Risks of Opportunistic Infections in People Living with HIV with Cancers Treated with Chemotherapy Alain Makinson MD, PhD1§, Lesley S. Park PhD2, Kimberly Stone MPH3, Janet Tate PhD4, Maria C. Roger Bedimo MD8, Matthew Bidwell Goetz MD9, Fatma Shebl MD10, Jacques Reynes PhD1, Vincent Le Moing PhD1, Keith M. Sigel, MD PhD3 1 2 University Hospital Montpellier, Inserm U1175 and University of Montpellier, Montpellier, France, Stanford University School of Medicine, Stanford, CA, USA, 3Icahn School of Medicine at Mt Sinai, New York, NY, USA, 4VA Connecticut Healthcare System, West Haven, CT, USA, 5Michael E. DeBakey VAMC and Baylor College of Medicine, Houston, TX, USA, 6James J. Peters VA Medical Center, Bronx, NY, USA, 7VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA, 8VA North Texas Health Care Center, Dallas, TX, USA, 9VA Greater Los Angeles Health Care System, Los Angeles, CA, USA, 10Massachusetts General Hospital, Boston, MA, USA § Corresponding Author: Alain Makinson, Département des Maladies Infectieuses, 80 Avenue Augustin Fliche, 34295 Cedex 5, Montpellier, France ; tel : 04 67 33 95 10 ; e-mail : amakinson@chu-montpellier.fr © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-ncnd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Rodriguez-Barradas MD5, Sheldon T. Brown MD6, Roxanne Wadia MD4, Kristina Crothers MD7, The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. Authors’ contribution: AM, JS, VLM conceived the analysis and interpreted the findings. AM and authors (AM, LP, KS, JT, MRB, SB, RW, KC, RB, MDG, FS, JR, VLM, KMS) read and approved the final manuscript. Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 KMS drafted the manuscript project. AM, JS and KMS performed the statistical analysis. All other Abstract Introduction: We ascertained incidence of OIs in people living with HIV (PLHIV) with cancer undergoing chemotherapy with non-HIV comparators. Methods: We identified 2,106 PLHIV and 2,981 uninfected Veterans with cancer who received at ascertained incident OIs within six months of chemotherapy amongst zoster, cytomegalovirus, tuberculosis, Candida esophagitis, Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, Cryptococcosis, atypical Mycobacterium infection, Salmonella bacteremia, histoplasmosis, coccidioidomycosis, or progressive multifocal leukoencephalopathy. We used Poisson methods to calculate OI incidence rates by HIV status, stratifying for hematological and non-hematological tumors. We compared OI rates by HIV status, using inverse probability weights of HIV status, further adjusting for PCP prophylaxis. Results: We confirmed 106 OIs in 101 persons. Adjusted OI incidence rate ratios (IRR) indicated higher risk in PLHIV for all cancers (IRR 4·8; 95% confidence interval [CI]: 2·8-8·2), hematological cancers (IRR 8·2; 95% CI 2·4-27·3), and non-hematological cancers (IRR 3·9; 95% CI: 2·1-7·2). IRRs were not significantly higher in those with CD4>200 cells/mm3 and viral load < 500 copies/mL (IRR 1·8; 95% CI: 0·9-3·2). All PCP cases (n=11) occurred in PLHIV, with two microbiologically unconfirmed cases among 1,467 PLHIV with non-hematological cancers, no PCP prophylaxis and CD4 counts >200/mm3. Conclusions: Veterans with HIV undergoing chemotherapy had higher rates of OIs than uninfected Veterans, particularly those with hematological cancers, but not in PLHIV with HIV controlled disease. Our study does not support systematic PCP prophylaxis in solid tumors in PLHIV with HIV controlled disease. Keywords: cancer; opportunistic infections; prophylaxis; toxoplamosis; chemotherapy; pneumocystis jirovecii pneumonia; 3 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 least one dose of chemotherapy between 1996 and 2017 from the Veterans Aging Cohort Study. We Funding: Work was realized with support from the US National Cancer Institute (R01CA210806) and U01AA013566 to support the Veterans Aging Cohort Study. AM benefitted from a grant from the Collège des Universitaires Maladies Infectieuses et Tropicales (CMIT). A donation for this work was also given by Merck Sharp & Dohme (MSD). Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 4 Introduction Since the advent of highly active combination antiretroviral therapy (CART), life expectancy has increased for persons living with HIV (PLHIV). Meanwhile, mortality and morbidity patterns for AIDS defining malignancies (1, 2). This change can be attributed to several factors including the aging of the PLHIV population (3), increased prevalence of cancer-causing coinfections and immunologic susceptibility to cancers (4-8) and increased carcinogenic exposures such as smoking (8). With current demographic trends among PLHIV it is expected that the burden of cancer in this group will continue to increase (9). Despite a growing cancer prevalence among PLHIV, there is limited information regarding cancer treatment complications specific to this group. PLHIV may have unique harm profiles related to cancer therapies, particularly with those that impact the immune system. Chemotherapy, in particular, is a cornerstone of treatment for cancer patients, but little is known regarding the interaction of HIV disease and this treatment modality. For HIV uninfected persons undergoing cytotoxic cancer chemotherapy, guidelines recommend Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis prophylaxis in persons with solid tumors and with a pneumocystis risk higher than 3.5% (10), or treated with a prednisone dose equivalent > 20 mg/day for more than one month, or purine analogues (11). Guidelines for hematological malignancies recommend PCP and toxoplasmosis primary prophylaxis for patients with hematopoietic stem cell transplantation, chronic lymphoid leukemia, alemtuzumab, or fludarabine-cyclophosphamide-rituximab use, administration of prednisone > 20 mg for more than one month, or in subjects with primary immunodeficiencies (12), with optional prophylaxis for persons undergoing R-CHOP intensified treatment, the BEECOPP protocol for Hodgkin disease, or autologous bone marrow transplant. These varied recommendations have no 5 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 PLHIV have shifted away from AIDS-related morbidity to non-communicable diseases such as non- guidance specificity for PLHIV leading to uncertainty related to prophylaxis in this growing and important group of patients. PLHIV with malignancies treated with chemotherapy may be at enhanced risk of OIs due to the infection, which, despite good viremic control, is still associated with adverse immune effects(13). Several studies have also suggested PLHIV may have persistently depressed CD4 counts after treatment with chemotherapy and/or radiotherapy (14-16), but most analyses had limited power to determine if this impacts the clinical risk for major OI complications. In this study, we used contemporary data from a large, national cohort of Veterans to clarify types and risks for OIs in PLHIV undergoing chemotherapy, and to compare OI incidence with uninfected comparators. Methods Population We used data from the Veterans Aging Cohort Study (VACS), a large cohort of PLHIV who, upon enrolment, are matched by age, race/ethnicity, sex, and Veterans Affairs clinical site to two uninfected comparators assembled from Veterans Affairs clinical and administrative data. To be included in this study, PLHIV and uninfected comparators had to be diagnosed with a malignancy between the 1 st of January 1996 and the 1st of November 2017, and undergo at least one administration of systemic chemotherapy as defined by the Surveillance, Epidemiology and End-Results Antineoplastic Drugs Database (seer.cancer.gov). 