stated. Population controls matched by age and sex at the time of HIV diagnose. IPD: Invasive Pneumococcal Disease

Matched population controls (n= 101,869)

HIV cases (n=5362)

p

Number of IPD cases 136 137 <0.001 Duration of follow-up (person-years) 1.066,577 46,076 Age at IPD, years 46.3 (35.2-58.7) 40.8 (33.3-47.1) <0.001 Time to IPD, years 7.2 (3.5-11.3) 4.5 (0.8-7.7) <0.001 IPD focus Bacteremia Meningitis

123 (90%) 13 (10%)

133 (97%) 4 (4%)

0.02

30–day mortality after IPD Total, n (%) Bacteremia Meningitis

19 (14%) 17 (14%) 2 (15%)

9 (6.5%) 7 (5%) 2 (50%)

0.04



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Table 2: Characteristics in HIV-infected individuals (n=5,362) with and without invasive pneumococcal disease (IPD) per December 31, 2012

Values are median and IQR unless otherwise stated. P are two tailed p-values from Fisher’s exact test. cART: combination antiretroviral therapy; MSM: Men who have sex with men; IDU: intravenous drug use; Other: blood transfusion, perinatal transmission, and unknown. MSM and individuals included in other HIV-exposure group who were active IDUs were considered as IDUs for the statistical analysis.

IPD (N=137) NON-IPD (N=5,225) p

Duration of follow-up (person-years) 1309 44,767 Age at HIV diagnosis, years 37.6 (30.0–43.4) 38.1 (30.5–44.5) 0.22 Male 93 (68%) 3,978 (76%) 0.03 Ethnicity Caucasian

109 (79%)

4137 (79%)

1.00

HIV-exposure group * Heterosexual MSM IDU Other Missing

47 (34%) 48 (35%) 36 (26%) 6 (5%) 0

1,912 (36%) 2,405 (46%) 533 (10%) 352 (7%) 23 (0.4%)

0.65 0.01 <0.001 0.38

Smoking status Current or ever smoker Never Missing

72 (52%) 18 (13%) 47 (20%)

2755 (52%) 1085 (21%) 1385 (26%)

0.1

cART at time of IPD 70 (51%) Median baseline CD4 T cell count, cells/µl 303 (IQR 87–450) 338 (120–484) 0.05 Median nadir CD4 T cell count, cells/µl 116 (IQR 20–189) 183 (53–263) <0.001



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Table 3: Incidence rates of invasive pneumococcal disease among HIV-infected individuals and matched population controls during pre-cART, early-cART and late-cART periods

cART: combination antiretroviral therapy. Periods: pre-cART years 1995-1996, early c-ART years 1997-1999, late-cART years 2000-2012. IPD: invasive pneumococcal disease; PYFU: person-years of follow-up; IR (95% CI): incidence rates with 95% confidence interval estimated per 100.000 PYFU; IRR: Incidence Rate Ratio with 95% confidence interval estimated for the incidence of IPD among HIV-infected vs. controls.

Population controls HIV-infected individuals

Period IPD cases PYFU IR (95% CI) IPD cases PYFU IR (95% CI) IRR (95% CI) p

Pre-cART 13 76,914 16.9 (9.8-29.1) 33 3811 865.6 (615.4-1217.7) 51.2 (26.9-97.3) <0.001

Early-cART 11 145,580 7.5 (4.1-13.6) 16 6439 248.4 (152.2-405.5) 32.8 (15.2-70.8) <0.001

Late-cART 112 835,818 13.4 (11.1-16.1) 88 34,708 253.5 (205.7-312.4) 18.9 (14.3-25.0) <0.001

Total 136 1.058,314 12.8 (10.8-15-2) 137 44,959 304.7 (257.7-360.2) 23.7 (22.9-24.4) <0.001



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Table 4: Crude and adjusted relative risk for invasive pneumococcal disease in the total study population and among HIV-infected individuals, Denmark 1995–2012 Crude Adjusted*

RR 95% CI P RR 95% CI p

Total study population

HIV-infection No Yes

1.00 23.7

22.9–24.4

<0.001

1.00 24.4

23.7–25.1

<0.001

Sex Female Male

1.00 1.00

0.76–1.33

0.96

1.00 1.20

1.16–1.24

<0.001

Age (per-year increment)

1.02 1.00-1.03 <0.001 1.03 1.03-1.04 <0.001

Time period Late-cART Early-cART Pre-cART

1.00 0.77 2.48

0.51–1.15 1.80–3.41

0.20 <0.001

1.00 0.87 2.80

0.83–0.91 2.70–2.91

<0.001 <0.001

HIV-infected individuals

Sex Female Male

1.00 1.39

1.33–1.46

<0.001

1.00 1.57

1.49–1.66

<0.001

Age (per-year increment)

0.98 0.98–0.99 <0.001 1.00 0.99–1.00 0.33

Ethnicity Non-caucasian Caucasian

1.00 0.96

0.91–0.1.02

0.22

1.00 0.96

0.91–1.03

0.95

Smoker No Yes

1.00 1.45

0.86-2.43

0.14

1.00 1.34

1.26–1.42

<0.001

HIV exposure group MSM IDU Heterosexual Other

1.00 3.48 1.00 1.21

3.29–3.68 0.89–1.12 1.15-1.28

<0.001 0.94 <0.001

1.00 2.51 0.68 0.80

2.26–2.67 0.61–0.76 0.75–0.85

<0.001 <0.001 <0.001

cART* No Yes

1.00 0.41

0.39–0.43

<0.001

1.00 0.81

0.77–0.86

<0.001

Viral Load* Non-detectable (< 500 copies/mL ) Detectable

1.00 3.22

3.07–3.38

<0.001

1.00 1.88

1.79–1.98

<0.001

CD4 T cell count* ≥ 500 cells/µl 350-499 cells/µl 100-349 cells/µl <100 cells/µl

1.00 1.64 3.52 11.8

1.52–1.77 3.30–3.75 11.0–12.7

<0.001 <0.001 <0.001

1.00 1.29 2.81 7.42

1.21–1.37 2.66–2.97 6.87–8.02

<0.001 <0.001 <0.001

Period Late-cART Early-cART Pre-cART

1.00 0.77 2.48

0.76–0.81 2.38–2.58

<0.001 <0.001

1.00 0.68 1.22

0.64–0.72 1.09–1.37

<0.001 <0.001

Multivariate model included all variables in the table. MSM. Men who sex with men; IDU: intravenous drug use. cART: combination antiretroviral therapy. Periods: pre-cART years 1995-1995, early c-ART years 1997-1999, late-cART years 2000-2012. HIV-RNA was only measurable since 1997 and onwards, the adjusted pre-cART estimate is then not adjusted for HIV-RNA in this table. *: time-updated variables



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