Publications

2018

Coghill AES, J. M.; Mahkoul, Z.; Orem, J.; Phipps, W.; Casper, C. Omega-3 decreases IL-6 levels in HIV and human herpesvirus-8 coinfected patients in Uganda. AIDS (London, England). 2018;32(4):505-12. Epub 2018/01/31. doi: 10.1097/qad.0000000000001722. PubMed PMID: 29381560.

Lombardo KAC, D. G.; Morales, A. J.; Carlson, C. S.; Towlerton, A. M. H.; Gerdts, S. E.; Nkrumah, F. K.; Neequaye, J.; Biggar, R. J.; Orem, J.; Casper, C.; Mbulaiteye, S. M.; Bhatia, K. G.; Warren, E. H. High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis. Blood advances. 2017;1(9):535-44. Epub 2018/01/04. doi: 10.1182/bloodadvances.2016000794. PubMed PMID: 29296973; PubMed Central PMCID: PMCPMC5728594 Inc. The remaining authors declare no competing financial interests.

Menon MC, A.; Mutyaba, I.; Okuku, F.; Phipps, W.; Harlan, J.; Orem, J.; Casper, C. Whom to treat? Factors associated with chemotherapy recommendations and outcomes among patients with NHL at the Uganda Cancer Institute. PloS one. 2018;13(2):e0191967. Epub 2018/02/02. doi: 10.1371/journal.pone.0191967. PubMed PMID: 29389998; PubMed Central PMCID: PMCPMC5794100.

2017

Coghill AES, J. M.; Mahkoul, Z.; Orem, J.; Phipps, W.; Casper, C. Omega-3 decreases interleukin-6 levels in HIV and HHV-8 co-infected patients: results from a randomized supplementation trial in Uganda. AIDS (London, England). 2017. Epub 2017/12/15. doi: 10.1097/qad.0000000000001722. PubMed PMID: 29239890.

Johnston CM, A.; Roychoudhury, P.; Greninger, A. L.; Reeves, D.; Schiffer, J.; Jerome, K. R.; Sather, C.; Diem, K.; Lingappa, J. R.; Celum, C.; Koelle, D. M.; Wald, A. Dual-strain genital herpes simplex virus type 2 (HSV-2) infection in the US, Peru, and 8 countries in sub-Saharan Africa: A nested cross-sectional viral genotyping study. PLoS medicine. 2017;14(12):e1002475. Epub 2017/12/28. doi: 10.1371/journal.pmed.1002475. PubMed PMID: 29281620; PubMed Central PMCID: PMCPMC5744910.

Low DM, E. C.; Menon, M.; Lyman, G. H.; Ddungu, H.; Namukwaya, E.; Leng, M.; Casper, C. Chemotherapy Use at the End of Life in Uganda. Journal of global oncology. 2017;3(6):711-9. Epub 2017/12/16. doi: 10.1200/jgo.2016.007385. PubMed PMID: 29244988; PubMed Central PMCID: PMCPMC5735970.

Low DM, E. C.; Menon, M.; Loggers, E.; Ddungu, H.; Leng, M.; Namukwaya, E.; Casper, C. End-of-Life Palliative Care Practices and Referrals in Uganda. Journal of palliative medicine. 2017. Epub 2017/10/24. doi: 10.1089/jpm.2017.0257. PubMed PMID: 29058504.
Matrajt LG, S.; Mayer, B. T.; Krantz, E. M.; Orem, J.; Wald, A.; Corey, L.; Schiffer, J. T.; Casper, C. Virus and host-specific differences in oral human herpesvirus shedding kinetics among Ugandan women and children. Scientific reports. 2017;7(1):13105. Epub 2017/10/14. doi: 10.1038/s41598-017-12994-0. PubMed PMID: 29026166; PubMed Central PMCID: PMCPMC5638921.

Okuku FK, E. M.; Kafeero, J.; Kamya, M. R.; Orem, J.; Casper, C.; Phipps, W. Evaluation of a Predictive Staging Model for HIV-Associated Kaposi Sarcoma in Uganda. Journal of acquired immune deficiency syndromes (1999). 2017;74(5):548-54. Epub 2017/01/21. doi: 10.1097/qai.0000000000001286. PubMed PMID: 28107226; PubMed Central PMCID: PMCPMC5340582.

