Risk for Non–AIDS-Defining and AIDS-Defining Cancer of Early Versus Delayed Initiation of Antiretroviral Therapy: A Multinational Prospective Cohort Study
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Visual Abstract. Non–AIDS-Defining and AIDS-Defining Cancer and Timing of ART Initiation.
This multinational prospective cohort study compared 10-year absolute risks for non–AIDS-defining and AIDS-defining cancer associated with immediate initiation of antiretroviral therapy (ART) versus deferral of ART until 2 thresholds of CD4 count were reached.
Abstract
Background:
Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non–AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 109 cells/L. Consequences of delayed ART on risk for non–AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear.
Objective:
To estimate the long-term risk difference for cancer with the immediate ART strategy.
Design:
Multinational prospective cohort study.
Setting:
The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.
Participants:
8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).
Measurements:
The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non–AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts <350 and <500 × 109 cells/L) ART initiation strategies.
Results:
During 64 021 person-years of follow-up, 231 cases of non–AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non–AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 109 cells/L and less than 350 × 109 cells/L were 0.12 percentage point (CI, −0.01 to 0.26 percentage point) and 0.29 percentage point (CI, −0.03 to 0.73 percentage point), respectively, for non–AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer.
Limitation:
Potential residual confounding due to observational study design.
Conclusion:
In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non–AIDS-defining cancer.
Primary Funding Source:
Highly Active Antiretroviral Therapy Oversight Committee.
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References
1.
Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel. JAMA. 2018;320:379-396. [ 30043070] doi: 10.1001/jama.2018.8431
2.
Guidelines on When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. World Health Organization; 2015.
3.
Lundgren JD, Babiker AG, Gordin F, et al; INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807. [ 26192873] doi: 10.1056/NEJMoa1506816
4.
Le Guillou A, Pugliese P, Raffi F, et al; Dat’AIDS Study Group. Reaching the second and third Joint United Nations Programme on HIV/AIDS 90-90-90 targets is accompanied by a dramatic reduction in primary human immunodeficiency virus (HIV) infection and in recent HIV infections in a large French nationwide HIV cohort. Clin Infect Dis. 2020;71:293-300. [ 31612225] doi: 10.1093/cid/ciz800
5.
Darling KE, Hachfeld A, Cavassini M, et al. Late presentation to HIV care despite good access to health services: current epidemiological trends and how to do better. Swiss Med Wkly. 2016;146:w14348. [ 27544642] doi: 10.4414/smw.2016.14348
6.
Yanik EL, Napravnik S, Cole SR, et al. Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy. Clin Infect Dis. 2013;57:756-64. [ 23735330] doi: 10.1093/cid/cit369
7.
Silverberg MJ, Lau B, Achenbach CJ, et al; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS. Cumulative incidence of cancer among persons with HIV in North America. A cohort study. Ann Intern Med. 2015;163:507-18. doi: 10.7326/M14-2768
8.
Cobucci RN, Lima PH, de Souza PC, et al. Assessing the impact of HAART on the incidence of defining and non-defining AIDS cancers among patients with HIV/AIDS: a systematic review. J Infect Public Health. 2015;8:1-10. [ 25294086] doi: 10.1016/j.jiph.2014.08.003
9.
Shepherd L, Borges Á, Ledergerber B, et al; EuroSIDA in EuroCOORD. Infection-related and -unrelated malignancies, HIV and the aging population. HIV Med. 2016;17:590-600. [ 26890156] doi: 10.1111/hiv.12359
10.
Gjærde LI, Shepherd L, Jablonowska E, et al. Trends in incidences and risk factors for hepatocellular carcinoma and other liver events in HIV and hepatitis C virus-coinfected individuals from 2001 to 2014: a multicohort study. Clin Infect Dis. 2016;63:821-829. [ 27307505] doi: 10.1093/cid/ciw380
11.
Wang Q, De Luca A, Smith C, et al; Hepatitis Coinfection and Non Hodgkin Lymphoma project team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Chronic hepatitis B and C virus infection and risk for non-Hodgkin lymphoma in HIV-infected patients. A cohort study. Ann Intern Med. 2017;166:9-17. doi: 10.7326/M16-0240
12.
