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Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1(PD-L1) Inhibitor Therapy in HIV Patients with Advanced Cancer

Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1(PD-L1) Inhibitor... Hindawi Journal of Oncology Volume 2019, Article ID 2989048, 5 pages https://doi.org/10.1155/2019/2989048 Research Article Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1(PD-L1) Inhibitor Therapy in HIV Patients with Advanced Cancer 1 2 2 3 Shahla Bari , Austin Chan, Sanjay R. Jain, and Christopher J. Hostler Internal Medicine, Morehouse School of Medicine, Atlanta GA, USA Morehouse School of Medicine, Atlanta GA, USA Division of Infectious Diseases, Duke University Health System, Durham VA Health Care System, Durham NC, USA Correspondence should be addressed to Shahla Bari; shahlabari19@gmail.com Received 18 June 2018; Revised 13 November 2018; Accepted 2 December 2018; Published 1 January 2019 Academic Editor: Akira Hara Copyright © 2019 Shahla Bari et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Due to HAART and consequent decline in mortality from infectious complications, HIV patients have an increasing burden of non-AIDS defining cancers. Data on their safety and efficacy is unknown as these patients were excluded from clinical trials due to concern of unforeseen side effects. Objectives. eTh main objective of our study was to evaluate the efficacy and safety profile of PD-1 and PD-L1 inhibitors in HIV patients being treated for advanced cancers and to assess the impact of these drugs on HIV status of the patients specifically CD4 count and HIV viral load. Materials and Methods. iTh s wasa retrospective analysisofdata of 17 patients HIV treated with one of the PD-1/PD-L1 inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, or Avelumab) for advanced cancer. Results. 10 out of 17 patients responded to therapy. 7 patients, all of whom had shown response to therapy, were alive and 4 were still on checkpoint inhibitor. 10 patients including all 7 nonresponders had died. Responders had minimum of 15 weeks of response while one had ongoing continued response at 34 weeks. Side effects were seen in 7 patients and only one patient needed cessation of therapy. CD4 counts were stable on treatment while HIV RNA remained undetectable. Conclusion.PD-1 and PD-L1 inhibitors appear to have comparable efficacy and tolerable side effect profile and have no effect on HIV markers when used in HIV patients with advanced cancers. 1. Introduction PD-1 blockers Nivolumab and Pembrolizumab and PD-L1 blockers Atezolizumab, Avelumab and Durvalumab. They are HIV patients have a 30% to 40% lifetime risk of malignancy, currently approved for nonsmall cell lung cancer (NSCLC), making cancer a major cause of morbidity and mortality in melanoma, bladder cancer, non-Hodgkin's lymphoma, renal this population [1]. Advances in highly active antiretroviral cell cancer, and hepatocellular cancer among the most com- therapy (HAART) have made the life expectancy of HIV mon and areexpected to beapproved for more in the patients similar to the general population [2], causing a future. In HIV patients, studies have shown an increased marked growth in the burden of HIV patients with cancer. expression of PD-1 on HIV-positive CD8 cells and its level Despite a dramatic decline in acquired immune deficiency correlated directly with disease progression and viremia [4]. syndrome (AIDS) defining cancers, AIDS patients continue As immune checkpoints play an important role in host to have elevated rates of lung, prostate, anal, and hepatocellu- response to chronic infections like HIV, trials involving these lar carcinoma and Hodgkin’s lymphoma [3]. drugs have typically excluded HIV patients due to concern Checkpoint inhibitors are revolutionizing cancer therapy. for unforeseen side effects. Further, the effect of immune Checkpoint inhibitors that have been approved by the Food checkpoint inhibitors on HIV suppression is unknown. Here and Drug Administration (FDA) include cytotoxic T lym- we present our experience with the use of PD-1 and PD-L1 phocyte associated protein 4 (CTLA-4) blocker Ipilimumab, inhibitors in HIV patients with advanced cancers. 