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Objectives: The value of Epstein-Barr virus (EBV) biomarkers on the prognosis of HIV-related non-Hodgkin's lymphoma (NHL) has been poorly explored in the combined antiretroviral therapy (cART) era., Design: We evaluated EBV DNA load and EBV antibodies in HIV-NHL patients enrolled in the French ANRS-CO16 Lymphovir Cohort between 2008 and 2015., Methods: Whole blood and plasma EBV DNA load and serological profiles were analyzed in 76 HIV-infected patients at diagnosis of NHL and 6 months after the initiation of chemotherapy., Results: Prechemotherapy whole blood (WB) and plasma EBV DNA loads were positive for 80 and 45% of HIV-NHL patients, respectively. Pretreatment WB EBV DNA positivity was associated with a positive plasma HIV-1 RNA load (relative risk (RR), 4.42 [1.33; 14.72]) and plasma EBV DNA positivity with EBV in situ detection (RR 10.62 [2.38; 47.49]). Following chemotherapy, the proportions of patients with positive WB or plasma EBV DNA declined from 81 to 23% (P < 0.0001) and from 43 to 8% (P < 0.0001), respectively. Estimated 2-year progression-free survival did not differ according to prechemotherapy WB positivity (82% versus 67%, P = 0.15) or plasma EBV DNA positivity (76% versus 81%, P  = 0.52)., Conclusions: The plasma EBV DNA load correlates with in situ EBV detection. The WB EBV DNA load correlates with HIV load. WB and plasma EBV DNA loads at NHL diagnosis do not constitute prognostic markers for HIV-NHL patients in the modern cART era., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are associated with increased risks of lymphomas in the non-HIV setting. Their impacts on HIV-associated lymphomas deserved further studies in the modern combined antiretroviral therapy (cART) era., Design: We evaluated the associations between HCV, HBV and HIV-related lymphomas in the Lymphovir-ANRS-CO16 cohort., Methods: Prevalence of HCV seropositivity and chronic HBV infections were compared with those observed in the French Hospital Database on HIV (FHDH-ANRS-CO4)., Results: Between 2008 and 2015, 179 patients with HIV-related lymphomas from 32 French hospitals were enrolled, 69 had Hodgkin's lymphoma (39%), and 110 non-Hodgkin's lymphoma (NHL) (61%). The prevalence of HCV infection was higher in patients with NHL than in the FHDH-ANRS-CO4 [26 versus 14%, odd ratio (OR): 2.15; 95% confidence interval (1.35-3.32)] whereas there was no association between Hodgkin's lymphoma and chronic HCV infection. Chronic HBV infection was not associated with NHL in our cohort with a prevalence of 5 versus 7% in FHDH-ANRS-CO4 but tended to be associated with Hodgkin's lymphoma [prevalence of 14%, OR: 2.16 (0.98-4.27)]. Chronic HCV infection tended to pejoratively impact 2-year overall survival in patients with NHL: 72% [57%, 91%] versus 82% [74%, 91%], hazard ratio: 2.14 [0.95-4.84]. In contrast, chronic HBV infection did not correlate with outcome., Conclusion: In the modern cART era, chronic HCV infection is associated with an increased risk of NHL in PLWHIV and tends to pejoratively impact overall survival. HBV infection is not associated with the risk of NHL but with a borderline increase of Hodgkin's lymphoma risk.

Objectives: Epstein-Barr virus (EBV) has been implicated in lymphomagenesis of HIV-related classical Hodgkin lymphoma (HIV-cHL). The utility of EBV molecular and serological biomarkers has scarcely been examined in HIV-cHL in the recent combined antiretroviral therapy (cART) era., Design: We evaluated EBV DNA load and a panel of EBV antibodies in HIV-cHL patients prospectively enrolled in the French ANRS-CO16 Lymphovir cohort between 2008 and 2015., Methods: Pretreatment whole blood, plasma EBV DNA load and serological profiles were analysed in 63 HIV-infected patients diagnosed with cHL. For the 42 patients with available material, comparisons were performed between values at diagnosis and 6 months after the initiation of chemotherapy., Results: Pretreatment whole blood and plasma EBV DNA loads were positive in 84 and 59% of HIV-cHL patients, respectively. Two-year progression-free survival estimates did not differ between the patients with pretreatment whole blood (n = 53) or plasma (n = 37) EBV DNA(+) and the patients with pretreatment whole blood (n = 10) or plasma (n = 26) EBV DNA(-) (92 vs. 80% or 89 vs. 92%, P = 0.36 and 0.47, respectively). At diagnosis, 47% of patients harboured an EBV reactivation serological profile. Following chemotherapy, whole blood and plasma EBV DNA levels significantly declined from medians of 1570 [interquartile range, 230-3760) and 73 (0-320) copies/ml to 690 (0-1830) and 0 (0-0) copies/ml, respectively (P = 0.02 and P < 0.0001, respectively]. Anti-EBV IgG antibody level significantly dropped at 6-month follow-up (P = 0.004)., Conclusion: Whole blood and plasma EBV DNA loads do not constitute prognostic markers in HIV-cHL patients in the modern cART era.

