This prospective single-centre study, with extended follow-up in the cART era, demonstrated that one-third of HIV-NHL occurred in patients with complete suppression of HIV replication. Most of these lymphomas occurred early after HIV-RNA became undetectable (65% within 18 months). However, some patients still develop NHL after long-term HIV suppression. We have previously reported a short series of 27 patients from the same cohort in the early cART era and did not found any difference in the characteristics of patients with controlled HIV infection as compared with patients with untreated or treated but uncontrolled HIV infection. Herein, we extended the analysis to 128 patients, with a centralized review of all available pathological specimens by a single pathologist, associated with the detection of EBV and HHV-8 in the tumour cells. We assumed that NHL that occurred in patients with long-term suppression of HIV replication had characteristics closer to that of non-HIV-associated NHL, with less severe characteristics, decreased EBV/HHV-8 association, and improved outcome. This study did not support this hypothesis. As expected, duration of HIV infection and duration of cART were longer in patients with longer HIV suppression. However, patients with long duration of HIV suppression had similar lymphoma characteristics than that observed in patients with recent HIV suppression or persistent HIV replication.
In these patients successfully treated with cART, immune reconstitution was effective, with a higher CD4 cell count (297 cells/μl) at diagnosis of NHL than that observed in uncontrolled patients (155 cells/μl) from the same cohort and than that reported in the literature.[4,11,12,17] The difference between the CD4 cell count at diagnosis of NHL and the CD4 cell count nadir, indirectly reflecting immune reconstitution, was above 100 cells/μl in the majority of patients (63.5%) (data not shown). Increase in the CD4 cell count level was associated with duration of HIV suppression, and NHL occurred at a significantly higher CD4 cell count after longer duration of HIV suppression (359 cells/μl) than early after HIV suppression (270 cells/μl). The distribution of CD4 cell count by strata showed that only one patient developed NHL while having a CD4 cell count below 100 cells/μl after the first year of HIV suppression. This finding is consistent with previously published data, suggesting that the decreased incidence in NHL observed in cART era was explained by the decrease in the proportion of patients with low CD4 cell counts. Several studies[9,33] have shown an association between the CD4 cell count nadir and the development of NHL; indeed, in this study, almost all patients had a CD4 cell count nadir below 200 cells/μl (median 112 cells/μl). This could argue for an earlier introduction of cART, before the nadir CD4 cell count drops below a critical level.
Characteristics of NHL arising in patients with undetectable HIV-RNA remain different from that of lymphoma observed in the general population. Most cases are aggressive, with advanced systemic disease, a performance status above 2 in almost half of the patients, presence of 'B' symptoms, and increased LDH level in more than two-third of patients. Involvement of extranodal sites was frequent, and a poor IPI was present in more than half of the patients. Interestingly, in patients with long-term HIV suppression, all these adverse prognostic factors were similar to that observed in patients with recently controlled or uncontrolled HIV infection. The spectrum of lymphoma subtypes did not differ with the duration of HIV suppression and was similar to that observed in patients with incomplete suppression of HIV replication from the same cohort or from the literature.[14,18,25] Thirty-six percent of cases were non-IBL-DLBCL and 24% were Burkitt lymphoma. The proportion of Burkitt lymphoma changed negligibly with duration of HIV suppression, despite an increased CD4 cell count at diagnosis from 281 to 357 cells/μl, and was not different from that observed in patients with uncontrolled HIV infection, whereas one could speculate that the proportion of Burkitt lymphoma, which occurs at higher level of CD4 cell count, would be increased in this population.[13,17] Several recent studies[4,6,17] reported stable or even decreased incidence of Burkitt lymphoma in cART era. In contrast, the immunoblastic variant of DLBCL, known to be associated with profound immunodeficiency, has nearly disappeared, representing only 7% of all NHL in this cohort, with only one case after 18 months of HIV suppression. Outside these main subtypes, unusual lymphoproliferative disorders were also present, particularly PEL, which represent 15% of NHL in the study population. Recently described solid PEL-like NHL accounted for five out of the 19 PELs.[31,32] PEL subtype is probably overrepresented in this series, whereas the department is a reference centre for HHV-8-associated lymphoproliferative diseases. However, interestingly, 19 out of the 33 PELs reported in cART era from the HIV lymphoproliferative cohort occurred in patients with HIV suppression.
