Epidemiology and Social
Prevention of invasive pneumococcal disease among HIV-infected adults in the era of childhood pneumococcal immunization
Cohen, Adam La; Harrison, Lee Hd; Farley, Monica Me; Reingold, Arthur Lf; Hadler, Jamesg; Schaffner, Williamh; Lynfield, Ruthi; Thomas, Ann Rj; Campsmith, Michaelb; Li, Jianminb; Schuchat, Annec; Moore, Matthew Ra; the Active Bacterial Core Surveillance Team
aRespiratory Diseases Branch, Division of Bacterial Diseases, USA
bDivision of HIV/AIDS Prevention, USA
cNational Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
dMaryland Emerging Infections Program and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
eEmory University School of Medicine and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA
fSchool of Public Health, University of California, Berkeley, California, USA
gConnecticut Emerging Infections Program, Hartford, Connecticut, USA
hDepartment of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
iMinnesota Department of Health, St. Paul, Minnesota, USA
jOregon Emerging Infections Program, Oregon Public Health Division, Portland, Oregon, USA.
Received 24 March, 2010
Revised 16 June, 2010
Accepted 16 June, 2010
Correspondence to Adam L. Cohen, MD, MPH, Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS C-23, Atlanta, GA 30333, USA. Tel: +1 404 639 6417; e-mail: email@example.com
Objective: Human immunodeficiency virus (HIV) infection and AIDS increase the risk of invasive pneumococcal disease (IPD). We evaluated IPD among HIV-infected adults over a 10-year period in the US to identify opportunities for prevention of IPD among HIV-infected adults.
Design: IPD and HIV surveillance in seven population-based and laboratory-based Active Bacterial Core surveillance areas.
Methods: IPD cases were adults 18–64 years old with pneumococcus isolated from a normally sterile site during 1998–2007. Isolates were serotyped using the Quellung reaction. HIV/AIDS status was determined by medical record review. We calculated incidence of IPD among adults with AIDS using national case-based surveillance data.
Results: Of 13 812 IPD cases among 18–64-year-olds, 3236 (23%) occurred among HIV-infected adults (with or without AIDS) and 1313 (10%) occurred among the subset of HIV-infected adults with AIDS. Compared with the period (1998–1999) before childhood 7-valent pneumococcal conjugate vaccine (PCV7) introduction in the US, the overall incidence of IPD among adults with AIDS decreased 25% from 399 to 298 cases per 100 000 by 2007 (P = 0.008). In 2006–2007, 8, 39 and 55% of IPD cases among adults with AIDS were caused by serotypes included in the 7-valent PCV, 13-valent PCV and 23-valent pneumococcal polysaccharide vaccines, respectively.
Conclusion: Sustained declines in IPD have occurred among adults with AIDS in the US, but incidence remained high 7 years after PCV7 introduction. More aggressive efforts, including HIV-prevention measures and the use of new PCVs in children and possibly HIV-infected adults, are necessary to further reduce IPD among HIV-infected adults.
The burden of invasive pneumococcal disease (IPD) in persons infected with human immunodeficiency virus (HIV) is substantial. Adults with HIV infection have incidence rates of IPD from 6–324-fold as high as HIV-uninfected adults . An estimated 56 300 persons aged 13 years and older were newly diagnosed with HIV in the US in 2006 . Adults living with HIV worldwide number more than 30 million, with most HIV-infected individuals found in sub-Saharan Africa .
The 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar, Pfizer) was licensed in the US in 2000 for use in children and is available in many countries worldwide ; the 13-valent pneumococcal conjugate vaccine (PCV13; Prevnar-13, Pfizer) was licensed in the US in February 2010 and has replaced PCV7 in the childhood immunization schedule . Pneumococcal conjugate vaccines (PCVs) are highly efficacious in preventing IPD in young children, although somewhat less so in HIV-infected children . Although PCV7 is not recommended for use in adults, introduction of PCV7 into the routine childhood immunization schedule of the US in 2000 was associated with a decline in IPD among HIV-infected adults through 2003, presumably due to the indirect effects of reduced transmission from vaccinated children to HIV-infected adults . We sought to describe clinical and epidemiologic trends in IPD among HIV-infected adults in the US through 2007 in an effort to determine if the earlier trends were sustained and to identify opportunities for further prevention of IPD among HIV-infected adults.
