High incidence of atypical mycobacteriosis in African HIV-infected adults with low CD4 cell counts: a 6-year cohort study in Côte d'Ivoire
Bonard, Dominiquea,b; Messou, Eugènea; Seyler, Catherinea; Vincent, Véroniquec; Gabillard, Delphined; Anglaret, Xaviera,d
aProgramme PAC-CI, Abidjan, Côte d'Ivoire; bCentre de Diagnostic et de Recherches sur le SIDA (CeDReS), Centre Hospitalier Universitaire de Treichville, Abidjan, Côte d'Ivoire; cCentre National de Référence des Mycobactéries, Institut Pasteur, Paris, France; and dINSERM U.593, Université Victor Segalen Bordeaux 2, Bordeaux, France.
Received: 27 February 2004; revised: 1 May 2004; accepted: 3 June 2004.
The role of non-tuberculous mycobacteriosis (NTM) in HIV-related diseases in sub-Saharan Africa has long been controversial. In a 6-year cohort of 721 HIV-infected adults with systematic BACTEC blood cultures in Abidjan, Côte d'Ivoire, the incidence of NTM was 1.8/100 person-years overall and 12.2/100 person-years in patients with baseline CD4 cell counts < 100 cells/mm3. In sub-Saharan Africa, where most patients start highly active antiretroviral therapy with low CD4 cell counts, improving the diagnosis of NTM may be relevant.
The spectrum of HIV-related morbidity in adults in sub-Saharan Africa shows some differences to that observed in Europe and north America. This includes a greater incidence of tuberculosis, a greater incidence of bacterial diseases, and a lower incidence of Pneumocystis carinii pneumonia [1–3]. However, the role of non-tuberculous mycobacteriosis (NTM) has long been controversial [4–8]. We report here the incidence of NTM in a 6-year therapeutic cohort study in Abidjan, Côte d'Ivoire.
The Cotrame ANRS 1203 cohort study has been described previously . In summary, from 1996 to the present, HIV-infected adults have been followed-up through standardized procedures, including monthly visits, standardized algorithms of investigation and treatment, and morbidity labelled through standardized definitions [1,9]. In patients with unexplained fever and fewer than 15% of CD4 cells, mycobacteria were sought systematically in the blood and in samples other than blood, depending on the other signs or symptoms .
Blood cultures for mycobacteria were performed by means of the BACTEC radiometric system (BACTEC 13A vials, Becton Dickinson, Aalst-Erembodegem, Belgium). Samples other than blood were processed using acid fast bacilli smear after auramine staining, and were then cultured on a BACTEC Middlebrook medium (BACTEC 12B) and on Loweinsten–Jensen agar . BACTEC 13A was enriched with 0.5 ml bovine albumin serum upon arrival in the laboratory. BACTEC 12B and 13A were incubated at 37°C for 6 weeks.When the growth index reached 30, the vials were assessed daily. An acid fast bacilli smear was performed as soon as the growth index reached 900. Positive vials were subcultured on Loweinsten–Jensen agar. Confirmed cultures were first separated into the tuberculous group and mycobacteria other than tuberculosis group by means of morphological examination and the radiometric NAP (p-nitro-alpha-acetylamino-beta-hydroxypropiophenone) inhibition test (Becton Dickinson). Specific identification was then performed at the Institut Pasteur (Paris) through polymerase chain reaction and restriction fragment length polymorphism analysis of the heat shock protein 65 000 Mr .
For the diagnosis of NTM, the isolation of a clinically significant mycobacterium other than tuberculosis on a normally sterile body fluid or tissue from a site other than the lungs was required .
The incidence of NTM was defined as the number of patients having at least one incident episode of NTM per 100 patient-years of at-risk follow-up. The at-risk follow-up began on the day of inclusion and continued to 31 October 2002 or the date of the episode of NTM, death or default if earlier than 31 October 2002. Default was the date of antiretroviral multitherapy initiation if earlier than 31 October 2002, or the date of the last contact with the Cotrame study team for all patients not receiving antiretroviral multitherapy, whose last contact was before 31 October 2002 and who were not found to be deceased within the 12 months after study termination.
A total of 721 adults were included in the Cotrame cohort before 31 October 2002. At baseline, their median CD4 cell count was 297 cell/mm3 [interquartile range (IQR) 155–509], and their median age was 31 years (IQR 18–72). Sixty-nine per cent were women. The 721 patients were followed-up for 1851 person-years, a median of 28 months per patient (IQR 13–47). As of 31 October 2002, 305 patients were deceased, 121 had initiated antiretroviral treatment, and 295 were alive with no antiretroviral treatment. Of the latter, 81% have been seen by the study team within the past 3 months.
Three patients were diagnosed as having prevalent NTM at inclusion. Among the remaining 718 patients, 34 had an incident episode of NTM during follow-up. Table 1 shows the incidence rate by baseline CD4 cell count and CD4 cell percentage.
At the time of the first symptoms, 73% of the 34 patients were at WHO clinical stage 4, 21% were at stage 3, and 6% were at stage 2. The mean body mass index was 18.7 kg/m2 (SD 2.5), and the median most recent CD4 cell count and CD4 cell percentage were 20 cells/mm3 (IQR 6–63) and 1.9% (IQR 0.6–4.2), respectively. The median time since the most recent CD4 cell measurement was 3.3 months (IQR 0.7–4.4).
During the episode, the mean maximal body temperature was 39.2°C (SD 0.8). Mycobacteria were isolated from blood culture in 32 episodes (including eight with positive sputum, one with positive urine, and one with positive stool cultures), from pleural fluid and sputum culture in one, and from urine and sputum culture in one. All isolated strains were identified as Mycobacterium avium or Mycobacterium intracellulare. Twenty-nine of the 34 patients died before the end of the study, within a median delay of 4 months after the first symptoms (IQR 2.3–5.9).
Twenty years after the HIV pandemic began, the spectrum of HIV morbidity has still not been fully described in sub-Saharan Africa. Diseases that were major AIDS-defining diseases in industrialized countries before the era of highly active antiretroviral therapy (HAART) have been thought to be less frequent in sub-Saharan Africa, but with the remaining doubt that the unavailability of the sophisticated biological and radiological tools required to diagnose such diseases may lead to underestimating their true frequency. NTM is one of these diseases [3–8]. Whereas an international prospective study showed that its incidence was five to 10-fold lower in Kenya than in the USA or northern Europe , a few hospital-based cross-sectional studies have reported contradictory estimates of prevalence [3–7].
Our study estimates for the first time the incidence of NTM in a west African cohort with long-term follow-up, with algorithms for managing morbidity, including systematic BACTEC blood cultures in prolonged unexplained fever. Under these cohort conditions, the incidence we observed in patients with fewer than 100 CD4 cells/mm3 was in the range of the incidences previously estimated in industrialized countries before the HAART era .
As long as access to HAART remains limited, patients receiving it will be those who need it most, i.e. more immunocompromised patients. In this context, HAART is often likely to be started either in patients receiving a curative treatment for NTM or in those with a low CD4 cell count and a high risk of developing NTM . Before the HAART era, improving the diagnosis of NTM in sub-Saharan Africa was not a relevant issue, as there was no efficient way to improve the prognosis of patients. Now that access to HAART is hopefully increasing, this may no longer be true.
Sponsorship: This study was supported by the Agence Nationale de Recherches sur le SIDA (ANRS, France)ce) 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.
Informed consent was obtained from patients, and the protocol was approved by the ethics committee of the PNLS/MST/TUB and the institutional review board of the ANRS.
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