HIV infection and Buruli ulcer in Africa
2014; Elsevier BV; Volume: 14; Issue: 9 Linguagem: Inglês
10.1016/s1473-3099(14)70882-5
ISSN1474-4457
AutoresQuentin B. Vincent, Marie-Françoise Ardant, Laurent Marsollier, Annick Chauty, Alexandre Alcaïs,
Tópico(s)Fungal Infections and Studies
ResumoIn a recent Personal View on Buruli ulcer, Daniel O'Brien and colleagues1O'Brien DP Comte E Serafini M et al.The urgent need for clinical, diagnostic, and operational research for management of Buruli ulcer in Africa.Lancet Infect Dis. 2014; 14: 435-440Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar highlighted the urgent need for research on HIV–Buruli ulcer co-infection. Whether HIV infection is a risk factor for Buruli ulcer is unknown, because the few studies published show contrasting results. In Ghana, HIV was not associated with Buruli ulcer (six of 116 Buruli ulcer cases with HIV versus one of 116 controls, p=0·89), whereas a significant association was found in Benin (11 of 426 versus two of 613, p=0·003).2Raghunathan PL Whitney EAS Asamoa K et al.Risk factors for Buruli ulcer disease (Mycobacterium ulcerans infection): results from a case-control study in Ghana.Clin Infect Dis. 2005; 40: 1445-1453Crossref PubMed Scopus (111) Google Scholar, 3Johnson RC Nackers F Glynn JR et al.Association of HIV infection and Mycobacterium ulcerans disease in Benin.AIDS. 2008; 22: 901-903Crossref PubMed Scopus (44) Google Scholar This discrepancy could result from HIV being differentially associated with subgroups of Buruli ulcer, such as severe Buruli ulcer. Sporadic case reports described patients with HIV with both severe and non-severe evolution, for example.4Toll A Gallardo F Ferran M et al.Aggressive multifocal Buruli ulcer with associated osteomyelitis in an HIV-positive patient.Clin Exp Dermatol. 2005; 30: 649-651Crossref PubMed Scopus (32) Google Scholar, 5Delaporte E Alfandari S Piette F Mycobacterium ulcerans associated with infection due to the human immunodeficiency virus.Clin Infect Dis. 1994; 18: 839Crossref PubMed Scopus (10) Google Scholar However, as emphasised by O'Brien and colleagues, no published epidemiological data exist on the association between HIV and severity of Buruli ulcer.We did a large cohort study in a highly endemic region of Benin, and addressed the question of the effect of HIV on the severity of Buruli ulcer. Clinical and laboratory data were prospectively obtained from all consecutive patients with Buruli ulcer seen between 2005 and 2011 at the Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) in Pobe, Benin. Clinical Buruli ulcer cases were confirmed by PCR and tested for HIV infection with two serological tests. As suggested in our study,6Vincent QB Ardant M-F Adeye A et al.Clinical epidemiology of laboratory-confirmed Buruli ulcer in Africa: a cohort study.Lancet Glob Health. 2014; 2: e422-e430Summary Full Text Full Text PDF Scopus (73) Google Scholar severe Buruli ulcer was defined as presenting with oedematous, bone, large (≥15 cm in diameter), or multifocal lesions. The effect of HIV on Buruli ulcer severity was tested by logistic regression, as implemented in the glm function of the R software. Access to the data registry was approved by the institutional review board of the CDTUB and the national Buruli ulcer control authorities.1511 Buruli ulcer cases were included, of whom 78% (n=1177) were PCR-confirmed. HIV testing was positive in 34 of all 1511 patients (2·3%) and in 25 of 500 patients (5·0%) aged 15–49 years. This proportion is significantly higher than is the 1·1% estimate reported for this age group in Benin in 2012 (p<0·0001).7UNAIDSCountry Epidemiology: Benin.http://www.unaids.org/en/regionscountries/countries/benin/Date: 2012Google Scholar More than 70% (n=24) of patients with HIV developed severe Buruli ulcer, compared with 50% (n=723) of HIV-negative patients (odds ratio [OR] 2·77, 95% CI 1·32–6·33; p=0·006). A focus on PCR-confirmed Buruli ulcer cases further validated this finding (OR 2·59, 1·06–7·27; p=0·037). The effect of HIV on Buruli ulcer severity was driven mainly by an increased frequency of