Objective: Non-Hodgkin's lymphoma (NHL) remains among the most frequent malignancies in persons living with HIV (PLWHIV). Survival among patients with HIV-associated diffuse large B-cell lymphoma (DLBCL), the most frequent NHL subtype, has improved markedly in recent years. We aimed to analyze characteristics and outcomes of DLBCL in HIV-infected patients in the era of modern combined antiretroviral therapy (cART)., Design: PLWHIV with lymphoma were prospectively enrolled in the French ANRS-CO16 Lymphovir cohort between 2008 and 2015. We compared the patients treated with R-CHOP) (rituximab, cyclophosphamide, daunorubicin, vin-cristine, prednisolone) with HIV-negative DLBCL patients enrolled simultaneously in the R-CHOP arms of Lymphoma Study Association trials., Results: Among 110 PLWHIV with NHL, 52 (47%) had systemic DLBCL. These 52 cases had frequent extranodal disease (81%), poor performance status (35%) and advanced age-adjusted international prognostic index (aaIPI) (58%), and were mainly treated with R-CHOP (n = 44, 85%). Their median CD4 T-cell count was 233 cells/μl, and 79% of patients were on cART. The 2-year overall and progression-free survival rates were both 75% (95% confidence interval: 64%, 88%). Factors associated with progression or death in univariate analysis were poor performance status [hazard ratio: 3.3 (1.2, 8.9)], more than one extranodal site [hazard ratio: 3.4 (1.1, 10.5)] and an advanced aaIPI [hazard ratio: 3.7 (1.0, 13.1)]. Progression-free survival after R-CHOP therapy did not differ from that of the HIV-negative counterparts (P = 0.11)., Conclusion: In the recent cART era, despite frequent high-risk features, the 2-year overall survival of HIV-DLBCL patients reaches 75%. Outcomes after R-CHOP therapy are similar to those of HIV-negative patients with similar aaIPI.

Objective: To establish the effectiveness of cidofovir for AIDS-related progressive multifocal leukoencephalopathy (PML) in patients concomitantly receiving combination antiretroviral therapy., Design: Analysis of raw data pooled from one prospective and five cohort studies., Setting: Tertiary care centers for the treatment of HIV-associated complications., Patients: Three hundred seventy HIV-infected PML patients diagnosed from 1996 treated with combination antiretroviral therapy with or without cidofovir. All studies had already published their results but for four of them, additional patients and followup data are included in this report. Follow-up was started from the date of first abnormal neuroimaging; those treated with cidofovir were entered at risk at the date of cidofovir initiation. Main study outcomes were time to PML-related death and odds of 12-month moderately severe to severe disability (Rankin score >or=4)., Results: Sixty-four percent of the PML cases were confirmed by histopathology or JC virus DNA detection in cerebrospinal fluid; 185 (50%) received cidofovir (median five cycles). During 463 person-years of follow-up, 167 PML-related deaths occurred (36.6 per 100 person-years of follow-up). Estimated 1 year survival was 0.56 (95%confidence interval, 0.50-0.61). In multivariate models stratified by cohort and adjusted for type of diagnosis and relevant prognostic confounders, cidofovir treatment was not associated with survival (hazard ratio for death 0.93, 0.66-1.32). Results were similar using time to death from any cause as the outcome. Furthermore, 12-month moderately severe to severe disability was not associated with the use of cidofovir., Conclusion: In combination antiretroviral therapy-treated PML patients, cidofovir use did not influence PML-related mortality or residual disability. New treatments for AIDS-related PML are urgently needed.

Objective: To investigate the dynamics of the lymphocyte HIV reservoir in patients on prolonged and effective highly active antiretroviral therapy (HAART)., Design: Nine HAART-treated patients were selected on the basis of long-term infection and long-term undetectable plasma viral RNA. Five patients had received antiretroviral therapy before HAART. We compared a polymorphic region of the env gene (C2V4), and the part of the pol gene encoding the reverse transcriptase in pre-HAART plasma and in the reservoir lymphocytes during HAART; the first plasma sample taken after structured treatment interruption was also studied in three patients., Methods: Both regions of interest were amplified from plasma HIV RNA and cellular proviral DNA, then cloned, sequenced and subjected to phylogenetic analysis., Results: Diversity of the lymphocyte reservoir was found in six of nine patients. Archiving of pre-HAART plasma clones was observed in six of nine patients. 'Wild-type' and zidovudine-resistant strains co-existed in reservoir T cells of two pre-HAART treated patients. In three patients, no resistant virus was found in the T-cell reservoir despite the detection of resistant virus in pre-HAART plasmas. However, virus archiving was documented in two of these three patients on the basis of C2V4 analysis. Latently infected T cells only partly accounted for the plasma viral load rebound after structured treatment interruption., Conclusions: The HIV lymphocyte reservoir is dynamic. Its diversity results mainly from successive archiving of circulating plasma viruses during the course of HIV infection. Archiving of resistant virus must be taken into account in therapeutic decisions.

