AIDS and Non-AIDS Morbidity and Mortality Across the Spectrum of CD4 Cell Counts in HIV-Infected Adults Before Starting Antiretroviral Therapy in Côte d’Ivoire

Clinical Infectious Diseases, Mar 2012

Background. In Western Europe, North America, and Australia, large cohort collaborations have been able to estimate the short-term CD4 cell count–specific risk of AIDS or death in untreated human immunodeficiency virus (HIV)–infected adults with high CD4 cell counts. In sub–Saharan Africa, these CD4 cell count–specific estimates are scarce. Methods. From 1996 through 2006, we followed up 2 research cohorts of HIV-infected adults in Côte d’Ivoire. This included follow-up off antiretroviral therapy (ART) across the entire spectrum of CD4 cell counts before the ART era, and only in patients with CD4 cell counts >200 cells/μL once ART became available. Data were censored at ART initiation. We modeled the CD4 cell count decrease using an adjusted linear mixed model. CD4 cell count–specific rates of events were obtained by dividing the number of first events occurring in a given CD4 cell count stratum by the time spent in that stratum. Results. Eight hundred sixty patients were followed off ART over 2789 person-years (PY). In the ≥650, 500–649, 350–499, 200–349, 100–199, 50–99, and 0–49 cells/μL CD4 cell count strata, the rates of AIDS or death were 0.9, 1.7, 3.7, 10.4, 30.9, 60.8, and 99.9 events per 100 PY, respectively. In patients with CD4 cell counts ≥200 CD4 cells/μL, the most frequent AIDS-defining disease was tuberculosis (decreasing from 4.0 to 0.6 events per 100 PY for 200–349 and ≥650 cells/μL, respectively), and the most frequent HIV non-AIDS severe diseases were visceral bacterial diseases (decreasing from 9.1 to 3.6 events per 100 PY). Conclusions. Rates of AIDS or death, tuberculosis, and invasive bacterial diseases are substantial in patients with CD4 cell counts ≥200 cells/μL. Tuberculosis and bacterial diseases should be the most important outcomes in future trials of early ART in sub–Saharan Africa.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://cid.oxfordjournals.org/content/54/5/714.full.pdf

AIDS and Non-AIDS Morbidity and Mortality Across the Spectrum of CD4 Cell Counts in HIV-Infected Adults Before Starting Antiretroviral Therapy in Côte d’Ivoire

Xavier Anglaret () 0 2 3 Albert Minga 0 2 3 Delphine Gabillard 0 2 3 Timothe e Ouassa 0 2 8 Eugene Messou 0 2 3 Brandon Morris 2 5 Moussa Traore 0 2 Ali Coulibaly 0 2 Kenneth A. Freedberg 2 4 5 6 Charlotte Lewden 0 2 3 Herve Me nan 0 2 8 Yao Abo 0 2 Nicole Dakoury-Dogbo 0 2 Siaka Toure 0 2 Catherine Seyler 0 1 2 The ANRS 2 Morbidity/Mortality Study Group 2 7 0 Programme PAC-CI , CHU de Treichville 1 Service de Sante Publique et d'Information Me dicale, Hopital de la Timone , Marseille , France 2 Received 12 July 2011; accepted 28 October 2011; electronically published 14 December 2011 3 INSERM U897 and the Universite Bordeaux Segalen , Bordeaux 4 Department of Health Policy and Management, Harvard School of Public Health , Boston, Massachusetts 5 Department of Medicine, Massachusetts General Hospital, Harvard University Center for AIDS Research, Harvard Medical School 6 Divisions of Infectious Disease and General Medicine and Medical Practice Evaluation Center 7 The ANRS 12222 Morbidity/Mortality Study Group members are listed in the Acknowledgments section. Treichville , 18 BP 1954, Abidjan , Cote d'Ivoire 8 Centre de Diagnostic et de Recherche sur le SIDA (CeDReS) , CHU de Treichville, Abidjan , Cote d'Ivoire Background. In Western Europe, North America, and Australia, large cohort collaborations have been able to estimate the short-term CD4 cell count-specific risk of AIDS or death in untreated human immunodeficiency virus (HIV)infected adults with high CD4 cell counts. In sub-Saharan Africa, these CD4 cell count-specific estimates are scarce. Methods. From 1996 through 2006, we followed up 2 research cohorts of HIV-infected adults in Co te d'Ivoire. This included follow-up off antiretroviral therapy (ART) across the entire spectrum of CD4 cell counts before the ART era, and only in patients with CD4 cell counts .200 cells/lL once ART became available. Data were censored at ART initiation. We modeled the CD4 cell count decrease using an adjusted linear mixed model. CD4 cell countspecific rates of events were obtained by dividing the number of first events occurring in a given CD4 cell count stratum