Yanik EL, Napravnik S, Cole SR, et al. Relationship of immunologic response to antiretroviral therapy with non-AIDS defining cancer incidence. AIDS. 2014;28:979-87. [ 24681415] doi: 10.1097/QAD.0000000000000167
13.
Worm SW, Bower M, Reiss P, et al; D:A:D Study Group. Non-AIDS defining cancers in the D:A:D Study—time trends and predictors of survival: a cohort study. BMC Infect Dis. 2013;13:471. [ 24106926] doi: 10.1186/1471-2334-13-471
14.
Pacheco YM, Jarrin I, Rosado I, et al; CoRIS. Increased risk of non-AIDS-related events in HIV subjects with persistent low CD4 counts despite cART in the CoRIS cohort. Antiviral Res. 2015;117:69-74. [ 25766861] doi: 10.1016/j.antiviral.2015.03.002
15.
Coghill AE, Shiels MS, Suneja G, et al. Elevated cancer-specific mortality among HIV-infected patients in the United States. J Clin Oncol. 2015;33:2376-83. [ 26077242] doi: 10.1200/JCO.2014.59.5967
16.
Smith CJ, Ryom L, Weber R, et al; D:A:D Study Group. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014;384:241-8. [ 25042234] doi: 10.1016/S0140-6736(14)60604-8
17.
Eyawo O, Franco-Villalobos C, Hull MW, et al; Comparative Outcomes And Service Utilization Trends (COAST) study. Changes in mortality rates and causes of death in a population-based cohort of persons living with and without HIV from 1996 to 2012. BMC Infect Dis. 2017;17:174. [ 28241797] doi: 10.1186/s12879-017-2254-7
18.
Nishijima T, Inaba Y, Kawasaki Y, et al. Mortality and causes of death in people living with HIV in the era of combination antiretroviral therapy compared with the general population in Japan. AIDS. 2020;34:913-921. [ 32039993] doi: 10.1097/QAD.0000000000002498
19.
Friis-Møller N, Sabin CA, Weber R, et al; Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993-2003. [ 14627784]
20.
Manual of Operations MOOP: Data Collection on Adverse Events of Anti-HIV Drugs. Copenhagen HIV Programme (CHIP); 2013.
21.
Castro KG, Ward JW, Slutsker L, et al. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Clin Infect Dis. 1993;17:802-10. doi: 10.1093/clinids/17.4.802
22.
Hernán MA, Robins JM. Causal Inference: What If. Chapman & Hill/CRC; 2020.
23.
Bruyand M, Ryom L, Shepherd L, et al; D:A:D study group. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the D:A:D study. J Acquir Immune Defic Syndr. 2015;68:568-77. [ 25763785] doi: 10.1097/QAI.0000000000000523
24.
Cancer in Germany 2013/2014. 11th ed. Robert Koch Institute; Association of Population-based Cancer Registries in Germany; 2018.
25.
Six J, Lorez M, Galli F, et al. Age-dependent risk and lifetime risk of developing cancer in Switzerland. Schweizer Krebsbulletin. 2017;3:284-91. doi: 10.5167/uzh-147848
26.
Borges ÁH, Neuhaus J, Sharma S, et al; INSIGHT SMART. The effect of interrupted/deferred antiretroviral therapy on disease risk: a SMART and START combined analysis. J Infect Dis. 2019;219:254-263. [ 30032171] doi: 10.1093/infdis/jiy442
27.
Bassler D, Briel M, Montori VM, et al; STOPIT-2 Study Group. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303:1180-7. [ 20332404] doi: 10.1001/jama.2010.310
28.
Gotti D, Raffetti E, Albini L, et al; Master Cohort Group. Survival in HIV-infected patients after a cancer diagnosis in the cART Era: results of an Italian multicenter study. PLoS One. 2014;9:e94768. [ 24760049] doi: 10.1371/journal.pone.0094768
29.
Vandenhende MA, Roussillon C, Henard S, et al; ANRS EN20 Mortalité 2010 study group. Cancer-related causes of death among HIV-infected patients in France in 2010: evolution since 2000. PLoS One. 2015;10:e0129550. [ 26083524] doi: 10.1371/journal.pone.0129550
30.