6 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 combined immunologic impairment of chemotherapy and disturbances caused by chronic HIV Study outcomes and variables VA databases were used to identify baseline sociodemographic variables at cancer diagnosis, clinical and oncological variables, and chemotherapy administered. We recorded the following demographics: age at cancer diagnosis, year of cancer diagnosis, sex, race/ethnicity, VA site, HIV status and smoking status (current, former, never), presence of alcohol use disorder, and a modified Charlson comorbidity bias) and hepatitis C virus status (17). Antimicrobial prophylaxis was identified using pharmacy data and defined by any agent prophylactically active against pneumocystis or toxoplasmosis: cotrimoxazole, dapsone, atovaquone, inhaled or intravenous pentamidine, or pyrimethamine. Tumor anatomic site was collected from linked cancer registry data; we analyzed hematological and non-hematological malignancies separately, as intrinsic risk of OIs for hematological malignancies is greater, and guidelines recommend systematic prophylaxis for pneumocystis and toxoplasmosis for most hematological malignancies (11, 12) and in some cases for Cytomegalovirus (CMV) reactivation (18). We also excluded Kaposi sarcoma, as any incident OI might reflect underlying immunodeficiency in PLHIV and/or HIV-uncontrolled viremia. Cutaneous cancers other than melanoma were also excluded, as these would be prone to differential diagnosis biases between veterans living with HIV or not, and not be treated with systemic chemotherapy. The following malignancies were considered hematological: non-Hodgkin lymphoma, Hodgkin disease, acute non lymphocytic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, plasma cell disorders and other hematological/reticuloendothelial cancers. Our primary outcome was incidence of OI within six months of chemotherapy initiation and occurring at least 14 days after first chemotherapy administration. We defined the following infections for our outcome: zoster, CMV, tuberculosis, Candida esophagitis, PCP, toxoplasmosis, Cryptococcosis, atypical Mycobacterium infection, Salmonella bacteremia, histoplasmosis, coccidioidomycosis, 7 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 index (CCI) at time of cancer diagnosis (removing both cancer and HIV/AIDS from the score to avoid cryptosporidiosis, isosporiasis, and/or progressive multifocal leukoencephalopathy. We used diagnostic codes to identify OIs. All OIs were then confirmed by an infectious diseases physician by chart review (See Supplement for OI diagnostic criteria). We first compared baseline patient characteristics by HIV status, testing for differences using the chisquare test for categorical variables and the Wilcoxon test for continuous variables. We then performed similar comparisons by HIV status, stratified by hematological versus non-hematological malignancy. Next, we compared the proportions of cancer anatomic site and OI type by HIV status. For analyses of OI incidence we included patients if they had received at least one dose of chemotherapy after their cancer diagnosis. Using Poisson methods we calculated the incidence rate of OIs and 95% confidence intervals (95% CI) using the binomial distribution, stratified by HIV status and hematological versus non-hematological malignancy type. To compare OI risk by HIV status we used inverse probability weighting (IPW) of HIV status to account for differences between PLHIV and controls potentially influencing OI risk. To generate inverse probability weights we first calculated estimated probabilities by fitting logistic regression models predicting HIV status based on baseline characteristics of age, sex, tumor site, race/ethnicity, year of cancer diagnosis, smoking status and alcohol use disorder. These probabilities were then used to directly calculate inverse probability of HIV status weights (19). We then fitted IPW Poisson models to evaluate the association between HIV and OI risk overall, stratified by hematological and non-hematological malignancies, adjusting for OI prophylaxis use. To assess differences in OI incidence over time, we divided the overall study period into four intervals (1996-2000, 2001-2006, 2007-2012, and 2013-2017) and calculated overall OI incidence for cohort subjects in each period by HIV status. We also recalculated the adjusted incidence rate ratio (IRR) for each period and compared age at cancer diagnosis, CD4 count, proportion of hematological cancers and prevalence of HIV virologic suppression at the time of cancer diagnosis. 