by the time spent in that stratum. Results. Eight hundred sixty patients were followed off ART over 2789 person-years (PY). In the $650, 500-649, 350-499, 200-349, 100-199, 50-99, and 0-49 cells/lL CD4 cell count strata, the rates of AIDS or death were 0.9, 1.7, 3.7, 10.4, 30.9, 60.8, and 99.9 events per 100 PY, respectively. In patients with CD4 cell counts $200 CD4 cells/lL, the most frequent AIDS-defining disease was tuberculosis (decreasing from 4.0 to 0.6 events per 100 PY for 200-349 and $650 cells/lL, respectively), and the most frequent HIV non-AIDS severe diseases were visceral bacterial diseases (decreasing from 9.1 to 3.6 events per 100 PY). Conclusions. Rates of AIDS or death, tuberculosis, and invasive bacterial diseases are substantial in patients with CD4 cell counts $200 cells/lL. Tuberculosis and bacterial diseases should be the most important outcomes in future trials of early ART in sub-Saharan Africa. CD4 lymphocyte count is one of the most important determinants of human immunodeficiency virus (HIV)related morbidity and mortality. In Western Europe, - North America, and Australia, large cohort collaborations have been able to estimate the short-term CD4 cell countspecific risk of AIDS or death in untreated HIV-infected adults across a wide spectrum of CD4 cell counts [1, 2]. On the basis of these estimates, recent models suggested that CD4 cell counts of 350 cells/lL was the minimum threshold to start antiretroviral treatment (ART) but that there might be benefits to starting earlier [3, 4]. Several trials of early ART are ongoing to address the latter issue. In subSaharan Africa, knowledge about HIV-related morbidity and mortality in untreated patients comes from a limited number of studies. Most were cross-sectional hospitalbased studies [5, 6]; very few were longitudinal [7, 8]. Of the latter, some were performed in the 1990s, when CD4 cell counts were not available, and most of the others described morbidity based on baseline and not follow-up CD4 cell counts [911]. Data are especially lacking in patients with high CD4 cell counts. Because of the incompleteness of existing data, it remains unclear whether HIV infection treatment guidelines should be region-specific. There is extensive evidence showing that some infectious diseases, such as tuberculosis, are more frequent in sub Saharan Africa than in Europe or in the United States, both in the general population and in the HIV-infected population [1217]. However, because CD4 cell countspecific rates of these diseases have not been estimated across the entire spectrum of CD4 cell counts before the ART era, the question of whether patients with similar CD4 cell counts should have different guidelines, depending on the region in which they live, has not been clearly addressed. This is particularly true when it comes to the crucial question of when to start ART. In this study, we describe the CD4 cell countspecific rates of morbidity and mortality across the full spectrum of CD4 cell counts in 2 cohorts of untreated HIV-infected adults. These cohort studies were funded by the French Agence Nationale de Recherche sur le SIDA (ANRS) in C ote dIvoire. METHODS Patients and Follow-up We collected data from 2 large cohort studies in C ote dIvoire. Both cohorts started at the end of the 1990s, before ART was available in Africa, and were followed up by the same team and with similar procedures. In both cohorts, CD4 cell counts were measured every 6 months in all patients, and documentation of morbidity was the primary goal. The cohorts have been described elsewhere. In summary, the ANRS 1203 study was followed up in Abidjan from 1996 through 2003. It was a prevalent cohort of adults who were already HIV-infected when they were enrolled and for whom the date of seroconversion was unknown [18]. The ANRS 1220 study is a cohort of adult HIV-infected blood donors whose date of seroconversion was estimated. Follow-up started in 1997 at the National Blood Bank of Abidjan and is ongoing [19]. The 2 cohorts were followed up similarly, and had in common (1) the objective of documenting morbidity, (2) CD4 cell count tests every 6 months, (3) the conditions of access to care, with all tests and treatment free of charge, (4) the types of recorded morbidities and standardized definitions, and (5) tracing procedures for patients lost to follow-up. Recorded Morbidities In both cohorts, the following events were systematically