The impact of antiretroviral treatment on the burden of... : AIDS (original) (raw)
Introduction
Human immunodeficiency virus (HIV) infection increases the risk of invasive pneumococcal disease (IPD) 10–100-fold compared to the general population [1–4]. This increase has been attributed to humoral and cell-mediated immune deficiencies caused by HIV infection [5]. Highly active antiretroviral therapy (HAART) for the management of AIDS, available since the mid-1990s, has reduced morbidity and mortality in HIV-infected individuals in industrialized countries [6,7]. HAART has also reduced opportunistic infections in HIV-infected children [8].
Access to HAART in sub-Saharan Africa has improved since 2003. In South Africa, where the prevalence of HIV infection in the general population was estimated to be approximately 10–12% between 2003 and 2008 [9–11] access to HAART was initiated in the public sector in 2004 [12]. In South Africa, the overall estimated coverage with HAART in individuals needing treatment gradually increased from 10% in 2004 to 51% by 2008 [9]. There were, however, regional and age-group differences in coverage over this period. Our study was undertaken in Soweto, Gauteng province in South Africa, where approximately 3% of under 18-year-olds are HIV-infected. The coverage with HAART in HIV-infected children increased gradually from less than 20% in 2003–2004 to 74% by 2007–2008 [9].
The study analyzed the impact of the HAART program in Soweto, Gauteng, South Africa, on the burden of IPD in children and adolescents over a 6-year period.
Methods
Study design and study population
We reviewed all laboratory-confirmed IPD episodes reported from Chris Hani-Baragwanath Hospital (CHBH) from January 2003 to December 2008. The hospital serves approximately 1.4 million mainly black urban South Africans [13]. Approximately 18% of the study population has private medical insurance [13], and consequently the majority of individuals requiring hospitalization from the Soweto community are admitted to CHBH. Neither pneumococcal polysaccharide nor pneumococcal conjugate vaccines (PCVs) were available as standard-of-care during the period reviewed. Although PCV became available to the private sector in South Africa in 2005, very few children, including HIV-infected children, in this study population would have been vaccinated against Streptococcus pneumoniae (pneumococcus) because of cost constraints. Approximately 20 000 children in Soweto were, however, vaccinated with an investigational 9-valent PCV between 1998 and 2000; [14] these children would have been at least 3 years old in 2003 and hence unlikely to affect the baseline incidence in children below 2 years old. In addition, although the 9-valent PCV was efficacious in preventing 65% of vaccine-serotype specific IPD in HIV-infected children after a mean follow-up of 2.3 years, there was loss of efficacy thereafter in the absence of booster doses and HAART [15].
HIV-infected children received their HIV care mainly at one of two HIV-clinics at CHBH, neither of which vaccinated with PCV or pneumococcal polysaccharide vaccine during the study period. The prevalence of HIV in pregnant women in this province was estimated to be 31% in 2003 and 29% in 2008 [16]; and 5% in children below 5 years between 2003 and 2008 [9]. In Soweto, the prevention of mother-to-child transmission (PMTCT) program during the study period involved single doses of nevirapine to the mother during labor and to the newborn following birth and coverage of the PMTCT program was approximately 95% of women eligible for prophylaxis (Dr A. Violari, personal correspondence). There was, however, also a gradual uptake of HAART in pregnant women with CD4+ cell count less than 200 cells/μl, starting from 2004 onward.
Since 2004, criteria for initiation of HAART in HIV-infected children included greater than two hospital admissions per year or hospitalizations for more than 4 weeks for HIV-related illness; or WHO stage III/IV disease; or CD4+ percentage below 20% if under 18 months of age or below 15% if over 18 months (www.doh.gov.za/docs/misc/hiv/manual/arv_children.pdf). First-line HAART, recommended in the national treatment guidelines, was the combination of stavudine, lamivudine and liponavir-ritonavir in children under 3 years of age; and combination of stavudine, lamivudine and efavirenz in children older than 3 years or who weighed more than 10 kg. In this study, the initial period of 2003–2004 when less than 20% of children requiring HAART were on treatment was designated as the early HAART era [9]. The periods 2005–2006 and 2007–2008 when an estimated 51 and 74%, respectively, of HIV-infected children needing HAART had been initiated on therapy, were designated as the ‘intermediate’ and ‘established’ HAART eras, respectively [9].