8 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Statistical analysis We then fitted a separate Poisson regression model of PLHIV to explore factors associated with incidence of OI among PLHIV, analyzing the association with age at cancer diagnosis, sex, race/ethnicity, hematological versus non-hematological malignancy, smoking status, CCI, CD4 count, presence of HIV virologic control (HIV-viral load  500 copies/mL) and use of PCP prophylaxis. We used Stata version 15 for statistical analyses. analysis of the data. Results During the study period we identified 2,106 PLHIV and 2,981 uninfected comparators with cancer treated with at least one administration of chemotherapy. Compared to uninfected Veterans, PLHIV were slightly younger (55 versus 59 years), had lower alcohol use disorder (14·0% versus 19·4%) (Table 1), had more hematological malignancies (30·3% versus 15·7% of all malignancies in PLHIV and uninfected persons respectively), and were more likely to be prescribed PCP prophylaxis (30·3% versus 4·2%). Though gender, race, and smoking status differed statistically between populations. CCI scores were similar in both populations. Baseline characteristics according to HIV status and hematological versus non-hematological cancer are shown in Table S1. In PLHIV with a CD4 count > 200/mm3, 261/1,443 (18%) were prescribed prophylaxis (26·5% and 15·0% in PLHIV with hematological cancers and non-hematological cancers respectively). Lung cancer was the most common non-hematological cancer type (19·0% of cancers among PLHIV, 29·5% of uninfected Veterans). The next most frequent were anal, liver, colorectal, pharynx and pancreas in PLHIV, and colorectal, liver, pharynx and oesophagus in uninfected Veterans (Table S2). For hematological cancers, lymphomas were the most frequent, with higher proportions in PLHIV (24·4%), followed by acute lymphocytic and non-lymphocytic leukemia, and plasma cell disorders. We confirmed a total of 106 incident OIs in 101 persons. Eighty-four occurred in PLHIV, 22 in uninfected Veterans (Table S3). Of the 47 OIs occurring in patients with hematological malignancies, 9 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Role of the funding source: Study funding sources had no role in the planning, collecting and 43 occurred in PLHIV; of the 59 OIs occurring in patients with non-hematological malignancies, 41 occurred in PLHIV. The predominant OI was Candida esophagitis (n=43), mostly in PLHIV (n=33), followed by herpes zoster (n=30), also mostly in PLHIV (n=21). Ten zoster cases occurred in persons with lymphomas, nine of whom were PLHIV, and five in persons with anal cancer, all PLHIV. Only one zoster case occurred in a PLHIV who had an indication for systematic valacyclovir prophylaxis (n=3) and five of the six non-tuberculous mycobacterial infection occurred in PLHIV. Toxoplasmosis diagnosed after chemotherapy was not identified in the cohort. Among PLHIV with CD4 counts >200/mm3, non-hematological cancers at diagnosis and not taking PCP prophylaxis, two (0·1%) were treated for possible but microbiologically unconfirmed PCP. Interstitial carcinomatosis was suspected for both cases; one case was virologically suppressed while the HIV viral load was 72 000 copies/mL for the second case. Incidence rates for OIs were 89·0/1000 person-years in PLHIV and 17·8/1000 person-years in uninfected Veterans (Table 2). Rates were 142·4/1000 person-years and 19·0/1000 person-years in patients with hematological cancers, and 66·6/1000 person-years and 17·6/1000 person-years in patients with non-hematological malignancies in PLHIV and uninfected Veterans respectively. OI incidence rates were higher in PLHIV for all cancers (IRR 4·8 ; 95% CI: 2·8-8·2), hematological cancers (IRR 8·2; 95% CI 2·4-27·3), and non-hematological cancers (IRR 3·9; 95% CI: 2·1-7·2), after accounting for IPW and adjusting for prophylaxis use (Table 2). We also explored OI incidence in subgroups of PLHIV; those with