Surveillance for invasive pneumococcal disease
Active laboratory-based and population-based surveillance for cases of IPD, defined as Streptococcus pneumoniae isolated from a normally sterile site, was conducted through the Centers for Disease Control and Prevention's (CDC) Active Bacterial Core surveillance (ABCs), part of the Emerging Infections Program Network. We included cases diagnosed between 1 January 1998 and 31 December 2007 among surveillance-area residents who were from 18 through 64 years of age. We limited the analyses to the seven surveillance sites that gathered data on HIV infection, including California (San Francisco County), Connecticut (entire state), Georgia (eight-county Atlanta metropolitan area), Maryland [Baltimore City and five neighboring counties (Baltimore metropolitan area)], Minnesota (seven-county Minneapolis–St. Paul metropolitan area), Oregon (three-county Portland metropolitan area), and Tennessee (Davidson, Hamilton, Knox, Shelby, and Williamson counties). In 2007, the resident adult population in these seven areas was 11.3 million (5.9% of the US population from 18 through 64 years of age).
Surveillance officers routinely contacted all clinical laboratories in their areas to identify cases of IPD and conducted periodic audits of laboratory records to ensure complete case ascertainment. All episodes of IPD, including recurrent episodes defined as IPD occurring more than 7 days after culture-proven diagnosis of a previous episode in a surveillance-area resident, were included in this analysis. We used a standard case report form1 to extract from medical records information related to clinical syndromes of IPD (e.g. pneumonia or meningitis), outcome of illness. HIV infection status and previous AIDS diagnosis were recorded if present in the medical record; patients with no record of HIV testing results or diagnosis were considered uninfected. Surveillance in Georgia did not prospectively collect information on HIV infection or AIDS status for case-patients until 2000; for case-patients in 1999 in Georgia, we retrospectively reviewed medical records to collect this information. Analyses for 1998 exclude Georgia. We also extracted demographic characteristics (e.g. sex, race, and ethnicity) from the medical record and, where race and ethnicity were not available, we assumed that the distribution of race and ethnicity among case-patients missing these data (3% of cases of IPD) was the same as among case-patients with known race and ethnicity and used simple proportions to fill in missing data.
Statistical evaluation of incidence of invasive pneumococcal disease
The metrics used to estimate the incidence of IPD among adults with HIV infection and adults with AIDS are given in Table 1. To evaluate incidence of IPD in these populations, we needed reliable estimates of the numbers of persons with HIV infection and persons with AIDS in ABC areas. With the collaboration of state AIDS surveillance coordinators, we obtained the estimated number of adults from 18 through 64 years of age with HIV infection and with AIDS, according to the 1993 CDC case definition2 , living in each of the seven surveillance areas on 30 June of each year from 1998 to 2007. These estimates are derived from case report data using a maximum likelihood method to account for delays in reporting new HIV infection, AIDS diagnoses, and deaths among persons with AIDS, and were recently revised to reflect improved diagnostic testing . Case-based estimates of persons with AIDS were available in all seven ABC areas for the 10-year study period (1998–2007). Case-based reporting of HIV infection has been adopted in many US states only recently, so we used estimates of persons infected with HIV from 2004 to 2007 in three ABC areas (Georgia, Minnesota, and Tennessee).
To assess changes in IPD among HIV-infected adults and adults living with AIDS before and after the introduction of the PCV7 for children, we calculated the percentage change during 1998–1999 (the baseline prevaccination period) to 2007. We calculated P values using chi-squared tests unless otherwise specified; P values less than 0.05 indicated statistical significance. Since we were limited by the years of case-based reporting of HIV infection in the surveillance areas, we adopted a proxy to evaluate trends in IPD incidence among HIV-infected adults without AIDS over the entire 10-year study period. Specifically, we calculated the ratio of the number of cases of IPD among adults with HIV infection (with or without AIDS) to the estimated adult population living with AIDS . Similarly, to estimate the incidence of IPD among adults not infected with HIV over the entire study period, we divided the number of cases of IPD in persons without documented HIV infection by the population of surveillance-area residents aged from 18 through 64 years without AIDS (calculated from total US census population less the estimated number of persons living with AIDS) .
The analysis was exempt from humans review as it was analyzed data collected as part of routine public health surveillance.
Laboratory testing and serotypes included in pneumococcal vaccines
Pneumococcal isolates from ABC cases were sent to reference laboratories at the Minnesota Department of Health, the University of Texas Health Science Center at San Antonio, or CDC for serotyping by the Quellung reaction and PCR  and susceptibility testing by broth microdilution . Nonsusceptible isolates were defined as those with minimum inhibitory concentrations (MICs) classified as intermediate or resistant for the antibiotic tested .
