During a national consensus meeting held in 1999 in Abidjan, Côte d'Ivoire  and an international WHO/UNAIDS meeting held in 2000 in Harare, Zimbabwe , the experts recommended that cotrimoxazole prophylaxis should be used in HIV-infected adults at WHO clinical stage 2, 3, or 4, and/or with CD4 T-cell counts < 500 × 106/l. Because bacterial diseases are the first target of cotrimoxazole prophylaxis in sub-Saharan Africa [3,4], there is some concern that the short-term proven benefit of taking cotrimoxazole may be reduced in the medium term by the emergence of bacterial diseases due to cotrimoxazole-resistant strains . In both meetings, the experts also recommended that bacterial diseases should be monitored over the longer term and in as many settings as possible in persons taking cotrimoxazole [1,2].
We describe here bacterial morbidity recorded in adults taking cotrimoxazole prophylaxis who were followed in the ANRS 1203 cohort study between April 1996 and June 2000 in Abidjan, Côte d'Ivoire.
Between 23 April 1996 and 17 March 1998, 545 adults participated in the ANRS 059 double-blind placebo-controlled trial assessing the efficacy of cotrimoxazole prophylaxis (160/800 mg daily) in preventing severe clinical events at early stages of HIV-1 infection. The study population and outcomes of this trial have been described elsewhere . At study termination, patients from the placebo group were systematically offered cotrimoxazole, and all subjects continued to be followed up in the same conditions as during the trial. For this study of morbidity under cotrimoxazole, baseline was defined as cotrimoxazole initiation (i.e., inclusion in the ANRS 059 trial in patients from the cotrimoxazole group, and cotrimoxazole initiation after the end of the trial in patients from the placebo group), and the date of study termination was 30 June 2000 or the day of antiretroviral multitherapy initiation if prior to 30 June 2000. The study protocol was approved by the ethics committee of the Ivoirian National Programme on AIDS, STDs and Tuberculosis (PNLS/MST/TUB, Côte d'Ivoire) and the institutional review board of the French Agency of Research on AIDS (ANRS, France).
During and after the ANRS 059 trial, patients had monthly visits with a social worker, a quarterly examination by a physician, and had open access to the study clinic whenever they had medical problems. As public hospitals in Abidjan often suffer from delays, patients necessitating parenteral treatment were tended to at the day-care hospital of the study clinic to better control rapidity and steadiness of care. When parenteral treatments had to be continued for more than 1 day, patients who found it difficult to reach the trial centre because they were too sick to travel on urban transport were transported by a taxi or by a trial centre vehicle. For life-threatening diseases, for diseases necessitating care overnight, or when a patient necessitating prolonged parenteral treatment could not be transported daily to the trial centre, patients were referred to the Yopougon University Hospital. All prescribed medications, investigations, hospital stays and transportation were offered free of charge. Patients were managed according to standardized algorithms, including investigations and treatments for the most frequent symptoms and syndromes. Laboratory and X-ray investigations systematically recommended in patients with fever have been described elsewhere . For all subjects who did not keep scheduled appointments, vital status was systematically investigated by experienced social workers through home visits, and by screening obituary sections of the national newspapers. Autopsies were not performed. All clinical events seen by the trial team at the study centre or at hospital were labelled through standardized definitions, and then referred for review by an event documentation committee. A bacterial infection was defined as ‘definitive’ when a clinically significant pathogen was isolated and as ‘presumptive’ when a consistent clinical picture was observed but no pathogen was isolated (see Appendix 1 for the most frequent diagnostic criteria). Serious bacterial diseases were defined as all bacterial diseases leading to at least 1 day in hospital with parenteral treatment (including the university hospital and the day-care hospital of the trial centre). An episode of morbidity was considered as a new one if the symptom-free interval starting at the end of the preceding episode of the same diagnosis exceeded 30 days.
HIV-1 and HIV-2 antibodies were screened by using an ELISA (Genelavia Mixt; Diagnostic Pasteur, Paris, France), with further confirmation and discrimination on the same serum sample by means of a synthetic peptide ELISA (Peptilav 1-2; Diagnostic Pasteur). HIV seroposivity was further confirmed by a single ELISA (Murex Ice 1-0-2; Murex Biotech Ltd, Dartford, UK) performed on a second serum sample. Percentages of CD3, CD4 and CD8 cells were measured by flow cytometry (FACScan; Becton Dickinson, Aalst-Erembodegem, Belgium). CD4 and CD8 lymphocyte counts were determined by multiplying the percentages of CD4 and CD8 cells by the total lymphocyte count (TLC). TLC was obtained by multiplying the percentage of lymphocytes measured manually by the total leukocyte count obtained by an automated blood cell counter (Coulter JT2; Coultronics, Paris, France).
