a Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, Centre Hospitalier Régional Universitaire de Lille, Tourcoing, France.
bGeneral Medicine Division and Partners AIDS Research Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
c INSERM Unit 330, University of Bordeaux II, Bordeaux, France.
d Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston University School of Medicine, Boston, MA, USA.
e Department of Health Policy and Management and Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
f Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA.
Yazdan Yazdanpanah, Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, 135, rue du Président Coty, BP 619, F 59208 Tourcoing, France. E-mail: yyazdan{at}yahoo.com
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Abstract |
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Methods We conducted our study on 2664 HIV-infected patients from the Tourcoing AIDS Reference Centre and the hospital-based information system of the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine enrolled from January 1987 to September 1995 and followed through December 1995. We estimated: (1) CD4-adjusted incidence rates of seven primary opportunistic infections in the absence of prophylaxis for that specific infection or any antiretroviral drugs other than zidovudine; and (2) CD4 lymphocyte count decline.
Results The highest incidence rates for all opportunistic infections studied occurred in patients with CD4 counts <200/µl. With CD4 counts <50/µl, the most common opportunistic infections were toxoplasmic encephalitis (12.6 per 100 person-years) and Pneumocystis carinii pneumonia (11.4 per 100 person-years). Mycobacterium tuberculosis was the least common opportunistic infection (<5.0/100 person-years). Even with CD4 counts >300/µl, cases of Pneumocystis carinii pneumonia and toxoplasmic encephalitis were reported. The mean CD4 lymphocyte decline per month was 4.6 cells/µl. There was a significant association between HIV risk behaviour and the incidence of cytomegalovirus infection, between calendar year and the incidence of Pneumocystis carinii pneumonia, toxoplasmic encephalitis and Candida esophagitis, and between geographical area and the incidence of Pneumocystis carinii pneumonia and cytomegalovirus infection.
Conclusions Geographical differences exist in the incidence of HIV-related opportunistic infections. These results can be used to define local priorities for prophylaxis of opportunistic infections.
Keywords Opportunistic infections, natural history, HIV, France, incidence rate
Accepted 11 December 2000
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Introduction |
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Few studies have been published on the clinical course of HIV disease in the absence of antiretroviral drugs and opportunistic infection prophylaxis. Most data have been derived from the Multicenter AIDS Cohort Study, a US study primarily of white men who have sex with men.2,3 Clinical guidelines for the prevention of opportunistic infections in those with HIV disease have been developed primarily on the basis of these natural history data collected in the US, combined with data on prophylaxis efficacy from clinical trials conducted both in the US and in Europe.4,5 Therefore, these recommendations reflect the incidence and the pattern of opportunistic infections in the US.
The pattern of opportunistic infections, however, may differ in other geographical areas. For instance, regional differences in the occurrence of Mycobacterium avium complex bacteraemia have been documented in the US,6 and differences in the incidence of tuberculosis among individuals with HIV have been reported in Europe.7 The number of individuals with AIDS who develop toxoplasmic encephalitis has been estimated to be higher in Western Europe than in the US.8
This geographical variability in the incidence of opportunistic infections suggests that priorities for prevention of specific opportunistic infections should also differ from one region of the world to another. To be most effective, clinical guidelines should reflect disease risk in the target population to which they are applied.9 Our objective was to describe the risk of opportunistic infections in HIV-infected individuals in France. For this purpose we estimated the incidence of primary opportunistic infections in patients not receiving prophylaxis and potent antiretroviral therapy, using two clinical databases, one from the Tourcoing AIDS Reference Center and the second from the regional hospital-based information system of the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA).
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Methods |
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Aquitaine, an administrative region in Southwest France with a population of 2.8 million, has a cumulative AIDS incidence rate of 790 cases per million inhabitants, one of the highest in France.10 The Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA) is a regional HIV infection surveillance system that includes Bordeaux University Hospital and four public hospitals in Aquitaine.11,12 In 1992, it was estimated that over 75% of all AIDS cases in the Aquitaine area were reported by physicians participating in GECSA.13
Since 1987, all patients referred to the Tourcoing AIDS Reference Centre who had HIV-1 infection confirmed by Western blot, were over 13 years of age, and could provide informed consent were enrolled in the Tourcoing Clinical Cohort. GECSA, also initiated in 1987, enrolled the Aquitaine Cohort using the same inclusion criteria. In both cohorts, an initial medical evaluation was performed on every new patient by both a physician and a nurse. Standardized questionnaires were used to collect extensive demographic, clinical, laboratory, and pharmaceutical information. Data included age, sex, probable transmission route, year of diagnosis, date of AIDS-defining events prior to inclusion, and CD4 lymphocyte count at inclusion. Follow-up data were collected at each outpatient visit, hospital admission, or at least every 6 months, by trained technicians who abstracted the information onto standardized computer records. These data included the occurrence of AIDS-defining events, CD4 lymphocyte counts, initiation and discontinuation of antiretroviral or opportunistic infection prophylactic therapies.
