Incidence and risk factors for invasive pneumococcal disease in HIV-positive individuals in the era of highly active antiretroviral therapy

Abstract

Invasive pneumococcal diseases (IPDs) remain a significant cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals despite the widespread use of highly active antiretroviral therapy (HAART) and availability of pneumococcal vaccines. The aim of this study was to measure temporal trends in incidence and risk factors for IPD (defined as culture of Streptococcus pneumoniae from blood, cerebrospinal fluid or both) in a cohort of HIV-positive patients attending an ambulatory HIV care centre in Dublin, Ireland over a 10-year period 2006–2015. Incidence of IPD was determined as events per 100,000 person-years’ follow-up. Poisson regression was used to assess linear trend in incidence over time. A nested case–control study (four controls per case) was undertaken to assess risk factors for IPD. Forty-seven episodes of IPD were identified in 42 HIV-positive individuals (median [IQR] age 38 years [33–43], 69% male, 86% injecting drug users (IDUs), median CD4 T-cell count 213 cells/mm³) over 16,008 person-years’ follow-up (overall incidence rate 293/100,000 person-years). Three patients had two episodes and one patient had three episodes of IPD during the study period. The overall case fatality rate was 15% (95% confidence interval [CI] 4–24%). The incidence of IPD per 100,000 person-years decreased from 728 (95% CI, 455–1002), to 242 (95% CI, 120–365) to 82 (95% CI, 40–154) in calendar periods 2006–2008, 2009–2012 and 2013–2015, respectively (p < 0.01 for linear trend). Older age (p = 0.02), male gender (p = 0.05), detectable HIV viral load (p < 0.01) and non-receipt of pneumococcal vaccine (p = 0.03) were associated with IPD while IDU as risk of acquisition of HIV was of borderline significance (p = 0.06). HIV-positive individuals remain at greater risk of IPD compared to the general population. Pneumococcal vaccine should be seen as a priority to ensure optimal protection for HIV-positive patients.

Keywords

Invasive pneumococcal disease human immunodeficiency virus pneumococcal vaccine

Background

Invasive pneumococcal diseases (IPDs) remain a significant cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals in the era of highly active antiretroviral therapy (HAART).¹ The incidence of IPD in HIV-positive individuals has been reported at up to 100 times that of the general population.^2,3 In addition, HIV-positive individuals are at increased risk of recurrent episodes of IPD with up one in four experiencing a recurrence during a 12-month period.^4,5

HIV infection causes defects in cell-mediated immunity, B-cell dysfunction, loss of memory B-cell subsets, and suboptimal humoral immune responses increasing the susceptibility of HIV-positive patients to S. pneumoniae infection.^6,7 Level of immunocompromise is considered the most important risk factor for IPD in HIV-positive individuals. Numerous studies have reported a decrease in the incidence of IPD following the introduction of HAART likely due to resultant immune reconstitution.⁸ However, this has not been a consistent finding.^9,10

Factors including older age, uncontrolled viral replication, alcohol consumption, injecting drug use (IDU) and smoking have also been shown to be associated with IPD in HIV-positive individuals.^11,12

Factors including vaccination with the 23-valent polysaccharide pneumococcal vaccine (PPV23) and antimicrobial prophylaxis for opportunistic infections such as co-trimoxazole have been identified in some studies as protective against IPD.¹³

PPV23 has been shown to be safe and effective for prevention of pneumococcal infection in the general adult population¹⁴ and covers the majority of pneumococcal serotypes implicated in IPD.^15,16 Given the burden of pneumococcal infection observed in HIV-positive individuals, PPV23 has been recommended in consensus immunisation guidelines in the United States (US) since 1996. However, clinical and immunological efficacy of PPV23 in HIV-positive adults remains debated.¹⁷

More recently, pneumococcal conjugate vaccine (PCV) has been added to immunisation recommendations for HIV-positive individuals.^18,19 PCV has been shown to prevent pneumococcal pneumonia in HIV-positive children,²⁰ to prevent recurrent IPD in HIV-positive adults²¹ and to elicit a greater immunological response in HIV-positive individuals when compared to polysaccharide pneumococcal vaccine.²²

PCV was introduced to the national infant immunisation programme in Ireland in 2008 and has consistently achieved a vaccine coverage rate of >85%. A 78% decline in IPD in all age groups due to serotypes covered by PCV7 has been observed due to both direct and indirect effect of the vaccine.²³ It is unknown whether these changes similarly have affected HIV-positive individuals.