Seremba ES, V.; Kalibbala, S.; Gray, R. H.; Wawer, M. J.; Nalugoda, F.; Casper, C.; Phipps, W.; Ocama, P.; Serwadda, D.; Thomas, D. L.; Reynolds, S. J. Hepatitis B incidence and prevention with antiretroviral therapy among HIV-positive individuals in Uganda. AIDS (London, England). 2017;31(6):781-6. Epub 2017/01/19. doi: 10.1097/qad.0000000000001399. PubMed PMID: 28099188; PubMed Central PMCID: PMCPMC5380792.
Duggan CD, A. L.; Tsu, V.; Jeronimo, J.; Constant, T. K. H.; Romanoff, A.; Scheel, J. R.; Patel, S.; Gralow, J. R.; Anderson, B. O. Resource-stratified implementation of a community-based breast cancer management programme in Peru. The Lancet Oncology. 2017;18(10):e607-e17. Epub 2017/10/04. doi: 10.1016/s1470-2045(17)30592-2. PubMed PMID: 28971827.

2016

Gantt SO, J.; Krantz, E. M.; Morrow, R. A.; Selke, S.; Huang, M. L.; Schiffer, J. T.; Jerome, K. R.; Nakaganda, A.; Wald, A.; Casper, C.; Corey, L. Prospective Characterization of the Risk Factors for Transmission and Symptoms of Primary Human Herpesvirus Infections Among Ugandan Infants. The Journal of infectious diseases. 2016;214(1):36-44. Epub 2016/02/27. doi: 10.1093/infdis/jiw076. PubMed PMID: 26917575; PubMed Central PMCID: PMCPMC4907408.

Mayer BTM, L.; Casper, C.; Krantz, E. M.; Corey, L.; Wald, A.; Gantt, S.; Schiffer, J. T. Dynamics of Persistent Oral Cytomegalovirus Shedding During Primary Infection in Ugandan Infants. The Journal of infectious diseases. 2016;214(11):1735-43. Epub 2016/09/22. doi: 10.1093/infdis/jiw442. PubMed PMID: 27651417; PubMed Central PMCID: PMCPMC5144733.

Phipps WN-J, E.; Krantz, E. M.; Selke, S.; Huang, M. L.; Kambugu, F.; Orem, J.; Casper, C.; Corey, L.; Wald, A. Genital Herpes Simplex Virus Type 2 Shedding Among Adults With and Without HIV Infection in Uganda. The Journal of infectious diseases. 2016;213(3):439-47. Epub 2015/10/22. doi: 10.1093/infdis/jiv451. PubMed PMID: 26486633; PubMed Central PMCID: PMCPMC4704673.

2015

Mutyaba IP, W.; Krantz, E. M.; Goldman, J. D.; Nambooze, S.; Orem, J.; Wabinga, H. R.; Casper, C. A Population-Level Evaluation of the Effect of Antiretroviral Therapy on Cancer Incidence in Kyadondo County, Uganda, 1999-2008. Journal of acquired immune deficiency syndromes (1999). 2015;69(4):481-6. Epub 2015/04/07. doi: 10.1097/qai.0000000000000620. PubMed PMID: 25844696; PubMed Central PMCID: PMCPMC4483147.

2014

Adebamowo CAC, C.; Bhatia, K.; Mbulaiteye, S. M.; Sasco, A. J.; Phipps, W.; Vermund, S. H.; Krown, S. E. Challenges in the detection, prevention, and treatment of HIV-associated malignancies in low- and middle-income countries in Africa. Journal of acquired immune deficiency syndromes (1999). 2014;67 Suppl 1:S17-26. Epub 2014/08/15. doi: 10.1097/qai.0000000000000255. PubMed PMID: 25117957; PubMed Central PMCID: PMCPMC4392880.