Borges AH, Dubrow R, Silverberg MJ. Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier combination antiretroviral therapy will alter this risk. Curr Opin HIV AIDS. 2014;9:34-40. [ 24225382] doi: 10.1097/COH.0000000000000025
31.
Borges ÁH, Silverberg MJ, Wentworth D, et al; INSIGHT SMART. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS. 2013;27:1433-41. [ 23945504] doi: 10.1097/QAD.0b013e32835f6b0c
32.
Borges ÁH, O’Connor JL, Phillips AN, et al; INSIGHT SMART Study and ESPRIT Groups. Interleukin 6 is a stronger predictor of clinical events than high-sensitivity C-reactive protein or D-dimer during HIV infection. J Infect Dis. 2016;214:408-16. [ 27132283] doi: 10.1093/infdis/jiw173
33.
Kuller LH, Tracy R, Belloso W, et al; INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:e203. [ 18942885] doi: 10.1371/journal.pmed.0050203
34.
Ledwaba L, Tavel JA, Khabo P, et al; Project Phidisa Biomarkers Team. Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease. PLoS One. 2012;7:e24243. [ 22448211] doi: 10.1371/journal.pone.0024243
35.
Grund B, Baker JV, Deeks SG, et al; INSIGHT SMART/ESPRIT/SILCAAT Study Group. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS One. 2016;11:e0155100. [ 27171281] doi: 10.1371/journal.pone.0155100
36.
Sereti I, Krebs SJ, Phanuphak N, et al; RV254/SEARCH 010, RV304/SEARCH 013 and SEARCH 011 protocol teams. Persistent, albeit reduced, chronic inflammation in persons starting antiretroviral therapy in acute HIV infection. Clin Infect Dis. 2017;64:124-131. [ 27737952] doi: 10.1093/cid/ciw683
37.
Hemkens LG, Bucher HC. HIV infection and cardiovascular disease. Eur Heart J. 2014;35:1373-81. [ 24408888] doi: 10.1093/eurheartj/eht528
38.
Serrano-Villar S, Sainz T, Lee SA, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014;10:e1004078. [ 24831517] doi: 10.1371/journal.ppat.1004078
39.
Castilho JL, Bian A, Jenkins C, et al. Increased cancer risk with lower CD4/CD8 ratio among adults with HIV in NA-ACCORD [Abstract]. Presented at Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 8–11 March 2020. Abstract no. 71.
40.
Schäfer J, Young J, Bernasconi E, et al; Swiss HIV Cohort Study. Predicting smoking cessation and its relapse in HIV-infected patients: the Swiss HIV Cohort Study. HIV Med. 2015;16:3-14. [ 24809704] doi: 10.1111/hiv.12165
41.
Shepherd L, Ryom L, Law M, et al; Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. Cessation of cigarette smoking and the impact on cancer incidence in human immunodeficiency virus-infected persons: the Data Collection on Adverse Events of Anti-HIV Drugs study. Clin Infect Dis. 2019;68:650-657. [ 29912335] doi: 10.1093/cid/ciy508
42.
Mbang PA, Kowalkowski MA, Amirian ES, et al. Association between time on protease inhibitors and the incidence of squamous cell carcinoma of the anus among U.S. male veterans. PLoS One. 2015;10:e0142966. [ 26629701] doi: 10.1371/journal.pone.0142966
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Published In
Annals of Internal Medicine
Volume 174 • Number 6 • June 2021
Pages: 768 - 776
History
Published online: 16 March 2021
Published in issue: June 2021
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© 2021 American College of Physicians.
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Risk for Non–AIDS-Defining and AIDS-Defining Cancer of Early Versus Delayed Initiation of Antiretroviral Therapy: A Multinational Prospective Cohort Study. Ann Intern Med.2021;174:768-776. [Epub 16 March 2021]. doi:10.7326/M20-5226
Risk for Non–AIDS-Defining and AIDS-Defining Cancer of Early Versus Delayed Initiation of Antiretroviral Therapy: A Multinational Prospective Cohort Study. Ann Intern Med.2021;174:768-776. [Epub 16 March 2021]. doi:10.7326/M20-5226
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