recorded: all World Health Organization (WHO) stages 2, 3, or 4 diseases or Centers for Disease Control and Prevention (CDC) stage 3 defining diseases; malaria; bacterial and fungal mucocutaneous infections; bacterial and parasitic enteritis; and all other morbidity events that had at least 1 of the following criteria: fever of .38 C, at least 1 day in the hospital (including day-care hospital), or leading to death. Furthermore, when a disease was classified at a WHO or CDC stage on the basis of a recurrent episode (eg, upper respiratory tract infection) or of an episode lasting .1 month (eg, unexplained fever or unexplained diarrhea), first episodes and episodes lasting ,1 month were also recorded. Each episode of morbidity was reviewed by an event documentation committee (standardized criteria are shown in Supplementary Appendix 1 for the most frequent diseases). Characteristic No. (%) of Participants (N 5 860) Data are no. (%) of participants, unless otherwise indicated. Abbreviations: ANRS, French Agence Nationale de Recherche sur le SIDA; ART, antiretroviral therapy; IQR, interquartile range; SD, standard deviation; WHO, World Health Organization. No. of Episodes Overall No. (%) of Episodes With Hospital Admission No. (%) of Episodes With Bacteremia Classification, No. (%) of Episodes Mycobacterial diseases Tuberculosis Nontuberculous mycobacteriosis Bacterial diseases Pneumonia Isolated bacteremia Pyelonephritis Prostatitis Orchitis/ epididymitis Salpingitis Bacterial enteritis Other bacterial invasive diseasea Otitis Sinusitis Mucocutaneous infections Fungal diseases Oral candidiasis Vaginal candidiasis Esophageal candidiasis Cryptococcosis Histoplasmosis Angular cheilitis Fungal nail infections Other fungal skin infections Virologic diseases Herpes zoster virus infection Genital HSV infection Visceral HSV or CMV infection Parasitic diseases Toxoplasmosis Pneumocystosis Cryptosporidiosis Nonclassifying parasitic enteritis Isosporosis Malaria Nonspecific diseases Unexplained diarrheab Unexplained feverc Unexplained pneumonia Unexplained central neurological Pruritic papular eruption Oral leucoplakia Oral ulcerations WHO Stage 2 149 (22) WHO Stage 3 WHO Stage 4 29 (10) 31 (10) Table 2 continued. Malignancies Overall Classification, No. (%) of Episodes Treatment In the ANRS 1220 cohort, all patients received cotrimoxazole regardless of CD4 cell count, even patients at WHO stage 1. In the ANRS 1203 cohort, patients at WHO stages 2, 3, or 4 received cotrimoxazole, irrespective of CD4 cell count, and patients at WHO stage 1 received cotrimoxazole only if their CD4 cell count dropped to ,500 cells/lL. In both cohorts, some patients initiated ART once ART became available in Abidjan, following WHO criteria. Statistical Analysis In this study, we included only patient-time receiving cotrimoxazole and prior to starting ART. We considered the following CD4 cell count strata: 049, 5099, 100199, 200349, 350499, 500649, and $650 cells/lL. We estimated CD4 cell countspecific rates of mortality and each morbidity group by dividing the number of events that occurred in a given CD4 cell count stratum by the cumulative time spent in the same stratum, expressed in person-years (PY). In the literature, CD4 cell count specific rates are frequently estimated using 6-month periods after the date of the latest CD4 cell count [2, 20]. In such analyses, events and follow-up time that occur .6 months after a CD4 cell count are omitted. In subSaharan Africa, such omissions would likely lead to underestimated death rates, because terminally ill patients are frequently transported to their village by their family to receive care at home. Consequently, deaths frequently occur .6 months after the last available CD4 cell count, even though they are appropriately documented in the databases through tracing procedures [21]. Thus, to determine the CD4 cell count at the onset of a given event and the time spent in a given stratum, we modeled the CD4 cell count decrease at the individual level by use of a linear mixed model adjusted for CD4 cell count evolution by whether or not people died. We confirmed that this approach was suitable for the data by drawing 2 curves for the distribution of individual CD4 cell counts at each follow-up time for patients remaining in care: the distribution of simulated individual CD4 cell counts over time (as estimated by the model), and the distribution of the