Gray GEM, Z.; Metch, B.; Gilbert, P. B.; Bekker, L. G.; Churchyard, G.; Nchabeleng, M.; Mlisana, K.; Laher, F.; Roux, S.; Mngadi, K.; Innes, C.; Mathebula, M.; Allen, M.; McElrath, M. J.; Robertson, M.; Kublin, J.; Corey, L. Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study. The Lancet Infectious diseases. 2014;14(5):388-96. Epub 2014/02/25. doi: 10.1016/s1473-3099(14)70020-9. PubMed PMID: 24560541; PubMed Central PMCID: PMCPMC4174314
Mackelprang RDC, M.; Thomas, K. K.; Hughes, J. P.; Baeten, J. M.; Wald, A.; Farquhar, C.; Fife, K.; Campbell, M. S.; Kapiga, S.; Gao, X.; Mullins, J. I.; Lingappa, J. R. Host genetic and viral determinants of HIV-1 RNA set point among HIV-1 seroconverters from sub-saharan Africa. Journal of virology. 2015;89(4):2104-11. Epub 2014/12/05. doi: 10.1128/jvi.01573-14. PubMed PMID: 25473042; PubMed Central PMCID: PMCPMC4338863.

Perti TN, M.; Gray, G.; De Bruyn, G.; Selke, S.; Magaret, A.; Huang, M. L.; Velaphi, S.; Corey, L.; Wald, A. Frequent genital HSV-2 shedding among women during labor in Soweto, South Africa. Infectious diseases in obstetrics and gynecology. 2014;2014:258291. Epub 2014/06/26. doi: 10.1155/2014/258291. PubMed PMID: 24963269; PubMed Central PMCID: PMCPMC4054931.
Phipps WS, M.; Selke, S.; Huang, M. L.; Jaoko, W.; Mandaliya, K.; Wald, A.; Casper, C.; McClelland, R. S. Oral HHV-8 replication among women in Mombasa, Kenya. Journal of medical virology. 2014;86(10):1759-65. Epub 2014/04/03. doi: 10.1002/jmv.23941. PubMed PMID: 24692069; PubMed Central PMCID: PMCPMC4289619.

2013

Cardoso FB, N.; Distelhorst, S. R.; Bevilacqua, J. L.; Ginsburg, O.; Grunberg, S. M.; Gralla, R. J.; Steyn, A.; Pagani, O.; Partridge, A. H.; Knaul, F. M.; Aapro, M. S.; Andersen, B. L.; Thompson, B.; Gralow, J. R.; Anderson, B. O. Supportive care during treatment for breast cancer: resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement. Breast (Edinburgh, Scotland). 2013;22(5):593-605. Epub 2013/09/05. doi: 10.1016/j.breast.2013.07.050. PubMed PMID: 24001709.

Cleary JD, H.; Distelhorst, S. R.; Ripamonti, C.; Rodin, G. M.; Bushnaq, M. A.; Clegg-Lamptey, J. N.; Connor, S. R.; Diwani, M. B.; Eniu, A.; Harford, J. B.; Kumar, S.; Rajagopal, M. R.; Thompson, B.; Gralow, J. R.; Anderson, B. O. Supportive and palliative care for metastatic breast cancer: resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement. Breast (Edinburgh, Scotland). 2013;22(5):616-27. Epub 2013/08/27. doi: 10.1016/j.breast.2013.07.052. PubMed PMID: 23972474.

Coghill AEN, P. A.; Madeleine, M. M.; Richardson, B. A.; Mutyaba, I.; Okuku, F.; Phipps, W.; Wabinga, H.; Orem, J.; Casper, C. Contribution of HIV infection to mortality among cancer patients in Uganda. AIDS (London, England). 2013;27(18):2933-42. Epub 2013/08/08. doi: 10.1097/01.aids.0000433236.55937.cb. PubMed PMID: 23921614; PubMed Central PMCID: PMCPMC4319357.

Ganz PAY, C. H.; Gralow, J. R.; Distelhorst, S. R.; Albain, K. S.; Andersen, B. L.; Bevilacqua, J. L.; de Azambuja, E.; El Saghir, N. S.; Kaur, R.; McTiernan, A.; Partridge, A. H.; Rowland, J. H.; Singh-Carlson, S.; Vargo, M. M.; Thompson, B.; Anderson, B. O. Supportive care after curative treatment for breast cancer (survivorship care): resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement. Breast (Edinburgh, Scotland). 2013;22(5):606-15. Epub 2013/09/07. doi: 10.1016/j.breast.2013.07.049. PubMed PMID: 24007941.

