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Invasive Pneumococcal Disease in HIV-Infected Adults: Clinical Changes After the Introduction of the Pneumococcal Conjugate Vaccine in Children

Burgos, Joaquin MD*; Peñaranda, Maria PhD; Payeras, Antoni PhD; Villoslada, Aroa MD; Curran, Adrian MD*; Garau, Margarita PhD§; Riera, Melcior PhD; Crespo, Manuel PhD*; Navarro, Jordi MD*; Van den Eynde, Eva PhD*; Planes, Ana Maria PhD; Ribera, Esteban PhD*; Pahissa, Albert PhD*; Falcó, Vicenç PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1st, 2012 - Volume 59 - Issue 1 - p 31–38
doi: 10.1097/QAI.0b013e31823d0f5f
Clinical Science
Free

Background Few data exist on the implications of widespread use of 7-valent pneumococcal conjugate vaccine in children in the invasive pneumococcal disease (IPD) in HIV-infected adults. We conducted a multicenter study to analyze differences in clinical presentation of IPD between HIV-infected and non–HIV-infected adults in the prevaccine and postvaccine era.

Methods Study of all cases of IPD in HIV-infected adults diagnosed since 1996 to 2010. Episodes were classified into prevaccine (1996–2001), early postvaccine (2002–2004), and late postvaccine period (2005–2010). For each case, we identified an HIV-negative control patient with IPD matched by hospital, age, and vaccine period.

Results Two hundred twenty-one episodes of IPD in HIV-infected patients were diagnosed. The incidence of IPD decreased from 7.81 to 3.69 episodes per 1000 patient-years (−53%; 95% confidence interval: −65% to −36%, P < 0.001) between prevaccine and late postvaccine period. There was an 81% (95% confidence interval: −88% to −69%, P < 0.001) decrease of IPD caused by vaccine serotypes. In late postvaccine period IPD in HIV-infected patients was associated to higher rates of respiratory failure (28.4% vs. 48.4%, P = 0.011), greater intensive care unit admission (8.2% vs. 21.7%, P = 0.02) and a higher need for mechanical ventilation (5.9% vs. 16.3%, P = 0.033). In the prevaccine period, non–HIV-infected patients had a more severe illness than in those with HIV infection; however, these differences disappeared in the late postvaccine period.

Conclusions In the late postvaccine era, the incidence of IPD in HIV-infected patients has decreased, however, clinical presentation seems to have changed to a more severe illness. The widespread use of highly active antiretroviral therapy, polyssacharide vaccine, and 7-valent pneumococcal conjugate vaccine has contributed to these changes.

*Department of Infectious Diseases, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Department of Internal Medicine, Hospital Son Dureta, Palma de Mallorca, Spain

Department of Internal Medicine, Hospital Son Llàtzer, Palma de Mallorca, Spain

§Department of Microbiology, Hospital Son Llàtzer, Palma de Mallorca, Spain

Department of Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Correspondence to: Vicenç Falcó, PhD, Department of Infectious Diseases, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Po Vall d'Hebron 119-129, 08035 Barcelona, Spain (e-mail: vfalcó@vhebron.net).

Supported by Red Temática de Investigación en SIDA (RIS G03/173-RETIC RD06/0006/0039). The study was not supported by the Pharmaceutical Industry.

Preliminary results of this work were presented at the 18th Conference of Retroviruses and Opportunistic infections, February 27 to March 2, 2011, Boston, MA. Abstract 901.

The authors Drs J.B., and V.F. had full access to all the data in the study and took the responsibility for the integrity of the data and the accuracy of the data analysis.

The authors contributions were as follows: Study concept and design: J.B., V.F. Acquisition of data: J.B., M.P., A.P., A.V., M.G., A.M.P., V.F., Analysis and interpretation of data: J.B., V.F., Drafting of the article: J.B., V.F., Critical revision of the article for important intellectual content: J.B., M.P., A.P., A.C., M.R., M.C., J.N., E.V., M.R., A.P., V.F. Statistical expertise: J.B., V.F. Study supervision: M.R., V.F.

All authors approved the final version of the article.

The authors have no conflicts of interest to disclose.