CD4>200 cells/mm3 still had increased risk of OIs during chemotherapy (IRR 4·1; 95% CI: 2·3-7·2) compared to uninfected persons, but those with CD4>200 cells/mm3 and viral load < 500 copies/mL did not have statistically significantly increased adjusted risk overall (IRR 1·8; 95% CI: 0·9-3·2) or when stratifying by non-hematological or hematological cancers (both p>0·05; results not shown). In our analyses exploring OI incidence over time, we found that incidence was highest for PLHIV in 2001-2006 (136·0/1000 person-years for PLHIV) with a successive decline over the subsequent two periods (2007-2012, and 2013-2017) (Figure 1). Adjusted IRRs significantly declined over time, with 10 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 (i.e., a plasma cell disorder). All PCP cases (n=11), 10 of the 11 CMV cases, all Cryptococcus cases an IRR of 3·0 (95% CI: 1·1-8·4) in the most recent time period. During the same periods, we found systematic and significant increase in age, median CD4 count, and proportions of PLHIV with HIVviremia < 500 copies/mL at cancer diagnosis, as well as a significant decrease of proportions of hematological cancer diagnosis (p<0·001 for all trends) (Figure 2) In analyses of predictive factors for OIs only among PLHIV, uncontrolled HIV viremia (IRR 11·8; 95% CI: 6·3-22·4) and CCI score (IRR Discussion In this study, we compared the incidence rates of OIs in PLHIV and uninfected veterans undergoing chemotherapy for cancer. We found that OI incidence was significantly higher in PLHIV for both hematological and non-hematological malignancies, even after accounting for imbalances in risk factors in both populations. Increased risk of OIs for PLHIV with cancer receiving chemotherapy persisted through recent years despite population-level improvements in HIV disease control, though there was a decrease in adjusted risk ratios. However, the increased risk of OIs in PLHIV was no longer statistically significant when selecting individuals with CD4 levels > 200 cells/mm3 and controlled viremia, irrespective of cancer types. The majority of OIs were candida esophagitis or herpes zoster and we found no toxoplasmosis infections nor definite PCP in PLHIV with nonhematological malignancies and a CD4 count > 200 cells/mm3. Uncontrolled HIV viremia and comorbidity burden were linked to OI risk for PLHIV. To our knowledge, this is the first study assessing incidence of OIs in PLHIV undergoing chemotherapy as a primary outcome with an uninfected comparison group. Series in PLHIV have largely focused on the effect of cancer treatments on CD4 counts, and highlighted the risk of CD4 count transient depletion after chemotherapy, and of more severe and prolonged depletion after radiotherapy (14, 16, 20). In these studies, OIs were described in PLHIV with AIDS-defining cancers: 8 (12%) and 10 (14%) OIs in Non-Hodgkin lymphoma series of 68 and 74 patients respectively (20, 21). Recent cohorts of PLHIV with non-hematological malignancies undergoing chemotherapy 11 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 1·2; 95% CI: 1·0-1·4) were independently associated with OI risk (Table 3). showed no OIs (16, 22, 23), though these results may simply be due to the limited numbers of PLHIV analyzed. Although our cohort spanned the early and more recent periods of the ART-era, we found continued elevated risk of OIs associated with HIV infection. This may relate to incomplete immune recovery in addition to the immunosuppressive effect of chemotherapy present in some PLHIV with cancer, despite the increasing median levels of CD4 counts at cancer diagnosis. Interestingly, this risk as adjusted incidence rate ratios of OIs in this subgroup were not significantly different from uninfected Veterans. Our decrease in IRR of OIs with calendar time may have several underlying explanations. Chemotherapy protocols may have been modified with time and accumulated experience in the oncologic care of PLHIV, inducing less immune toxicities and interactions. The most substantial contributor, however, is likely to be the