INTRODUCTION: Since the beginning of the HIV epidemic in resource-rich countries, Pneumocystis jirovecii pneumonia (PjP) is one of the most frequent opportunistic AIDS-defining infections. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) has shown that primary Pneumocystis jirovecii Pneumonia (PjP) prophylaxis can be safely withdrawn in patients with CD4 counts of 100 to 200 cells/µL if plasma HIV-RNA is suppressed on combination antiretroviral therapy. Whether this holds true for secondary prophylaxis is not known, and this has proved difficult to determine due to the much lower population at risk. METHODS: We estimated the incidence of secondary PjP by including patient data collected from 1998 to 2015 from the COHERE cohort collaboration according to time-updated CD4 counts, HIV-RNA and use of PjP prophylaxis in persons >16 years of age. We fitted a Poisson generalized additive model in which the smoothed effect of CD4 was modelled by a restricted cubic spline, and HIV-RNA was stratified as low (<400), medium (400 to 10,000) or high (>10,000copies/mL). RESULTS: There were 373 recurrences of PjP during 74,295 person-years (py) in 10,476 patients. The PjP incidence in the different plasma HIV-RNA strata differed significantly and was lowest in the low stratum. For patients off prophylaxis with CD4 counts between 100 and 200 cells/µL and HIV-RNA below 400 copies/mL, the incidence of recurrent PjP was 3.9 (95% CI: 2.0 to 5.8) per 1000 py, not significantly different from patients on prophylaxis in the same stratum (1.9, 95% CI: 0.1 to 3.7). CONCLUSIONS: HIV viraemia importantly affects the risk of recurrent PjP. In virologically suppressed patients on ART with CD4 counts of 100 to 200/µL, the incidence of PjP off prophylaxis is below 10/1000 py. Secondary PjP prophylaxis may be safely withheld in such patients. While European guidelines recommend discontinuing secondary PjP prophylaxis only if CD4 counts rise above 200 cells/mL, the latest US Guidelines consider secondary prophylaxis discontinuation even in patients with a CD4 count above 100 cells/µL and suppressed viral load. Our results strengthen and support this US recommendation.

4th Department of Internal Medicine ATTIKON University Hospital National and Kapodistrian University of Athens Athens Greece

Amsterdam Institute for Global Health and Development and HIV Monitoring Foundation Amsterdam The Netherlands

Centre for Clinical Research Epidemiology Modelling and Evaluation Institute for Global Health UCL London UK

CHIP Department of Infectious Diseases Rigshospitalet University of Copenhagen Copenhagen Denmark

Clinic of Infectious Diseases University of Modena and Reggio Emilia Modena Italy

Clinical Epidemiology Unit National Institute for Infectious Diseases L Spallanzani IRCCS Rome Italy

Department of Global Health Amsterdam University Medical Centers University of Amsterdam Amsterdam The Netherlands

Department of Infectious Diseases Bern University Hospital Inselspital University of Bern Bern Switzerland

Department of Infectious Diseases St Pierre University Hospital Université Libre de Bruxelles Brussels Belgium

Department of Mathematics and Statistics Masaryk University Brno Czech Republic

Infectious Diseases Service Hospital Clinic IDIBAPS University of Barcelona Barcelona Spain

Infectious Diseases Unit at Medical Center no 2 Frankfurt University Hospital Goethe University Frankfurt Germany

INSERM U 1137 IAME Université de Paris Paris France

Institute of Social and Preventive Medicine University of Bern Bern Switzerland

Internal Medicine and Infectious Diseases Department University Hospital of Bordeaux Bordeaux France

Paediatric Infectious Diseases Unit St George's University Hospital London UK

Service des Maladies Infectieuses et Tropicales Groupe Hospitalier Universitaire Bichat Claude Bernard Paris France

See more in PubMed

Masur H, Michelis MA, Greene JB, Onorato I, Stouwe RA, Holzman RS, et al. An outbreak of community‐acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med. 1981;305(24):1431–8. PubMed

Kaplan JE, Hanson DL, Navin TR, Jones JL. Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus‐infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis. J Infect Dis. 1998;178(4):1126–32. PubMed