2 Journal of Oncology 2. Materials and Methods response could be assessed and two had progressive dis- ease on therapy. Both patients with hepatocellular cancer This is a retrospective evaluation of HIV patients treated responded, one had PR and the other SD. One patient with with a PD-1 or PD-L1 inhibitor at Grady Memorial Hospital, renal cell carcinoma and one with invasive basal cell also Atlanta, GA, and Duke University Hospital, Durham, NC. responded to therapy. Seven patients did not respond to ther- Institutional approval was obtained at both sites. We eval- apy, of whom 4 died before response could be assessed. There uated HIV patients treated with one of the PD-1 or PD-L1 were 2 anal carcinoma patients, and neither showed response inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Dur- to therapy. At the time of data analysis, 7 patients were alive valumab, or Avelumab) for any cancer. We collected patient (all patients alive had responded to therapy), and 4 are contin- demographics, type and stage of cancer, drug given, response, uing their treatment drug. Of the 4 patients who continue to and side eeff cts. We also looked at type of ARV therapy, be on treatment with continued response, 2 have lung cancer, HIV viral load, and CD4 count trends. We used the response one has hepatocellular cancer, and one has invasive basal cell evaluation criteria in solid tumors (RECIST) to evaluate carcinoma. Ten patients died, including all 7 nonresponders. radiologic response to therapy. Patients were categorized as Eight patients died due to progression of cancer and 2 from responders to therapy if they achieved complete response, sepsis. One of the patients who died from sepsis (patient 2) partial response, or stable disease as per the RECIST criteria died within a few days of getting his first dose of Nivolumab [5]. Safety was assessed by evaluating the incidence of clinical and his cause of death was not attributed to the drug. Patient adverse events and laboratory abnormalities which were 15 had stable disease but stopped Nivolumab after 11 doses due graded according to National Cancer Institute’s Common to disease progression and was placed on a tyrosine kinase Terminology Criteria for Adverse Events (CTCAE v.4.0). inhibitor (TKI). He had stopped HAART (reason unknown), Patients were asked at each visit for occurrence of adverse leading to a drop in CD4 count and rise in HIV viral load. He events known to be associated with use of PD-1/PDL-1 died about 18 weeks after last dose of Nivolumab. inhibitors. yr Th oid and cortisol levels were included with routine labs at each visit. At our infectious disease clinic, HIV viral load, and CD4 counts are checked every 4 to 6 weeks as 5. HIV Markers and Adverse Events part of follow up of HIV patients. At 12 weeks median CD4 count was 402 cells/𝜇 l(range 120-597 cells/𝜇 l) while HIV RNA remained below detection 3. Results threshold in 11 patients whose data was available. One of the patients with low level HIV viremia at the initiation of therapy A total of 17 HIV-positive cancer patients were treated with had complete suppression of HIV RNA with rise in CD4 either a PD-1 or PD-L1 inhibitor. There were 3 females and from 163 to 285 cells/𝜇 l. One patient showed a fall in CD4 14 male patients with a median age of 54 years at cancer count from 150 to 120 cells/𝜇 l, but his viral load remained diagnosis. Lung cancer was the most common cancer seen undetectable and he remains on treatment with a continued in 10 patients. Two patients had hepatocellular cancer, 2 anal partial response. cancers, 1 kidney cancer, 1 Non-Hodgkin’s lymphoma, and 1 Four patients had concomitant hepatitis C and 1 had advanced basal cell carcinoma. Thirteen patients had stage 4 chronic hepatitis B; none experienced reactivation. Nau- disease (Table 1). sea/vomiting (4 patients), thyroid abnormalities (3 hypothy- All patients were receiving HAART with HIV related data roidism and 2 with decreased TSH), and fatigue (2 patients) available for 16 of the 17 patients. Emtricitabine/Tenofovir were themostcommonsideeeff cts(Table 1). One patient and Dolutegravir were the most commonly used HAART (patient 3), who had NSCLC developed pneumonitis after combination used in 7 patients. The median CD4 count at receiving 10th dose, managed with high dose steroids and his initiation of therapy was 425 cells/𝜇 l (range 150-795 cells/𝜇 l). Nivolumab was stopped permanently. One patient developed Low level HIV viremia was detected in 2 patients, while in grade 2 colitis after the 6th dose which recovered with holding the other 14 patients, HIV RNA level was below detection therapy and did not recur with restarting the drug. Both these threshold (Table 2). patients were alive at the time of analysis. The 3 patients Nivolumab was the most commonly used drug (n=13) with hypothyroidism were given thyroid replacement while followed by Pembrolizumab (n=3) and Atezolizumab (n=1). the 2 patients with low TSH had normal free T4 and were PD-L1 expression was tested in 5 patients, of