actual CD4 cell counts measured every 6 months. As shown in Supplementary Appendix 2, the curves fit each other well. For a given CD4 cell countspecific morbidity or mortality rate, follow-up within the stratum was censored at the onset of the first event, death, time of ART initiation, or date of last contact with the clinic. RESULTS Patients and Follow-up Eight hundred sixty patients were included in the analysis, of whom 94% were HIV-1 positive, 5% had dual HIV-1 and HIV-2 positivity, and 1% were HIV-2 positive. Their baseline characteristics are shown in Table 1. These patients were followed up while receiving cotrimoxazole and without ART for 2788 PY (mean follow-up per patient, 35.9 months). During this follow-up, 262 patients died (33%). The mean number of available CD4 cell counts was 6 per patient. Clinical Events Table 2 shows the overall number of episodes documented for each specific and nonspecific disease. During follow-up, 5267 episodes of morbidity were recorded. Of these, 696 were WHO stage 2, 1034 WHO stage 3, 283 WHO stage 4, and 338 AIDSdefining episodes. Within the episodes of WHO stages 3 or 4 or AIDS-defining diseases, the most frequent were oral candidiasis (n 5 676), invasive bacterial diseases (n 5 129), esophageal candidiasis (n 5 110), tuberculosis (n 5 84), prolonged unexplained fever and/or diarrhea (n 5 63), and nontuberculous mycobacteriosis (n 5 31). The 84 episodes of tuberculosis included 55 pulmonary cases and 29 disseminated cases. The 254 episodes of invasive bacterial diseases were 90 enteritis cases, 59 isolated bacteremia cases, 50 pneumonia cases, 45 invasive urogenital infections, and 10 infections in other locations. Of these invasive bacterial disease episodes, 39% had positive blood culture, 86% were first episodes, and 14% were recurrent episodes. Of the 5267 recorded morbidity episodes, 923 required hospital admission. Of the hospital admissions, 39% were due to nonspecific symptoms (unexplained fever, diarrhea, or pulmonary or neurologic symptoms), 23% to bacterial diseases, 7% to malaria, and 6% to tuberculosis. CD4 Cell CountSpecific Rates of Diseases Figure 1 shows the CD4 cell countspecific rates of death; AIDS or death; and AIDS, death, or severe non-AIDS diseases; the 95% confidence intervals (CIs) are shown in Supplementary Appendix 3. As expected, the rates of AIDS or death were highest in patients with CD4 cell counts ,200 cells/lL, ranging from 30.9 events per 100 PY in the 100199 cells/lL stratum to 99.9 events per 100 PY in the 049 cells/lL stratum. Although they were lower, the rates were still substantial in patients with CD4 cell counts $200 cells/lL, reaching 10.4 events per 100 PY in the 200349 cells/lL stratum, 3.7 events per 100 PY in the 350499 cells/lL stratum, 1.7 events per 100 PY in the 500649 cells/lL stratum, and 0.9 events per 100 PY in the $650 cells/lL stratum. In CD4 cell count strata of $200 cells/lL, the most frequent WHO stages 3 or 4 or AIDS-defining diseases were invasive bacterial diseases, oral candidiasis, and tuberculosis (Table 3; 95% CIs are given in Supplementary Appendix 3). DISCUSSION In this study, we describe for the first time in Africa the CD4 cell countspecific rates of morbidity and mortality across the full spectrum of CD4 cell counts in HIV-infected patients receiving cotrimoxazole but no ART. We derived these estimates from 2 long-term research cohorts in which patients had free access to transportation and care, including diagnosis and treatment, before the ART era. Facilities are limited in most low-resource settings. Many patients followed under routine conditions can afford neither the tests required to document morbidity nor the medications to treat it. In this context, cohorts with free access to care are likely to generate better estimates of morbidity than are routine program databases. On the other hand, participants in cohorts with free access to tests and medications are also less likely to die, because of appropriate and more rapid diagnosis and treatment. As a result, the spectrum we describe likely reflects with reasonable accuracy the full spectrum of HIV-related morbidity in untreated HIVinfected patients in Co te dIvoire, while underestimating mortality from these diseases in this population (Figure 2). These data support the following points. First, although mortality (4.2 events per 100 PY) and rates of AIDS or death (10.4 events per 100 PY) in patients