Invasive pneumococcal disease surveillance
An IPD episode was defined as identification of pneumococcus from a normally sterile site [e.g. cerebrospinal fluid (CSF), blood, pleural fluid or joint fluid]. Repeat IPD episodes from the same individual more than 21 days apart were considered as new cases. The standard culture methods at the hospital included blood and CSF cultured for pneumococcal growth with the BacT/Alert microbial detection system (Organon Teknika, Durham, North Carolina, USA). Autolyzed blood culture specimens, macroscopically chocolate-colored with or without pleomorphic Gram-positive cocci on microscopy, were tested with a latex agglutination kit (Wellcogen Bacterial Antigen Kit, Remel Europe Ltd, Dartford, UK). As a quality control, blood cultures positive for pneumocccal antigen were confirmed by PCR during 2004, and 2007 onwards at the surveillance reference laboratory and documented 99.7% (332/333) concordance with the diagnostic laboratory [17,18]. Peritoneal, pericardial and other fluid samples were processed according to standard procedures [19].
Invasive pneumococcal disease episodes were categorized as: pneumococcal meningitis, if pneumococci were cultured from CSF, if the latex antigen detection was positive on CSF, or when the CSF white cell count and/or biochemistry was suggestive of purulent meningitis with pneumococci isolated from blood; pneumococcal pneumonia was based on the identification of pneumococci from pleural fluid or blood in individuals with a physician-based diagnosis of pneumonia; bacteremia without a focus was culture of pneumococci from blood without any localizing illness; other IPD included pneumococci cultured from sterile sites other than blood or CSF in the absence of meningitis or pneumonia.
Cases were reported through a surveillance system for IPD to the National Institute for Communicable Diseases (NICD) [20], and included clinical and demographic data. Audits comparing cases reported to the NICD against the hospital's electronic laboratory database ensured completeness of identification of IPD episodes. Audits revealed that 99.5, 97.3 and 96.1% of the IPD episodes in the early, intermediate and established HAART eras, respectively, had been reported to the NICD. Cases not reported to the NICD were included in the final database, despite not being available for serotyping.
Capsular serotyping was undertaken by Quellung with specific antisera (Statens Serum Institut, Copenhagen, Denmark). Serotype 6C was distinguished from serotype 6A by PCR [21]. Vaccine serotypes were defined as the seven serotypes included in the 7-valent pneumococcal conjugate vaccine, that is serotypes 4, 6B, 9V, 14, 18C, 19F, 23F and the vaccine-related serotype 6A [22]. Nonvaccine serotypes included all other pneumococcal serotypes, including serotype 19A against which cross-protection was not observed in the US postintroduction of PCV into the childhood immunization program [23].
Determination of HIV prevalence
HIV infection status was based on HIV testing done as standard-of-care by attending physicians. This included HIV enzyme-linked immunosorbent assay (ELISA) testing in children older than 18 months of age and HIV PCR testing in younger children. For the primary analysis we inferred the HIV status in children not tested for HIV by assuming that the prevalence of HIV infection was the same as for those children who were tested, stratified by each of the three individual study periods (Fig. 1). The reason for not testing some children for HIV may have been due to the absence of other clinical stigmata of AIDS. We undertook a sensitivity analysis based on the conservative assumption that all children not tested for HIV were presumed to be HIV-uninfected, so as not to overestimate any decline in IPD among HIV-infected children.
Number of total IPD cases for the three study periods. The bottom row illustrates the number of cases used in the primary analysis by age group. Latex/PCR: blood culture specimens tested with latex agglutination kit. HAART, highly active antiretroviral treatment.