Serotypes were classified as serotypes included in the following vaccines: 7-valent PCV (PCV7), Prevnar, Pfizer – serotypes include 4, 6B, 9V, 14, 18C, 19F, and 23F; 10-valent PCV (PCV10), Synflorix, GlaxoSmithKline – PCV7 types and serotypes 1, 5, and 7F; 13-valent PCV (PCV13), Prevnar-13, Pfizer – PCV10 types and serotypes 3, 6A, and 19A; and 23-valent pneumococcal polysaccharide vaccine (PPV23), Pneumovax 23, Merck – PCV13 and serotypes 2, 6B, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F and not 6A. For all analyses involving serotype data, we assumed that cases without isolates available for serotyping had the same serotype distribution as cases for which serotype was known and used simple proportions to fill in missing data.
Invasive pneumococcal disease in persons living with and without HIV/AIDS
Of 13 812 IPD cases among 18–64-year-olds identified from 1998 through 2007, 3236 (23.4%) occurred among HIV-infected persons (with and without AIDS) and 1313 (9.5%) occurred among the subset of HIV-infected persons with AIDS (Fig. 1). Approximately 90% of the isolates were serotyped, and the proportion of serotyped isolates was similar among persons with and without HIV infection (Fig. 1).
From 2004 to 2007, the incidence of IPD in HIV-infected adults (with or without AIDS) and in adults with AIDS was 385 and 332 cases per 100 000, respectively, and was approximately 40 times as high among HIV-infected adults as among HIV-uninfected adults (nine cases per 100 000 adults without AIDS; please refer to Table 1 for description of how incidences were calculated). HIV-infected adults with IPD were younger than HIV-uninfected case-patients with IPD [median 42 years (5th–95th percentile, 29–56 years) vs. 49 years (5th–95th percentile, 26–63 years), respectively; P < 0.001 by Wilcoxon rank sum test; Table 2]. Bacteremic pneumonia was the most common clinical syndrome in cases of IPD among individuals with HIV infection (2621 cases, 81.0%), followed by bacteremia without focus (440 cases, 13.6%), and meningitis (131 cases, 4.0%). Among adults less than 35 years of age, the case-fatality rate was higher among HIV-infected adults (6.1% among HIV-infected adults vs. 4.9% among HIV-uninfected adults); in contrast, the case-fatality rate increased with age and among adults 35 years of age or older was higher for HIV-uninfected adults (Table 2). Of the 3035 cases of IPD among HIV-infected adults when recurrent cases could be identified, 545 (18.0%) were recurrent infections (an estimated 69 recurrent IPD infections per 100 000 adults with HIV infection); this percentage was significantly higher than the proportion of recurrent cases among HIV-uninfected adults [299 cases (3.0%) of 10 003 cases when recurrent cases could be identified (an estimated 0.27 cases per 100 000 adults without HIV infection, P < 0.001 compared with rate among HIV-infected adults)].
Invasive pneumococcal disease by serotype
Compared with the period before PCV7 introduction in the US (1998–1999), the incidence of IPD among adults with AIDS decreased 25% from 399 to 298 cases per 100 000 by 2007 (P < 0.008; Table 3). Over the same time period, the incidence of IPD caused by serotypes included in PCV7 decreased 88% from 231 to 29 cases per 100 000 (P < 0.001) and the incidence of IPD caused by serotypes not included in PCV7 increased 60% from 168 to 269 cases per 100 000 (P < 0.001). The trends among adults with and without HIV infection were similar to the trends in adults with AIDS (Table 3, Fig. 2). For PCV7 serotypes, the proxy incidence ratio of cases of IPD among HIV-infected persons to the number of persons living with AIDS declined consistently from baseline to 2007, and among the other serotypes, no others except 19A showed a consistent increase among HIV-infected patients during the study period (Fig. 3).
In 2006–2007, 8.7% of cases of IPD in HIV-infected individuals were caused by serotypes included in PCV7, 11.4% of IPD cases were caused by serotypes included in PCV10, 38.9% were caused by serotypes included in the PCV13, and 57.7% were caused by serotypes included in PPV23 (Table 2). The proportion of serotypes included in PCV10 and PPV23 was higher in HIV-uninfected adults than adults with HIV infection (Table 2), in part due to a higher proportion of IPD in HIV-uninfected adults caused by serotypes 1, 3, and 7F.