Received July 20, 2011

Accepted October 13, 2011

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INTRODUCTION

The introduction of highly active antiretroviral therapy (HAART) in the mid-1990s led to dramatic improvements in the length and quality of life of HIV-infected patients, with an important declined incidence of common opportunistic illnesses and AIDS death. Indeed, different studies demonstrated a greater than 50% decrease in the incidence of invasive pneumococcal disease (IPD) in HIV-infected adults.1–5 Nevertheless, despite the introduction of HAART, the incidence rates of IPD in HIV-infected patients remain significantly higher than in non–HIV-infected population.2 Moreover, some studies suggest that mortality may have increased in the HAART period.3,6

The 7-valent pneumococcal conjugate vaccine (PCV7) was developed to prevent IPD in high-risk population such as children younger than 2 years. After the implementation of the PCV7 in children, significant declines in the incidence of IPD caused by vaccine serotypes were reported both in children and adults.7–12 However, this change has been accompanied to the emergence of serotypes not included in the PCV7, and increases in the incidence of IPD due by this serotypes were also observed in different populations. These changes in serotype distribution of IPD have been accompanied by changes in disease characteristics and complications, such as high rates of empyema in children and adults.13–16 In Spain, PCV7 was introduced in June 2001 and has been extensively used in the private medicine, thus in 2006, it was estimated that about 50% of children had been vaccinated.17

To our knowledge, there are very few published data regarding the changes in the serotypes causing IPD and the potential clinical implications in HIV-infected adults after the widespread use of the PCV7 in children. The aim of our study was to evaluate possible changes in incidence, clinical presentation, and serotypes causing IPD in adults with HIV infection during the last decade. In addition, we have conducted a case–control study to analyze the differences in clinical presentation and outcome of IPD between HIV-infected and non–HIV-infected adults in the prevaccine and postvaccine era.

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MATERIALS AND METHODS

Study Population and Setting

We performed a multicenter observational study of all HIV-infected adults hospitalized with IPD from January 1996 to December 2010 in 3 hospitals from Spain; the University Hospital Vall d'Hebron (a 1200-bed tertiary care teaching hospital in Barcelona, that serves an estimated population of 500,000 people), the Hospital Son Dureta (a 900-bed tertiary care teaching hospital in Palma de Mallorca, that serves an estimated population of 295,000 people), and Hospital Son Llàtzer (a 350-bed community hospital in Palma de Mallorca, that serves an estimated population of 225,000 people). Our institutions have an active program for HIV-infected patients (inpatients and outpatients care) that provide care to most of this population in our reference areas. All HIV-infected patients are included in a computerized database. At the end of the study, 4692 HIV-infected patients were included in this database.

The study was approved by the Commission of Medical Ethics of Hospital Vall d'Hebron.

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Study Variables and Data Collection

From each patient, the following variables were recorded: (1) sociodemographic data (age, gender, current tobacco smoking, long-term alcohol abuse, and active prior injecting drug use); (2) prior vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV), (3) predisposing factors for pneumococcal infection other than HIV infection (chronic lung disease, chronic liver disease, solid neoplasm and hematological malignancy, and other underlying diseases); (4) HIV infection–related data (HIV infection risk factors, current or prior AIDS-defining illnesses, CD4 lymphocyte count, HIV-1 viral load, trimethoprim–sulfamethoxazole (TMT-SMZ) prophylaxis, and current use of HAART); (5) clinical syndrome (pneumonia, meningitis, peritonitis, arthritis, endocarditis and primary bacteraemia); (6) severity of the illness at presentation (respiratory failure, septic shock, Pneumonia Severity Index at the moment of admission to the Emergency Department and chest radiograph pattern); (7) microbiological data (serotype and antibiotic resistance pattern of the Streptococcus pneumoniae causal strain); (8) antimicrobial therapy; and (9) variables related to clinical outcomes [hospital mortality, intensive care unit (ICU) admission, orotracheal intubation requirement, suppurative lung complications, and length of hospital stay]. The measurement of CD4 lymphocyte count and HIV-1 viral load was performed during or a maximum of 2 months around the episode. Information was extracted from hospital medical records using a standard data collecting form.