which 3 had monitored periodically. All immune related adverse events expression of less than 1%. One patient had PD-L1 expression were seen between the 3rd and 5th doses of the treatment; of 20% and another of 90%; both received Pembrolizumab. the colitis developed after the 6th dose while pneumonitis developed aeft r the 10th dose of the drug. 4. Outcome The patients received a median of 10 doses of the drug. 6. Discussion Ten patients responded to treatment, of whom 5 had partial response (PR) and 5 had stable disease (SD) (Table 1). In The success of HAART has brought a dramatic improvement the lung cancer group, (the largest group with 10 patients), in HIV control with a steep decline in mortality from 3 patients achieved PR and 3 had SD leading to an overall opportunistic infections and AIDS defining cancers, with response rate (ORR) of 60%. Two patients died before corresponding increased prevalence of non-AIDS defining Journal of Oncology 3 Table 1: Clinical characteristics, response, and toxicity profile of patients. PD-L Cancer Previous lines of Best Patient Age/sex expression. Length of therapy Toxicity (grade) Alive or dead and stage therapy response Other mutation Lung SCC Carbo Tax 2 57/F <1% NA NA D (PD) IV AT - 3 doses Lung ADC Carbo Tax 3 then 40/M NA NA NA D(sepsis) IV Nivo 1 Lobectomy then Cis Lung SCC Docetaxel 1 then 28 weeks. stopped 62/M NA SD Pneumonitis (3) Alive II Carbo Tax 1 then due to pneumonitis Nivo 10 Lung ADC NA Carbo Alimta 4 then Colitis (2) 45/M PR 24 and ongoing Alive IV BRAF V600 Alimta 4 then Nivo 10 Rash (1) Carbo Alimta 4 then Lung ADC 45/F <1% Alimta 13 then Nivo PR 34 weeks Alive IV 17 then Docetaxel Lung SCC Pembro 6 then Carbo 56/M NA SD 16 weeks D(PD) IV Tax 2 Carbo Alimta 4 then Lung ADC 20% Alimta 3 then Pembro Fatigue (1) 55/M SD 22 weeks alive IV HER 2 Neu 7then Trastu + Hypothyroidism Pertuzumab Lung ADC Carbo Alimta 4 then 60/M NA PR 16 and ongoing Elevated TSH alive IV Alimta 10 then Nivo 8 Lung Cis Etopo x5 then 58/M NA PD NA D(PD) mixed IV Nivo 5 Lung ADC 90% Erlotinib 5 months 48/M PD NA D(PD) IV EGFR then Pembro 2 Chemo RT hen Anal SCC 40/F NA CarboTax 5 then Nivo NA NA D (PD) IV Anal SCC Mitomycin Xeloda 54/M NA PD 26 weeks Hypothyroidism D(PD) IV then Nivo 13 Regorafinib 24 then 43/M HCC III NA SD 25 weeks Fatigue (1) D(PD) Nivo 12 RFA, TACE hen Hyperglycemia, 44/M HCC IV NA Soafenib 3 months PR 25 and ongoing Alive Hypothyroidism then Nivo 12 Sorafenib then Sunitinib then 59/M RCC III NA SD 22 weeks Elevated TSH D(sepsis) Everolimus the Nivo 11 then Axitinib RCHOP then RICE 42/M DLBCL IV NA PBSCT then Nivo 10 PD 22 weeks D(PD) then Rev Rtux 1 Invasive Vsmodegib 6 then 24 weeks and 56/M NA PR Elevated TSH alive basal Nivo 10 ongoing Abbreviations: SCC: squamous cell cancer. ADC: adenocarcinoma. RCC: renal cell cancer. HCC: hepatocellular cancer. DLBCL: diffuse large B cell lymp homa. Nivo: Nivolumab. Pembro: Pembrolizumab. AT: Atezolizumab. NA: not available. SD: stable disease. PR: partial response. PD: progressive disease. Carbo Tax: Carboplatin and Paclitaxel. Cis: Cisplatin. Trastu: Trastuzumab. Cis Etopo: Cisplatin Etoposide. RT: Radiation therapy. RFA: radiofrequencyablation. RCHOP: Rituximab, Cyclophosphamide, Adriamycin, Oncovin, Prednisone. RICE: Rituximab, Ifosfamide, Carboplatin, Etoposide. SCT: stem cell transplant. RR: Rituximab, Revlimid. D: Dead. cancers and their emergence as a cause of mortality [6]. The imperative that promising therapeutic options like check- rates of lung and prostate cancer are expected to continue point point inhibitors remain available to this population of increasing in the coming decades [3]. As a result, it is cancer patients. 4 Journal of Oncology Table 2: HIV-related markers while on immune checkpoint inhibitor therapy. CD  (cells/𝜇 l) CD  (cells/𝜇 l) VL (copies/ml) VL (copies/ml) Patient HAART regimen at baseline at  weeks at baseline at  weeks FTC/TDF + DTG 573 NA∗ 0NA∗ EVG/c/FTC/TDF 242 NA∗<400 NA∗ DTG, DRV/r 795 552 <400 0 ABC/DTG/3TC 424 460 0 0 FTC/TDF + DTG 427 402 0 <400 FTC/TDF + DRV 626 517 0 0 ETR, DTG, DRV/r 607 597 <20 <20 EFV/FTC/TDF 305 NA <20 NA FTC/TAF+DTG NANA NANA RPV/FTC/TDF 469 NA∗<20 NA∗ FTC/TDF + DTG 624 NA∗ 500 NA∗ ABC/3TC/DTG 250 262 <20 <20 FTC/TDF + DTG 326 431 0 0 FTC/TDF + DTG 150 120 <20 <20 TDF/RAL 461 376 <400 <400 DRV/c + DTG 163 285 89 <20 FTC/TDF + DTG 264 370 0 <400 Abbreviations: NA: data not available.∗: died before response could be assessed. VL: viral load. HAART regimen: FTC/TDF: emtricitabine/tenofovir disoproxil fumarate. DTG: dolutegravir. EVG/c: elvitegravir/cobicistat. DRV/r: darunavir/ritonavir. ABC: abacavir. 