Aims of this study

The aim of this study was to examine temporal trends in the incidence of IPD in a cohort of HIV-positive individuals attending a single tertiary referral centre in Dublin, Ireland from 2006 and 2015. Findings are interpreted in the context of both an integrated immunisation programme for the attending HIV-positive cohort and the establishment of a national infant pneumococcal immunisation programme in the wider community. Risk factors associated with the occurrence of IPD were also assessed.

Methods

Study population and setting

This study was undertaken in St James’s Hospital, Dublin, a 1000-bed acute tertiary referral adult hospital which serves a catchment area of approximately 270,000 adults in a socially deprived area of Dublin city. The majority of patients admitted through the emergency department are in the highest quintile of deprivation index.²⁴ Compared with other parts of the country, it is also an area of high HIV prevalence, with a crude prevalence rate of 2/1000 population.²⁵

The Department of GU Medicine and Infectious Diseases (GUIDE) is the largest HIV specialist centre in Ireland with an active attending cohort of 2191 persons in 2015. Attending patients have universal access to HAART and vaccination. All patients attending GUIDE are recorded in a clinic database. Every patient who has attended within a 12-month period is counted in the active attending cohort for that year.

In 2002, an integrated vaccine unit with a data manager, specialist nurse and pharmacist was established onsite in the GUIDE clinic to address poor vaccination uptake within the attending cohort. Vaccination records for all patients are maintained in a database within the unit.

Loss to follow-up in the cohort, defined as more than 12 months without contact, is approximately 10%. Approximately 90% of the attending cohort are on HAART, while 89% have been vaccinated with PPV23.²⁶

This study was approved by the St James’s Hospital Intuitional Review Board.

Definitions

For the purpose of the study, IPD was defined as isolation of S. pneumoniae from blood, cerebrospinal fluid (CSF) or both. Blood cultures were performed routinely in the evaluation of HIV-infected patients with fever or pulmonary infiltrates on chest radiography throughout the study period.

Blood culture processing and detection techniques at the institution were not substantively altered during the study period.

A recurrent episode of IPD was considered to have occurred when more than 30 days separated isolation of S. pneumoniae from blood.

HAART was defined as the use of at least three antiretroviral agents from two or more classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or protease inhibitors).

IDU was determined by self-report at the time of initial enrolment in the cohort.

Microbiology

Isolates of S. pneumoniae were identified by standard laboratory methods. Isolates were tested for susceptibility to penicillin, cefotaxime, tetracycline, erythromycin, clindamycin and levofloxacin using the E-test method (BioMerieux, Solna, Sweden). Minimum inhibitory concentration to penicillin and cefotaxime was routinely performed on all sterile site isolates by the E-test, used in accordance with the manufacturer’s instructions (AB BioMérieux, Solna, Sweden) and were interpreted according to the 2013 Clinical and Laboratory Standards Institute guidelines.²⁷

Isolates were considered antimicrobial resistant if they were non-susceptible or had intermediate susceptibility to at least one of the antimicrobials. Multi-drug resistant isolates were defined as resistant to three antimicrobials or more.

Isolates were serotyped using a combination of multiplex PCR and serological co-agglutination with pneumococcal antisera (Statens Serum Institut, Copenhagen, Denmark).

Statistical analysis

Data were analysed using Statistical Package for the Social Sciences (SPSS) for Windows Version 23 (SPSS, Chicago, IL, USA). Incidence rates of IPD were calculated as events per 100,000 person-years of follow-up and were compared during three calendar periods: 2006–2008, 2009–2012 and 2013–2015.