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Definitions

IPD was defined as isolation of S. pneumoniae from a normally sterile site (blood, cerebrospinal fluid, pleural fluid, peritoneal fluid). Invasive pneumococcal pneumonia was diagnosed when a patient had consistent clinical findings plus a new pulmonary infiltrate on chest radiography and isolation of S. pneumoniae in blood and/or pleural fluid culture. Other clinical syndromes (eg, empyema, meningitis, peritonitis. and bacteremia without focus) were defined according to current accepted criteria. AIDS was diagnosed on the basis of the 1993 Centers for Disease Control and Prevention AIDS case definition.18 HAART was defined as the use of an antiretroviral agent combination based on current guidelines for HIV infection management.19,20 Chronic liver disease was defined according to the presence of typical clinical, laboratory, ultrasonography signs, and/or the presence of histological findings in liver biopsy. Chronic lung disease was defined on the basis of clinical and/or functional tests and included chronic obstructive pulmonary disease, severe asthma, and interstitial lung disease.

Septic shock was considered when vasoactive drugs were necessary to obtain appropriate arterial pressure values after fluid replacement.

Vaccinated patients included all patients who had written record of receipt of 23-valent polysaccharide pneumococcal vaccine before the IPD episode.

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Microbiological Procedures

S. pneumoniae strains were identified by gram staining, optoquin susceptibility, bile solubility testing, and latex agglutination testing. Antimicrobial susceptibility was tested using the microdilution method, in accordance with Clinical and Laboratory Standards Institute procedures.21 For the purpose of this study, isolates were classified as penicillin susceptible (MIC ≤ 0.06 ug/mL), penicillin intermediate (MIC 0.12–1 ug/mL), or penicillin resistant (MIC ≥2 ug/mL). Intermediate or resistant isolates were considered to be nonsusceptible.

Serotypes were performed by capsular swelling reaction using commercial serogrup and serotype-specific antisera, using the quellung reaction at the Spanish Reference Laboratory (Instituto Carlos III, Madrid, Spain). Serotypes classified as PCV7 serotypes were those that matched serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F); all other serotypes were designated as non-PCV7 serotypes. We have available information of serotypes in 46.7% of S. pneumoniae strains.

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Clinical and Microbiological Changes After the Implementation of PCV7 in Children

To evaluate possible changes in clinical presentation and serotypes causing IPD in adults with HIV infection during the period of study, we classified the patients into 3 groups according to the introduction of PCV7 in our area: prevaccine period (1996–2001), early postvaccine period (2002–2004), and late postvaccine period (2005–2010). We subdivided the postvaccine era into 2 periods because in the years immediately after the introduction de PCV7 in Spain, the coverage was low, and so in consequence, the replacement of serotypes could have not occurred. This classification has been used in previous studies.9 The comparison between periods was performed excluding the early postvaccine period because we consider it as a transition period.

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Estimation of the Incidence of IPD

The annual incidence of IPD was calculated using as the denominator the number of HIV-infected persons alive each year registered in the database and is expressed as cases per 1000 HIV patients per year. We also estimated the incidence of IPD by group vaccine serotype and specific serotype.

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Case–Control Study

To asses differences between HIV and non-HIV population, we conducted a case–control study.

A case was defined as the occurrence of IPD in HIV-infected patients in the period of study, and controls were non–HIV-infected patients with an IPD. One control was selected for each patient and matched by hospital, age (±3 years) and time period. We selected the matched control in alphabetical order from the microbiological register of all adults admitted to hospital with isolation of S. pneumoniae from a normally sterile site. The same clinical and microbiological variables (except those related to HIV infection) were collected for cases and controls. With this approach, we avoid the possible bias due to age differences between both populations.

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Statistical Analysis

Statistical analyses were performed using the statistical software package SPSS for Windows, version 15.0. Differences in means of incidence between periods were tested using Mantel–Haenszel Chi test. The percent reduction in incidence was reported with their associated 95% confidence interval (CI). The χ2 test or Fischer exact test, when appropriate, were used to compare the distribution of categorical variables and the Student T test for continuous variables. Results were considered statistically significant if the 2-tailed P value was <0.05.

