HIV infection is associated with an increased risk of B-cell non–Hodgkin lymphoma (B-NHL). Those lymphomas are preferentially high-grade B-NHL, namely diffuse large B-cell lymphoma (DLBCL), primary cerebral lymphomas, and Burkitt lymphomas.1 Increased risk of B-NHL is strongly correlated to the severity of the underlying immunodeficiency.2 Introduction of combined antiretroviral therapy (cART) has reduced the incidence of lymphoma among HIV-infected individuals.3 However, due to the decrease of other causes of death, B-NHL has become one of the most frequent causes of death among persons with HIV.4 Hepatitis C virus (HCV) infection is frequent among HIV-infected individuals. It has also become an important cause of morbidity and mortality.
Non–HIV-infected patients with chronic active HCV infection have a 2-fold to 3-fold increased risk of B-NHL compared with HCV-negative population.5 Most common NHL subtypes associated with HCV are small B-cell lymphomas, namely lymphoplasmacytic lymphoma (LPL) and marginal zone lymphomas (MZL), in particular splenic marginal zone lymphoma (SMZL) or mucosal-associated lymphoid tissue (MALT) lymphomas. DLBCL incidence is also increased among HCV-infected patients frequently resulting from transformed small B-cell NHL.6 Remarkably, clearance of HCV infection with antiviral therapy has been shown to lead to regression of the tumor burden in patients with HCV-related MZL,7 supporting a causal relationship between HCV chronic antigenic stimulation and lymphomagenesis.
The clinicopathological characteristics of B-NHL in the setting of such coinfection have not been reported to date. In the present study, we describe the characteristics of B-NHL among HIV/HCV-coinfected patients and point out the remarkable occurrence of MZL and LPL in these patients.
The multicentric prospective French Cohort of HIV-related lymphomas—French National Agency for Research on AIDS and Viral Hepatitis ANRS-CO16 Lymphovir cohort—enrolled 47 HIV-infected patients with B-NHL from 22 centers between October 2007 and August 2009. We studied the 6 adult patients with B-NHL and HIV/HCV coinfection included prospectively in the cohort. HCV infection was defined by the detection of anti-HCV antibodies using enzyme-linked immunosorbent assay and by positive polymerase chain reaction at diagnosis of NHL. Diagnosis of B-NHL was based on World Health Organization criteria.8 Data collection concerned HIV and HCV infections history; clinical, biological, and histological presentation; treatment and evolution of B-NHL and HIV and HCV infections. The 6 HIV/HCV-coinfected patients were compared with the 41 HIV-monoinfected patients. Investigations were performed after approval of the ethics committee and national competent authority, and informed consent was obtained from each patient.
Biological and Immunological Markers, Histology, and Immunohistochemistry
Laboratory evaluation included complete blood count and peripheral blood smear, serum chemistry profile, liver enzymes and lactate dehydrogenase (LDH), serum protein electrophoresis and immunofixation, and rheumatoid factor. None of the patients was tested for cryoglobulinemia. Serial peripheral blood lymphocyte phenotype analysis was reviewed (Y.T.) in patient 6 with SMZL. Pathological materials were centralized to allow their review by expert hematopathologists (review co-ordinated by M.R. and S.P.). The 5 coinfected cases for whom the NHL diagnosis was based on histological material (cases 1 to 5) and 33 HIV only–infected cases were reviewed. Immunohistochemistry was performed after a 3-step immunoperoxidase method to precisely define histological subtypes. Materials were assessed for CD20, CD3, bcl-2, CD5, CD10, bcl-6, IRF-4, CD138, Ki67, kappa, and lambda. The detection of Epstein-Barr virus (EBV) was performed with Epstein-Barr encoded RNA in situ hybridization.
Continuous variables were summarized as median (minimum to maximum) and categorical variables as frequency and percentage. The nonparametric Mann–Whitney and Fisher exact tests were used to compare continuous and categorical variables. Statistical tests were 2-tailed; P < 0.05 was considered statistically significant. We used SAS, version 9.2 (SAS Institute Inc, Cary, NC).