The results of the present study confirm the possible occurrence of NHL in patients with suppressed HIV infection treated with cART. Pathogenesis of HIV-NHL is not univocal, and several factors are thought to play a role, including not only immune deficiency but also genetic abnormalities, cytokine deregulation, and chronic B-cell stimulation by HIV and/or other viruses in the absence of effective T-cell control.[13,34–36]
Most of the malignancies observed in the late cART era are related to infective agents, including hepatitis viruses, human papilloma virus, EBV, and HHV-8, similarly to that observed after solid organ transplantation.[37,38] Several viruses have been associated with lymphomagenesis, including EBV and HHV-8.[13,18,20,21,23,24] In this study, more than 80% of the tumours were tested for the presence of EBV and HHV-8. More than half of the HIV-NHL arising in this population of patients with undetectable HIV-RNA was still virus associated, without any decline with the duration of HIV suppression. Patients with virus-associated tumour have more frequently a history of Kaposi sarcoma and presented subtypes of lymphoma known to be HHV-8/EBV associated (PEL, LBCL arising in HHV-8 MCD, and IBL-DLCBCL). However, when compared with patients with nonvirus-associated NHL, these patients had no specific characteristics, even though the nadir CD4+ cell count appeared to be slightly lower. In this study, 37% of tumours were associated with EBV, in accordance with literature, in which EBV has been reported to be detected in 25–60% of all HIV-related lymphoma.[13,18,23] This rate did not decrease with longer duration of HIV suppression, and EBV remains present in 43% of NHL arising after long duration of HIV suppression. HHV-8 has been detected in rare lymphoproliferative diseases: PEL, MCD, and LBCL arising in HHV-8 MCD.[20,21,24] In the study population, 23% of NHL was associated with HHV-8, a higher rate than described in the literature, probably reflecting the referral bias mentioned above. However, no significant decrease in HHV-8-associated tumours was observed with the duration of HIV suppression. One limitation of this study is the absence of detection of tumour virus association for the entire NHL cohort of 388 patients, as it was limited to the 128 studied patients, so we could not compare the rate of virus association between patients with and without HIV suppression.
Another limitation of the study is that we could not calculate the incidence rate of NHL in the population of HIV-infected patients with undetectable HIV-RNA. Patients were referred to our department, and we could not evaluate the total population at risk of developing lymphoma. However, in most epidemiological studies, plasma HIV-RNA is not available at the time of NHL diagnosis, and to our knowledge, this incidence has never been evaluated.
HIV-infected patients may still develop NHL after suppression of HIV replication. However, most of these patients had a recent control of HIV infection, and NHL occurred mainly within the 18 months following the suppression of HIV replication. In patients developing NHL after prolonged suppression of HIV replication, no significant impact on the characteristics of NHL was observed, despite a higher CD4 cell count. These NHL remain aggressive, associated with poor prognosis, and the prevalence of virus-associated tumour did not decrease with duration of HIV suppression, despite immune restoration.
Support for this work was provided by the Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS).
The authors thank Sylvie Legac, Leopold Tegna, and Jean-Luc Lagneau for providing clinical information on patients, and the pathologists for providing pathological specimens for centralized review.
L.Gér. did the conception and design of the study, data collection, data analysis, drafting, and revising of the manuscript. V.M. did the conception and design of the study, pathological analysis, and critical revising of the manuscript. L.Gal. and C.F. did the data collection and care for the patients. N.L. did the data monitoring and data management. C.P. and L.F. did the enrolment of patients and critical revising of the manuscript. F.A. did the virological analysis. E.O. did the conception and design of the study, drafting and revising of the manuscript, and supervising of the overall study. All authors approved the final version of the manuscript.
AIDS. 2009;23(17):2301-2308. © 2009
Cite this: Characteristics of non-Hodgkin Lymphoma Arising in HIV-infected Patients with Suppressed HIV Replication - Medscape - Nov 01, 2009.