Fulminant mpox as an AIDS-defining condition: useful or stigmatising?

The 2022 mpox outbreak was declared a public health emergency of international concern in July, 2022, by WHO within 2 months of the initial reports.1WHOWHO Director-General's statement at the press conference following IHR Emergency Committee regarding the multi-country outbreak of monkeypox.https://www.who.int/director-general/speeches/detail/who-director-general-s-statement-on-the-press-conference-following-IHR-emergency-committee-regarding-the-multi--country-outbreak-of-monkeypox--23-july-2022Date: July 23, 2022Date accessed: January 28, 2023Google Scholar With over 85 000 confirmed cases and 86 deaths, the outbreak has mainly affected men, many of whom identify as men who have sex with men (MSM).2WHO2022 monkeypox outbreak: global trends.https://worldhealthorg.shinyapps.io/mpx_global/Date accessed: January 28, 2023Google Scholar, 3Núñez I García-Grimshaw M Ceballos-Liceaga SE et al.Epidemiological and clinical characteristics of patients with human monkeypox infection in Mexico: a nationwide observational study.Lancet Reg Health Am. 2023; 17100392PubMed Google Scholar, 4Thornhill JP Barkati S Walmsley S et al.Monkeypox virus infection in humans across 16 countries—April–June 2022.N Engl J Med. 2022; 387: 679-691Crossref PubMed Scopus (685) Google Scholar, 5Torres Silva MS Coutinho C Silva Torres S et al.Ambulatory and hospitalized patients with suspected and confirmed mpox: an observational cohort study from Brazil.Lancet Reg Health Am. 2023; 17100406Google Scholar, 6Philpott D Hughes CM Alroy KA et al.Epidemiologic and clinical characteristics of monkeypox cases—United States, May 17–July 22, 2022.MMWR Morb Mortal Wkly Rep. 2022; 71: 1018-1022Crossref PubMed Scopus (0) Google Scholar In the current outbreak, a high proportion of people with mpox are people living with HIV.3Núñez I García-Grimshaw M Ceballos-Liceaga SE et al.Epidemiological and clinical characteristics of patients with human monkeypox infection in Mexico: a nationwide observational study.Lancet Reg Health Am. 2023; 17100392PubMed Google Scholar, 4Thornhill JP Barkati S Walmsley S et al.Monkeypox virus infection in humans across 16 countries—April–June 2022.N Engl J Med. 2022; 387: 679-691Crossref PubMed Scopus (685) Google Scholar, 5Torres Silva MS Coutinho C Silva Torres S et al.Ambulatory and hospitalized patients with suspected and confirmed mpox: an observational cohort study from Brazil.Lancet Reg Health Am. 2023; 17100406Google Scholar, 6Philpott D Hughes CM Alroy KA et al.Epidemiologic and clinical characteristics of monkeypox cases—United States, May 17–July 22, 2022.MMWR Morb Mortal Wkly Rep. 2022; 71: 1018-1022Crossref PubMed Scopus (0) Google Scholar These findings have raised the concern that advanced HIV could predispose to more severe mpox.3Núñez I García-Grimshaw M Ceballos-Liceaga SE et al.Epidemiological and clinical characteristics of patients with human monkeypox infection in Mexico: a nationwide observational study.Lancet Reg Health Am. 2023; 17100392PubMed Google Scholar, 4Thornhill JP Barkati S Walmsley S et al.Monkeypox virus infection in humans across 16 countries—April–June 2022.N Engl J Med. 2022; 387: 679-691Crossref PubMed Scopus (685) Google Scholar, 5Torres Silva MS Coutinho C Silva Torres S et al.Ambulatory and hospitalized patients with suspected and confirmed mpox: an observational cohort study from Brazil.Lancet Reg Health Am. 2023; 17100406Google Scholar, 6Philpott D Hughes CM Alroy KA et al.Epidemiologic and clinical characteristics of monkeypox cases—United States, May 17–July 22, 2022.MMWR Morb Mortal Wkly Rep. 2022; 71: 1018-1022Crossref PubMed Scopus (0) Google Scholar However, although mpox outcomes are similar regardless of HIV status, current evidence indicates that mpox deaths—to the best of our knowledge—have occurred only in people living with HIV.3Núñez I García-Grimshaw M Ceballos-Liceaga SE et al.Epidemiological and clinical characteristics of patients with human monkeypox infection in Mexico: a nationwide observational study.Lancet Reg Health Am. 2023; 17100392PubMed Google Scholar, 7Miller MJ Cash-Goldwasser S Marx GE et al.Severe monkeypox in hospitalized patients—United States, August 10–October 10, 2022.MMWR Morb Mortal Wkly Rep. 2022; 71: 1412-1417Crossref PubMed Scopus (5) Google Scholar In The Lancet, Oriol Mitjà and colleagues8Mitjà O Alemany A Marks M et al.Mpox in people with advanced HIV infection: a global case series.Lancet. 