large or oedematous lesions in patients with HIV and Buruli ulcer. The effect of HIV on Buruli ulcer severity was driven mainly by an increased frequency of large or oedematous lesions in patients with HIV and Buruli ulcer (OR for large lesions in patients with Buruli ulcer with and without HIV 2·32, 95% CI 1·16–4·76, p=0·0174; OR for oedematous lesions 1·93, 0·94–3·86, p=0·0740; OR for bone lesions 0·96, 0·15–3·24, p=0·95; and OR for multifocal lesions 1·55, 0·25–5·29, p=0·58). Adjustment for age and sex did not modify the results.Although HIV-Buruli ulcer co-infection is a rare clinical event, our data support O'Brien and colleagues' hypothesis of a significant effect of HIV infection on Buruli ulcer severity. We also report evidence suggestive of a higher incidence of HIV infection in patients with Buruli ulcer compared with the general population, although the absence of local controls in our design calls for further confirmation. This evidence offers insights of profound significance with regards to Buruli ulcer physiopathology, and opens new avenues for the development of novel preventive and therapeutic strategies.We declare no competing interests. We thank staff at the Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB), Pobè, Bénin; staff of the Laboratoire de Bactériologie, CHU, Angers, France; and staff from the Institut National de la Santé et de la Recherche Médicale (INSERM) U1163 for helpful discussions; and acknowledge support from la Fondation Raoul Follereau. VBQ acknowledges support from the Fondation Imagine. ML and AA acknowledge support from the Agence Nationale de la Recherche (ANR). AA acknowledges support from the Fondation pour la Recherche Médicale (FRM, grant number DMI20091117308 ). AA and ML acknowledge support from the INSERM. In a recent Personal View on Buruli ulcer, Daniel O'Brien and colleagues1O'Brien DP Comte E Serafini M et al.The urgent need for clinical, diagnostic, and operational research for management of Buruli ulcer in Africa.Lancet Infect Dis. 2014; 14: 435-440Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar highlighted the urgent need for research on HIV–Buruli ulcer co-infection. Whether HIV infection is a risk factor for Buruli ulcer is unknown, because the few studies published show contrasting results. In Ghana, HIV was not associated with Buruli ulcer (six of 116 Buruli ulcer cases with HIV versus one of 116 controls, p=0·89), whereas a significant association was found in Benin (11 of 426 versus two of 613, p=0·003).2Raghunathan PL Whitney EAS Asamoa K et al.Risk factors for Buruli ulcer disease (Mycobacterium ulcerans infection): results from a case-control study in Ghana.Clin Infect Dis. 2005; 40: 1445-1453Crossref PubMed Scopus (111) Google Scholar, 3Johnson RC Nackers F Glynn JR et al.Association of HIV infection and Mycobacterium ulcerans disease in Benin.AIDS. 2008; 22: 901-903Crossref PubMed Scopus (44) Google Scholar This discrepancy could result from HIV being differentially associated with subgroups of Buruli ulcer, such as severe Buruli ulcer. Sporadic case reports described patients with HIV with both severe and non-severe evolution, for example.4Toll A Gallardo F Ferran M et al.Aggressive multifocal Buruli ulcer with associated osteomyelitis in an HIV-positive patient.Clin Exp Dermatol. 2005; 30: 649-651Crossref PubMed Scopus (32) Google Scholar, 5Delaporte E Alfandari S Piette F Mycobacterium ulcerans associated with infection due to the human immunodeficiency virus.Clin Infect Dis. 1994; 18: 839Crossref PubMed Scopus (10) Google Scholar However, as emphasised by O'Brien and colleagues, no published epidemiological data exist on the association between HIV and severity of Buruli ulcer. We did a large cohort study in a highly endemic region of Benin, and addressed the question of the effect of HIV on the severity of Buruli ulcer. Clinical and laboratory data were prospectively obtained from all consecutive patients with Buruli ulcer seen between 2005 and 2011 at the Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) in Pobe, Benin. Clinical Buruli ulcer cases were confirmed by PCR and tested for HIV infection with two serological tests. As suggested in our study,6Vincent QB Ardant M-F Adeye A et al.Clinical epidemiology of laboratory-confirmed Buruli ulcer in Africa: a cohort study.Lancet Glob Health. 