Statistical analysis
Estimated incidences of IPD were calculated for the three HAART eras stratified by age and HIV status to yield stratum-specific incidence rates. Incidence risk ratios (IRRs) were calculated by comparing group-specific incidences for the established and early HAART eras. The numerators for era-specific incidences were the numbers of IPD episodes hospitalized during each era, and the population denominator was based on the Gauteng Department of Health and Social Development, Statistics South Africa, population estimates for Region D (i.e. Soweto) in Johannesburg, South Africa [13]. HIV prevalence in the study population was estimated from the 2010 projections of the AIDS and Demographic model developed by the Actuarial Society of South Africa [9]. These estimates have been shown to correlate with estimates from population-based studies [10]. We analyzed our data dividing the population into three age groups: below 2 years, 2–4 years and 5–17 years (see Supplementary Table S1, https://links.lww.com/QAD/A100 which shows the total population and HIV-prevalence by age-group).
χ2 test (or Fisher's exact test) were used to compare the distribution of categorical variables. 95% confidence intervals (CIs) are reported and P values below 0.05 were considered statistically significant. Demographic data and estimates of incidence and risk ratio were analyzed using STATA version 11.0 and Epi Info 3.5.1 (CDC, Atlanta, Georgia, USA).
Results
A total of 1171 hospitalized IPD episodes were identified in individuals below 18 years old at CHBH between 2003 and 2008. Of these, 1075 isolates (91.8%) were available for serotyping, including 94.2% (n = 404/429) in the early HAART era, 92.3% (n = 374/405) in the intermediate HAART era and 88.1% (n = 297/337) in the established HAART era (Fig. 1). Repeat episodes of IPD were identified in 35 children, including 28 (80.0%) who were HIV-infected.
HIV status was determined in 938 cases (80.1%) (Fig. 1). The proportion of children not tested for HIV decreased from 26.8% (n = 115/429) in the early HAART era, to 20.5% (n = 83/405) in the intermediate HAART era and 10.4% (n = 35/337) in the established HAART era (P < 0.0001). The patients' sex did not differ across the study period and 46.0% were female.
Changes in incidence of invasive pneumococcal disease
The incidence of IPD decreased steadily across the age groups over the study periods (Tables 1 and 2; Fig. 2; Supplementary Table S2, https://links.lww.com/QAD/A100 showing the incidence of IPD over the three HAART eras for 2–4 years-old and Supplementary Table S3, https://links.lww.com/QAD/A100 showing the incidence of IPD over the three HAART eras for 5–17-year-olds). There was a 30.6% (95% CI 20.0–39.8, P < 0.0001) overall reduction in IPD from the early compared to the established HAART era in individuals below 18 years old (Table 1). This temporal reduction was primarily due to a reduction in incidence of IPD in HIV-infected individuals, in whom the incidence decreased by 50.8% (95% CI 41.5–58.7) between the early compared to established HAART eras (Table 1). The reduction in IPD comparing the early to the established HAART era in HIV-infected children was 40.9% (95% CI 25.1–53.4) in children below 2 years, 61.5% (95% CI 41.8–74.6) in 2–4-year-old children and 46.0% (95% CI 25.3–61.0) in the 5–17-year age group (Table 2; Supplementary Tables S2 and S3, https://links.lww.com/QAD/A100).
Incidence of IPD for the three study periods, incidence risk ratios and percentage of reduction in incidence of disease between the early- and established-HAART eras for less than 18-year-olds.
Incidence of IPD for the three study periods, incidence risk ratios and percentage of reduction in incidence of disease between the early and established HAART eras for less than 2-year-olds.
Incidence of IPD by vaccine and nonvaccine serotypes. Graphs represent incidence of IPD per 100 000 for the three HAART eras. (a) Incidence of IPD in the overall population by age group; (b) incidence in HIV-infected children; (c) incidence in HIV-uninfected children. Vertical bars represent 95% confidence intervals, P values calculated from a χ 2-test for trend. VT: seven serotypes included in 7-valent pneumococcal conjugate vaccine and serotype 6A. NVT: all other pneumococcal serotypes.