Buchacz K, Lau B, Jing Y, Bosch R, Abraham AG, Gill MJ, et al. Incidence of AIDS‐defining opportunistic infections in a multicohort analysis of HIV‐infected persons in the United States and Canada, 2000–2010. J Infect Dis. 2016;214(6):862–72. PubMed PMC

Mocroft A, Lundgren JD, Sabin ML, et al. Risk factors and outcomes for late presentation for HIV‐Positive persons in Europe: results from the collaboration of observational HIV epidemiological research Europe study (COHERE). PLoS Med. 2013;10:e1001510. PubMed PMC

Chaisson RE, Keruly J, Richman DD, Moore RD. Pneumocystis prophylaxis and survival in patients with advanced human immunodeficiency virus infection treated with zidovudine. The Zidovudine Epidemiology Group. Arch Intern Med. 1992;152(10):2009–13. PubMed

Girard PM, Landman R, Gaudebout C, Lottin P, Truchis P, Camus F, et al. Prevention of Pneumocystis carinii pneumonia relapse by pentamidine aerosol in zidovudine‐treated AIDS patients. Lancet. 1989;1(8651):1348–53. PubMed

Wojtowicz A, Bibert S, Taffe P, Bernasconi E, Furrer H, Günthard HF, et al. IL‐4 polymorphism influences susceptibility to Pneumocystis jirovecii pneumonia in HIV‐positive patients. AIDS. 2019;33(11):1719–27. PubMed PMC

Masur H. Prevention and treatment of pneumocystis pneumonia. N Engl J Med. 1992;327(26):1853–60. PubMed

Weverling GJ, Mocroft A, Ledergerber B, Kirk O, Gonzales‐Lahoz J, Monforte A, et al. Discontinuation of pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV‐1 infection. Lancet. 1999;353(9161):1293–8. PubMed

Ledergerber B, Mocroft A, Reiss P, Furrer H, Kirk O, Bickel M, et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. N Engl J Med. 2001;344(3):168–74. PubMed

Furrer H, Egger M, Opravil M, Bernasconi E, Hirschel B, Battegay M, et al. Discontinuation of primary prophylaxis against pneumocystis carinii pneumonia in HIV‐1 infected adults treated with combination antiretroviral therapy. N Engl J Med. 1999;340(17):1301–6. PubMed

Mussini C, Pezzotti P, Govoni A, Borghi V, Antinori A, d'Arminio Monforte A, et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I‐infected patients: the changes in opportunistic prophylaxis study. J Infect Dis. 2000;181(5):1635–42. PubMed

Bernaldo L, de Quiros JC, Miro JM, Pena JM, Podzamczer D, Alberdi JC, Martínez E, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98. N Engl J Med. 2001;344(3):159–67. PubMed

Mussini C, Pezzotti P, Antinori A, Borghi V, d'Arminio Monforte A, Govoni A, et al. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus‐infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis. 2003;36(5):645–51. PubMed

Mocroft A, Reiss P, Kirk O, Mussini C, Girardi E, Morlat P, et al. Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/microL? Clin Infect Dis. 2010;51(5):611–9. PubMed

Atkinson A, Zwahlen M, Barger D, d'Arminio Monforte A, De Wit S, Ghosn J, et al. Withholding primary PcP prophylaxis in virologically suppressed HIV patients: an emulation of a pragmatic trial in COHERE. Clin Infect Dis. 2020:ciaa615. 10.1093/cid/ciaa615 [Epub ahead of print]. PubMed DOI PMC

D'Egidio GE, Kravcik S, Cooper CL, Cameron DW, Fergusson DA, Angel JB. Pneumocystis jiroveci pneumonia prophylaxis is not required with a CD4+ T‐cell count <200 cells/microl when viral replication is suppressed. AIDS. 2007;21(13):1711–5. PubMed

Cheng CY, Chen MY, Hsieh SM, Sheng W‐H, Sun H‐Y, Lo Y‐C, et al. Risk of pneumocystosis after early discontinuation of prophylaxis among HIV‐infected patients receiving highly active antiretroviral therapy. BMC Infect Dis. 2010;10:126. PubMed PMC

Soriano V, Dona C, Rodriguez‐Rosado R, Barreiro P, Gonzalez‐Lahoz J. Discontinuation of secondary prophylaxis for opportunistic infections in HIV‐infected patients receiving highly active antiretroviral therapy. AIDS. 2000;14(4):383–6. PubMed

