Kaposi sarcoma in antiretroviral therapy-treated people with HIV: a wake-up call for research on human herpesvirus-8

Introduction Kaposi sarcoma remains the strongest stigma of the AIDS epidemic and a harbinger of severe immunodeficiency. Introduction of antiretroviral therapy (ART) allowed the control of HIV replication and dramatically decreased Kaposi sarcoma prevalence in people with HIV (PWH). However, recent data suggest that Kaposi sarcoma remains a concern for ART-treated PWH, despite recovered CD4+ T-cell count and undetectable HIV viremia. The risk of Kaposi sarcoma in this setting has thus been estimated as 35–60-fold higher than in the general population [1]. In a French study conducted between 2010 and 2015, Kaposi sarcoma in virologically suppressed PWH represented 11.4% of epidemic Kaposi sarcoma cases [2]. By constituting both a puzzling clinical observation and a recall for patients of the darkest days of the AIDS epidemic, Kaposi sarcoma arising or persisting in the context of successful ART raises questions about the physiopathology of this disease. In particular, the contribution of viral replication and specific immune response against human herpesvirus-8 (HHV-8), the causing agent of Kaposi sarcoma, remains unknown. Reported cases in the literature Since the first report of Kaposi sarcoma in ART-treated PWH in 2003, increasing cases of Kaposi sarcoma in virally suppressed ART-treated PWH have been reported in the literature (patient characteristics reviewed in Table 1). The three most recent reports arose from France. Two studies identified 21 and 54 cases of Kaposi sarcoma, respectively, in PWH with undetectable HIV viral load on ART for at least 6 months [3,4] and another study reported 12 cases of Kaposi sarcoma in PWH with undetectable viral load for at least 12 months [5]. Overall, described patients were mostly middle-aged men (90% male, median age 49 years), with a median HIV infection duration of 9 years before Kaposi sarcoma development (Table 1) and limited cutaneous Kaposi sarcoma lesions. None of these patients had a previous history of opportunistic infections or multicentric Castleman disease or primary effusion lymphoma, two conditions associated with HHV-8. Notably, two of the French studies as well as our ongoing prospective cohort study in Montréal identified elevation of CD8+ T-cell count and lower CD4+/CD8+ T-cell ratio as factors associated with Kaposi sarcoma development [3–6]. Similarly, Caby et al.[7] recently published a large collaborative study evaluating the impact of CD4+/CD8+ T-cell ratio on Kaposi sarcoma and non-Hodgkin lymphoma in PWH from 27 European cohorts. Among 19 133 PWH with CD4+ T-cell counts above 500 cells/μl, 65 presented with Kaposi sarcoma including 51 with HIV viral control, and a strong inverse association between CD4+/CD8+ T-cell ratio and Kaposi sarcoma development was found. Table 1 - Clinical characteristics of virally suppressed antiretroviral therapy-treated HIV-positive patients at Kaposi sarcoma onset. Study Location Period No. of cases HIV characteristics % of men % of MSM Median age (years) Median HIV duration (years) Median ART duration (years) CD4+ cell count, median CD4+/CD8+ Nasti (2003)a Italy 1996–2003 10 UD VL, on ART for at least 3 months NA NA NA NA NA NA NA Maurer (2007)b USA 2004–2006 9 VL < 300 copies/ml for at least 2 years, CD4+ > 300 cells/μl NA NA 51 (range 47, 74) 18 (range 4, 25) 8 (range <1, 19) 340 (range 90, 455) NA Mani (2009)c USA 1996–2008 20 UD VL, CD4+ > 300 cells/μl 95 80 42 (range 25, 59) 4.25 (range 0, 15) 5 (range 0, 12) 350 (range 10, 973) NA Stebbing (2008)d UK NA 18 UD VL, CD4+ > 300 cells/μl 83 NA 42 (IQR 32, 46) 4.5 (IQR 1.1, 12) NA NA NA Palich (2019)e France 2014–2017 21 VL <50 copies/ml, on ART for at least 6 months 81 NA 54 (IQR 35, 61) 14 (IQR 6, 22) NA 449 (IQR 241, 625) 0.58 (IQR 0.33, 0.45) Poizot (2020)f France 2010–2015 24 VL < 50 copies/ml, on ART for at least 6 months 87.5 58 48 (IQR 39, 54.7) 7.4 (IQR 2.8, 20.7) 4.1 (IQR 1.0, 10.3) 467 (IQR 255, 819) 0.5 (IQR 0.2, 0.9) Séverin (2020)g France 2010–2017 12 VL < 50 copies/ml for at least 12 months, on ART 100 NA 54 (range 38, 60) 8.2 (range 0.4, 9,4) NA 723 (range 520, 881) 0.68 (0.52, 0.94) ART, antiretroviral therapy; IQR, interquartile range; NA, not applicable; UD, undetectable; VL, viral load.aNasti G, Martellotta F, Berretta M, Mena M, Fasan M, Di Perri G, et al. Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related Kaposi sarcoma. Cancer (2003) 98:2440–2446.bMaurer T, Ponte M, Leslie K. HIV-Associated Kaposi's sarcoma with a high CD4 count and a low viral load. New England Journal of Medicine (2007) 357:1352–1353.cMani D, Neil N, Israel R, Aboulafia DM. A retrospective analysis of AIDS-associated Kaposi's sarcoma in patients with undetectable HIV viral loads and CD4 counts greater than 300 cells/μl. Journal of the International Association of Physicians in AIDS Care (2009) 8:279–285.dStebbing J, Powles T, Bower M. AIDS-associated Kaposi's sarcoma associated with a low viral load and a high CD4 cell count. AIDS (2008) 22:551–552.ePalich R, Veyri M, Valantin M-A, Marcelin A-G, Guihot A, Pourcher V, et al. Recurrence and occurrence of Kaposi's sarcoma in patients living with human immunodeficiency virus (HIV) and on antiretroviral therapy, despite suppressed HIV viremia. Clin Infect Dis (2019).fPoizot-Martin I, Obry-Roguet V, Duvivier C, Lions C, Huleux T, Jacomet C, et al. Kaposi sarcoma among people living with HIV in the French DAT’AIDS cohort between 2010 and 2015. J Eur Acad Dermatol Venereol (2020) 34:1065–1073.gSéverin D, Faiza B, Nadia M, Aurelie DT, Brigitte T, Bernard G, Alain M. Kaposi sarcoma in people living with HIV: a comparative study of classic and HIV-viremic and aviremic AIDS Kaposi Sarcoma. AIDS (2020). Physiopathology of Kaposi sarcoma in antiretroviral therapy-treated people living with HIV: influence of immunosenescence? Increasing evidence suggests that chronic viral infections with HIV, cytomegalovirus (CMV), or hepatitis B and C viruses induce senescence of the immune system through persistent immune activation. Senescent T cells lose their inherent properties, ranging from proliferative capacities to IFN-γ production, and exhibit shorter telomere length due to telomerase loss [8,9]. Markers of immunosenescence include a decrease of the CD4+/CD8+ T-cell ratio, an upregulated expression of immune checkpoint molecules as programmed cell death 1 (PD-1) and an increased frequency of immunosenescent CD57+CD28− T cells [10,11]. In ART-treated PWH, low CD4+/CD8+ T-cell ratio has become a surrogate marker of immune dysregulation and T-cell activation, and has been associated with age-related diseases, non-AIDS comorbidities and even mortality [12,13]. Normalization of CD4+/CD8+ T-cell ratio is seldom observed after ART introduction, even with optimal CD4+ T-cell count recovery and early ART initiation. Chronic CMV or Epstein–Barr virus infections, that frequently coexist with HIV, have been associated with CD8 T cells expansion and might contribute to this dysregulation [14,15]. Whether a similar impact of HHV-8 coinfection on CD8+ T cells expansion in ART-treated people exists is, however, unknown. Independently of the cause, increased CD8+ T-cell counts and overproduction of CD8+ T cells inflammatory cytokines have been associated with Kaposi sarcoma development and progression, and with a lack of anti-HHV-8 T-cell response [16,17]. Patients with Kaposi sarcoma were also found to exhibit decreased HHV-8-specific T-cell responses compared with asymptomatic HHV-8 carriers, independently of age or CD4+ T-cell counts [16,18]. Moreover, in skin biopsies of patients with epidemic or endemic Kaposi sarcoma, CD8+ T cells and macrophages did not colocalize with HHV-8-infected cells indicating that cytotoxic cells are kept at bay from infected cells [19]. Altogether, the exact role of T-cell response in controlling HHV-8-related diseases constitutes an important knowledge gap, probably owing to the frequent concurrent immunosuppression of the host. Other factors involved in this reemergence of Kaposi sarcoma have been proposed. Long-term viral synergy between HHV-8 and HIV should be further explored, as HIV-1 regulatory Tat and Nef proteins have been reported to enhance HHV-8 infectivity and trigger replication after latency establishment [20]. In addition, the impact of new genetic HHV-8 variants with distinct oncogenic potential, the influence of protease inhibitors regiments or microbiota alterations are also suspected [21–23]. Clinical management: immunomodulation beyond CD4+ T-cell count restoration Regarding clinical management, controlling HIV replication and restoring CD4+ T-cell