3TC: lamivudine. TDF: tenofovir disoproxil fumarate. RAL: raltegravir. DRV/c: darunavir. ETR: etravirine. EFV: efavirenz. TAF: tenofovir alafenamide. RPV: rilpivirine. Checkpoint inhibitors have induced significant responses and effective in HIV patients with cancer. However, larger studies are needed to address questions about their efficacy in NSCLC [7],melanoma [8],Hodgkin’s lymphoma [9], kidney [10], and bladder cancer [11]. However, due to the role and adverse effect profile in this patient population. Many of PD-1/PD-L1 pathway in chronic HIV infection and fear of clinical trials with Nivolumab in HIV patients with NSCLC unforeseen adverse events, HIV patients were excluded from (NCT03304093) and Pembrolizumab in relapsed refractory these trials. or disseminated neoplasms (NCT02595866) are underway. Several case reports have been published showing the efficacy of PD-1 inhibitors in HIV patients in lung cancer [12– Data Availability 14], Hodgkin’s lymphoma [15], melanoma [16, 17], and anal cancer [18]. In these reports and another large series involving The data used to support the findings of this study are 7 NSCLC patients [19], checkpoint inhibitors were tolerated available from the corresponding author upon request. well. Our series is the largest study so far, comprising 17 patients and encompassing a variety of cancers. The duration Conflicts of Interest of response in our study ranged from 15 weeks to 34 weeks ongoing which is similar to that reported in clinical trials The authors declare that there are no conflicts of interest involving non-HIV patients. In our lung cancer patients, we regarding the publication of this paper. saw response in 60% of patients. Our series is small and retrospective, and we cannot draw definitive conclusions, Acknowledgments but we see excellent tolerability of PD-1/PD-L1 inhibitors in HIV patients. Only 1 patient needed to discontinue the The resultsof thisstudy were presentedas anabstractat drug due to pneumonitis. Nine patients experienced immune the Infectious Disease Society of America, ID week, October, related side effects which were grade 1 or 2 and were easily 2018 at San Francisco CA. managed. None of the patients had reactivation of HIV and all had stable CD4 counts. We did not see any activation References or flare of autoimmune disorders. Our series aims to add to the accumulating knowledge and experience regarding [1] J.-P. Spano, D. Atlan, J.-L. Breau, and D. Farge, “AIDS and the efficacy of checkpoint inhibitors in HIV patients with non-AIDS-related malignancies: A new vexing challenge in cancer. One advantage of our study is the demonstration of HIV-positive patients - Part I: Kaposi’s sarcoma, non-Hodgkin’s benefit across a variety of cancers. In conclusion, our series, lymphoma, and Hodgkin’s lymphoma,” European Journal of though small, shows that anti-PD1 therapy appears to be safe Internal Medicine,vol. 13, no.3, pp. 170–179, 2002. Journal of Oncology 5 [2] H.Samji,A.Cescon,R.S.Hoggetal.,“Closingthegap:increases in HIV-positive patients,” Annals of Oncology,vol.28,no. 12,pp. in life expectancy among treated HIV-positive individuals in 3104–3106, 2017. the United States and Canada,” PLoS ONE, vol.8,no. 12, Article [18] V. K. Morris, M. E. Salem, and H. Nimeiri, “Nivolumab for pre- ID e81355, 2013. viously treated unresectable metastatic anal cancer (NCI9673): [3] M. S.Shiels, J. Y.Islam,P. S.Rosenberg,H. I.Hall,E.Jacobson, a multicentre, single-arm, phase 2 study,” The Lancet Oncology , and E. A. Engels, “Projected Cancer Incidence Rates and Burden vol.18,no.4,pp.446–453,2017. of Incident Cancer Cases in HIV-Infected Adults in the United [19] L. Ostios-Garcia, J. Faig,G. C.Leonardietal.,“Safety and States rTh ough 2030,” Annals of Internal Medicine,vol.168, no. Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With 12, p.866,2018. Non–Small Cell Lung Cancer,” Journal of oTh racic Oncology , [4] J.-Y. Zhang, Z. Zhang, X. Wang et al., “PD-1 up-regulation is vol.13,no. 7,pp.1037–1042,2018. correlated with HIV-specific memory CD8 T-cell exhaustion in typical progressors but not in long-term nonprogressors,” Blood,vol.109, no.11,pp. 4671–4678,2007. [5] E. A. Eisenhauer, P. Therasse, J. Bogaerts et al., “New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1),” European Journal of Cancer, vol.45, no.2, pp. 228– 247, 2009. [6] H.A. Robbins,R.M. Pfeieff r,M. S.Shiels, J. Li,H. I.Hall,and E. A. Engels, “Excess cancers among HIV-infected people in the United States,” Journal of the National Cancer Institute,vol. 107, no.4,2015. [7] H.Borghaei,L.Paz-Ares,L.Hornetal.,“Nivolumabversusdoc- etaxel in advanced nonsquamous