Comparison of B-NHL in HIV/HCV-Coinfected and HIV-Monoinfected Patients
Among the 47 patients included in the cohort, we compared the 6 HIV/HCV-coinfected patients with the 41 HIV-monoinfected patients (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A400). Gender ratio (male to female ratio 5:1 versus 34:7 in the HIV-monoinfected patients) and age distribution (median 47 versus 45 years) were similar between groups. Coinfected patients had more frequently intravenous drug abuse (4:6 versus 2:41 in the HIV-monoinfected patients) and a tendency to higher CD4 T-cell count [median 449 (range 200–1322) versus 292 cells/mm3 (range: 9–1106) P = 0.15]. HIV viral load did not differ between groups [nondetectable HIV viral load (<50 copies/mL) in 4:6 versus 16:41]. Of the 6 coinfected cases, 5 cases had features of MZL/LPL associated (n = 2) or not (n = 3) with high-grade component. Among the 33 reviewed cases of B-NHL from HIV only–infected patients, only 1 patient had features of MZL/LPL (Helicobacter pylori–related gastric MALT lymphoma), and none had features of DLBCL transformed from low-grade NHL (P < 0.0001; see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A400).
Characteristics of Coinfected Patients With B-NHL
Baseline characteristics of HIV/HCV coinfection and B-NHL treatment and outcome are summarized in Table 1. Duration from HIV diagnosis to B-NHL ranged from 1 to 20 years (median: 11 years) and the nadir CD4 T-cell count from 151 to 746 cells per cubic millimeter (nadir not available for 2 patients). HIV load was below 50 copies per milliliter in 4 patients. They had been under cART for a median duration of 10 years (range: 4–12). HIV load was 2.1 and 5.9 log10 for the 2 patients who were given cART only after B-NHL diagnosis. HCV genotypic distribution was as follows: genotype 1 (n = 3), genotype 2 (n = 1), genotype 4 (n = 1), and genotype not available (n = 1). HCV load ranged from 5.4 to 7.1 log10. With the exception of patient 5 who had severe liver fibrosis (metavir fibrosis score ≥ 3) and did not respond to previous antiviral therapy, no patient had been treated for HCV infection before the lymphoma diagnosis. Monoclonal immunoglobulin M Kappa was detected in 1 patient (patient 1). No patient had rheumatoid factor positivity. The median follow-up after B-NHL diagnosis was 17 months (range: 0.1–32).
All coinfected patients had extranodal involvement [digestive tract (n = 3), liver (n = 2), bone marrow (n = 2), and spleen (n = 1)]. Patient 1 had a bone marrow LPL with a monoclonal IgM component of 61 g/L consistent with Waldenstrom macroglobulinemia. Synchronously, the patient had a large inguinal lymph node which was diagnosed as an EBV-positive plasmablastic lymphoma. This patient died of cardiac ischemia due to hyperviscosity syndrome before the initiation of chemotherapy. Patient 2 had an EBV-negative gastric DLBCL with features of transformed low-grade Helicobacter pylori–negative lymphoma. This patient received R-CHOP with a partial response, and experienced during follow-up a neuromeningeal relapse that was treated with COPADM and CYVE regimen, resulting in a complete and sustained response. Patient 3 had a liver and bone marrow EBV-negative DLBCL, he received 2 courses of R-CHOP associated with methotrexate and died of aspergillosis and septic shock after treatment. Patient 4 had a small intestine LPL and was treated with R-CVP allowing a long-lasting complete response. Patient 5 had a duodenal B-cell lymphoid infiltration classified as suggestive of Helicobacter pylori–negative MALT lymphoma. He was treated with chlorambucil allowing a long-lasting complete response. Patient 6 was diagnosed with SMZL diagnosed on immunophenotypic and cytological analyses. He first received cART followed by a virological response but no hematological response. Then, he received anti-HCV treatment with Peg-interferon alpha and ribavirin, allowing a dramatic decrease of clonal B cells in peripheral blood which correlated with HCV virological response. His clonal B-cell count decreased from 759 at baseline to 102 × 106/L at 24 weeks after initiation of anti-HCV therapy (Fig. 1).