We conducted this analysis on patients from the Tourcoing Clinical Cohort and patients from the Aquitaine Cohort enrolled from January 1987 to September 1995 and followed through December 1995.
The following patients were excluded from the analysis: (1) patients receiving potent antiretroviral therapy other than zidovudine monotherapy or prophylaxis at inclusion; and (2) patients with fewer than three overall CD4 counts. Patients who experienced an opportunistic infection prior to their first visit, or presented to the clinic for the first time with an opportunistic infection, and those receiving prophylaxis for a particular opportunistic infection were excluded from the analysis concerning that specific opportunistic infection.
Variables
We estimated the incidence of seven specific opportunistic infections, including Pneumocystis carinii pneumonia, toxoplasmic encephalitis, cytomegalovirus infection, Mycobacterium avium complex bacteraemia, Mycobacterium tuberculosis, Candida esophagitis, and recurrent bacterial pneumonia. The incidence of recurrent bacterial pneumonia, classified as an AIDS-defining event by the CDC in 1993, was not estimated in the Aquitaine Cohort because of reporting problems prior to 1993. Diagnostic criteria included: (1) Pneumocystis carinii pneumonia: microbiological identification using induced sputum or bronchoalveolar lavage fluid or symptomatic presentation with compatible chest radiograph and clinical response to an appropriate therapeutic regimen; (2) toxoplasmic encephalitis: symptomatic clinical presentation with compatible computed tomographic scan or magnetic resonance image of the brain and response to therapy; (3) cytomegalovirus infection: retinitis diagnosis by an ophthalmologist; colitis and oesophagitis: diagnosis by histopathological confirmation of cytomegalovirus inclusion; (4) Mycobacterium avium complex bacteraemia: isolation from blood culture; (5) Mycobacterium tuberculosis: isolation in culture from pulmonary specimen, blood, or other tissue; (6) Candida esophagitis: difficulty in swallowing or odynophagia with endoscopic evidence of invasive fungi or with clinical response to appropriate therapy; (7) recurrent bacterial pneumonia: more than one episode in a one-year period, acute pneumonia (new x-ray evidence) diagnosed by both culture obtained from a reliable clinical specimen of a pathogen that typically causes pneumonia, and radiological evidence of pneumonia (other than Pneumocystis carinii or Mycobacterium tuberculosis); cases that did not have laboratory confirmation of a causative organism for one of the episodes of pneumonia were considered to be presumptively diagnosed.
Four probable HIV transmission categories were defined: injection drug use, men who have sex with men, heterosexual contact, and others. Patients with multiple risks of HIV transmission were coded hierarchically in the order above. The CD4 lymphocyte counts were grouped into six strata: 50, 51100, 101200, 201300, 301500 and >500 cells/µl. Three calendar periods were defined based on years of access to prophylaxis and new antiretrovirals : 19871990, 19911993 and 19941995.
Statistical analysis
We estimated the incidence rates of each of the seven opportunistic infections among HIV-infected patients initially free of that specific condition, regardless of previous AIDS-defining illnesses. Patients were considered at risk for developing a particular opportunistic infection or disease from their date of entry into the study until their last date of visit, unless they either developed that specific disease or started an antiretroviral drug other than zidovudine monotherapy. For specific opportunistic infections for which prophylaxis became available, the day prophylaxis was initiated was considered the study endpoint. Prophylactic agents included: trimethoprim-sulfamethoxazole, aerosolized pentamidine or dapsone for Pneumocystis carinii pneumonia; trimethoprim-sulfamethoxazole, or dapsone and pyrimethamine for toxoplasmic encephalitis; and azithromycin, clarithromycin, or rifabutin for Mycobacterium avium complex bacteraemia. Since trimethoprim-sulfamethoxazole, azithromycin, and clarithromycin have been associated with a lower incidence of bacterial respiratory disease,4,14,15 the initiation of any of these agents as prophylaxis was also considered the study endpoint for recurrent bacterial infections. Patients who experienced an opportunistic infection prior to their first visit, or presented to the clinic for the first time with an opportunistic infection, were excluded from the risk set for the incidence analysis of that particular opportunistic infection.