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RESULTS

Sociodemographic Variables and Underlying Diseases in HIV-Infected Patients

In the 15 years of the study, 221 episodes of IPD in HIV-infected patients were diagnosed. The mean age of the patients was 39.9 (±10.2) years, and 72.4% of the episodes occurred in men. A chronic medical illness, other than HIV infection, was present in 47.3% of the patients. One hundred thirteen (59%) patients had a previous diagnosis of AIDS, and 150 (68%) patients were injection drug users. To note, in 49% episodes, patients had a CD4 cell count >200 cells per microliter.

Table 1 shows a comparison of the basal characteristics of HIV-infected patients between the prevaccine and late postvaccine periods. The mean age of the patients increased from 37.7 to 42.5 years (P = 0.002). We did not observe significant differences in the comorbid conditions between prevaccine and postvaccine periods. In contrast, we found some changes in the characteristics of HIV infection. In the late postvaccine era, there was a greater number of patients on HAART (47.3% vs. 32.1%, P = 0.043), patients had a higher CD4 cell counts (289 cells/μL vs. 214 cells/μL, P = 0.045), and a higher proportion of them had a viral load <400 HIV-1 RNA copies per milliliter (37.6% vs. 13.6%, P = 0.01).

TABLE 1

TABLE 1

Polysaccharide vaccine had been previously administered to 6% of patients in the prevaccine period and 27.5% in the late postvaccine period (P < 0.001).

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Incidence of IPD in HIV-Infected Patients

The overall incidence of IPD in HIV-infected patients decreased significantly from 7.81 episodes per 1000 patients-years in the prevaccine period to 3.78 and 3.69 episodes per 1000 patients-year in the early and late postvaccine periods, respectively (Fig. 1). Compared with the prevaccine period, there was a 53% decrease of the incidence (95% CI: −65% to −36%, P < 0.001) in the late postvaccine period.

FIGURE 1

FIGURE 1

Reductions in the incidence of the IPD in the late postvaccine era were due mostly to an 81% reduction of IPD caused by PCV7 serotypes (from 5.04 to 0.96 episodes per 1000 patients-year (95% CI: −88% to −69%, P < 0.001), although the incidence of IPD caused by nonvaccine serotypes remained unchanged (−2%, 95% CI: −36% to 53%, P = 0.94). Nonvaccine serotypes comprised 35.6% of the isolates in the prevaccine period, 53.3% in the early postvaccine period, and 73.9% in the late postvaccine period (P <0.001).

Reductions in PCV7 serotypes in the late postvaccine era were due mostly to a 95% reduction of IPD caused by serotype 6B (95% CI: −99% to −66%), a 75% reduction of infections by serotype 14 (95% CI: −90% to −49%), and a 92% reduction of infections due serotype 23F (95% CI: −98% to −61%). Although no significant changes in other specific serotypes were seen, we observed an important increase in the incidence of nonvaccine serotype 19A (311%; 95% CI: −47% to 3088%, P = 0.141) and serotype 8 (199%; 95% CI: −62 to 2293%, P = 0.277).

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Clinical Presentation and Outcomes in HIV-Infected Patients

The most common clinical presentation of IPD was bacteremic pneumonia, which accounted for 86.3% of all 221 episodes, followed by peritonitis for 5.5% and meningitis for 4.6%. Overall, 5.8% of patients developed empyema (Table 1).

In the late postvaccine period, IPD in HIV-infected patients was associated with a more severe clinical presentation, with higher rates of respiratory failure (28.4% vs. 48.4%, P = 0.011), greater ICU admission (8.2% vs. 21.7%, P = 0.02), and a higher need for mechanical ventilation (5.9% vs. 16.3%, P = 0.033). When we analyzed only the group of patients with pneumonia, we found similar findings, with a higher Pneumonia Severity Index score (score IV or V: 25.4% vs. 49.4%, P = 0.003) and a trend to a higher proportion of patients with bilateral infiltrates in the chest radiograph (12.5% vs. 27.5%, P = 0.170) in the late postvaccine era. These changes were also observed when patients were stratified by CD4 count more or less than 200 cells/μl (data not shown). The case-fatality rate remained unchanged, with mortality of 11.6% in the prevaccine period and 11.8% in the late postvaccine period. Worth to note, in the postvaccine period, only 1 patient with previous PPV vaccination died, compared with 23 in the group without previous PPV vaccination (3.6% vs. 20.2%, P = 0.042).