with CD4 cell counts of 200349 cells/lL are lower than in those with CD4 cell counts of ,200 cells/lL, the absolute rates are still high. This is consistent with data previously reported from South Africa (death rate, 8.0 events per 100 PY; rate of AIDS or death, 14.0 events per 100 PY) [8] and Haiti [22], suggesting that mortality in adults at CD4 cell counts of 200349 cells/lL is high in some low-resource settings compared with rates reported from Western Europe (CHIC cohort death rate, 0.58 events per 100 PY; CHIC cohort AIDS or death rate, 4.91 events per 100 PY; Eurosida death rate, 2.7 events per 100 PY; Eurosida AIDS rate, 6.1 events per 100 PY) [2, 20]. The novelty of the data here is what happens at CD4 cell counts above these values, with 2 important findings: that rates of death or AIDS in patients with CD4 cell counts of 350499 cells/lL remain substantial (death rate, 1.6 events per 100 PY; rate of AIDS or death, 3.7 events per 100 PY) compared with rates among HIV-infected adults with CD4 cell counts of 350499 cells/lL reported from Western Europe (UK Collaborative HIV Cohort [CHIC] study death rate, 0.32 events per 100 PY; CHIC cohort AIDS or death rate, 2.49 events per 100 PY) [2, 20] and with death rates from causes other than HIV infection or AIDS in the overall population (ie, HIV-infected and noninfected individuals) of subSaharan African adults aged 1559 years (global and regional burden of disease and risk factor estimates from 2001, 0.6 deaths per 100 PY) [23]; and that there is a trend toward decreasing rates of mortality with increasing CD4 cell counts, even above 350 cells/lL. Second, tuberculosis and invasive bacterial diseases are clearly the most frequent severe diseases in patients with higher CD4 cell counts. The CD4 cell countspecific rates of tuberculosis in this study are lower than those reported from South Africa [7, 24] but far higher than those reported from France [25] and Great Britain [26]. For invasive bacterial diseases, it is not possible to compare our rates to those in other settings, because studies that reported CD4 cell countspecific rates of bacterial morbidity focused only on AIDS-defining recurrent episodes [25, 26]. By doing so, they did not capture the importance of first episodes, which in our study accounted for 85% of the overall number of episodes of invasive bacterial diseases. A key difference in the way in which high- and low-resource countries consider tuberculosis and bacterial diseases is that in rich countries these diseases are increasingly classified as nonsevere events, even when they are AIDS-defining diseases [27]. In subSaharan Africa, autopsy studies have shown that tuberculosis and bacterial diseases are the 2 most frequent causes of death in HIV-infected adults [1217], even though they are easier to diagnose and treat than many other types of opportunistic infections. This is due to a combination of 3 factors: poor access to healthcare facilities, poor access to specific diagnostic tests, and poor access to treatment [28]. Because of the first 2 factors, WHO estimates that only 50% of active tuberculosis cases are diagnosed in subSaharan Africa [29]. As a consequence of all 3 factors, not only is the frequency of active tuberculosis underestimated in most HIV infection care programs, but mortality from tuberculosis is also likely to be underestimated. This underestimation is seen in routine programs, because most patients with undiagnosed tuberculosis die without tuberculosis being identified as the cause of death, and in cohort studies with clear follow-up, because diagnosed patients receive adequate treatment (Figure 2). $650 cells/lL 500649 cells/lL 350499 cells/lL 200349 cells/lL 100199 cells/lL 5099 cells/lL WHO stage 4, overall Tuberculosis, disseminated a Recurrent bacterial pneumonia Recurrent NTS bacteremia Nontuberculous mycobacteriosis Cryptococcosis Toxoplasmosis Cryptosporidiosis, microsporidiosis Malignancy (Kaposi sarcoma or lymphoma) Isosporosis Visceral HSV or CMV infection Esophageal candidiasis Chronic genital HSV infection Wasting syndrome WHO stage 3, overall Tuberculosis, pulmonarya Invasive bacterial diseases, overall Bacterial enteritis Pneumonia Isolated bacteremia Urogenital infectionb Infection with any other organ involvementc Unexplained diarrhea for .1 month Unexplained fever for .1 month Oral candidiasis WHO stage 2, overall Herpes zoster virus infection Angular