The incidence rate of each opportunistic infection was defined as the number of new cases of that specific infection divided by the total number of person-years at risk for that infection.16 To estimate the incidence rate of each infection within particular CD4 strata, we first estimated the CD4 cell count decline using a mixed-effect model.17 For each patient CD4 decline was modelled as a linear function of time (SAS 6.12 software, SAS Institute Inc., Cary, North Carolina, USA). For this analysis, a median number of 2.0 CD4 counts per year of follow-up and per patient were available (25th percentile, 1.3; 75th percentile, 3.0). The model allowed individuals to have both CD4 declines and increases, but since we considered subjects receiving either no antiretroviral therapy or zidovudine alone, increases in CD4 count were rare. The time spent in each CD4 stratum was calculated and summed to estimate the person-years in each of the CD4 strata. We repeated the analysis using each opportunistic infection as the outcome event. The CD4 lymphocyte counts at the time of each opportunistic infection occurrence were estimated using a similar model based on the date of infection.
We assessed the association between gender, HIV transmission category, calendar period, geographical area, and the incidence of each opportunistic infection using multivariable Poisson regression with adjustment for CD4 lymphocyte count.18 In the model where all covariates were included, regression coefficients may be interpreted as relative rates (RR) in the logarithmic scale. Independent variables were considered statistically significant at the P < 0.05 level.
We compared characteristics of included and excluded patients using 2 test and Wilcoxon rank-sum test.
We conducted several sensitivity analyses to test the robustness of the results. We included the first 3 months following potent antiretroviral therapy and prophylaxis initiation in the risk set of the analysis and tested its impact on incidence estimates. We also estimated incidence rates using alternative models of CD4 decline: log CD4 as a linear function of time, and square root of CD4 as a linear function of time.
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Results |
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Table 2 shows the incidence rate for each opportunistic infection stratified by CD4 cell count. Among the opportunistic infections studied, the highest incidence rates occurred in the CD4 strata <200/µl, particularly in the lowest CD4 stratum of <50/µl. With CD4 counts <50/µl, incidence rates ranged from 3.1 per 100 person-years for Mycobacterium tuberculosis to 11.4 per 100 person-years for Pneumocystis carinii pneumonia and 12.6 per 100 person-years for toxoplasmic encephalitis.
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Primary opportunistic infections incidence estimates were influenced neither by including the first 3 months following the initiation of potent antiretroviral therapy in the risk set of the analysis nor by the use of alternative CD4 decline models. Incidence rates derived from each of these analyses were within the 95% CI of the incidence of the disease in the baseline analysis (Table 3).
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Discussion |
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In this study, as with observations in the US, the highest incidence rates occurred in the lowest CD4 strata.3 Like the Multicenter AIDS Cohort Study (MACS) findings3 and results from the Swiss HIV Cohort Study,19 cases of opportunistic infection were also reported in patients with higher CD4 counts. Consistent with previous reports, after adjustment for CD4 count, sex, calendar year and geographical area, the incidence of cytomegalovirus infection was significantly associated with HIV transmission category.15,2022
We found that the incidence rate of specific opportunistic infections, based on local data from two geographically distinct regions in France, differed from previously reported incidence rates. For example, in patients with CD4 counts <50/µl, the incidence of Pneumocystis carinii pneumonia, cytomegalovirus infection, and Mycobacterium avium complex bacteraemia in MACS was above the upper bound of the 95% CI of the incidence of these opportunistic infections in the French cohorts. In contrast, the incidence of toxoplasmic encephalitis in the MACS was below the 95% CI of the incidence of toxoplasmic encephalitis in the French cohorts.3,23 Because of differences in the design of these cohorts, and particularly differences in patient populations, patients' stage of disease at inclusion, diagnostic strategies, and length of follow-up, we must be cautious about these comparisons. Nevertheless, these findings are consistent with previously reported data.