These calendar intervals approximately correspond with the period prior to the introduction of conjugate pneumococcal vaccine to the infant immunization programme (2006–2008), introduction of PCV7 to the national infant immunization programme (2009–2012) and introduction of the 13-valent conjugate pneumococcal vaccine (PCV13) to the infant immunization programme (2013–2015). Poisson regression was used to assess the linear trend in incidence rates over calendar time.

To assess risk factors for IPD, four controls per case were selected from the HIV-positive cohort under observation during the calendar period in which IPD occurred in the case (incidence–density sampling). Controls were not matched with cases in any other characteristics.

Variables examined included age, gender, risk of acquisition of HIV, smoking status, hepatitis C PCR status, pneumococcal vaccine status, CD4 cell count and HIV viral load. Measures for cases were taken from most recent labs which were not greater than six months or not less than one week before the IPD episode. This avoided an acute illness effect on these laboratory markers in the cases.

A bivariate analysis using the Chi square and Fisher’s exact test was conducted with a significance level of 0.05. A multivariate analysis was performed using binary logistic regression that incorporated variables associated with pneumococcal infection in the bivariate analysis.

Results

Overall, 212 cases of IPD were identified in St James’s Hospital during the study period. Forty-seven (22%) cases of IPD occurred in 42 HIV-positive individuals over 16,008 person-years of follow-up (crude incidence rate of IPD in HIV-positive individuals, 293/100,000 person-years). Three patients had two episodes of IPD and one patient had three episodes of IPD during the study period. The overall case fatality rate was 15% (95% confidence interval [CI], 4–24).

The crude incidence of IPD per 100,000 person-years decreased from 728 (95% CI, 455–1002), to 242 (95% CI, 120–365) to 82 (95% CI, 40–154) in calendar periods 2006–2008, 2009–2012 and 2013–2015, respectively (p < 0.01 for linear trend) (Figure 1).

Figure 1.

Incidence of IPD 2006–2015 per 100,000 person-years’ follow-up.

Factors associated with IPD

There were 168 controls selected for the 42 individuals who presented with IPD during the study period. Baseline demographics for cases and controls are outlined in Table 1.

Table 1.

Risk factors associated with invasive pneumococcal disease on bivariate and multivariate analysis.

Characteristic			Bivariate analysis	Multivariate analysis
	Case	Control	OR (95% CI)	OR (95% CI)
	(n = 42)	(n=168)	p	p
Mean age (years [SD])	38 (6)	35 (9)	1.05 (1.01–1.09), 0.02	1.10 (1.01–1.20), 0.02
Race (no. [%])
Caucasian	38 (90)	121 (72)	3.69 (1.25–10.91), 0.02	0.34 (0.04–3.15), 0.34
Non-Caucasian	4 (10)	47 (28)
Gender (No. [%])
Male	29 (69)	108 (64)	1.24 (0.60–2.56), 0.56	4.00 (1.03–15.54), 0.05
Female	13 (31)	60 (36)
Risk of acquisition of HIV
IDU	36 (86)	59 (35)	13.38 (5.31–33.72), <0.01	9.67 (0.90–104.30), 0.06
Other
Heterosexual	4 (10)	61 (36)
MSM	0	42 (25)
Other	2 (5)	6 (4)
CD4 cell count <200 cells/mm³	20 (48)	32 (19)	3.99 (1.93–8.22), <0.01	1.23 (0.35–4.35), 0.75
Hepatitis C RNA positive	32 (76)	39 (23)	10.26 (4.63–22.73), <0.01	3.65 (0.78–17.13), 0.10
Undetectable HIV VL on HAART	3 (7)	110 (65)	52.96 (15.21–184.39), <0.01	47.39 (8.85–253.83), <0.01
Smoker	34 (81)	62 (37)	6.99 (3.04–16.07), <0.01	1.19 (0.20–7.07), 0.85
PPV23 vaccine	13 (31)	121 (72)	6.28 (2.99–13.17), <0.01	4.20 (1.18–14.98), 0.03

HAART (defined as the use of at least three antiretroviral agents from two or more antiretroviral classes): highly active antiretroviral therapy; IQR: interquartile range; IDU: injecting drug user; MSM: men who have sex with men; PPV23: 23-valent polysaccharide pneumococcal vaccine; HIV VL: HIV viral load. OR: odds ratio.