cheilitis Fungal nail infections Pruritic papular eruption Recurrent oral ulcerations Recurrent otitis or sinusitis Nonclassifying diseases Oral ulcerations, first episode Otitis or sinusitis, first episode Sinusitis, first episode Otitis, first episode Bacterial mucocutaneous infectionsd Nonclassifying fungal skin infectionse Acute genital HSV infection Nonclassifying parasitic enteritisf Malaria, any episode Malaria with hospital admission 0.0 0 0 0 0 0 0 0 Table 3 continued. Disease Nonspecific illness with hospital admission Unexplained fever for #1 month Unexplained diarrhea for #1 month Unexplained central neurological symptomsg Unexplained pneumoniag Any other disease with hospital admissionh $650 cells/lL 500649 cells/lL 350499 cells/lL 200349 cells/lL 100199 cells/lL 5099 cells/lL There are several limitations to this study. First is the lack of facilities to diagnose some diseases. As in most studies in Africa, even in cohort studies with the primary objective of documenting morbidity, rates of all diseases are underestimated, but some of them are underestimated to a greater extent because their diagnosis requires sophisticated diagnostic tools. Our data showing that the rate of nonspecific diseases that lead to hospital admissions is high, and that this rate increases with decreasing CD4 cell counts, illustrate this fact. In this study, we wanted to give a comprehensive overview of the entire spectrum of morbidity in our cohorts, so we recorded and reported all specific and nonspecific episodes in order to provide a clear idea of what diagnoses could have been missed. All nonspecific diseases are not equivalent in terms of their likelihood of being missed. Diarrhea lasting #1 month and fever lasting #1 month are very unlikely to be undiagnosed AIDS-defining diseases, because they resolve spontaneously either without specific treatment or with empiric antibacterial or antimalarial treatment. Thus, some episodes of these groups may be undiagnosed bacterial diseases, undiagnosed malaria, or undiagnosed non-AIDS parasitic or viral diarrhea, rather than undiagnosed AIDS-defining diseases. In contrast, diarrhea lasting .1 month, fever lasting .1 month, unexplained pneumonia, and unexplained central nervous system symptoms could cover a wide range of undiagnosed AIDS diseases, including severe viral diseases. However, these groups are far smaller than the groups with diarrhea lasting #1 month and fever lasting #1 month, and these events are almost all restricted to CD4 cell count strata of ,350 cells/lL. Another limitation is censoring due to loss to follow-up and ART initiation, both of which could have been informative. The consequence of such informative censoring is likely to be an underestimation of deaths rather than an overestimation, because death rates are more likely to be higher in patients lost to follow-up, and because patients who start ART at CD4 cell counts of .200 cells/lL are likely to have more advanced clinical stages of disease than patients with .200 cells/lL who remain off ART. Had these patients not started treatment, they would have had higher risks of death. This, together with the discussion above regarding lower mortality from curable disease in cohort studies compared with treatment programs, lead us to believe that our results should be considered as lower bound estimates. The third limitation is that we merged databases from 2 different studies. Although both studies used the same follow-up procedures and the same standardized definitions, we cannot rule out some heterogeneity in the results. Finally, another limitation is the sample size, which is smaller than collaborative cohorts in industrialized countries. The mortality we found in our study has wide confidence intervals compared with those in such cohorts. Future collaborations of cohorts of untreated patients in lowresource settings should be developed to refine such estimates. In conclusion, we draw 2 key messages from these findings. First, the very concept of HIV non-AIDSdefining diseases, which is crucial to the current debate over when to start ART, does not cover the same spectrum in subSaharan Africa as in Western Europe, North America, and Australia. Our study shows that rates of tuberculosis and non-AIDS infectious diseases are substantial in patients with high CD4 cell counts. Previous studies have consistently shown that tuberculosis and bacterial diseases were the most