Toxoplasmic encephalitis has been reported more frequently in Western Europe than in the US. For example, neuropathological reviews of HIV-infected patients have shown that in New York, toxoplasmic encephalitis occurs in 11% of cases24 while it is found in 48% of cases in France.25 In a recent comparative international study, post-mortem toxoplasmic encephalitis was found to be five times more likely in Paris than in Baltimore.26 These differences are probably related to setting-specific exposure of the general population to this parasite.27
In contrast to toxoplasmic encephalitis, disseminated Mycobacterium avium complex bacteraemia disease has been reported to be less frequent in Europe than in the US. In 1990, among patients whose first CD4 count was <50/µl, the 2-year cumulative probability of disseminated disease due to Mycobacterium avium complex bacteraemia was estimated to be 22% in the Swiss HIV Cohort Study and 31% in the American Zidovudine Epidemiology Study Group.28,29 In a multicentre randomized trial of clarithromycin prophylaxis for disseminated disease due to Mycobacterium avium complex bacteraemia, among recipients of placebo the incidence of Mycobacterium avium complex bacteraemia during a mean follow-up of 9.5 months was 11% in the European and 21% in the US participants.4
The cytomegalovirus infection incidence rate was lower in our cohorts than in the MACS study. However, in contrast to the French cohorts, the members of the MACS cohort were primarily men who have sex with men. In our study, and in several previous studies, men who have sex with men were found to be at higher risk of developing cytomegalovirus infection compared with other HIV risk groups.2022 The observed geographical difference may therefore be due to differences in HIV risk behaviour within the population. In fact, when we restricted our analysis to men who have sex with men with CD4 counts <50/µl, the incidence of cytomegalovirus disease in the MACS was within the 95% CI of the incidence of the disease in our analysis.23 However, in our analysis, even after adjustment for CD4 count, risk of HIV transmission and calendar period, we still found differences in the incidence of cytomegalovirus infection between Tourcoing and Aquitaine. Similar trends towards geographical differences in cytomegalovirus retinitis occurrence have been reported in the past.20
There are several limitations to this analysis. First, we restricted our analysis to patients who did not receive opportunistic infection prophylaxis and antiretroviral drugs other than zidovudine, and to those who had not experienced the opportunistic infection of interest prior to or at their first visit. Thus, we may have excluded patients at greatest risk of progression and patients at higher risk for developing these infections. Comparison of excluded and included patients confirms this hypothesis. Excluding these patients from the analysis may have caused us to underestimate the true incidence rate of these diseases and may explain the relatively low incidence rate of Pneumocystis carinii pneumonia in the French cohorts compared to the MACS study. Pneumocystis carinii pneumonia was the most common AIDS-defining illness occurring prior to study enrolment and the opportunistic infection for which prophylaxis is the most prescribed.
Second, in our analysis, patients were not considered at risk for developing a particular opportunistic infection after starting prophylaxis and potent antiretroviral therapy. In HIV-infected patients, treatment and prophylaxis may be started because patients deteriorate, and this may be due to the first symptoms of an opportunistic infection. Ledergerber et al. have shown that the incidence of opportunistic infections continues to be high in the first 3 months after initiating antiretroviral therapy.30 As a result, we may have underestimated the true incidence of opportunistic infections. However, incidence estimates were not influenced by including these 3 months in the risk set of the analysis.
Last, in order to estimate the incidence rate of each infection within each particular CD4 stratum, we used a mixed-effect model and characterized the CD4 decline as a linear function of time. The assumption of linearity may be viewed as overly simplistic. However, we restricted our analysis to patients who did not receive antiretroviral drugs other than zidovudine, which has been shown to have a small and transient effect on CD4 cell counts.31 Moreover, we rarely had data from the initial period after seroconversion where sharp falls in CD4 are reported, and CD4 monitoring was often discontinued in late HIV disease when counts were near zero; therefore, our data generally do not cover periods where the assumption of linearity is likely to break down.32 We also used alternative models of CD4 decline to test their impact on our final results. Regardless of the model used, the results were similar to our baseline analysis.
In our analysis, we found that the incidence of Pneumocystis carinii pneumonia and toxoplasmic encephalitis decreased over time. One explanation may be the increasing number of excluded patients from the analysis over time; patients remaining in the risk set of the analysis are those at lower risk of developing infections, leading to an underestimation of the true incidence of opportunistic infections in recent years. The increasing incidence of Candida esophagitis over time is probably related to the evolution of diagnostic strategies for this particular disease.
We sought to distinguish the incidence and pattern of opportunistic infections in two geographically distinct French cohorts from that reported in the literature. These data suggest that clinical guidelines, developed based on US observations, may not accurately reflect local needs and realities. These findings may be used by health care providers to guide clinical decision making and by policy makers to define priorities for prevention of opportunistic infections in these regions. Finally, if used in decision models, the methods presented here can assist clinicians and policy makers to tailor global opportunistic infection prevention guidelines to the particular circumstances of a given clinical setting.9
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Appendix |
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KEY MESSAGES
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Acknowledgments |
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References |
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