2023; (published online Feb 21.)https://doi.org/10.1016/S0140-6736(23)00273-8Summary Full Text Full Text PDF PubMed Google Scholar provide a comprehensive and timely description of mpox among people with advanced HIV, defined as those with a CD4 cell count of less than 350 cells per mm3. In this global case series, the authors evaluated 382 people from 19 countries through the international research networks of the Sexual Health and HIV All East Research (SHARE) Collaborative and the Network of the Skin Neglected Tropical Diseases and Sexually Transmitted Infections Unit of the Hospital Germans Trias i Pujol in Barcelona, Spain. This study included a culturally and ethnically diverse cohort of young (median age 35 [IQR 30–43] years) people living with HIV. Individuals came from three regions and sexually diverse backgrounds, 367 (96%) identified as cisgender male and 277 (73%) came from the Americas, with more than half from Latin America. Altogether, 225 (59%) were Latin-American, 85 (22%) White, 55 (14%) Black, and seven (2%) Asian. Regarding HIV status, nearly 60% of people were already cognisant of their HIV status and already receiving antiretroviral treatment (ART), but in 33 (9%) HIV was detected in connection with mpox diagnosis. Altogether, disseminated and necrotising lesions, extra-cutaneous complications, and intensive care unit admission (henceforth defined as a fulminant mpox) were far more common in people with CD4 cell counts of less than 100 cells per mm3 than among those with CD4 cell counts of more than 100 cells per mm3. The study also provides extensive information on 27 people who died, which comprises almost a third of all the deaths reported worldwide so far. Among those who died, the highest CD4 cell count was 171 cells per mm3 and they were either not receiving ART or not adherent to it. 193 (51%) individuals in this cohort had undetectable HIV viraemia. Not surprisingly, HIV titres were directly proportional to CD4 cell counts and those with CD4 cell counts of more than 300 cells per mm3 were four-times more likely to have undetectable HIV viral load than those with CD4 cell counts of less than 100 cells per mm3 (65% vs 17%); the opposite was true for those with high-titre HIV viraemia defined as log4 or more copies per mL (13% vs 55%). Lesion burden was also inversely proportional to CD4 cell count; for instance, metastatic skin lesions (ie, those distant to the point of primary infection) were six-fold more likely, and anorectal involvement was twice as likely, to be in those with CD4 cell counts of less than 100 cells per mm3 than those with CD4 cell counts of more than 300 cells per mm3. Along the same line, although generally uncommon, concurrent opportunistic infections occurred almost exclusively among people with CD4 cell counts of less than 100 cells per mm3. Finally, pulmonary involvement was more common and CNS involvement was almost exclusively detected among individuals with very low CD4 cell counts. These findings add to the growing evidence indicating that the most severe presentations of mpox could occur in advanced HIV due to decreased total CD4 cell counts, particularly T follicular cells, leading to unsuccessful mpox mucosal recognition, induction of B-cell response, and viral clearance.9Lum FM Torres-Ruesta A Tay MZ et al.Monkeypox: disease epidemiology, host immunity and clinical interventions.Nat Rev Immunol. 2022; 22: 597-613Crossref PubMed Scopus (69) Google Scholar The authors also observed what appeared to be immune reconstitution inflammatory syndrome in 21 (25%) of 85 patients with advanced HIV who initiated ART concomitantly with active mpox infection. Moreover, of those who developed immune reconstitution inflammatory syndrome, 12 (57%) died.8Mitjà O Alemany A Marks M et al.Mpox in people with advanced HIV infection: a global case series.Lancet. 2023; (published online Feb 21.)https://doi.org/10.1016/S0140-6736(23)00273-8Summary Full Text Full Text PDF PubMed Google Scholar This finding raises the question about the timing of ART initiation in people with newly diagnosed advanced HIV and concurrent fulminant mpox infection, and whether delaying ART could be the safer strategy. The study has several strengths, including its global, multiethnic scope. However, since individuals were mostly seen in clinics that specialised in HIV and sexually transmitted diseases, only the most unwell people living with HIV or those with the most severe mpox manifestations might be included in the study, thus making generalisability difficult. The role of mpox vaccination in people living with HIV is still not clear, particularly in people with a depleted CD4 cell