increased proportion of PLHIV with virologic control over time and increases in median CD4 levels at cancer diagnosis. Our findings reflect broader trends in OI incidence as illustrated by a large study using data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) that found decreased incidence of OIs during 2000-2010 era in PLHIV without cancer, which correlated with increasing CD4 values and better virologic control with time (24). Notably, incidence rates for OIs among all cancer patients in our study were substantially higher than OIs among the general PLHIV population during the most recent period for NA-ACCORD (2008-2010; 14·5 cases per 1000/p-y; 95% CI: 13·7-15·4) but were broadly similar to cancer patients in our cohort with good HIV disease control. Candida esophagitis and herpes zoster represented nearly three quarters of OIs and disproportionally affected PLHIV. Candida esophagitis can result in pain, dysgeusia, anorexia, and malnutrition, reducing tolerance to cancer therapies. Herpes zoster can lead to severe neuralgia as well as more serious sequelae such as blindness or encephalitis. Herpes zoster in PLHIV undergoing chemotherapy 12 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 seems to be substantially lower in PLHIV with CD4 levels > 200/mm3 and HIV virologic suppression, may have resulted from combined effects of HIV-related immune disturbances and added immunosuppression from chemotherapeutics (25, 26). ECIL guidelines recommend acyclovir or valacyclovir prophylaxis administered after allogeneic or autologous hematopoietic stem cell transplants (27) and as optional prophylaxis in persons with plasma cell disorders or chronic lymphocytic leukemia. How much these recommendations were applied in our study for patients with cancers. Our study supports evaluations of preventive herpes zoster strategies specifically in PLHIV with malignancies, particularly lymphomas and anal cancer, as previously evaluated in persons with non-hematological malignancies in the general population (28). Increased coverage with inactivated zoster vaccine may decrease the risk for herpes zoster in this population. Incidence of PCP in this study was low, and our analysis found no toxoplasmosis infections. These results may reflect adequate PCP prophylaxis in PLHIV with low CD4 levels in our study cohort, as recommended by the NCCN guidelines (29). Additionally, the two unconfirmed PCP in PLHIV > 200/mm3 CD4 cell counts without PCP prophylaxis, one of the two with uncontrolled viremia, provide evidence against systematic PCP prophylaxis in PLHIV with cancer and higher levels of CD4, particularly if there is controlled viremia. Our results conflict with the European AIDS Clinical Society (http://www.eacsociety.org) and the British HIV association guidelines (30), in which PCP prophylaxis is suggested in PLHIV with solid cancers, irrespective of CD4 counts. However, proven PCP in uninfected subjects with solid organ malignancies and chemotherapy have been published (31, 32), including a PLHIV with a CD4 count > 500 cells/mm3 who was not taking ART (33). Thus, if prophylaxis is not used, clinicians should be aware of the possibility of PCP when confronted with interstitial lung disease, even in patients with high CD4 counts. The association between OIs and uncontrolled HIV-viremia highlights the importance of continuing effective ART in all PLHIV with cancer, carefully selecting for antiretrovirals that minimize 13 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 plasma cell disorders is unknown, but herpes zoster cases generally occurred in patients without these interactions with cytotoxic agents. Comorbidity burden was also independently associated with OI risk, and may reflect PLHIV populations that may have ongoing immune dysfunction despite CD4 recovery, as these more subtle immune disturbances have also been associated with the risk of noncancer comorbidities (34). Veterans, justifying the use of IPW to account for non-HIV related factors that may have contributed to imbalances in OI