Blood films for malaria were examined using May–Grünwald–Giemsa staining. Stool specimens were directly examined fresh and after being concentrated using Ritchie's method. Blood, urine, stools, cerebrospinal fluid (CSF), pleural fluid, abdominal fluid or pus from other origins were examined microscopically using Gram staining, and then cultured on appropriate media. Antimicrobial susceptibility of pathogens was determined by disk diffusion.
CSF was also systematically examined using India ink staining, and cryptococcal antigen was screened by Latex agglutination (Diagnostic Pasteur). Samples other than blood were screened for mycobacteria using Auramine staining, and then cultured on Löwenstein–Jensen medium and Bactec 13A medium (Becton Dickinson). Blood cultures for mycobacteria were performed on Bactec 12B medium (Becton Dickinson). Mycobacteria were identified biochemically.
The incidence rate of a given disease was defined as the number of patients having at least one incident episode of this disease per 100 patient-years (PY) of at-risk follow-up. The at-risk period began at cotrimoxazole initiation and continued to the end of the study (30 June 2000 or the day of antiretroviral multitherapy initiation if prior to 30 June 2000), death, default or first event-date. Default was the date of the last contact with trial team for all patients whose last contact was prior to 30 June 2000 and who were not found to be deceased prior to 30 June 2000 when investigating their vital status as described above. Survival and event-free survival times were estimated using the Kaplan–Meier method. Multivariate Cox proportional hazards regression models for first events were used to study the association between the occurrence of the first bacterial infection (overall, by diseases and by groups of severity) and the CD4 cell count groups at baseline (< 200 × 106/l and ≥ 200 × 106/l), adjusting for the possible confounding effect of the other baseline variables associated with the first bacterial infection with a P < 0.25 in univariate analyses. Incidence rates, hazard ratios and survival probabilities are given with their 95% confidence intervals (CI). Analyses were done with STATA statistical software version 6.0 (Stata Corporation, College Station, Texas, USA).
Of the 545 adults who participated in the ANRS 059 trial, 448 received cotrimoxazole once and were included in the present study, including 272 from the cotrimoxazole group of the trial and 176 from the placebo group who began cotrimoxazole after the trial was stopped. Of these 448 patients, 31 started an antiretroviral multitherapy before 30 June 2000. Table 1 summarizes the baseline characteristics at cotrimoxazole initiation and the characteristics of follow-up under cotrimoxazole.
Serious morbidity and mortality
The overall number of days in hospital was 2464, including 1364 days in the day-care hospital of the study centre and 1100 days in the university hospital. Two-hundred and sixty patients had 536 episodes of morbidity with at least 1 day in hospital, including 435 episodes (81%) with only day-care hospital stay, 32 (6%) with only university hospital stay, and 69 (13%) with both day-care hospital and university hospital stay. The overall mean number of days in hospital in these 536 episodes was 4.6 days [standard deviation (SD), 7.7; median, 2; interquartile range (IQR), 1–4; range, 1–49]. The overall hospital admission rate was 41.8/100 PY (95% CI, 37.0–47.2), and the estimated median survival time without being admitted to hospital was 1.6 years (IQR, 0.6–3.5). Table 2 shows the incidence rates of the most common reasons for hospital admission. Bacterial diseases was the group with highest hospital admission rate, followed by non-specific enteritis, acute unexplained fever, tuberculosis, non-specific bronchitis, malaria, and atypical mycobacteriosis. One hundred and sixty-three persons (36%) died during follow-up. The overall mortality rate was 18.6/100 PY (95% CI, 15.9–21.7).
Two-hundred and sixteen of the 448 patients had 430 episodes of bacterial morbidity, including 277 (64%) presumptive episodes and 153 (36%) definitive episodes (DE) with isolation of one clinically significant pathogen. One hundred and fourteen (27%) of these 430 bacterial episodes were with hospital admission (HAE). The 430 episodes were 135 episodes of cutaneous infections (DE, five; HAE, six), 119 episodes of otitis and/or sinusitis (DE, three; HAE, 17), 45 episodes of enteritis (DE, 45; HAE, 28), 39 episodes of cystitis (DE, 35; HAE, none), 29 episodes of invasive abdomino-uro-genital infections (DE, 20; HAE, 23), 24 episodes of pneumonia (DE, seven; HAE, 21), 19 episodes of bacteraemia with no focus (DE, 19; HAE, 17), 18 episodes of sexually transmitted diseases (DE, 17; HAE, none), one episode of meningitis and one episode of endocarditis. For each group of bacterial disease involved, the overall incidence rate and the incidence rate of hospital admission are summarized in Table 3. The 135 episodes of cutaneous infection were: cutaneous or mucous abscess (68), bartholinitis (two), erysipela (one), furuncle/furunculosis (60), external otitis (three), and chalazion (one). The 29 episodes of invasive abdomino-uro-genital infection were: pyelonephritis (13), prostatitis (seven), orchi-epididymitis (four) salpingitis (two), cholecystitis (one), and liver abscess (two). The 18 episodes of sexually transmitted diseases were: urethritis (nine), cervicitis (eight), and chancroid (one).