count. The small number of individuals who were vaccinated pre-exposure or post-exposure does not allow us to understand the real-world value of vaccines in people living with HIV, particularly those with low CD4 cell counts. This can be seen as a limitation of the study, but also a call to action to evaluate the clinical role of, and the immune response to, mpox vaccines in people living with HIV. Based on their findings, the authors also propose that fulminant mpox could be considered an AIDS-defining condition. AIDS-defining conditions were introduced primarily for public health purposes as a mechanism of monitoring the AIDS pandemic, rather than being bedside determinants of care.10US Centres for Disease Control and Prevention1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults.https://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htmDate accessed: January 28, 2023Google Scholar Currently, ART is recommended for every person living with HIV, such that labelling fulminant mpox as an AIDS-defining condition will not modify this guidance.11US Department of Health and Human ServicesGuidelines for the use of antiretroviral agents in adults and adolescents with HIV.https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arvDate: Sept 21, 2022Date accessed: January 28, 2023Google Scholar Unlike low CD4 cell counts, the presence of mpox does not lead to antimicrobial chemoprophylaxis. Lastly, the suspicion of mpox grants a thorough search for sexually transmitted diseases independently of HIV status or, in the case of people living with HIV, CD4 cell count. Hence, we are uncertain as to what clear advantages placing that label would convey. Mpox serves as a magnifying glass to identify people living with HIV who otherwise would have gone longer without realising their status with vast individual and societal consequences. The concomitant diagnoses of mpox and HIV are a stark reminder that governments, health-care professionals, and advocacy groups can, and should, do better at detecting and treating HIV earlier. Mpox diagnosis has prompted medical personnel to test for HIV and other sexually transmitted diseases.6Philpott D Hughes CM Alroy KA et al.Epidemiologic and clinical characteristics of monkeypox cases—United States, May 17–July 22, 2022.MMWR Morb Mortal Wkly Rep. 2022; 71: 1018-1022Crossref PubMed Scopus (0) Google Scholar Involving the label of AIDS-defining condition will not change this practice adopted by health personnel. Unfortunately, the label of AIDS—from cultural, religious, or even lifestyle perspectives—continues to be stigmatising. Labelling fulminant mpox as an AIDS-defining condition could have the unintended potential of sparking further stigma around both mpox and HIV. This stigma is so central to the global outbreak that monkeypox came to be called mpox, precisely to reduce discrimination regarding race and sexual orientation.12Damaso CR Phasing out monkeypox: mpox is the new name for an old disease.Lancet Reg Health Am. 2023; 17100424PubMed Google Scholar, 13WHOWHO recommends new name for monkeypox disease.https://www.who.int/news/item/28-11-2022-who-recommends-new-name-for-monkeypox-diseaseDate: Nov 28, 2022Date accessed: January 28, 2023Google Scholar Considering mpox in general as an opportunistic infection (a term that applies to any-cause immunosuppression and not only HIV) rather than labelling fulminant mpox as an AIDS-defining condition could have the same positive connotations regarding bedside care (eg, increasing suspicion of other opportunistic infections) and preventing stigma.14US Department of Health and Human ServicesOpportunistic infections.https://www.hiv.gov/hiv-basics/staying-in-hiv-care/other-related-health-issues/opportunistic-infectionsDate: Sept 20, 2022Date accessed: February 6, 2023Google Scholar AIDS-defining conditions were introduced during a different time, and adding that label to mpox in this time is perhaps something that could result in undesired consequences, especially if clinical practice will not change because of it. We should rethink the label of AIDS-defining condition and ask if it is still current and altogether useful. We thank Pablo F Belaunzarán-Zamudio and Juan Sierra-Madero for their insightful feedback. We declare no competing interests. Mpox in people with advanced HIV infection: a global case seriesA severe necrotising form of mpox in the context of advanced immunosuppression appears to behave like an AIDS-defining condition, with a high prevalence of fulminant dermatological and systemic manifestations and death. Full-Text PDF