Trends of invasive pneumococcal disease by race, ethnicity and sex
We used the proxy incidence ratio of IPD case-patients with HIV per 100 000 persons with AIDS to evaluate trends by race, ethnicity and sex. Non-Hispanic black adults were of the race that comprised the highest percentage of IPD cases among HIV-infected adults (Table 2). In 2007 the proxy incidence ratio was highest among black women, followed by white, non-Hispanic women, and black, non-Hispanic men (Table 3). Declines in trends were seen in all race and sex subpopulations over the study period, although the trends were not statistically significant for white, non-Hispanic women and Hispanic men and women.
Of 537 pneumococcal isolates in 2006–2007 from HIV-infected adults with penicillin susceptibility testing results, 43 (8.0%) were nonsusceptible (MIC ≥4 μg/ml); this proportion was higher than the 30 (5.5%) of 546 isolates with penicillin nonsusceptibility during the baseline period (1998–1999) (P = 0.06; Table 2). The occurrence of serotype 19A pneumococcal isolates not susceptible to penicillin isolated from HIV-infected adults rose from 0 of 25 isolates in 1998–1999 to 28 (23.1%) of 121 isolates in 2006–2007 (P = 0.004), driving much of the penicillin nonsusceptibility. Nonsusceptibility to erythromycin (MIC ≥4 μg/ml) increased during the study period from 57 (10.4%) of 546 isolates at baseline to 144 (26.8%) of 537 isolates in 2006–2007 (P < 0.001). Approximately one-quarter of pneumococcal isolates (24.7%) were not susceptible to trimethoprim-sulfamethoxazole in 2006–2007.
The study reports encouraging and sustained declines in IPD among HIV-infected adults in the US 7 years after routine pneumococcal vaccination in children began. This continues the half to two-thirds reduction in IPD among HIV-infected individuals that followed the introduction of highly active antiretroviral therapy in the US in the 1990s [13,14]. In this high-risk population, serotype replacement disease with serotypes not included in PCV7 has occurred but is small relative to the benefit of PCV7-seotype reduction. Despite these large reductions in IPD among HIV-infected adults, IPD still causes substantial morbidity and mortality among HIV-infected individuals, especially black adults in whom the burden of both IPD and HIV is high. The resident adult population in the surveillance areas included approximately 10.2% of the estimated number of adults living with AIDS in the US; on the basis of this, we estimate that there were 1294 cases of IPD in adults with AIDS in the US in 2007. The high rate of IPD among adults with HIV – 40-fold as high as in HIV-uninfected adults of the same age and nearly twice as high as the rate of IPD among children below 2 years of age before PCV7 introduction in that age group  – calls for more aggressive prevention measures.
PCV13 has just been introduced into the routine childhood immunization schedule of the US and will be used in other countries soon . Given the indirect effects of PCV7 use in children on IPD among adults, one might expect that introduction of PCV13 into the routine childhood vaccination schedule will cause further declines in IPD among HIV-infected adults, obviating the need for direct use of PCV13 among HIV-infected adults. However, carriage and transmission dynamics of the six serotypes unique to PCV13 may differ from the PCV7 types . Non-PCV7 serotypes typically colonize the nasopharynx for shorter periods of time and, similar to other serotypes, cause IPD shortly after colonization. As a result, the precise reservoir of serotypes unique to PCV13 is uncertain.
Whereas PCVs are used routinely for children in many countries, they are not currently licensed nor recommended for use in adults. However, 10 and 13-valent formulations are being tested in adults and could provide promising new alternatives for directly preventing IPD in HIV-infected adults. A randomized, double-blind, placebo-controlled trial in Malawi suggested that PCV7 is efficacious in preventing recurrent IPD among HIV-infected adults . Immunogenicity studies suggest that HIV-infected adults can mount an antibody response to administration of PCV7 that is similar to or better than the response to PPV23 [18–20]. HIV-infected adults are more likely than HIV-uninfected adults to be carriers of pneumococcus , so directly interrupting carriage in the HIV-infected adult population could interrupt pneumococcal transmission and reduce disease beyond that which could be achieved with pediatric immunization alone.
Another consideration is to increase vaccination of HIV-infected adults with PPV23. Although the evidence for the effectiveness of PPV23 against IPD and pneumonia in HIV-infected adults is inconsistent , vaccination with PPV23 in adults with HIV infection and a CD4+ T-cell count of above 200 cells/μl is currently recommended in the US [23,24]. PPV23 is not widely used in HIV-infected adults outside of the US, particularly in low-income countries, due to concerns about its effectiveness in HIV-infected persons with low CD4+ T-cell counts  or viral load above 100 000 copies/ml  and an unexpected increased risk of pneumococcal disease and pneumonia after vaccination in adults with untreated HIV and AIDS found during a trial in Uganda . Due to the low level of evidence, the World Health Organization does not recommend PPV23 vaccination of HIV-infected adults in resource-limited settings . In the US, we do not have national estimates of coverage for PPV23 among HIV-infected adults. The vaccination coverage of PPV23 among adults at least 65 years of age in the US, another group for which universal vaccination of PPV23 is recommended, was 65.9% in 2007 , and the PPV23 coverage has been reported to be as high as 77.7% among adults with HIV infection who were patients at a large, academic, HIV referral clinic . This suggests that high vaccination coverage among HIV-infected adults is possible.