The reduction in IPD in HIV-infected children observed between the early and established HAART era was evident for individual syndromes of bacteremic pneumococcal pneumonia (56.3%; 95% CI 43.7–66.1), pneumococcal meningitis (32.6%; 95% CI 6.8–51.2) and pneumococcal bacteremia without a focus (59.2%; 95% CI 39.7–72.4) (Table 1). In addition, reductions were observed in bacteremic pneumococcal pneumonia and bacteremia without specific focus in HIV-infected children in the below 2 years and 2–4 and 5–17-year age groups (Table 2; Supplementary Tables S2 and S3, https://links.lww.com/QAD/A100). Similar trends in reduction were also observed for pneumococcal meningitis (Table 2; Supplementary Tables S2 and S3, https://links.lww.com/QAD/A100). Incidence (per 100 000) of IPD-associated mortality in HIV-infected children below 18 years decreased from 334.2 (95% CI 261.6–420.7) in the early HAART era to 267.0 (95% CI 206.5–339.5) in the intermediate HAART era and 116.4 (95% CI 79.6–164.2) in the established HAART era (P < 0.0001).
No overall changes in the incidence of IPD were observed over the three periods of observation among HIV-uninfected children under 18 years of age (Table 1). The incidence of the different disease syndromes remained consistent during the three study periods in HIV-uninfected children below 2 years and in those between 5 and 17 years old (Table 2 and Supplementary Table S3, https://links.lww.com/QAD/A100). An increase in the incidence of overall IPD (4.17-fold; P = 0.005) and bacteremic pneumococcal pneumonia (3.51-fold; P = 0.04) was, however, observed in HIV-uninfected children aged 2–4 years when comparing the early to established HAART era (Supplementary Table S2, https://links.lww.com/QAD/A100). This was, however, not evident in other age groups of HIV-uninfected children.
Seven-valent PCV-associated and non-PCV serotypes showed parallel declines in incidence among HIV-infected individuals across all age groups (Fig. 2). There were no changes in the incidence of either vaccine serotype or nonvaccine serotype IPD in HIV-uninfected children, except for an increase in vaccine serotype IPD in HIV-uninfected children 2–4 years old (Fig. 2).
Relative burden of invasive pneumococcal disease
Despite the reduction of IPD in HIV-infected children over time, the risk of IPD remained 21.1-fold (95% CI 16.1–27.7) greater in HIV-infected than in HIV-uninfected children in those under 2 years of age during the established HAART era. This risk was, however, less than the 39.6-fold (95% CI 30.5–51.6) increased risk of IPD observed in HIV-infected children under 2 years during the early HAART era (P = 0.001). For HIV-infected children aged 2–4 years the risk of IPD was 32.0-fold (95% CI 18.1–56.4) greater than for HIV-uninfected children during the established HAART era, compared to 346.8-fold (95% CI 126.8–948.4) increased risk in the early HAART era. The heightened risk of IPD in HIV-infected compared with HIV-uninfected children aged 5–17 years did not differ between the established HAART compared to the early HAART era (P = 0.59; see Supplementary Table S3, https://links.lww.com/QAD/A100).
Sensitivity analysis on changes in invasive pneumococcal disease in HIV-infected children
The sensitivity analysis in which children not tested for HIV were presumed to be HIV-uninfected did not change the trend in the reduction of IPD observed in HIV-infected children in the primary analysis comparing the early to the established HAART period. The only significant change in HIV-infected children was a lack of significance in the 26.2% reduction of IPD in the 5–17-year age group (Supplementary Table S3, https://links.lww.com/QAD/A100; Fig. 3).
Overall incidence of IPD by age group in confirmed HIV-infected children. Graph represents incidence of IPD per 100 000 for the three HAART eras assuming that all HIV-untested cases were HIV-uninfected. Vertical bars represent 95% confidence intervals, P values calculated from a χ 2-test for trend.