non-small-cell lung cancer,” eTh New England Journal of Medicine ,vol.373,no.17,pp. 1627– 1639, 2015. [8] J. D. Wolchok, H. Kluger, M. K. Callahan et al., “Nivolumab plus ipilimumab in advanced melanoma,” eTh New England Journal of Medicine,vol.369,no.11,pp.122–133,2013 (Arabic). [9] A. Younes, A. Santoro, M. Shipp et al., “Nivolumab for classical Hodgkin’s lymphoma aeft r failure of both autologous stem- cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial,” The Lancet Oncology ,vol. 17,no.9,pp.1283–1294, 2016. [10] R. J. Motzer,B. Escudier,and D. F.McDermott,“Nivolumab versus everolimus in advanced renal-cell carcinoma,” The New England Journal of Medicine,vol.373,no.19, pp. 1803–1813,2015. [11] P. Sharma, M. Retz, A. Siefker-Radtke et al., “Nivolumab in metastatic urothelial carcinoma aeft r platinum therapy (Check- Mate 275): a multicentre, single-arm, phase 2 trial,” The Lancet Oncology, vol. 18, no. 3, pp. 312–322, 2017. [12] B. McCullar, T. Alloway, and M. Martin, “Durable complete response to nivolumab in a patient with HIV and metastatic non-small cell lung cancer,” Journal of oTh racic Disease ,vol.9, no.6,pp.E540–E542,2017. [13] M. Hentrich, K. Schipek-Voigt, H. Jag ¨ er et al., “Nivolumab in HIV-related non-small-cell lung cancer,” Annals of Oncology, vol. 28, no. 11, p. 2890, 2017. [14] A. Guihot, A.-G. Marcelin, M.-A. Massiani et al., “Dras- tic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer,” Annals of Oncology,vol. 29,no.2, pp. 517-518, 2018. [15] J.D. Sandoval-Sus,F.Mogollon-Duoff , A. Patel et al., “Nivolumab as salvage treatment in a patient with HIV- related relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy,” Journal for ImmunoeTh rapy of Cancer, vol.5,no. 1, 2017. [16] D.Davar,M. Wilson,C. Pruckner, and J. M.Kirkwood,“PD- 1 Blockade in Advanced Melanoma in Patients with Hepatitis Cand/orHIV,” Case Reports in Oncological Medicine,vol.2015, Article ID 737389, 5 pages, 2015. 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Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1(PD-L1) Inhibitor Therapy in HIV Patients with Advanced Cancer

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Copyright © 2019 Shahla Bari et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Journal of Oncology Volume 2019, Article ID 2989048, 5 pages https://doi.org/10.1155/2019/2989048 Research Article Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1(PD-L1) Inhibitor Therapy in HIV Patients with Advanced Cancer 1 2 2 3 Shahla Bari , Austin Chan, Sanjay R. Jain, and Christopher J. Hostler Internal Medicine, Morehouse School of Medicine, Atlanta GA, USA Morehouse School of Medicine, Atlanta GA, USA Division of Infectious Diseases, Duke University Health System, Durham VA Health Care System, Durham NC, USA Correspondence should be addressed to Shahla Bari; shahlabari19@gmail.com Received 18 June 2018; Revised 13 November 2018; Accepted 2 December 2018; Published 1 January 2019 Academic Editor: Akira Hara Copyright © 2019 Shahla Bari et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Due to HAART and consequent decline in mortality from infectious complications, HIV patients have an increasing burden of non-AIDS defining cancers. Data on their safety and efficacy is unknown as these patients were excluded from clinical trials due to concern of unforeseen side effects. Objectives. eTh main objective of our study was to evaluate the efficacy and safety profile of PD-1 and PD-L1 inhibitors in HIV patients being treated for advanced cancers and to assess the impact of these drugs on HIV status of the patients specifically CD4 count and HIV viral load. Materials and Methods. iTh s wasa retrospective analysisofdata of 17 patients HIV treated with one of the PD-1/PD-L1 inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, or Avelumab) for advanced cancer. Results. 10 out of 17 patients responded to therapy. 7 patients, all of whom had shown response to therapy, were alive and 4 were still on checkpoint inhibitor. 10 patients including all 7 nonresponders had died. Responders had minimum of 15 weeks of response while one had ongoing continued response at 34 weeks. Side effects were seen in 7 patients and only one patient needed cessation of therapy. CD4 counts were stable on treatment while HIV RNA remained undetectable. Conclusion.PD-1 and PD-L1 inhibitors appear to have comparable efficacy and tolerable side effect profile and have no effect on HIV markers when used in HIV patients with advanced cancers. 