Regarding antibiotic susceptibility, the proportion of IPD caused by penicillin nonsusceptible strains decreased along the 3 periods, from 53.5% in the prevaccine period to 26% in early postvaccine period and to 20.2% in the late postvaccine period (P < 0.001). Rates of resistance to cephalosporins also decreased, and resistance to macrolides also tended to decrease (Table 2).

TABLE 2

TABLE 2

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Comparison Between HIV-Infected and Non–HIV-Infected Patients With IPD: Case–Control Study

We have compared the characteristics of the IPD between HIV-infected and non–HIV-infected patients (Table 3). In the prevaccine period, IPD was associated to a more severe illness in non–HIV-infected patients than in those with HIV infection with higher rates of septic shock (17.6% vs. 32.1%, P = 0.034) and ICU admission (8.2% vs. 38.8%, P < 0.001). In contrast, in the late postvaccine period, the severity of the disease in HIV-infected patients tend to be equal than in non–HIV-infected patients with similar rates of septic shock (20.4% vs. 25.3%, P = 0.489) and ICU admission (21.7% vs. 26.3%, P = 0.497). Interestingly, rates of empyema were higher in non–HIV-infected patients in the late postvaccine period (5.8% vs. 19.3%, P = 0.01)

TABLE 3

TABLE 3

The pattern of serotypes was somehow different in both populations (Fig. 2). In the prevaccine period, the percentage of infections caused by PCV7 serotypes were 64.4% and 41.7% in HIV-infected and non–HIV-infected patients, respectively (P = 0.01). This percentage decreased to 26.7% and 16.7% (P = 0.157) in the late postvaccine period. Regarding to specific serotypes, in the late postvaccine period, we observed a trend to increase in illness caused by serotype 19A (1.7% vs. 10.9%, P = 0.084) and serotype 8 (1.7% to 8.7%, P = 0.166) in HIV-infected patients, and significant increases in infections caused by serotypes 1 (8.3% to 29.2%, P = 0.004) and 7F (3.3% to 14.8%, P = 0.043) in non-HIV infected. Penicillin susceptibility of the pneumococcal isolates was also different; in the prevaccine period, the rates of penicillin susceptibility were significantly higher in non–HIV-infected patients (76.8% vs. 46.5%, P = 0.001), however, this difference disappeared in the late postvaccine period (93.5% vs. 89.8%, P = 0.625).

FIGURE 2

FIGURE 2

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DISCUSSION

In this study, we have confirmed a marked reduction in the incidence of IPD in HIV-infected patients. Several factors may explain this phenomenon such as the widespread use of HAART,1–3 the improvement in the immunological status of the patients, and probably the expanded use of the PPV.4,22–24 Indeed, we believe that the implementation of PCV7 has also played a key role in this effect, which is reflected in the pattern of serotypes causing IPD. These data are consistent with those previously observed in other studies. A large population-based study in United States observed a significant 19% decrease in IPD among HIV-infected patients between 1998 and 2003.25 Seven years after the implementation of the PCV7, overall reductions of 41% in IPD were noted in the same setting with a decrease of 91% in infections due to vaccine serotypes.26 Other epidemiological studies in United States have noted similar results with overall reductions of 62.5% from 1998–1999 to 2004–2005.27

In our study, several factors may probably have influenced the trends on incidence observed during this period. Thus, in our centers, an informative campaign to encourage doctors to vaccinate their HIV-infected patients with the polysaccharide vaccine was performed in 2003, and in 2005, about 50% of them had been vaccinated.4 In fact, in our setting, we have observed a beneficial effect on the incidence of IPD and bacterial pneumonia in HIV-infected patients after the implementation of this campaign.4,21 Nevertheless, the change in the pattern of serotypes with an important reduction of vaccine serotypes and the timing of these changes suggest that the implementation of the conjugate vaccine should have played an important role.