Discussion
To our knowledge this is the first study on the impact of HAART on the burden of IPD in a setting with a high prevalence of HIV infection. Our study indicates an inverse temporal association between improved HAART coverage and the burden of IPD in HIV-infected children; which declined by 40.9% in the less than 2 years age group, 61.5% in the 2–4-year-old age group and 46.0% in the 5–17-year age group. The incidence of IPD, however, generally remained unchanged in HIV-uninfected children during the study period.
Previous studies performed in Soweto mainly during the pre-HAART era reported an incidence of IPD similar to that in the early HAART period in this study [2,24–26]. The point-estimate incidence of IPD (per 100 000), in the absence of HAART in less than 2-year-old children in 1997–1998 was similar to that during the early HAART era of this study, including 3036 vs. 3564, respectively, in HIV-infected children and 73 vs. 90, respectively, in HIV-uninfected children [2]. This indicates that although HAART was available to a limited extent during the early HAART era, it did not have much effect on the baseline estimates of IPD compared to the pre-HAART era.
A retrospective cohort study of 260 HIV-infected children and adolescents in the USA which involved 23 episodes of IPD over a 17-year period [27] suggested that HAART was associated with an 84% reduction in the burden of IPD (90% bacteremia without a focus) in HIV-infected children. The greater reduction in IPD observed in that study may, however, reflect the aging of that cohort with a declining pool of younger HIV-infected children due to prevention of vertical HIV transmission programs. In our study the burden of IPD in HIV-infected individuals decreased exponentially with age.
Another analysis from the USA reported a paradoxical upward trend in pneumococcal disease hospitalization in HIV-infected individuals below 18 years old, following introduction of HAART [28]. The study used International Classification of Diseases, Ninth Revision (ICD-9) codes to identify cases with pneumococcal infection, and indicated that HIV-infected children remain at heightened risk of pneumococcal disease even in the HAART era. A more recent follow-up of that study [29], which included HIV-infected individuals under 25 years of age, reported a 78.7% reduction in ICD-9 coded IPD episodes, including nonculture confirmed pneumococcal pneumonia, between 1994/1995 and 2004/2005. This more recent decrease was most pronounced in younger children and was attributed to the introduction of PCV in the USA, which occurred subsequent to widespread use of HAART.
The findings of residual susceptibility to IPD in HIV-infected children with access to HAART in our study are in keeping with a report on HIV-infected adults from the USA. Heffernan _et al._[30] reported that the burden of IPD among adults with AIDS during the HAART era remained 35-fold greater compared to the general population. The residual susceptibility of HIV-infected individuals on HAART for IPD may relate to incomplete immune reconstitution following initiation of HAART [30]. This may include the absence of anamnestic responses, evident in relation to both immunogenicity and efficacy studies using PCV in African HIV-infected children [15,31].
Whereas our study provides evidence of a significant temporal association between increased access to HAART and declines in IPD in HIV-infected children and adolescents, this study nevertheless has limitations. It is possible that improved access to HAART in the latter years led physicians to test for HIV in a higher proportion of individuals during the established HAART era. The incorrect attribution of a proportion of HIV-untested children as HIV-infected, in the primary analysis, may have been greater during the early HAART period. Hence, the burden of IPD may have been overestimated in the HIV-uninfected group and underestimated in the HIV-infected group during the early HAART period. This would have resulted in our analysis underestimating the effect of the HAART program on the burden of IPD in HIV-infected individuals.
A further limitation of our study was the absence of information on HAART status for individual patients. Nevertheless, the decline in IPD was based on a temporal increase in HAART coverage in HIV-infected children with AIDS from 19% in 2003 to 74% in 2008 [9]. The decrease in IPD observed in HIV-infected individuals in our study may also be related to changes in physician care of HIV-infected children on HAART, such as a higher threshold for hospitalization and taking of blood cultures. There were, however, similarities in reductions of pneumococcal meningitis, the diagnosis of which is less likely to be subject to changes in physician behavior. The most likely hypothesis remains that improved access and treatment with HAART was responsible for the observed decline in IPD in HIV-infected children.