Strengths of this analysis include the large population under active surveillance and 7 years of postintroduction surveillance. Our results are further supported by similar rates and trends reported in a recent study from a smaller urban population in the US with a relatively high (2%) prevalence of HIV/AIDS (Newark, New Jersey, which is not an ABCs surveillance site) . This is an ecologic analysis in which it could be difficult to tease out whether declines in IPD are attributed to childhood PCV7 introduction or other interventions such as HAART or PPV23 use. However, the laboratory serotyping of nearly all isolates shows clearly that only PCV7-serotype disease has declined since PCV7 introduction in adults both with and without HIV infection, and it is unlikely that interventions such as HAART would selectively impact the serotypes included in PCV7.
The analysis is also subject to a number of limitations. First, because we were limited by case-based reporting of HIV infection in the surveillance areas, for some analyses we used a ratio of IPD cases in adults with HIV infection (with and without AIDS) to adults with AIDS instead of a true incidence. As the majority of adults with HIV infection in the US do not yet have AIDS, this ratio is an overestimate of the incidence of IPD in HIV-infected adults. This calculation allowed us to evaluate trends and compare rates of IPD by sex, race, and ethnicity and serotype, but may have introduced other biases. Second, the data we used to calculate incidence of IPD in HIV-infected adults came from only three sites, and they may over-represent HIV infection in African American and lower-income populations. Third, the racial and ethnic disparities may be due in part to unmeasured confounders such as socioeconomic status and injection drug use, and as we had very few cases of IPD in Hispanic adults, it is difficult to draw conclusions about trends in this population. Fourth, some patients with IPD may have been misclassified as having HIV infection without AIDS when in fact they had AIDS, which would underestimate the incidence of IPD in adults living with AIDS. The CDC case definition classifies a patient as living with AIDS if they have ever met the case definition for AIDS ; however, available medical records may not have listed all previous AIDS-defining illnesses in HIV-infected adults. Similarly, HIV infection status of patients with IPD may be an underestimate if clinicians did not test for HIV infection. Lastly, we have no data on antiretroviral therapy or CD4+ T-cell counts and viral load, which can improve with treatment.
Although most countries with a high burden of HIV infection are currently not using PCVs routinely, South Africa recently started vaccinating children with PCV7 . Although our results may not be generalizable to settings in lower-income countries, this and previous studies suggest that the incidence of IPD among HIV-infected adults could remain high many years after introduction of both childhood PCV and widespread use of antiretroviral therapy. Prevention of HIV infection is crucial to preventing opportunistic infections, including those from pneumococcus, especially as much of the pneumococcal disease is caused by serotypes that are not included in the currently available pneumococcal vaccines. The World Health Organization recommends that countries with a high burden of HIV and pneumococcal disease should use PCV in their routine childhood vaccination schedules  and should initiate antiretroviral treatment when appropriate. Whereas these vaccination recommendations target children, our results indicate that vaccinating children may benefit adults as well. Future research should include evaluating indirect effects of childhood PCV on adults with HIV infection in settings with high prevalence of HIV and testing direct effects of future pneumococcal vaccines in adults with HIV infection.
We would especially like to thank Bernard W. Beall, PhD, and the CDC Streptococcal Laboratory for their laboratory testing and critical review of the manuscript. A.L.C. and M.R.M. conceived and designed the study, conducted the analysis and interpretation, and drafted the paper. L.H.H., M.M.F., A.L.R., J.H., W.S., R.L., and A.R.T. acquired the pneumococcal data in the field sites, contributed to analysis and interpretation of the results, and revised the manuscript critically for important intellectual content. M.C. and J.L. acquired the HIV surveillance data, contributed to analysis and interpretation of the results, and revised the manuscript critically for important intellectual content. A.S. contributed to conception, design, analysis and interpretation of the results, and revised the manuscript critically for important intellectual content. All authors approved the final version to be published. Funded by Centers for Disease Control and Prevention (CDC) Emerging Infections Program.
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