Background: JC virus (JCV) is ubiquitous among the general population. However, only individuals with severely impaired immunity, mainly AIDS patients, develop progressive multifocal leukoencephalopathy (PML). Here, we examined the role of specific CD4 T cells in the control of JCV infection., Methods and Design: JCV-specific CD4 T-cell responses were investigated by assaying peripheral blood mononuclear cell proliferation in response to the purified virus. Four groups of individuals without PML were examined: 14 HIV-seronegative healthy donors and 25 HIV-infected patients without PML, separated into urinary JCV excretors (active infection) and non-excretors, according to JCV PCR on urine. Two groups of patients with PML were also studied: 14 HIV-infected patients with active PML; and 10 PML survivors on effective and prolonged antiretroviral therapy. All of the patients were PCR-positive for JCV in the cerebrospinal fluid at the time of diagnosis of PML., Results: No significant anti-JCV CD4 T-cell proliferation was found in any of the non-excretors tested. All nine healthy donors and seven of the 13 non-PML HIV-infected patients with urinary JCV excretion had positive JCV-specific CD4 T-cell responses. No significant response was found in the 14 patients with active PML, while nine of the 10 PML survivors had positive responses. Restoration of JCV-specific CD4 T-cell responses was associated with JCV clearance from the cerebrospinal fluid., Conclusion: JCV-specific CD4 T-cell responses appear to play a critical role in the control of JCV infection, preventing PML development. Such responses can be restored in PML survivors following effective and prolonged antiretroviral therapy.

Objective: To investigate the phenotypic features of infected lymphocytes in patients on prolonged and effective highly active antiretroviral therapy (HAART)., Design: We examined highly purified subsets of memory and naive CD4 T lymphocytes for the presence of replication-competent virus., Methods: In 11 highly selected HAART-treated patients, we isolated highly purified CD45RO CD45RA CD4 T cells using a magnetic bead-based procedure. In some patients, a subsequent cell separation according to CD62L expression was performed. We quantified total viral DNA in freshly isolated T-cell subsets. To verify whether the virus was replication-competent, HIV RNA was measured in supernatants following cell activation., Results: HIV DNA was detectable in the CD45RO and CD45RA CD4 T-cell subsets in 100% and 90% of the patients tested, respectively. In central memory CD45ROCD62L, effector memory CD45RO+CD62L-, truly naive CD45RACD62L, and CD45RA+CD62L- CD4 T cells, HIV DNA was found in 100%, 55%, 88%, and 50% of the patients tested respectively. HIV DNA was significantly higher in the CD45RO fraction than in the CD45RA subset and in the CD45ROCD62L fraction than in the three other CD45RA/ROCD62L+/- subsets. Detectable HIV RNA was found in the culture supernatants of CD45RO and CD45RA CD4 T-cell subsets in 80% and 66% of the patients tested respectively, and in CD45ROCD62L, CD45RO+CD62L-, CD45RACD62L, and CD45RA+CD62L- CD4 T cells in 100%, 100%, 100% and 50% of the patients tested respectively., Conclusions: In patients on prolonged and effective HAART, the pool of infected CD4 T lymphocytes consists predominantly of memory cells but also contains naive cells.

Objectives: To examine the antigen specificities of HIV reservoir CD4 T cells in patients on prolonged and effective highly active antiretroviral therapy (HAART)., Design: Five HIV-infected patients, who were highly adherent to antiretroviral treatment, were selected on the basis of long-term undetectable plasma viral RNA on unmodified HAART. To investigate the antigen specificities of infected memory CD4 T cells, we examined the capacity of recall antigens, including HIV antigens, to induce virus production by peripheral blood mononuclear cells (PBMC)., Methods: To quantify CD4 T cells infected by replication-competent virus, and to determine their antigen specificities, we used a limiting dilution-based culture assay. CD8 T cell-depleted PBMC at several cell densities were activated by using Tuberculin purified protein derivative, cytomegalovirus, or HIV-1 p24 with and without HIV-1 Nef., Results: We found that the pool of infected CD4 T cells includes HIV-specific cells with apparent frequencies between 5- and 100-fold higher than those of the common specificities for cytomegalovirus or Tuberculin., Conclusion: Our findings suggest that a significant proportion of replication-competent HIV-infected CD4 T cells in these patients are memory cells directed against HIV determinants. This may provide a rationale for the therapeutic use of recombinant HIV antigens to reduce the pool of HIV-reservoir cells., (Copyright 2002 Lippincott Williams & Wilkins)