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Comment on “Characteristics of B-Cell Lymphomas in HIV/HCV-Coinfected Patients During the Combined Antiretroviral Therapy Era: An ANRS CO16 LYMPHOVIR Cohort Study”

Chang, Po-Yin PhD*; Detels, Roger MD, MS*; Martínez-Maza, Otoniel PhD*,†,‡; Zhang, Zuo-Feng MD, PhD*,†; Jacobson, Lisa P. ScD§; Margolick, Joseph B. MD, PhD; Variakojis, Daina MD; Rinaldo, Charles R. Jr PhD#; Hussain, Shehnaz K. PhD†,*,**

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1st, 2014 - Volume 67 - Issue 2 - p e84–e86
doi: 10.1097/QAI.0000000000000204
Letters to the Editor
Free

*Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA

Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA

Department of Microbiology, Immunology, and Molecular Genetics and Department of Obstetrics and Gynecology, David Geffen School of Medicine, UCLA, Los Angeles, CA

§Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL

#Department of Infectious Diseases and Microbiology, Graduate School of Public Health and Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA

**Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA

This work was supported by grants from the NIH (K07-CA-140360), UCLA AIDS Institute, UCLA Center for AIDS Research (AI28697), and the UCLA Jonsson Comprehensive Cancer Center (CA016042).

The authors have no funding or conflicts of interest to disclose.

Data in this article were collected by the Multicenter AIDS Cohort Study (MACS) with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: J.B.M. (PI), Todd Brown, Barbara Crain, Adrian Dobs, Homayoon Farzadegan, Lisette Johnson-Hill, Sean Leng, Cynthia Munro, Michael W. Plankey, Ned Sacktor, Jennifer Schrack, Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: S.M.W. (PI), John P. Phair, Sheila Badri, Maurice O'Gorman, David Ostrow, Frank Palella, Ann Ragin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: R.D. (PI), O.M-M. (Co-PI), Aaron Aronow, Robert Bolan, Elizabeth Breen, Anthony Butch, Beth Jamieson, Eric N. Miller, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Z-F.Z.; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: C.R.R. (PI), Lawrence A. Kingsley (Co-PI), James T. Becker, Ross D. Cranston, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, Ronald D. Stall; and the Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: L.P.J. (PI), Alvaro Munoz (Co-PI), Alison, Abraham, Keri Althoff, Christopher Cox, Jennifer Deal, Gypsyamber D'Souza, Priya Duggal, Janet Schollenberger, Eric C. Seaberg, Sol Su, Pamela Surkan. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR000424 (JHU CTSA). Website located at http://www.statepi.jhsph.edu/macs/macs.html. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH).

To the Editors:

In their recent article reporting on the French National Agency for Research on AIDS and Viral Hepatitis ANRS-CO16 Lymphovir cohort, Terrier et al observed a high proportion of a distinct B-cell non-Hodgkin lymphoma (NHL) subtype in patients coinfected with HIV/HCV, when compared with HIV-monoinfected patients, in the era of combined antiretroviral therapy (cART): 5 of 6 (83%) coinfected patients versus 1 of 33 (3%) monoinfected patients presented with marginal zone/lymphoplasmacytic lymphoma (MZL/LPL).1 These coinfected patients were more likely to be intravenous drug users and had a tendency toward higher CD4+ T-lymphocyte counts than HIV-monoinfected patients with NHL. Patients in both groups showed comparable plasma HIV RNA concentrations. The authors described the clinical and epidemiological characteristics of NHL patients coinfected with HIV/HCV and concluded that chronic antigenic stimulation by HCV may contribute to lymphomagenesis among HIV-infected patients, resulting in the development of lymphomas of the MZL/LPL subtype. This is a striking observation and led us to explore this hypothesis in the Multicenter AIDS Cohort Study (MACS).