2012

de Bruyn GM, A.; Baeten, J. M.; Lingappa, J. R.; Ndase, P.; Celum, C.; Wald, A. Mortality in members of HIV-1 serodiscordant couples in Africa and implications for antiretroviral therapy initiation: results of analyses from a multicenter randomized trial. BMC infectious diseases. 2012;12:277. Epub 2012/11/08. doi: 10.1186/1471-2334-12-277. PubMed PMID: 23130818; PubMed Central PMCID: PMCPMC3582549.

2011

El Saghir NSA, C. A.; Anderson, B. O.; Carlson, R. W.; Bird, P. A.; Corbex, M.; Badwe, R. A.; Bushnaq, M. A.; Eniu, A.; Gralow, J. R.; Harness, J. K.; Masetti, R.; Perry, F.; Samiei, M.; Thomas, D. B.; Wiafe-Addai, B.; Cazap, E. Breast cancer management in low resource countries (LRCs): consensus statement from the Breast Health Global Initiative. Breast (Edinburgh, Scotland). 2011;20 Suppl 2:S3-11. Epub 2011/03/12. doi: 10.1016/j.breast.2011.02.006. PubMed PMID: 21392996.

Harford JBO, I. V.; Anderson, B. O.; Cazap, E.; Gradishar, W. J.; Gralow, J. R.; Kane, G. M.; Niens, L. M.; Porter, P. L.; Reeler, A. V.; Rieger, P. T.; Shockney, L. D.; Shulman, L. N.; Soldak, T.; Thomas, D. B.; Thompson, B.; Winchester, D. P.; Zelle, S. G.; Badwe, R. A. Problem solving for breast health care delivery in low and middle resource countries (LMCs): consensus statement from the Breast Health Global Initiative. Breast (Edinburgh, Scotland). 2011;20 Suppl 2:S20-9. Epub 2011/03/08. doi: 10.1016/j.breast.2011.02.007. PubMed PMID: 21376593.

2010

Gantt SK, A.; Wald, A.; Walusansa, V.; Corey, L.; Casper, C.; Orem, J. Clinical presentation and outcome of epidemic Kaposi sarcoma in Ugandan children. Pediatric blood & cancer. 2010;54(5):670-4. Epub 2010/03/06. doi: 10.1002/pbc.22369. PubMed PMID: 20205254; PubMed Central PMCID: PMCPMC2839022.

Phipps WS, F.; Nguyen, H.; Saracino, M.; Wald, A.; Corey, L.; Orem, J.; Kambugu, A.; Casper, C. Gender differences in clinical presentation and outcomes of epidemic Kaposi sarcoma in Uganda. PloS one. 2010;5(11):e13936. Epub 2010/11/26. doi: 10.1371/journal.pone.0013936. PubMed PMID: 21103057; PubMed Central PMCID: PMCPMC2980479

2009

Johnston CO, J.; Okuku, F.; Kalinaki, M.; Saracino, M.; Katongole-Mbidde, E.; Sande, M.; Ronald, A.; McAdam, K.; Huang, M. L.; Drolette, L.; Selke, S.; Wald, A.; Corey, L.; Casper, C. Impact of HIV infection and Kaposi sarcoma on human herpesvirus-8 mucosal replication and dissemination in Uganda. PloS one. 2009;4(1):e4222. Epub 2009/01/22. doi: 10.1371/journal.pone.0004222. PubMed PMID: 19156206; PubMed Central PMCID: PMCPMC2625442.

2008

Abu-Raddad LJM, A. S.; Celum, C.; Wald, A.; Longini, I. M., Jr.; Self, S. G.; Corey, L. Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa. PloS one. 2008;3(5):e2230. Epub 2008/05/22. doi: 10.1371/journal.pone.0002230. PubMed PMID: 18493617; PubMed Central PMCID: PMCPMC2377333.