2014; 2: e422-e430Summary Full Text Full Text PDF Scopus (73) Google Scholar severe Buruli ulcer was defined as presenting with oedematous, bone, large (≥15 cm in diameter), or multifocal lesions. The effect of HIV on Buruli ulcer severity was tested by logistic regression, as implemented in the glm function of the R software. Access to the data registry was approved by the institutional review board of the CDTUB and the national Buruli ulcer control authorities. 1511 Buruli ulcer cases were included, of whom 78% (n=1177) were PCR-confirmed. HIV testing was positive in 34 of all 1511 patients (2·3%) and in 25 of 500 patients (5·0%) aged 15–49 years. This proportion is significantly higher than is the 1·1% estimate reported for this age group in Benin in 2012 (p<0·0001).7UNAIDSCountry Epidemiology: Benin.http://www.unaids.org/en/regionscountries/countries/benin/Date: 2012Google Scholar More than 70% (n=24) of patients with HIV developed severe Buruli ulcer, compared with 50% (n=723) of HIV-negative patients (odds ratio [OR] 2·77, 95% CI 1·32–6·33; p=0·006). A focus on PCR-confirmed Buruli ulcer cases further validated this finding (OR 2·59, 1·06–7·27; p=0·037). The effect of HIV on Buruli ulcer severity was driven mainly by an increased frequency of large or oedematous lesions in patients with HIV and Buruli ulcer. The effect of HIV on Buruli ulcer severity was driven mainly by an increased frequency of large or oedematous lesions in patients with HIV and Buruli ulcer (OR for large lesions in patients with Buruli ulcer with and without HIV 2·32, 95% CI 1·16–4·76, p=0·0174; OR for oedematous lesions 1·93, 0·94–3·86, p=0·0740; OR for bone lesions 0·96, 0·15–3·24, p=0·95; and OR for multifocal lesions 1·55, 0·25–5·29, p=0·58). Adjustment for age and sex did not modify the results. Although HIV-Buruli ulcer co-infection is a rare clinical event, our data support O'Brien and colleagues' hypothesis of a significant effect of HIV infection on Buruli ulcer severity. We also report evidence suggestive of a higher incidence of HIV infection in patients with Buruli ulcer compared with the general population, although the absence of local controls in our design calls for further confirmation. This evidence offers insights of profound significance with regards to Buruli ulcer physiopathology, and opens new avenues for the development of novel preventive and therapeutic strategies. We declare no competing interests. We thank staff at the Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB), Pobè, Bénin; staff of the Laboratoire de Bactériologie, CHU, Angers, France; and staff from the Institut National de la Santé et de la Recherche Médicale (INSERM) U1163 for helpful discussions; and acknowledge support from la Fondation Raoul Follereau. VBQ acknowledges support from the Fondation Imagine. ML and AA acknowledge support from the Agence Nationale de la Recherche (ANR). AA acknowledges support from the Fondation pour la Recherche Médicale (FRM, grant number DMI20091117308 ). AA and ML acknowledge support from the INSERM. Supplementary Material Download .pdf (.47 MB) Help with pdf files Supplementary appendix Download .pdf (.47 MB) Help with pdf files Supplementary appendix The urgent need for clinical, diagnostic, and operational research for management of Buruli ulcer in AfricaDespite great advances in the diagnosis and treatment of Buruli ulcer, it is one of the least studied major neglected tropical diseases. In Africa, major constraints in the management of Buruli ulcer relate to diagnosis and treatment, and accessibility, feasibility, and delivery of services. In this Personal View, we outline key areas for clinical, diagnostic, and operational research on this disease in Africa and propose a research agenda that aims to advance the management of Buruli ulcer in Africa. Full-Text PDF
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