The MACS, established in 1983, enrolled 6,972 men who have sex with men (MSM) from 4 metropolitan areas between 1984 and 2003.2–5 NHL is ascertained through self-report with confirmation by pathology records and state cancer registries or is identified at autopsy. NHL subtypes are also defined through review of pathology reports. HCV status is determined by testing both antibodies to HCV (anti-HCV) using enzyme immunoassay (ADVIA Centaur HCV assay), and serum HCV RNA levels by PCR (COBAS AmpliPrep TaqMan HCV Assay). Anti-HCV and HCV RNA testing were performed at multiple time points retrospectively on stored serum from the baseline study visit through 2001, and prospectively every 6 months since 2001. Only 38 (0.6%) of MACS participants had either no HCV test at all (n = 19) or inconclusive status at their enrollment visit (n = 19).

For this analysis, we examined 190 HIV-infected MACS participants diagnosed with NHL by July 2010, as described in previous studies.6,7 HCV testing was done within 1 year of the baseline study visit in 184 of these 190 cases (97%), and 189 (99%) cases had at least 1 HCV follow-up test after baseline. The average time from baseline study visit to NHL diagnosis was 7.6 years (median, 7.3; interquartile range, 4.8–10.1 years). A participant was considered HCV-negative if all available HCV antibody tests before NHL diagnosis date were negative. A participant was considered to have cleared his HCV infection if he had a negative HCV RNA test result before NHL diagnosis date preceded by either (1) at least 2 positive anti-HCV test results, (2) at least 2 results of detectable HCV RNA, or (3) a detectable HCV RNA level at study baseline. A participant was considered chronically HCV-infected if he had a positive HCV RNA test result at the time of NHL diagnosis preceded by either a positive anti-HCV or HCV RNA result. Of the 190 NHL cases, 164 were HCV-negative (HIV-monoinfected), 18 were chronically HCV-infected, and 7 had cleared their HCV infection.

Table 1 shows distributions of selected characteristics for NHL cases by HCV status. Most NHL cases were diagnosed in the pre-cART era, and only 14 of them, all HIV-monoinfected, received cART with a median of 2.8 years (interquartile range, 1.3–4.9 years) from cART initiation to NHL diagnosis. All case groups had a similar distribution of HIV RNA levels at the time of NHL diagnosis (P = 0.910). Among HIV/HCV-coinfected cases, more than half had their first positive results of anti-HCV and/or HCV RNA level at least 5 years before NHL diagnosis (71% and 56% of cases with cleared HCV and chronic HCV infection, respectively). A higher percentage of HIV/HCV-coinfected cases who cleared their HCV infection (71%) had NHL of the central nervous system compared with the other case groups (71% versus 29% and 22%, P = 0.056). Among cases of systemic NHL, we did not observe a difference in subtype distributions across case groups (P = 0.679), although sample size limits statistical power. No cases with HIV/HCV-coinfection were diagnosed with MZL/LPL. Two HIV-monoinfected cases, who never received cART, were diagnosed with lymphoplasmacytic lymphoma.

TABLE 1

TABLE 1

In contrast to the article by Terrier et al, there were no cases of MZL/LPL among HIV/HCV-coinfected patients in the MACS. Therefore, their suggestion that lymphomagenesis results from chronic HCV antigenic stimulation requires further study for confirmation. Further work to assess the association between HCV and specific B-cell NHL subtypes in HIV-infected populations is warranted.

There are several important differences between participants in the MACS and the French ANRS-CO16 Lymphovir cohort that should also be noted. The MACS is a population of MSM, and the majority of the NHL diagnoses were in the pre-cART era. Only 14 participants with NHL had received cART; 7/14 (50%) of these cases had diffuse large B-cell lymphoma. One important limitation of the MACS data is a lack of tumor samples to verify subtypes through immunohistochemistry staining for all cases, as was done in the article by Terrier et al.

cART was introduced 18 years ago, yet surprisingly only one-third of people living with HIV in the United States are receiving treatment.8 Although there is an ongoing HCV outbreak among HIV-infected MSM,9,10 very few studies have examined HCV status in patients with NHL in this population. Inspired by the recent work of Terrier et al, we presented NHL subtypes of mostly cART naive patients by HCV status in a MSM cohort.

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