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Haematological Care Priorities in sub-Saharan Africa 3 Haematological malignancies in sub-Saharan Africa: east Africa as an example for improving care

Lancet Haematol

2021 Nixon Niyonzima; Katherine Tarlock; Thomas Uldrick; Henry Ddungu; Clement Okello; Jackson Orem; Abrahams Omoding

Haematological malignancies account for almost 10% of all cancers diagnosed in sub-Saharan Africa, although the exact incidences and treatment outcomes are difficult to discern because population-based cancer registries in the region are still underdeveloped. More research on haematological malignancies in sub-Saharan Africa is required to establish whether these cancers have a natural history similar to those diagnosed in high-income countries, about which more is known. Several factors negatively affect the outcome of haematological malignancies in sub-Saharan Africa, showcasing a need for improved understanding of the clinicobiological profile of these cancers to facilitate prevention, early detection, diagnosis, and appropriate treatment through increased capacity building, infrastructure, community awareness, coordinated resource mobilisation, and collaboration across the world. The east African governments have pooled resources for common investments to tackle non-communicable diseases, developing the East Africa's Centres of Excellence for Skills and Tertiary Education project funded by the African Development Bank, an initiative that could be replicated for the care of haematological malignancies in other countries in sub-Saharan Africa. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Factors and Outcomes Related to the Use of Guideline-Recommended Antibiotics in Patients With Neutropenic Fever at the Uganda Cancer Institute

Open Forum Infect Dis

2021 Scott Adams; Warren Phipps; Catherine Liu; Abrahams Omoding; Elizabeth Gulleen

Background: Neutropenic fever (NF) is associated with significant morbidity and mortality for patients receiving cancer treatment in sub-Saharan Africa (sSA). However, the antibiotic management of NF in sub-Saharan Africa has not been well described. We evaluated the timing and selection of antibiotics for patients with NF at the Uganda Cancer Institute (UCI). Methods: We conducted a retrospective chart review of adults with acute leukemia admitted to UCI from 1 January 2016 to 31 May 2017, who developed NF. For each NF event, we evaluated the association of clinical presentation and demographics with antibiotic selection as well as time to both initial and guideline-recommended antibiotics. We also evaluated the association between ordered antibiotics and the in-hospital case fatality ratio (CFR). Results: Forty-nine NF events occurred among 39 patients. The time to initial antibiotic order was <1 day. Guideline-recommended antibiotics were ordered for 37 (75%) NF events. The median time to guideline-recommended antibiotics was 3 days. Fever at admission, a documented physical examination, and abdominal abnormalities were associated with a shorter time to initial and guideline-recommended antibiotics. The in-hospital CFR was 43%. There was no difference in in-hospital mortality when guideline-recommended antibiotics were ordered as compared to when non-guideline or no antibiotics were ordered (hazard ratio, 0.51 [95% confidence interval {CI}, .10-2.64] and 0.78 [95% CI, .20-2.96], respectively). Conclusions: Patients with acute leukemia and NF had delayed initiation of guideline-recommended antibiotics and a high CFR. Prospective studies are needed to determine optimal NF management in sub-Saharan Africa, including choice of antibiotics and timing of antibiotic initiation.

COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies

J Immunother Cancer

2021 Jason Goldman; Thomas Uldrick

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. COVID-19 has highly variable disease severity and a bimodal course characterized by acute respiratory viral infection followed by hyperinflammation in a subset of patients with severe disease. This immune dysregulation is characterized by lymphocytopenia, elevated levels of plasma cytokines and proliferative and exhausted T cells, among other dysfunctional cell types. Immunocompromised persons often fare worse in the context of acute respiratory infections, but preliminary data suggest this may not hold true for COVID-19. In this review, we explore the effect of SARS-CoV-2 infection on mortality in four populations with distinct forms of immunocompromise: (1) persons with hematological malignancies (HM) and hematopoietic stem cell transplant (HCT) recipients; (2) solid organ transplant recipients (SOTRs); (3) persons with rheumatological diseases; and (4) persons living with HIV (PLWH). For each population, key immunological defects are described and how these relate to the immune dysregulation in COVID-19. Next, outcomes including mortality after SARS-CoV-2 infection are described for each population, giving comparisons to the general population of age-matched and comorbidity-matched controls. In these four populations, iatrogenic or disease-related immunosuppression is not clearly associated with poor prognosis in HM, HCT, SOTR, rheumatological diseases, or HIV. However, certain individual immunosuppressants or disease states may be associated with harmful or beneficial effects, including harm from severe CD4 lymphocytopenia in PLWH and possible benefit to the calcineurin inhibitor ciclosporin in SOTRs, or tumor necrosis factor-α inhibitors in persons with rheumatic diseases. Lastly, insights gained from clinical and translational studies are explored as to the relevance for repurposing of immunosuppressive host-directed therapies for the treatment of hyperinflammation in COVID-19 in the general population.

Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases

Blood Adv

2021 Thomas Uldrick

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Washout Period and Concomitant Medication Work Group

Clin Cancer Res

2021 Thomas Uldrick

PURPOSE: Washout periods and concomitant medication exclusions are common in cancer clinical trial protocols. These exclusion criteria are often applied inconsistently and without evidence to justify their use. The authors sought to determine how washout period and concomitant medication allowances can be broadened to speed trial enrollment and improve the generalizability of trial data to a larger oncology practice population without compromising the safety of trial participants. EXPERIMENTAL DESIGN: A multistakeholder working group was convened to define problems associated with excessively long washout periods and exclusion of patients due to concomitant medications. The group performed a literature search and evaluated study data from the Pancreatic Cancer Action Network (PanCAN), Emory University School of Medicine (Atlanta, GA), and the FDA to understand recent approaches to these eligibility criteria. The group convened to develop consensus recommendations for broadened eligibility criteria. RESULTS: The data analysis found that exclusion criteria based on washout periods and concomitant medications are frequently inconsistent and lack scientific rationale. Scientific rationale for appropriate eligibility criteria are presented in the article; for washout periods, rationale is presented by treatment type. CONCLUSIONS: Arbitrary or blanket washout and concomitant medication exclusions should be eliminated. Where there is evidence to support them, clinically relevant washout periods and concomitant medication-related eligibility criteria may be included.

Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO-Friends of Cancer Research Joint Research Statement

Clin Cancer Res

2021 Thomas Uldrick

PURPOSE: Restrictive clinical trial eligibility criteria (EC) limit the number of patients who can enroll and potentially benefit from protocol-driven, investigational treatment plans and reduce the generalizability of trial results to the broader population. Following publication of expert stakeholder recommendations for broadening EC in 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) convened working groups to produce additional recommendations and analyze the potential impact on clinical trials using real-world data. EXPERIMENTAL DESIGN: Multistakeholder working groups were appointed by an ASCO-Friends leadership group to propose recommendations for more inclusive EC related to: washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status. RESULTS: The four working groups, ASCO Board of Directors, and Friends leadership support the recommendations included in this statement to modernize EC related to washout periods, concomitant medications, prior therapies, laboratory references ranges and test intervals, and performance status to make trial populations more inclusive and representative of cancer patient populations. CONCLUSIONS: Implementation of the recommendations is intended to result in greater ease of determining patient eligibility. Increased opportunities for patient participation in research will help address longstanding underrepresentation of certain groups in clinical trials and produce evidence that is more informative for a broader patient population. More patients eligible will also likely speed clinical trial accrual.

Impact of Broadening Trial Eligibility Criteria for Patients with Advanced Non-Small Cell Lung Cancer: Real-World Analysis of Select ASCO-Friends Recommendations

Clin Cancer Res

2021 Thomas Uldrick

PURPOSE: Cancer clinical trials often accrue slowly or miss enrollment targets. Strict eligibility criteria are a major reason. Restrictive criteria also limit opportunities for patient participation while compromising external validity of trial results. We examined the impact of broadening select eligibility criteria on characteristics and number of patients eligible for trials, using recommendations of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research. EXPERIMENTAL DESIGN: A retrospective, observational analysis used electronic health record data from ASCO's CancerLinQ Discovery database. Study cohort included patients with advanced non-small cell lung cancer treated from 2011 to 2018. Patients were grouped by traditional criteria [no brain metastases, no other malignancies, and creatinine clearance (CrCl)&nbsp; 60 mL/minute] and broadened criteria (including brain metastases, other malignancies, and CrCl&nbsp; 30 mL/minute). RESULTS: The analysis cohort included 10,500 patients. Median age was 68 years, and 73% of patients were White. Most patients had stage IV disease (65%). A total of 5,005 patients (48%) would be excluded from trial participation using the traditional criteria. The broadened criteria, however, would allow 98% of patients (10,346) to be potential participants. Examination of patients included by traditional criteria (5,495) versus those added (4,851) by broadened criteria showed that the number of women, patients aged 75+ years, and those with stage IV cancer was significantly greater using broadened criteria. CONCLUSIONS: This analysis of real-world data demonstrated that broadening three common eligibility criteria has the potential to double the eligible patient population and include trial participants who are more representative of those encountered in practice.