In addition, the absence of any decline in bacteremia among HIV-uninfected children across the study periods, suggests that it is unlikely that there were any other changes in physician behavior in the management of hospitalized children or indications for performing blood culture. Indeed, paradoxically, we observed an increase in bacteremia in HIV-uninfected children aged 2–4 years between the early compared with established HAART era. A possible explanation for this may be that some children in the community from this age group during the early HAART era were protected against IPD through their participation in the efficacy trial, during which approximately 85% of the eligible birth cohort was recruited between March 1998 and October 2000 [14]. Children in this age group may have therefore received PCV in the early HAART era, hence, the possible explanation for the increase in IPD which was specific to the serotypes included in 7-valent PCV in HIV-uninfected children.
Whereas improved access to HAART was the main change in the care of HIV-infected individuals during this period, concurrent improvement in management with co-trimoxazole prophylaxis cannot be excluded. The use of co-trimoxazole prophylaxis has been associated with a reduction in bacterial infections in HIV-infected African children [32,33]. Although our study was not designed to evaluate whether there were any changes in co-trimoxazole coverage in HIV-infected individuals, the standard-of-care for use of co-trimoxazole prophylaxis in the study during the observation period followed the 2001 WHO recommendations [34].
A further limitation of our study is a lack of data on the coverage of PCV in the study population, since it became available to the private sector in South Africa in 2005. PCV was, however, unavailable until April 2009 as standard-of-care in the study population, who were dependent on public healthcare service for their treatment and most unlikely to have been able to afford the vaccine. Furthermore, the observed decline in incidence of IPD across all age groups was similar for vaccine serotypes and nonvaccine serotypes which also made it unlikely that there was any significant use of PCV in the study population.
In conclusion, whereas the introduction of HAART has significantly reduced the burden of IPD in HIV-infected African children, these children remain predisposed to significant IPD-associated morbidity and mortality. The impact of the HAART program in other southern-African settings may, however, differ to that of ours based on the success of the program. Primary prevention of pediatric HIV infection, through PMTCT, is central to limit the burden of childhood IPD in our setting; however, in those with HIV infection, improved access to HAART and immunization with PCV is warranted. Catch-up campaigns targeting HIV-infected children not vaccinated during infancy should be included in the national immunization program to optimize the prevention of pneumococcal disease in settings such as ours.
Acknowledgement
We are grateful to all the patients whose data were used in this study. We would like to thank the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) for their efforts in collecting the isolates and the all staff of RMPRU for their support. M.C.N. had financial support from Fundação para a Ciência e Tecnologia, Portugal and from the University of the Witwatersrand.
Author contribution: The analysis were designed by M.C.N., S.A.M., Av.G., K.P.K. and C.C. and carried out by M.C.N. D.P.M., Ld.G. and Av.G. acquired and managed the data. M.C.N. and S.A.M. wrote the paper with critical input from all other authors.
Conflict of interest: Receipt of research funding (S.A.M., Av.G., K.P.K.) and consultancy from Pfizer (S.A.M., K.P.K.). Receipt of research funding (S.A.M., Av.G., K.P.K.), consultancies and honoraria from G.S.K. (S.A.M., K.P.K.). Consultancy for Merck (K.P.K.).
Disclaimer statements: This study was funded in part in 2003–2006 by the United States Agency for International Development's Antimicrobial Resistance Initiative, transferred via a cooperative agreement (number U60/CCU022088) from the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia. In 2005–2007, the study was also supported by the CDC, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Global AIDS Program (GAP) Cooperative Agreement U62/PSO022901. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC.
The results of this study were presented at the 7th International Symposium on Pneumococci and Pneumococcal Diseases, Tel Aviv, Israel, 14–18 March 2010, abstract number 82.
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Keywords:
antiretroviral treatment; HIV; invasive pneumococcal disease; Streptococcus pneumoniae
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