1. Introduction PD-1 blockers Nivolumab and Pembrolizumab and PD-L1 blockers Atezolizumab, Avelumab and Durvalumab. They are HIV patients have a 30% to 40% lifetime risk of malignancy, currently approved for nonsmall cell lung cancer (NSCLC), making cancer a major cause of morbidity and mortality in melanoma, bladder cancer, non-Hodgkin's lymphoma, renal this population [1]. Advances in highly active antiretroviral cell cancer, and hepatocellular cancer among the most com- therapy (HAART) have made the life expectancy of HIV mon and areexpected to beapproved for more in the patients similar to the general population [2], causing a future. In HIV patients, studies have shown an increased marked growth in the burden of HIV patients with cancer. expression of PD-1 on HIV-positive CD8 cells and its level Despite a dramatic decline in acquired immune deficiency correlated directly with disease progression and viremia [4]. syndrome (AIDS) defining cancers, AIDS patients continue As immune checkpoints play an important role in host to have elevated rates of lung, prostate, anal, and hepatocellu- response to chronic infections like HIV, trials involving these lar carcinoma and Hodgkin’s lymphoma [3]. drugs have typically excluded HIV patients due to concern Checkpoint inhibitors are revolutionizing cancer therapy. for unforeseen side effects. Further, the effect of immune Checkpoint inhibitors that have been approved by the Food checkpoint inhibitors on HIV suppression is unknown. Here and Drug Administration (FDA) include cytotoxic T lym- we present our experience with the use of PD-1 and PD-L1 phocyte associated protein 4 (CTLA-4) blocker Ipilimumab, inhibitors in HIV patients with advanced cancers. 2 Journal of Oncology 2. Materials and Methods response could be assessed and two had progressive dis- ease on therapy. Both patients with hepatocellular cancer This is a retrospective evaluation of HIV patients treated responded, one had PR and the other SD. One patient with with a PD-1 or PD-L1 inhibitor at Grady Memorial Hospital, renal cell carcinoma and one with invasive basal cell also Atlanta, GA, and Duke University Hospital, Durham, NC. responded to therapy. Seven patients did not respond to ther- Institutional approval was obtained at both sites. We eval- apy, of whom 4 died before response could be assessed. There uated HIV patients treated with one of the PD-1 or PD-L1 were 2 anal carcinoma patients, and neither showed response inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Dur- to therapy. At the time of data analysis, 7 patients were alive valumab, or Avelumab) for any cancer. We collected patient (all patients alive had responded to therapy), and 4 are contin- demographics, type and stage of cancer, drug given, response, uing their treatment drug. Of the 4 patients who continue to and side eeff cts. We also looked at type of ARV therapy, be on treatment with continued response, 2 have lung cancer, HIV viral load, and CD4 count trends. We used the response one has hepatocellular cancer, and one has invasive basal cell evaluation criteria in solid tumors (RECIST) to evaluate carcinoma. Ten patients died, including all 7 nonresponders. radiologic response to therapy. Patients were categorized as Eight patients died due to progression of cancer and 2 from responders to therapy if they achieved complete response, sepsis. One of the patients who died from sepsis (patient 2) partial response, or stable disease as per the RECIST criteria died within a few days of getting his first dose of Nivolumab [5]. Safety was assessed by evaluating the incidence of clinical and his cause of death was not attributed to the drug. Patient adverse events and laboratory abnormalities which were 15 had stable disease but stopped Nivolumab after 11 doses due graded according to National Cancer Institute’s Common to disease progression and was placed on a tyrosine kinase Terminology Criteria for Adverse Events (CTCAE v.4.0). inhibitor (TKI). He had stopped HAART (reason unknown), Patients were asked at each visit for occurrence of adverse leading to a drop in CD4 count and rise in HIV viral load. He events known to be associated with use of PD-1/PDL-1 died about 18 weeks after last dose of Nivolumab. inhibitors. yr Th oid and cortisol levels were included with routine labs at each visit. At our infectious disease clinic, HIV viral load, and CD4 counts are checked every 4 to 6 weeks as 5. HIV Markers and Adverse Events part of follow up of HIV patients. At 12 weeks median CD4 count was 402 cells/𝜇 l(range 120-597 cells/𝜇 l) while HIV RNA remained below detection 3. Results threshold in 11 patients whose data was available. One of the patients with low level HIV viremia at the initiation of therapy A total of 17 