risk. Chemotherapy types were not accounted for in our adjustments, and there may have been differences in frequencies and doses of administration, and number of cycles by HIV status. However, chemotherapy characteristics were indirectly accounted for by tumor type, age, and comorbidity burden, as these factors help guide cancer therapeutic strategies, and were included in the calculation of the IPW scheme. Adjustment on PCP prophylaxis further accounted for chemotherapeutic associated risk for PCP and toxoplasmosis infection (10, 11). We did not assess for OI incidence beyond six months after chemotherapy administration, nor did we specifically evaluate the risk of OIs after radiotherapy. Studies on CD4 depletion post cancer treatments in PLHIV have shown a fast recovery of CD4 counts after chemotherapy interruption within six months, but possible prolonged depletion particularly after radiotherapy (14-16). Furthermore, cervical cancers were absent from our analysis, as nearly all Veterans were men, and our conclusions may not be generalizable to all HIV populations. Last, we did not account for other sources of immunosuppression outside of HIV and cancer-related factors. The strengths of our study reside in its large, national, well-characterized cohort of Veterans thanks to the different VA databases derived from extensive, long-standing electronic health record systems, and the systematic chart review by an Infectious Diseases specialist of all OI cases in Veterans with cancer. 14 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Our study has some limitations. Underlying cancer risk differs among PLHIV and uninfected In conclusion, our study showed increased risk of incident OIs in the 6 months following chemotherapy in PLHIV with hematological and non-hematological malignancies compared to uninfected veterans. A statistically significant increased risk did not persist in PLHIV with CD4 counts > 200/mm3 and controlled viremia. Most OIs reported were esophagitis candida and herpes zoster. Our study does not support systematic PCP prophylaxis in solid tumors in PLHIV with CD4 > Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 200 cells/mm3 and controlled viremia. 15 Potential Conflicts of Interest: the authors declare no conflict of interests. Patient Consent Statement: This research was approved by the Yale University School of Medicine Institutional Review Board which granted a waiver of informed consent. donation from Merck Sharp & Dohme (MSD). This research was supported by the National Cancer Institute (R01CA210806) and the National Institute on Alcohol Abuse and Alcoholism (U01AA013566) to support the Veterans Aging Cohort Study 16 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Acknowledgements: AM received a grant from the CMIT (Collège des Maladies Infectieuses), and a Table 1. Baseline characteristics by HIV status for patients with cancer treated with chemotherapy. Characteristics Age (median, IQR) Uninfected Veterans (n=2,106) (n=2,981) p 55 (49-62) 59 (54-64) <0·001 2,077 (98·6) 2,913 (97·7%) 0·02 <0·001 Race/Ethnicity, n (%) Non-Hispanic white 944 (44·8) 1,183 (39·7) Non-Hispanic black 963 (45·7) 1,537 (51·6) Hispanic 147 (7·0) 211 (7·1) Other 52 (2·5) 50 (1·7) <0·001 Smoking, n (%) Never 389 (18·5) 451 (15·1) Current 1,127 (53·5) 1,723 (57·8) Former 324 (15·4) 545 (18·3) Unknown 266 (12·6) 262 (8·8) 1 (0-2) 1 (0-2) 0·8 295 (14·0) 577 (19·4) <0·001 CCI (median, IQR)* Alcohol Use Disorder, n (%) <0·001 Malignancies, n (%) Hematological Non-hematological PCP prophylaxis use, n (%) 639 (30·3) 469 (15·7) 1,467 (69·7) 2,512 (84·3) 638 (30·3) 124 (4·2) NA HIV-related characteristics Recent CD4, <0·001 cells/mm3, median 287 (140-506) NA 1,302 (68·7) NA (IQR) Controlled viremia (< 500 copies/mL)(%) 17 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Male, n (%) PLHIV CD4 count >200 cells/mm3 (%) CD4 count >200 cells/mm3 and 1,441 (68·4) NA 909 (43·2) NA 161 (7·6) NA controlled viremia (%) CD4 count controlled >200 cells/mm3 and viremia and PCP CCI : Charlson Comorbidity Index. IQR: Intraquartile range. PCP: pneumocystic jirovecii pneumonia. * Our modified CCI omits AIDS, solid or non-solid cancer diagnoses. 