On univariate analysis, Caucasian race, IDU as risk of acquisition of HIV, CD4 cell count <200 cells/mm³, hepatitis C infection, not taking HAART, smoking and non-receipt of PPV23 vaccine were associated with IPD (Table 1).

On multivariate analysis, age, male gender, detectable HIV VL and non-receipt of pneumococcal vaccine remained associated with IPD, while IDU was of borderline significance (Table 1).

Vaccination with PPV23 was documented in 31% (n = 13) of cases prior to presentation with IPD (8 of 13 who had received PPV23 were infected with a vaccine serotype) and median (IQR) time from receipt of vaccine to IPD episode was 3 (2–5) years.

Microbiology

In 46 (98%) of episodes of IPD, S. pneumoniae was isolated from blood alone. In one case, S. pneumoniae was isolated from both blood and CSF.

Serotype distribution of pneumococcal isolates causing IPD

Serotype was available for 34 (72%) pneumococcal isolates identified during the study period. There were 21 different serotypes identified (Table 2).

Table 2.

Frequency and diversity of pneumococcal serotypes identified.

Pneumococcal serotype	Frequency observed
1	1
4	3
6	1
6C	2
7F	1
8	2
9N	1
9v	3
11A	1
12F	1
15A	1
18C	1
19a	3
19f	1
20	3
22F	1
23F	1
28A	2
33f	3
34	1
35F	1

Seventy-six per cent of serotypes isolated were contained in the PPV23 vaccine, 26% were contained in PCV7, while 41% of serotypes isolated were contained in PCV13.

Penicillin non-susceptible S. pneumoniae

Six of 47 (13%) pneumococcal isolates from HIV-infected individuals were resistant to at least one antimicrobial. Four of 47 (9%) isolates were penicillin non-susceptible (all with intermediate level resistance).

Discussion

While the incidence of IPD observed in our cohort has decreased during the study period (2006–2015), it remains higher than the incidence observed in the general population in Ireland (8–10/100,000).²³ The downward trends in incidence of IPD reported in our study are similar to those reported in other studies examining IPD in HIV-positive individuals.¹³ However, not all studies have reported such significant decreases in incidence of IPD.²⁸ Differences observed may relate to differing social, economic and geographical factors between cohorts.

The decrease in incidence of IPD observed in our HIV-positive cohort mirrors the decrease in IPD observed in the general population in Ireland following introduction of PCV7 to the Irish childhood immunisation programme in 2008 (replaced by PCV13 in 2010). Uptake of PCV in the infant immunisation programme has been reported consistently at >85% since the introduction of the programme.²³

Factors beyond herd immunity that may have influenced the decrease in IPD episodes include improved influenza and pneumococcal vaccination coverage in the cohort, earlier initiation of HAART and changing demographics of those presenting with HIV infections.

Over 85% of cases presenting with IPD in our study were IDUs, the majority had low CD4 cell count (48% CD4 < 200 cells/mm³) and detectable viral load (93%) indicating they were not actively engaged in HIV care. These findings would support findings from other studies which have similarly identified persistent high risk of IPD in IDUs.¹¹ Other risk factors for IPD identified in our study such as smoking, non-receipt of PPV23 and lower CD4 T-cell count reflect findings from other studies.¹³

Achieving and maintaining an undetectable HIV viral load is the primary aim of HAART. Our study found that having an undetectable HIV viral has a significant protective effect against the occurrence of IPD which further supports initiation of antiretroviral therapy for all regardless of CD4 cell count.

Patients from our cohort have universal access to pneumococcal vaccine and HAART. An integrated vaccine unit was established in the GUIDE clinic in 2002 to address poor vaccination coverage in the attending HIV-positive cohort.