Chaiwarith R, Praparattanapan J, Nuntachit N, Kotarathitithum W, Supparatpinyo K. Discontinuation of primary and secondary prophylaxis for opportunistic infections in HIV‐infected patients who had CD4+ cell count <200 cells/mm(3) but undetectable plasma HIV‐1 RNA: an open‐label randomized controlled trial. AIDS Patient Care STDs. 2013;27(2):71–6. PubMed

Costiniuk CT, Fergusson DA, Doucette S, Angel JB. Discontinuation of Pneumocystis jirovecii pneumonia prophylaxis with CD4 count <200 cells/microL and virologic suppression: a systematic review. PLoS One. 2011;6:e28570. PubMed PMC

Sidhu VK, Foisy MM, Hughes CA. Discontinuing pneumocystis jirovecii pneumonia prophylaxis in HIV‐Infected Patients With a CD4 cell count <200 cells/mm3 . Ann Pharmacotherapy. 2015;49(12):1343–8. PubMed

Lin X, Garg S, Mattson CL, Luo Q, Skarbinski J. Prescription of pneumocystis jiroveci pneumonia prophylaxis in HIV‐infected patients. J Int Assoc Provid AIDS Care. 2016;15(6):455–8. PubMed PMC

Chene G, Phillips A, Costagliola D, et al. Cohort profile: collaboration of observational HIV epidemiological research Europe (COHERE) in EuroCoord. Int J Epidemiol. 2017;46(3):797. PubMed PMC

R Core Team, R . Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna Austria: 2019.

Wood SN. Generalized additive models: an introduction with R. 2nd edn. Boca Raton (FL): Chapman and Hall; 2017.

Brown AE, Hayes R, Noori T, Azad Y, Amato‐Gauci AJ, Pharris A, et al. HIV in Europe and Central Asia: progress in 2018 towards meeting the UNAIDS 90–90‐90 targets. Euro Surveill. 2018;23(48):622. PubMed PMC

Fenner L, Atkinson A, Boulle A, Fox MP, Prozesky H, Zürcher K, et al. HIV viral load as an independent risk factor for tuberculosis in South Africa: collaborative analysis of cohort studies. J Int AIDS Soc. 2017;20:21327. PubMed PMC

Veit O, Domingo C, Niedrig M, Staehelin C, Sonderegger B, Héquet D, et al. Long‐term immune response to yellow fever vaccination in human immunodeficiency virus (HIV)‐infected individuals depends on HIV RNA suppression status: implications for vaccination schedule. Clin Infect Dis. 2018;66(7):1099–108. PubMed

Evison J, Farese S, Seitz M, Uehlinger DE, Furrer H, Muhlemann K. Randomized, double‐blind comparative trial of subunit and virosomal influenza vaccines for immunocompromised patients. Clin Infect Dis. 2009;48(10):1402–12. PubMed

Potsch DV, Camacho LA, Tuboi S, Villar LM, Miguel JC, Ginuíno C, et al. Vaccination against hepatitis B with 4‐double doses increases response rates and antibodies titers in HIV‐infected adults. Vaccine. 2012;30(41):5973–7. PubMed

U.S. Department of Health and Human Services . Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV‐Infected Adults and Adolescents. 2020. [cited 2020 12 Oct]. Available from: https://clinicalinfo.hiv.gov/en/guidelines/adult‐and‐adolescent‐opportunistic‐infection

European AIDS Clinical Society . EACS guidelines version 10.0. 2019. [cited 2020 Oct 12]. Available from: https://www.eacsociety.org/files/2019_guidelines‐10.0_final.pdf

Walker AS, Ford D, Gilks CF, Munderi P, Ssali F, Reid A, et al. Daily co‐trimoxazole prophylaxis in severely immunosuppressed HIV‐infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort. Lancet. 2010;375(9722):1278–86. PubMed PMC

Suthar AB, Vitoria MA, Nagata JM, Anglaret X, Mbori‐Ngacha D, Sued O, et al. Co‐trimoxazole prophylaxis in adults, including pregnant women, with HIV: a systematic review and meta‐analysis. Lancet HIV. 2015;2(4):e137–50. PubMed

HIV replication and tuberculosis risk among people living with HIV in Europe: A multicohort analysis, 1983-2015