18 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 prophylaxis (%) Table 2: Comparison of incidence rates and adjusted rate ratios of first Opportunistic infection in all cancers, and according to hematological and non-hematological cancers in PLHIV and Uninfected veterans. Incidence rates and ratios of first OI in all cancers OI Incidence rate/1000 p-y first OI) (95%CI) PLHIV Uninfected (n=2,106) (n=2,981) PLHIV Uninfected IRR for 95% CI PLHIV* 89·0 (71·378 (3·7%) 23 (0·8%) 17·8 (11·9-26·9) 4·8 2·8-8·2 111·2) Incidence rates and ratios of first OI in hematological cancers PLHIV Uninfected (n=639) (n=469) PLHIV Uninfected IRR for 95% CI PLHIV* 142·4 37 (5·8%) 4 (0·9%) (103·2- 19·0 (7·1-50·6) 8·2 2·4-27·3 196·5) Incidence rates and ratios of first OI in non-hematological cancers PLHIV Uninfected (n=1,467) (n=2,512) 41 (2·8%) 219 (8·7%) PLHIV Uninfected IRR for 95% CI PLHIV* 66·6 (49·117·6 (11·2-27·6) 3·9 2·1-7·2 90·4) 19 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Number of events (persons with Incidence rates and ratios of first OI in all cancers for PLHIV with CD4>200 cells/mm 3 compared to all uninfected patients PLHIV Uninfected (n=1,441) (n=2,981) 48 (3·3%) 23 (0·8%) PLHIV Uninfected IRR for 95% CI PLHIV* 17·8 (11·9-26·9) 4·1 2·3-7·2 106·2) Incidence rates and ratios of first OI in all cancers for PLHIV with CD4>200 cells/mm3 and HIV RNA < 500 copies/ml compared to all uninfected patients PLHIV Uninfected (n=909) (n=2,981) 13 (1·4%) 23 (0·8%) PLHIV Uninfected IRR for 95% CI PLHIV* 33·5 (19·417·8 (11·9-26·9) 1·82 0·86-3·90 57·6) OI: Opportunistic infection. P-y: Person-year. IRR: Incidence rate ratio. *Inverse probability weighted and adjusted for PCP prophylaxis use. Total 106 OIs in 101 persons, as some patients had multiple events. OI: Opportunistic infection. CMV: Cytomegalovirus 20 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 80·0 (60·3- Table 3· Adjusted Poisson regression model predicting opportunistic infection incidence in PLHIV Characteristics Incidence Rate 95% CI p Ratio 1·01 0·99-1·04 0·30 Male 0·55 0·07-4·09 0·55 Non-Hispanic white Reference Reference Reference Non-Hispanic black 0·98 0·59-1·64 0·95 Hispanic 1·43 0·67-3·05 0·36 Other 1·22 0·28-5·31 0·79 Reference Reference Reference Current 0·92 0·51-1·63 0·77 Former 1·40 0·71-2·74 0·33 1·17 1·01-1·35 0·04 Reference Reference Reference 1·35 0·83-2·20 0·22 Reference Reference Reference 350-500 1·67 0·78-3·60 0·19 200-349 0·95 0·44-2·10 0·89 100-199 0·50 0·20-1·24 0·13 50-100 0·44 0·14-1·31 0·14 Race/Ethnicity Smoking Never Charlson comorbidity index Malignancy type Non-Hematological Hematological HIV-related characteristics Recent CD4, cells/mm3 >500 21 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Age <50 1·21 0·53-2·76 0·65 Uncontrolled viremia 11·82 6·25-22·35 <0·001 PCP prophylaxis use 1·48 0·88-2·48 0·13 PCP: Pneumocystis jirovecii pneumonia Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 22 Figure 1. Incidence of opportunistic infections (OI) after cancer chemotherapy by HIV status during four time periods: 1996-2000, 2001-2006, 2007-2012, 2013-2017. Incidence was highest for PLHIV in 2001-2006 and then declined. Adjusted incidence rate ratios (inverse probability weighted and adjusted for PCP prophylaxis use) for OIs for PLHIV versus uninfected also shown (red triangles) and was highest in 2001-2006, with a decline for subsequent periods (see main text for further details). proportion with HIV-control (HIV<500 copies/mL) (2c) during study time periods at cancer diagnosis for Veterans with HIV during study time periods. 23 Downloaded from https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab389/6324075 by guest on 19 July 2021 Figure 2. Trends in age (2a), median CD4 count (2b), proportion of hematological cancers and REFERENCES 1. Kowalska JD, Reekie J, Mocroft A, Reiss P, Ledergerber B, Gatell J, et al. 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