Severe aplastic anemia (SAA) is a rare disease, which has been exceptionally reported in the setting of HIV. Here we describe the outcomes of eight patients who were diagnosed with SAA in the context of HIV infection.
A decrease in the incidence of several AIDS-defining diseases, and so, longer-life expectancy of HIV-infected patients, after the introduction of highly active anti-retroviral therapy (HAART) in 1995,1 runs parallel with an increase in other non-commonly AIDS-related pathologies, such as autoimmune disorders.2 Idiopathic SAA is considered to be a rare immune-mediated bone marrow failure disorder. Although hematological abnormalities are frequent in patients infected with HIV3 and may have a complex origin, there have been only anecdotal case reports of SAA in the setting of HIV infection.4, 5 Advances in hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have improved survival in SAA and at least 80% of patients are alive at 5 years post diagnosis.6 Nevertheless, the management of SAA in the setting of HIV infection remains a challenge.
We retrospectively assessed the characteristics of eight HIV-infected patients who presented wıth SAA and describe outcomes after both transplanted and non-transplanted strategies. All HIV-infected patients who received a diagnosis of SAA according to Camitta criteria7 between January 1988 and December 2011 were identified in the databases of the Severe Aplastic Anemia Working Party (SAAWP) of the European Society of Bone Marrow Transplantation, as well as in the one of the Center for International Blood and Marrow Transplant Research (CIBMTR). All cases of secondary bone marrow failure disorders, because of uncontrolled infections, drug-related toxicity or neoplastic bone marrow infiltration were excluded. Both classification and staging of HIV infection, as well as disease activity were made for all patients accordingly to Atlanta revised criteria.8 All types of conditioning regimens, GVHD prophylaxis, stem cell sources and donor origin were considered in the transplant group, whereas all therapeutic approaches were recorded in the non-transplanted group (IST or not). A specific questionnaire was sent to all participating centers to collect data about HIV infection and specific treatment before and after the diagnosis of SAA.
Thus, we identified eight patients worldwide, who developed truly SAA after being diagnosed with HIV infection. Six patients were found in the SAAWP database and two in the CIBMTR registry. Four patients underwent HSCT and four received non-transplant treatments. Patient characteristics, data about SAA, HIV infection and treatment approaches are reported in Table 1 and Table 2.
The non-transplanted group had worse outcome: two patients showed no response (one to androgens and one to Cyclosporine A (CSA) and corticosteroids), one partially responded to anti-thymocyte globuline (ATG) associated with CSA. All these three patients died because of infections not HIV related (Table 1). Only one patient in the non-transplanted group had an early and durable remission on treatment with eltrombopag for a 23-month period of follow-up (this latter report has been recently published by Bart-Smith et al.).9 Conversely, three of four patients in the HSCT group were long-term survivors with a median follow-up of 59 months (54–101 months). All of them received a reduced intensity conditioning (RIC) regimen, based on cyclophosphamide (200 mg/kg total dose) and thymoglobulin (12.5 mg/kg), whereas the patient who died was the only one to receive a myeloablative conditioning (MAC) regimen, consisting of busulphan (12 mg /kg) and cyclophosphamide (150 mg/kg). This latter experienced veno-occlusive disease and died of multiorgan failure at 39 months post transplant. Doses of chemotherapy are not shown in the Table 2. It should be noted that all the patients had full donor chimerism at 3 months post transplant.
In our data, main causes of mortality were neutropenic infections that do not seem properly HIV related. Indeed, all dead patients were not in CR for SAA at 6 months after beginning therapy. We can speculate that in these kinds of patients, when HIV had been effectively managed with HAART, hematological response after therapy was the major determinant of survival. Although no immunological data were available in our cohort, a pathophysiological explanation for treatment failure in the non-transplanted group could be the particular immunological setting of HIV patients that continues to be impaired even after introduction of HAART. HIV infection is associated with a progressive depletion of CD4+ T lymphocytes and defective HIV-specific T-cell responses, resulting in established chronic immune activation that has a central role in the progression to AIDS.10 Regarding the onset of AA in the context of HIV, it can be speculated that given the counteracting role of T-regs in the onset of autoimmune phenomena,11 HAART treatment, which is reported to reduce the frequency of these cells,12 might have potentially contributed to the occurrence of this disease. In patients successfully treated with anti-retroviral therapy, immune activation dramatically decreases with viral suppression but, even if the absolute CD4+ T-cell count is fully restored, T-cell immune reconstitution may still be impaired compared with non-HIV patients.13 This may explain the infectious death of the two patients treated with immunosuppression that in turn might have further weakened the immune defenses. In contrast, immune reconstitution may be more efficient after HSCT, as the infused stem cells are naïve from HIV infection and more likely to improve immune reconstitution in this setting. Furthermore, a HIV-1-specific CD8+ donor T-cell response has been demonstrated early after allogeneic HSCT in HIV-infected patients under HAART,14 despite the absence of plasma HIV-1 RNA, suggesting that naïve T cells can be primed by HIV antigens expressed in lymphatic tissue and contribute to a competent immunological reconstitution.
This may be an explanation for the better outcome of transplanted patients for whom, furthermore, RIC regimens are also likely to be better tolerated than MAC. In general, allotransplant experiences in the setting of HIV for hematological disorders are limited to some small reports15 and only one single successful experience is described in the specific context of SAA.5 Drug interactions with anti-retroviral therapy, comorbidities and co-infections in HIV-infected patients are major issues that make more difficult these kinds of transplants.
Our study is limited by its retrospective nature and by the relatively small number of patients, but SAA is a rare disorder. The heterogeneous characteristics of treatments in the non-transplanted group preclude analysis of the underlying mechanisms explaining the worse outcome of this group. The observation that no patients received the standard fırst-line treatment for the SAA (combination of horse ATG and CSA) likely reflected the reluctance to use full IST in the setting of HIV with the anticipated higher risk of severe infection. Hence, new alternative therapeutic approaches, such as eltrombopag, warrant further evaluation for SAA patients who are not eligible for HSCT. However, three out of four transplanted patients survived long term, whereas the same proportion of non-transplanted patients failed treatment and died. Regarding HSCT, positive outcomes are obtained in patients transplanted after a RIC regimen under combined anti-retroviral therapy (see table 2), with a potential risk of drug interactions.
The descriptive character of this study and the small number of patients impedes comparative statements between the two groups. However, HSCT as an approach that should not be contraindicated in HIV-infected patients associated with SAA.
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We are particularly thankful to all centers of the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT), and of the Center for International Blood and Marrow Transplant Research (CIBMTR) who kindly agreed to participate in this study. SP and RPL have full access to all of the data and take responsibility for their integrity.
Conception and design: SP, RPL and JM. Data collection and assembly: SP, CKB, MAS, HM, JM, ME. Data analysis and interpretation: SP, RPL. Manuscript: SP, RPL. Final approval of manuscript: SP, LG, HM, MAS, CKB, ME, DB, AK, CD, RPL and JM.
The authors declare no conflict of interest.
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Pagliuca, S., Gérard, L., Kulasekararaj, A. et al. Characteristics and outcomes of aplastic anemia in HIV patients: a brief report from the severe aplastic anemia working party of the European Society of Blood and Bone Marrow Transplantation. Bone Marrow Transplant 51, 313–315 (2016). https://doi.org/10.1038/bmt.2015.252