Impact of Antiretroviral Therapy on Cancer Treatment Outcomes among People Living with HIV in Low- and Middle-Income Countries: a Systematic Review

Curr HIV/AIDS Rep

2021 Thomas Uldrick; Rachel Bender Ignacio

PURPOSE OF REVIEW: The relationship between antiretroviral therapy (ART) and cancer treatment outcomes among people living with HIV (PLWH) in low- and middle-income countries (LMICs) is complex and poorly understood for many cancers. We aimed to summarize existing evidence from LMICs regarding the benefit of ART on cancer treatment-related outcomes. RECENT FINDINGS: We included twelve observational studies that reported associations between ART status and cancer treatment outcomes among HIV-positive patients in LMICs. Most confirmed ART was associated with improved cancer treatment outcomes. Heterogeneity in cancers under study, outcome measurement, categorization of ART status, and reporting of HIV-related immune function made formal comparison between studies untenable. Where evaluated, ART generally has a positive effect on cancer outcomes in people with HIV in LMICs. However, there remains a substantial gap in the literature regarding the impact of ART on treatment outcomes for most cancer types. Future research should focus on the optimal timing and integration of ART and cancer treatment for PLWH with strategies applicable to constrained-resource settings.

Use of pembrolizumab with or without pomalidomide in HIV-associated non-Hodgkin's lymphoma

J Immunother Cancer

2021 Martin Cheever; Thomas Uldrick

BACKGROUND: Non-Hodgkin's lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control. METHODS: We conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumabpomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute. RESULTS: We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200mg intravenously every 3 weeks, three received pembrolizumab 200mg intravenously every 4 weeks plus pomalidomide 4mg orally every day for days 1-21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95%CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2-3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide. CONCLUSIONS: Treatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL.

Immune response to the hepatitis B vaccine among HIV-infected adults in Uganda

Vaccine

2021 Warren Phipps; Scott Adams; Emmanuel Seremba; Corey Casper; Jackson Orem

BACKGROUND: Co-infection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) is common in sub-Saharan Africa (SSA) and can rapidly progress to cirrhosis and hepatocellular carcinoma. Recent data demonstrate ongoing HBV transmission among HIV-infected adults in SSA, suggesting that complications of HIV/HBV co-infection could be prevented with HBV vaccination. Because HBV vaccine efficacy is poorly understood among HIV-infected persons in SSA, we sought to characterize the humoral response to the HBV vaccine in HIV-seropositive Ugandan adults. METHODS: We enrolled HIV-infected adults in Kampala, Uganda without serologic evidence of prior HBV infection. Three HBV vaccine doses were administered at 0, 1 and 6months. Anti-HBs levels were measured 4weeks after the third vaccine dose. "Response" to vaccination was defined as anti-HBs levels10IU/L and "high response" as100IU/L. Regression analysis was used to determine predictors of response. RESULTS: Of 251 HIV-positive adults screened, 132 (53%) had no prior HBV infection or immunity and were enrolled. Most participants were women [89 (67%)]; median (IQR) age was 32years (27-41), and 68 (52%) had received antiretroviral therapy (ART) for>3months. Median (IQR) CD4 count was 426 (261-583), and 64 (94%) of the 68 receiving ART had undetectable plasma HIV RNA. Overall, 117 (92%) participants seroconverted to the vaccine (anti-HBs10IU/L), with 109 (86%) participants having high-level response (anti-HBs100IU/L). In multivariate analysis, only baseline CD4>200 cells/mm3 was associated with response [OR=6.97 (1.34-34.71), p=0.02] and high-level response [OR=4.25 (1.15-15.69)], p=0.03]. CONCLUSION: HBV vaccination was effective in eliciting a protective humoral response, particularly among those with higher CD4 counts. Half of the screened patients did not have immunity to HBV infection, suggesting a large at-risk population for HBV infection among HIV-positive adults in Uganda. Our findings support including HBV vaccination as part of routine care among HIV-positive adults.