Of the 153 bacterial strains isolated, 130 were tested for cotrimoxazole susceptibility; of these 22% were susceptible. The 153 strains were 48 Escherichia coli [9% cotrimoxazole susceptible (CMX-S)], 35 non-typhi Salmonella (26% CMX-S), 25 Shigella sp. (16% CMX-S), 16 Neisseria gonorrheae (untested), 12 Streptococcus pneumoniae (78% CMX-S), eight Klebsiella pneumoniae (25% CMX-S), five Staphylococcus aureus (75% CMX-S), two Pseudomonas aeruginosa (untested), one Chlamydia trachomatis (untested) and one Streptococcus mitis (resistant). Of the 48 E. coli strains, 31 were isolated during uncomplicated lower urinary tract infections, four during bacteraemia with no focus, and 13 during invasive abdomino-uro-genital infections. Seventy-five of the 153 overall strains were isolated during episodes with hospital admission, including 29 non-typhi Salmonella, 14 E. coli, 12 Shigella sp, 12 S. pneumoniae, four K. pneumoniae, two P. aeruginosa, one S. aureus and one S. mitis.
Association of bacterial morbidity with baseline CD4 cell count
Compared with patients with baseline CD4 cell counts ≥ 200 × 106/l, patients with baseline CD4 cell counts < 200 × 106/l had a hazard ratio of overall bacterial diseases of 1.54 (95% CI, 1.17–2.04; P = 0.002) and a hazard ratio of serious bacterial diseases of 2.88 (95% CI, 1.89–4.39; P < 0.001) in univariate analysis. When adjusting for age, sex, number of persons at home and marital status, the adjusted hazard ratios were 1.56 (95% CI, 1.18–2.07; P = 0.002) for overall bacterial diseases and 3.05 (95% CI, 2.00–4.67; P < 0.001) for serious bacterial diseases. Fig. 1 shows the Kaplan–Meier curve of probability of remaining free from serious bacterial disease over time by baseline CD4 cell count. Table 4 compares the incidence rates of diseases with hospital admission by baseline CD4 cell count, for each group of bacterial infection.
We describe here the incidence figures of bacterial morbidity, by specific diseases, pathogens, and CD4 cell count in 448 HIV-1 infected adults receiving cotrimoxazole prophylaxis and followed-up during a median of 26 months in Abidjan, the economic capital of Côte d'Ivoire.
In these patients – tended to in a dedicated centre with standardized algorithms of diagnoses and treatments – all new clinical conditions were exhaustively labelled through aetiologic or syndromic diagnoses. However, the incidence figures reported here deserve several comments.
First, only the episodes of morbidity actually seen by the study team were recorded. Although patients had free access to health care (including free transport), additional episodes may have been managed elsewhere, especially mild episodes with short duration or episodes occurring when patients were far from Abidjan.
Second, the care centre had more available diagnostic procedures compared with most other outpatient clinics in Abidjan, but these remain field conditions in which pathogen isolation (a necessary criterion for a diagnosis to be definitive) was likely to be limited compared with hospital conditions in industrialized countries. In addition, patients were taking cotrimoxazole which could have inhibited the growth of some bacteria. Presumptive diagnostic criteria based on clinical conditions with no pathogen isolation were acceptable for diseases such as pneumonia or invasive urogenital infections, but cannot be adopted for diseases such as occult bacteraemia or bacterial enteritis. Some episodes of the latter, which would have been diagnosed as ‘bacterial diseases’ under optimal conditions and in patients with no prophylaxis, are thus likely to have been recorded as ‘acute unexplained fever’ or ‘non-specific enteritis’ under these field conditions and in patients receiving cotrimoxazole. Finally, some of the episodes of presumptive bacterial otitis, sinusitis or cutaneous infections may have been non-bacterial episodes, while part of the episodes of non-specific bronchitis could have been of bacterial aetiology. Because describing morbidity entails more subjectivity in sub-Saharan African than in industrialized countries, descriptions of specific causes of morbidity should also include, whenever possible, incidence figures of the most frequent presumptive or non-specific diagnoses concomitantly recorded.
Third, our definition of severity based on hospital admission (mainly at the day-care hospital of the study centre) is subjective. In our practice a day-care hospital admission with parenteral treatment corresponds to patients presenting with serious clinical symptoms, as reflected by the proportion of admissions according to specific diseases. In industrialized countries, all of these patients (and probably more of them) would have been admitted to a public hospital. However, reports from African teams using other severity criteria may provide different figures, and comparison with our data would be possible only if data on the overall bacterial morbidity were presented together with those on serious morbidity.