important cause of death in HIV-infected adults in subSaharan Africa [1216]. Deaths related to tuberculosis or bacterial diseases could be avoided by 2 means: improving diagnosis and treatment, and decreasing incidence. Starting ART earlier than currently recommended could help achieve the latter. Thus, the ongoing and future trials of early ART in subSaharan Africa should carefully document these diseases and consider them as major outcomes. Second, because of this spectrum of illnesses, and because of the difference in access to care, trials exploring the benefits and risks of initiating ART at very high CD4 cell counts make more sense in low-resource settings similar to Co te dIvoire than in rich countries. Within the context of low-resource settings, starting ART very early might make even more sense in rural settings, which have limited facilities to diagnose tuberculosis and invasive bacterial diseases than in urban settings, where these diseases can be diagnosed and treated more easily. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online (http://www.oxfordjournals.org/our_journals/cid/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author. Acknowledgments. We are indebted to all patients who participated in this trial. We also gratefully acknowledge the valuable contributions of the Centre de Diagnostic et de Recherche sur le SIDA (CeDReS), Centre de Prise en Charge et de Formation (CePReF), Centre National de Transfusion Sanguine (CNTS), CEPAC International, and INSERM U897 teams. Members of the ANRS 1203 and 1220 Study Groups Clinical care in Abidjan, Cote dIvoire. CNTS: Hugues Abe, Nicole Abe, Yao Abo, Emma Amon Anini, Isidore Bohouo, Ali Coulibaly, Issouf Coulibaly, Vafoungbe Diabate, Lambert Dohoun, Daniel Ekra, Gwenola Gourvellec, Charlotte Huet, Jules Hyda, Mamadou Konate, Seidou Konate, Reine Kore, Charlotte Lewden, Albert Minga, Minata Ouattara, Marie-Julie NDri, Sayouba Ouedraogo, Abdelh Sidibe, and Liliane Siransy. CePReF: Xavier Anglaret, Amani Anzian, Edwidge Cisse, Nicole Dakoury-Dogbo, Christine Danel, Joachim Gnokoro, Marie-Cecile Kassi, Mamadou Kone, Bertin Kouadio, Yao Kouakou, Georgette Labibi, Jean Lehou, Euge`ne Messou, There`se NDri-Yoman, Marie-Pascale Nogbout, Catherine Seyler, Amah-Cecile Tchehy, Siaka Toure, Moussa Traore, and Marcel Zaho. Biology, Abidjan, Cote dIvoire. CeDReS, CHU de Treichville: Dominique Bonard, Patrice Combe, Arlette Emieme, Andre Inwoley, Herve Menan, Timothee Ouassa, Franxcois Rouet, Thomas-dAquin Toni, Ramatou Toure, and Vincent Yapo. Epidemiology and biostatistics, Bordeaux, France. INSERM U897: Delphine Gabillard and Roger Salamon. Members of the ANRS 12222 Study Group Steering committee. Xavier Anglaret, Robert Colebunders, Franxcois Dabis, Joseph Drabo, Serge Eholie, Delphine Gabillard, Pierre-Marie Girard, Karine Lacombe, Christian Laurent, Vincent Le Moing, and Charlotte Lewden. Other representatives of participating studies. Gerard Allou, Clarisse Amani-Bosse, Divine Avit, Aida Benalycherif, Pierre de Beaudrap, Patrick Coffie, Eric Delaporte, Lise Denoeud, Serge Diagbouga, Didier Koumavi Ekouevi, Jean-Franxcois Etard, Sabrina Eymard-Duvernay, Isabelle FournierNicolle, Herve Hien, Issouf Konate, Sinata Koulla-Shiro, Valeriane Leroy, Olivier Marcy, Nicolas Meda, Eitel Mpoudi-Ngole, Philippe Msellati, Boubacar Nacro, Nicolas Nagot, Ibra Ndoye, Abdoulaye Ouedraogo, Men Pagnaroat, Roger Salamon, Vonthanak Saphonn, Olivier Segeral, Philippe Van de Perre, and Marcel Zannou. Financial support. This work was supported by the French Agence Nationale de Recherche sur le SIDA et les hepatites virales, Paris, France (grants ANRS 1203, ANRS 1220, and ANRS 12222) and the US National Institute of Allergy and Infectious Diseases (grant NIAID AI058736). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.


This is a preview of a remote PDF: http://cid.oxfordjournals.org/content/54/5/714.full.pdf

Xavier Anglaret, Albert Minga, Delphine Gabillard, Timothée Ouassa, Eugene Messou, Brandon Morris, Moussa Traore, Ali Coulibaly, Kenneth A. Freedberg, Charlotte Lewden, Hervé Ménan, Yao Abo, Nicole Dakoury-Dogbo, Siaka Toure, Catherine Seyler, The ANRS 12222 Morbidity/Mortality Study Group. AIDS and Non-AIDS Morbidity and Mortality Across the Spectrum of CD4 Cell Counts in HIV-Infected Adults Before Starting Antiretroviral Therapy in Côte d’Ivoire, Clinical Infectious Diseases, 2012, 714-723, DOI: 10.1093/cid/cir898