Not only the pattern of serotypes has changed but we have also observed important changes in the clinical presentation of IPD with a higher proportion of patients with severe manifestations. Despite the clinical presentation of IPD seems to have worsened in the late postvaccine period, case-fatality rate has not changed significantly. Conflictive data on the evolution of mortality in patients with IPD have been reported. Although Grau et al6 observed an increase in 30-day mortality in the postvaccine period (8% to 25%, P = 0.017), others not only have not found an increased mortality but also a slight but significant decrease (8.4% to 6.3%, P < 0.0001).26

Several factors might have contributed to explain these changes in the clinical pattern of the disease. It has been suggested that the impairment of immunity may decrease the inflammatory response in HIV-infected patients with IPD, so it would be expected that an improvement of immunity may enhance the inflammatory response against a bacterial infection and consequently, this would be associated with increased severity.6,28 We have not evaluated the inflammatory response in our study, however, interestingly, we have observed that IPD in non–HIV-infected patients in the prevaccine period had a more severe illness than HIV-infected patients. In the postvaccine period, in which HIV-infected patients have a better immunological status, the severity of IPD tends to be equal to what occurs in non–HIV-infected patients. The increasing severity could also be related to the increased age and associated comorbidities in this population. This age distribution probably reflects the overall aging of HIV-infected population as a result of their prolonged survival.

In contrast, other factors may explain that, despite severity of the illness has increased, mortality remains stable. We can hypothesize that because the proportion of vaccinated patients with the PPV is high in the postvaccine period, in those in whom PPV fails to prevent the pneumococcal infection, it protects against mortality. In a previous study, we have observed that prior vaccination with PPV may provide some beneficial effects improving clinical outcomes in those who develop IPD.29 Thus, in our study, in the postvaccine era, when a large number of patients had received PPV vaccine, only 1 (3.6%) patient with previous PPV vaccination died, compared with 23 (20.2%) in the group without previous administration of PPV. Finally, changes in the pattern of pneumococcal serotypes causing IPD might also play an important role in this increased severity of IPD. Studies in general population in adults have found that IPD caused by the nonvaccine serotypes 3, 11A and 19A, were independently associated to higher mortality in the postvaccine period.30 In the same way, high rates of empyema associated to serotypes 1 and 3 have been reported in children and adults.13,16,31 In our study, the limited number of isolates for each specific serotype has not led us to find significant associations.

In our setting, after the implementation of the PCV7 vaccine, the serotype distribution has been somehow different in HIV-infected population than in non-HIV. Thus, although in non-HIV population, we have observed an increase of nonvaccine serotypes with high invasive potential, such as 1 and 7F, in HIV-infected population, the number of infections caused by nonvaccine serotypes with low invasive disease potential such as serotypes 8 and 19A tend to increase. Other studies have also reported similar findings with an emergence of infections caused by serotypes 8 and 19A, both with low potential for invasiveness.6,27,32 The reason of this different distribution of serotypes is not clearly established but, in our opinion, it is possible that the different PPV vaccine coverage between both populations have played a role in the causal serotypes. This difference in the pattern of serotypes could also contribute to the differences observed in the trends of severity of illness in both populations.

Some limitations of our study must be pointed out. First, because it is not a population-based study, our cohort could differ from other HIV-infected populations and the incidence estimates might not be extrapolated to other settings, however, the multicenter nature of the study could mitigate this limitation. Second, the number of episodes for some serotypes is too small to explore in more detail potential correlations with clinical presentation. Third, in the case–control study, the selection bias is possible because controls were chosen retrospectively and matched only by hospital, age, and time period. Finally, other factors that might also modulate the epidemiology and clinical presentation of IPD (eg, genetic properties of S. pneumoniae strains, viral coinfections, and inflammatory response) have not been evaluated in our study.

In conclusion, our study confirms the progressive decline of the incidence of IPD in HIV-infected patients. The cumulative effect of widespread use of HAART, use of polyssacharide vaccine, and also the introduction of the conjugate vaccine in children play a key role in this change. The disease seems to have changed to a more severe illness and tend now to be similar to what occurs in non–HIV-infected patients. Despite infections caused by vaccine serotypes have significantly decreased in both populations, the change in serotypes causing IPD is somehow different in HIV-infected and non–HIV-infected population. These findings require a continued surveillance and new strategies for prevention of IPD in HIV-infected patients.

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Keywords:

HIV-infected patients; invasive pneumococcal disease; pneumococcal conjugated vaccine; Streptococcus pneumonia

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