counts through ART initiation, which has long been considered as the primary therapeutic option for Kaposi sarcoma in PWH, is obviously irrelevant in long-term ART-treated PWH. Liposomal anthracyclines or paclitaxel chemotherapies constitute the first line of treatment in these patients, with inherent toxicities [24,25]. Immunomodulating capacities of HHV-8 and the suspected role of immunosenescence would suggest a potential role for immunotherapies and immunomodulating drugs. In this sense, thalidomide-derivate pomalidomide has shown substantial efficacy and is approved for Kaposi sarcoma since 2020 by the United States Food and Drug Administration, including in PWH [26]. Blockade of PD-1 and its ligand programmed cell death protein 1 (PD-1) also constitutes a promising option, given its success for other cancers and also considering the known upregulation of PD-1 expression following HHV-8 infection in vitro[27,28]. Another potential benefit of PD-1/PD-L1 blockade therapies in the context of HIV-related Kaposi sarcoma is their potential ability to revert latent HIV infection and decrease HIV reservoir size [29]. A small clinical trial reported remission with these immunotherapies in six out of nine patients with endemic Kaposi sarcoma [30]. Clinical trials are underway and will shed light on the efficacy of novel therapies in this population. Concluding remarks Altogether, increasing reports bring to light the risk of Kaposi sarcoma development in well treated and virologically controlled PWH. Occurrence of Kaposi sarcoma in this population is no longer anecdotic and becomes a new challenge, given the large number of aging ART-treated patients worldwide. PWH with successful virological suppression still harbor immune dysregulation and experience aging-related comorbidities, opening up unchartered new conditions where HHV-8-related comorbidities may develop. Could this new wave of Kaposi sarcoma represent its fifth form, where persons may have developed Kaposi sarcoma even in absence of HIV, likely at an older age? Inflammaging may lead to inadequate control of HHV-8 and early emergence of Kaposi sarcoma in this setting, and possibly also to other HHV-8-related diseases. Immunomodulating therapies that have revolutionized cancer treatments should offer an alternative to chemotherapy in these cases. Technological improvements in viral detection could also be used to fill the gap of HHV-8-specific assays, still lacking validation in clinical practice. Such re-emergence of Kaposi sarcoma justifies the implementation of large international cohorts of PWH, with or without Kaposi sarcoma, in developed and developing countries, with detailed information on patient characteristics including sexual practice, along with epidemiologic, pathologic, immunologic and virologic assessment. Comparison with non-HIV case of Kaposi sarcoma will also be needed to identify common or divergent factors associated with tumor development. After 40 years into the HIV epidemic, this reoccurrence of Kaposi sarcoma that came as a harbinger of AIDS emerges as an unaddressed medical concern paired with social stigma justifying urgent multidisciplinary research. We strongly suspect that Kaposi sarcoma in ART-treated PWH constitutes a novel form of the disease that is emerging and needs further investigation. Acknowledgements We thank Mario Legault, Angie Massicotte, Cezar Iovi, Josée Girouard, and Luciana Ruppenthal for coordination and assistance. We are grateful to all participants. Financial support. This study was financed by the Fonds de la Recherche Québec-Santé (FRQ-S): Réseau SIDA/Maladies infectieuses and Thérapie cellulaire; the Canadian Institutes of Health Research (CIHR; grant numbers MOP 103230 and PTJ 166049); the Vaccines and Immunotherapies Core of the CIHR Canadian HIV Trials Network (grant number CTN 257); and the CIHR-funded Canadian HIV Cure Enterprise (team grant number HB2-164064). L.R. is a postdoctoral fellow supported by the ‘Fonds de perfectionnement’ of the Geneva University Hospitals, Switzerland and by the CIHR-CTN. S. I. is a postdoctoral fellow supported by the FRQ-S and CIHR-CTN. J. P. R. is the holder of the Louis Lowenstein Chair in Hematology and Oncology, McGill University. Conflicts of interest There are no conflicts of interest.

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