Within these limitations, this exhaustive prospective description points to bacterial diseases as being one of the major groups of infections in HIV-infected adults in sub-Saharan Africa. With some exceptions , when discussing the issue of opportunistic infections in Africa this prominent role has long been underestimated for at least four reasons. First, studies providing a global overview of the role of bacterial diseases in a given HIV-infected population have been rare [7–11]. Until now, each of the bacterial diseases involved has mostly been described separately through studies focusing on one specific type of infection (mainly bloodstream infections, pneumonia, or enteritis) [9,12–25] or one specific pathogen (mainly S. pneumoniae) [23,24,26]. These studies did not include part of the spectrum that we describe here, as to our knowledge there has been no previous description of HIV-related cutaneous or urogenital tract invasive infections in the African context. Second, most of the studies describing HIV-associated bacterial morbidity in Africa have been cross-sectional hospital-based ones so did not provide incidence data. The only well documented community-based incidence rates of specific bacterial diseases were those of acute pneumonia and of S. pneumoniae infections, described in the cohort study by Gilks et al. in Kenya  and in the trial of pneumococcal vaccine by French et al. in Uganda , providing similar rates of pneumonia to estimated rates in HIV-infected adults in the USA . Third, only part of the HIV-associated bacterial diseases in Africa (recurrent sinusitis, pneumonia, pyomyositis, non-typhoidal salmonella septicaemia) are included in the clinical stages of CDC and/or WHO definitions for HIV infection. Epidemiological studies strictly using these definitions thus systematically miss the other bacterial diagnoses , which represented 83 (73%) of the 114 serious bacterial episodes with hospital admission in our study. Fourth, bacterial diseases are well known widespread infections in the general population and are curable diseases with short-term curative treatments, unlike most other serious HIV-related infections. When they are identified and treated early with appropriate therapy in hospital-based or cohort centre-based studies in resource-poor settings, the mortality rate can be low [6,7,14,28]. A significant improvement in the survival rate can be reached by improving standard clinical management . This could have contributed to diverting attention from this group of diseases, although it has been shown to represent 23% of causes of HIV-related death in the sole extended population-based autopsy study done in sub-Saharan Africa .
To our knowledge, this is the first study reporting the incidence rate of bacterial diseases in HIV-infected adults receiving cotrimoxazole in sub-Saharan Africa. In our patients, the medium-term rate of serious bacterial diseases (11.3/100 PY) was less than half that of the short-term rate estimated from 1996 through 1998 in the same centre in adults receiving placebo during the ANRS 059 randomized trial of cotrimoxazole prophylaxis (26.1/per 100 PY) [3,8]. Meanwhile, the rates of mortality and of other causes of severe morbidity did not increase [3,8]. In these patients taking cotrimoxazole, there was an increasing rate of cotrimoxazole-resistant strains among the four main groups of isolated bacteria, compared with the observed resistance rates during the ANRS 059 trial . This is not surprising, and should not be considered as a cause of major concern as long as: (i) the incidence figures of severe morbidity remain lower than figures reported in patients with no prophylaxis; (ii) mortality doesn't increase with time under cotrimoxazole; (iii) the extensive use of cotrimoxazole prophylaxis doesn't accelerate resistance to cotrimoxazole and cross-resistance to other drugs of some pathogens in the community. Our study doesn't address the latter point which remains an important concern and should be the subject of further studies as recommended by the UNAIDS/WHO experts . In addition, our study addresses the first and second points in only one setting and in the medium term; similar descriptive studies of the pattern of bacterial diseases in patients receiving cotrimoxazole are now needed with longer follow-up and in as many settings as possible in sub-Saharan Africa. Longer follow-up should permit examination of temporal trends in disease incidences.
In conclusion, in this population of HIV-infected Ivoirian adults, bacterial diseases remained the first identified causes of hospital admission even if reduced by cotrimoxazole prophylaxis. Together with improving access to well-managed highly antiretroviral therapies and with improving early detection and treatment of tuberculosis, monitoring long-term bacterial morbidity under cotrimoxazole, optimizing early detection and treatment of bacterial diseases and assessing the risk that cotrimoxazole may accelerate cross-resistance in the community are important issues for HIV care in sub-Saharan Africa.
Sponsorship: This study was supported by the Agence Nationale de Recherches sur le SIDA (ANRS, France), and the Programme National de Lutte contre le SIDA, les maladies sexuellement transmissibles et la tuberculose (PNLS/MST/TUB, Côte d'Ivoire) within the collaborative Programme PAC-CI.
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Most frequent diagnostic criteria used by the event documentation committee
Keywords:Copyright © 2003 Wolters Kluwer Health, Inc.
HIV-1; natural history; Africa; adults; cotrimoxazole; bacterial diseases