HIV-positive cancer patients were treated with had complete suppression of HIV RNA with rise in CD4 either a PD-1 or PD-L1 inhibitor. There were 3 females and from 163 to 285 cells/𝜇 l. One patient showed a fall in CD4 14 male patients with a median age of 54 years at cancer count from 150 to 120 cells/𝜇 l, but his viral load remained diagnosis. Lung cancer was the most common cancer seen undetectable and he remains on treatment with a continued in 10 patients. Two patients had hepatocellular cancer, 2 anal partial response. cancers, 1 kidney cancer, 1 Non-Hodgkin’s lymphoma, and 1 Four patients had concomitant hepatitis C and 1 had advanced basal cell carcinoma. Thirteen patients had stage 4 chronic hepatitis B; none experienced reactivation. Nau- disease (Table 1). sea/vomiting (4 patients), thyroid abnormalities (3 hypothy- All patients were receiving HAART with HIV related data roidism and 2 with decreased TSH), and fatigue (2 patients) available for 16 of the 17 patients. Emtricitabine/Tenofovir were themostcommonsideeeff cts(Table 1). One patient and Dolutegravir were the most commonly used HAART (patient 3), who had NSCLC developed pneumonitis after combination used in 7 patients. The median CD4 count at receiving 10th dose, managed with high dose steroids and his initiation of therapy was 425 cells/𝜇 l (range 150-795 cells/𝜇 l). Nivolumab was stopped permanently. One patient developed Low level HIV viremia was detected in 2 patients, while in grade 2 colitis after the 6th dose which recovered with holding the other 14 patients, HIV RNA level was below detection therapy and did not recur with restarting the drug. Both these threshold (Table 2). patients were alive at the time of analysis. The 3 patients Nivolumab was the most commonly used drug (n=13) with hypothyroidism were given thyroid replacement while followed by Pembrolizumab (n=3) and Atezolizumab (n=1). the 2 patients with low TSH had normal free T4 and were PD-L1 expression was tested in 5 patients, of which 3 had monitored periodically. All immune related adverse events expression of less than 1%. One patient had PD-L1 expression were seen between the 3rd and 5th doses of the treatment; of 20% and another of 90%; both received Pembrolizumab. the colitis developed after the 6th dose while pneumonitis developed aeft r the 10th dose of the drug. 4. Outcome The patients received a median of 10 doses of the drug. 6. Discussion Ten patients responded to treatment, of whom 5 had partial response (PR) and 5 had stable disease (SD) (Table 1). In The success of HAART has brought a dramatic improvement the lung cancer group, (the largest group with 10 patients), in HIV control with a steep decline in mortality from 3 patients achieved PR and 3 had SD leading to an overall opportunistic infections and AIDS defining cancers, with response rate (ORR) of 60%. Two patients died before corresponding increased prevalence of non-AIDS defining Journal of Oncology 3 Table 1: Clinical characteristics, response, and toxicity profile of patients. PD-L Cancer Previous lines of Best Patient Age/sex expression. Length of therapy Toxicity (grade) Alive or dead and stage therapy response Other mutation Lung SCC Carbo Tax 2 57/F <1% NA NA D (PD) IV AT - 3 doses Lung ADC Carbo Tax 3 then 40/M NA NA NA D(sepsis) IV Nivo 1 Lobectomy then Cis Lung SCC Docetaxel 1 then 28 weeks. stopped 62/M NA SD Pneumonitis (3) Alive II Carbo Tax 1 then due to pneumonitis Nivo 10 Lung ADC NA Carbo Alimta 4 then Colitis (2) 45/M PR 24 and ongoing Alive IV BRAF V600 Alimta 4 then Nivo 10 Rash (1) Carbo Alimta 4 then Lung ADC 45/F <1% Alimta 13 then Nivo PR 34 weeks Alive IV 17 then Docetaxel Lung SCC Pembro 6 then Carbo 56/M NA SD 16 weeks D(PD) IV Tax 2 Carbo Alimta 4 then Lung ADC 20% Alimta 3 then Pembro Fatigue (1) 55/M SD 22 weeks alive IV HER 2 Neu 7then Trastu + Hypothyroidism Pertuzumab Lung ADC Carbo Alimta 4 then 60/M NA PR 16 and ongoing Elevated TSH alive IV Alimta 10 then Nivo 8 Lung Cis Etopo x5 then 58/M NA PD NA D(PD) mixed IV Nivo 5 Lung ADC 90% Erlotinib 5 months 48/M PD NA D(PD) IV EGFR then Pembro 2 Chemo RT hen Anal SCC 40/F NA CarboTax 5 then Nivo NA NA D (PD) IV Anal SCC Mitomycin Xeloda 54/M NA PD 26 weeks Hypothyroidism D(PD) IV then Nivo 13 Regorafinib 24 then 43/M HCC III NA SD 25 weeks Fatigue (1) D(PD) Nivo 12 RFA, TACE hen Hyperglycemia, 44/M HCC IV NA Soafenib 3 months PR 25 and ongoing Alive Hypothyroidism then Nivo 12 Sorafenib then Sunitinib then 59/M RCC III NA SD 22 weeks Elevated TSH D(sepsis) Everolimus the Nivo 11 then Axitinib RCHOP then RICE 42/M DLBCL IV NA PBSCT then Nivo 10 PD 22 weeks D(PD) then Rev Rtux 1 