The most striking observations drawn from the present study are the high frequency of features of MZL and LPL in HCV/HIV-coinfected patients and the hematological response after anti-HCV therapy observed in one coinfected patient with SMZL. The link between MZL/LPL and HCV infection, although well known in HCV-monoinfected patients, had not been previously reported in HCV/HIV-coinfected patients. Remarkably in our series, among 6 coinfected patients with active HCV infection, 5 had features of MZL or LPL. Those lymphomas were previously rarely described in HIV-infected patients.9–13 Among those, few observations of regression of lymphoma after cART were reported.9 In our series, although cART and HIV virological response were not followed with hematological response, the patient with SMZL responded to anti-HCV antiviral therapy like previously reported in HCV-monoinfected individuals.7 This supports the hypothesis that HCV infection can be associated with antigen-driven B-cell transformation in the context of HIV infection in the cART era.14
To investigate the link between HCV coinfection, immune deficiency, and lymphoma, we compared the present series with coinfected patients with B-NHL before the cART era.15 (Table 1 online only). Eight coinfected patients were recruited in 1993–1994 through a case–control epidemiological study performed at Pasteur hospital in a study of the link between HCV and NHL among HIV-infected patients. Pre-cART B-NHL occurred in patients with severe immunodeficiency as follows: 6 of 8 patients had developed AIDS before the diagnosis of NHL versus 1 of 6 in the present series, median CD4 T-cell count at B-NHL diagnosis was 15 cells per cubic millimeter (range: 4–385) before the cART era compared with 449 cells per cubic millimeter. Histological subtypes and localization were strikingly different from those observed in the cART era, with 6 DLBCL (central nervous system in 3, and cutaneous, cavum, and gastric in 1 case each), 1 Burkitt-like lymphoma, 1 plasmacytoma. There was no feature of small B-cell lymphoma among these coinfected patients. This finding supports that restored immunity in HIV-infected patients could modify the spectrum of lymphomas in coinfected patients. HIV-associated exhaustion of T cells16 and B cells17 was largely reported in HIV-viremic individuals and perturbations in the cooperation between T cells and B cells. The control of HIV due to cART in the presence of chronic active HCV infection could be associated with a restored T cell and B cell co-operation facilitating antigen-driven lymphomagenesis.
HCV-associated cases are expected to represent a low proportion of HIV-associated NHL. Indeed, the prevalence of active HCV infection among HIV-infected patients with NHL included in our cohort does not seem different than among HIV-infected patients without NHL [6 of 47 (12.8%) versus 17%18]. This is consistent with previous epidemiological studies that did not find an association between HCV infection and B-NHL in HIV-infected patients.15,19 However, because most of these epidemiological studies included a high proportion of patients from the pre-cART era, further epidemiological evaluation of the impact of HCV infection in HIV-associated NHL should be carried out to explore further this issue in view of our data.
Given the low number of patients with MZL/LPL described in the present work, our findings need to be confirmed in further studies. In particular, the impact of anti-HCV treatment should be evaluated in additional patients to demonstrate its beneficial impact on B-cell lymphoma in the context of HCV/HIV coinfection.
In conclusion, the present study points out for the first time the occurrence of MZL and LPL in HIV/HCV-coinfected patients in the cART era like described previously among HCV only–infected patients. The correlation between virological and hematological responses in a coinfected patient with SMZL supports the efficacy of anti-HCV therapy in low-grade NHL, as observed in HCV-monoinfected patients. Altogether, this suggests that chronic antigenic stimulation by HCV may contribute in lymphomagenesis also in HIV-infected patients and supports a new path for improvement of their treatment. Therefore, in view of these new findings, HCV antiviral therapy in coinfected patients with B-NHL should be given further evaluation.
The authors gratefully thank Claudine Bolliot, Valérie Boutant, Didier Branquet, Delphine Brosseau, Danielle Canioni, Agnès Carlotti, Odile Casiraghi, Catherine Chassagne-Clément, Jean-Philippe Dales, Claire Delattre, Bettina Fabiani, Laure Gibault, Isabelle Goubin, Thierry Lazure, Delphine Mercier, Francois Plénat, Marc Polivka, Jacqueline Vaudrot, Hassiba Remidi, and Simone Wassoumbou for contribution to examination of pathological specimen and for pathological review; and Anne-Aurélie Mazet for viral load measurements.
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