In this study, 72% of controls and 31% of cases had been vaccinated with PPV23. Of the IPD cases who had received PPV23 vaccine 8 of 13 were infected with a vaccine serotype and median (IQR) time from receipt of vaccine to IPD episode was 3 (2–5) years.

Suboptimal protection and vaccine failure with PPV23 in HIV-positive patients is well recognized.^21,29 The conjugate pneumococcal vaccine has been shown to elicit a greater and more durable immunologic response and has been added to immunisation guidelines for HIV-infected individuals.^18,19

Of the serotypes identified in our study, PCV7 would have covered only 26%, PCV13 would have covered 41%, while PPV23 would have covered 76% of disease causing serotypes.

While our study is too small to reliably comment on serotype shifts, the last PCV 13 serotype causing IPD in our cohort occurred in early 2011 shortly shortly after the introduction of PCV13 to the national infant immunisation programme. Our findings indicate that PPV23 may cover more relevant serotypes than PCV13 in the future given the shift in disease-causing serotypes observed due to direct and indirect effects of introduction PCV to the infant immunisation programme.

It will be important for policy makers to continue to monitor the epidemiology of IPD serotypes at both national level and within risk groups such as HIV-positive individuals, so appropriate immunisation recommendations can be made.

The benefit of PCV13 alone may be limited if non-PCV13 serotypes become the main circulating serotypes responsible for pneumococcal infections in HIV-positive individuals. It may be that recommendation for the combination of PCV13 and PPV23¹⁹ or development of extended valency conjugate pneumococcal vaccines offers the broadest and most appropriate coverage.

Ireland had one of the highest proportions of penicillin non-susceptible streptococci in Europe (17.5% in 2014), ranked fifth out of 29 countries. The proportion of pneumococcal isolates from cases in our study demonstrating antimicrobial resistance (13%) reflects findings in the general Irish population.³⁰

Higher antimicrobial resistance rates have been reported in other HIV-positive cohorts and it has been hypothesized that resistance is promoted by antibiotic use for other infections and selective pressure from chronic antimicrobial use as may be the case with prophylaxis for opportunistic infections in individuals with low CD4 cell counts in these cohorts.³¹

Our study has a number of limitations. This was a single centre study undertaken in Dublin Ireland, thus risk factors for IPD, circulating pneumococcal serotypes as well as the baseline characteristics and general health of our HIV-positive population may differ from other populations. As IPD is a rare occurrence, the case number over the study period was relatively small limiting power of statistical analysis. Controls were matched to cases based solely on HIV diagnosis and attendance during interval in which IPD episode occurred. We cannot account for all factors that may have contributed to risk of IPD in the cohort.

The burden of IPD has decreased significantly in our HIV-positive cohort from 2006 to 2015. However, incidence remains significantly greater than that of the general Irish population.²³

Individuals with additional risk factors beyond HIV such as IDU as identified in our study are at greater risk of IPD and should be targeted with preventative interventions such as vaccine.

The burden of pneumococcal disease in HIV-positive individuals highlights the need for reduction of modifiable risk factors and development of more effective vaccine strategies to further reduce pneumococcal-related morbidity and mortality in this high-risk group.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Pneumococcal serotype	Frequency observed
1	1
4	3
6	1
6C	2
7F	1
8	2
9N	1
9v	3
11A	1
12F	1
15A	1
18C	1
19a	3
19f	1
20	3
22F	1
23F	1
28A	2
33f	3
34	1
35F	1

Pneumococcal serotype	Frequency observed
1	1
4	3
6	1
6C	2
7F	1
8	2
9N	1
9v	3
11A	1
12F	1
15A	1
18C	1
19a	3
19f	1
20	3
22F	1
23F	1
28A	2
33f	3
34	1
35F	1

Pneumococcal serotype	Frequency observed
1	1
4	3
6	1
6C	2
7F	1
8	2
9N	1
9v	3
11A	1
12F	1
15A	1
18C	1
19a	3
19f	1
20	3
22F	1
23F	1
28A	2
33f	3
34	1
35F	1