Invasive Vsmodegib 6 then 24 weeks and 56/M NA PR Elevated TSH alive basal Nivo 10 ongoing Abbreviations: SCC: squamous cell cancer. ADC: adenocarcinoma. RCC: renal cell cancer. HCC: hepatocellular cancer. DLBCL: diffuse large B cell lymp homa. Nivo: Nivolumab. Pembro: Pembrolizumab. AT: Atezolizumab. NA: not available. SD: stable disease. PR: partial response. PD: progressive disease. Carbo Tax: Carboplatin and Paclitaxel. Cis: Cisplatin. Trastu: Trastuzumab. Cis Etopo: Cisplatin Etoposide. RT: Radiation therapy. RFA: radiofrequencyablation. RCHOP: Rituximab, Cyclophosphamide, Adriamycin, Oncovin, Prednisone. RICE: Rituximab, Ifosfamide, Carboplatin, Etoposide. SCT: stem cell transplant. RR: Rituximab, Revlimid. D: Dead. cancers and their emergence as a cause of mortality [6]. The imperative that promising therapeutic options like check- rates of lung and prostate cancer are expected to continue point point inhibitors remain available to this population of increasing in the coming decades [3]. As a result, it is cancer patients. 4 Journal of Oncology Table 2: HIV-related markers while on immune checkpoint inhibitor therapy. CD  (cells/𝜇 l) CD  (cells/𝜇 l) VL (copies/ml) VL (copies/ml) Patient HAART regimen at baseline at  weeks at baseline at  weeks FTC/TDF + DTG 573 NA∗ 0NA∗ EVG/c/FTC/TDF 242 NA∗<400 NA∗ DTG, DRV/r 795 552 <400 0 ABC/DTG/3TC 424 460 0 0 FTC/TDF + DTG 427 402 0 <400 FTC/TDF + DRV 626 517 0 0 ETR, DTG, DRV/r 607 597 <20 <20 EFV/FTC/TDF 305 NA <20 NA FTC/TAF+DTG NANA NANA RPV/FTC/TDF 469 NA∗<20 NA∗ FTC/TDF + DTG 624 NA∗ 500 NA∗ ABC/3TC/DTG 250 262 <20 <20 FTC/TDF + DTG 326 431 0 0 FTC/TDF + DTG 150 120 <20 <20 TDF/RAL 461 376 <400 <400 DRV/c + DTG 163 285 89 <20 FTC/TDF + DTG 264 370 0 <400 Abbreviations: NA: data not available.∗: died before response could be assessed. VL: viral load. HAART regimen: FTC/TDF: emtricitabine/tenofovir disoproxil fumarate. DTG: dolutegravir. EVG/c: elvitegravir/cobicistat. DRV/r: darunavir/ritonavir. ABC: abacavir. 3TC: lamivudine. TDF: tenofovir disoproxil fumarate. RAL: raltegravir. DRV/c: darunavir. ETR: etravirine. EFV: efavirenz. TAF: tenofovir alafenamide. RPV: rilpivirine. Checkpoint inhibitors have induced significant responses and effective in HIV patients with cancer. However, larger studies are needed to address questions about their efficacy in NSCLC [7],melanoma [8],Hodgkin’s lymphoma [9], kidney [10], and bladder cancer [11]. However, due to the role and adverse effect profile in this patient population. Many of PD-1/PD-L1 pathway in chronic HIV infection and fear of clinical trials with Nivolumab in HIV patients with NSCLC unforeseen adverse events, HIV patients were excluded from (NCT03304093) and Pembrolizumab in relapsed refractory these trials. or disseminated neoplasms (NCT02595866) are underway. Several case reports have been published showing the efficacy of PD-1 inhibitors in HIV patients in lung cancer [12– Data Availability 14], Hodgkin’s lymphoma [15], melanoma [16, 17], and anal cancer [18]. In these reports and another large series involving The data used to support the findings of this study are 7 NSCLC patients [19], checkpoint inhibitors were tolerated available from the corresponding author upon request. well. Our series is the largest study so far, comprising 17 patients and encompassing a variety of cancers. The duration Conflicts of Interest of response in our study ranged from 15 weeks to 34 weeks ongoing which is similar to that reported in clinical trials The authors declare that there are no conflicts of interest involving non-HIV patients. In our lung cancer patients, we regarding the publication of this paper. saw response in 60% of patients. Our series is small and retrospective, and we cannot draw definitive conclusions, Acknowledgments but we see excellent tolerability of PD-1/PD-L1 inhibitors in HIV patients. Only 1 patient needed to discontinue the The resultsof thisstudy were presentedas anabstractat drug due to pneumonitis. Nine patients experienced immune the Infectious Disease Society of America, ID week, October, related side effects which were grade 1 or 2 and were easily 2018 at San Francisco CA. managed. None of the patients had reactivation of HIV and all had stable CD4 counts. We did not see any activation References or flare of autoimmune disorders. Our series aims to add to the accumulating knowledge and experience regarding [1] J.-P. Spano, D. Atlan, J.-L. Breau, and D. Farge, “AIDS and the efficacy of checkpoint inhibitors in HIV patients with non-AIDS-related malignancies: A new vexing challenge in cancer. 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