Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral-Treated People With Human Immunodeficiency Virus
Authors: Chammartin Frédérique , Mocroft Amanda , Egle Alexander , Zangerle Robert , Smith Colette , Mussini Cristina , Wit Ferdinand , Vehreschild Jörg Janne , d’Arminio Monforte Antonella , Castagna Antonella , Bailly Laurent , Bogner Johannes , de Wit Stéphane , Matulionyte Raimonda , Law Matthew , Svedhem Veronica , Tallada Joan , Garges Harmony P , Marongiu Andrea , Borges Álvaro H , Jaschinski Nadine , Neesgaard Bastian , Ryom Lene , Bucher Heiner C ,   for the RESPOND Study Group, Wit F , van der Valk M , Hillebregt M , Petoumenos K , Law M , Zangerle R , Appoyer H , Stephan C , Bucht M , Chkhartishvili N , Chokoshvili O , d’Arminio Monforte A , Rodano A , Tavelli A , Fanti I , Casabona J , Miro J M , Llibre J M , Riera A , Reyes-Urueña J , Smith C , Lampe F , Sönnerborg A , Falconer K , Svedhem V , Günthard H , Ledergerber B , Bucher H , Kusejko K , Wasmuth J C , Rockstroh J , Vehreschild J J , Fätkenheuer G , Ryom L , Law M , Campo R , De Wit S , Garges H , Günthard H , Lundgren J , McNicholl I , Rooney J , Smith C , Vannappagari V , Wandeler G , Young L , Zangerle R , Lundgren J , Günthard H , Begovac J , Bruguera A , Bucher H , Castagna A , Campo R , Chkhartishvili N , D’Arminio Monforte A , Dedes N , Garges H , Kowalska J , Law M , McNicholl I , Mussini C , Necsoi C , Peters L , Petoumenos K , Pradier C , Raben D , Rockstroh J , Rooney J , Ryom L , Smith C , Sönnerborg A , Stephan C , Vannappagari V , Vehreschild J J , Volny Anne A , Wandeler G , Wasmuth J C , Williams E D , Wit F , Young L , Zangerle R , Ryom L , Mocroft A , Neesgaard B , Greenberg L , Jaschinski N , Timiryasova A , Bansi-Matharu L , Raben D , Peters L , Tusch E , Bannister W , Roen A , Byonanebye D , Fursa O , Pelchen-Matthews A , Reekie J , Svedhem-Johansson V , Van der Valk M , Wit F , Grabmeier-Pfistershammer K , Zangerle R , Hoy J , Bloch M , Braun D , Calmy A , Schüttfort G , Youle M , De Wit S , Mussini C , Zona S , Castagna A , Antinori A , Chkhartishvili N , Bolokadze N , Fontas E , Dollet K , Pradier C , Miro J M , Llibre J M , Vehreschild J J , Schwarze-Zander C , Wasmuth J C , Rockstroh J , Petoumenos K , Hutchinson J , Law M , Begovac J , Duvivier C , Dragovic G , Radoi R , Oprea C , Vasylyev M , Kowalska J , Matulionyte R , Mulabdic V , Marchetti G , Kuzovatova E , Coppola N , Aho I , Martini S , Bucher H , Harxhi A , Wæhre T , Pharris A , Vassilenko A , Fätkenheuer G , Bogner J , Maagaard A , Jablonowska E , Elbirt D , Marrone G , Leen C , Wyen C , Dahlerup Rasmussen L , Hatleberg C , Kundro M , Dedes N , Dixon Williams E , Gallant J , Cohen C , Dunbar M , Marongiu A , Vannappagari V , Garges H , Campo R , Young L , Volny Anne A , Dedes N , Mendao L , Dixon Williams E , Jaschinski N , Neesgaard B , Timiryasova A , Fursa O , Valdenmaier O , Larsen J F , Gardizi M , Raben D , Peters L , Ryom L , Elsing T W , Ramesh Kumar L , Shahi S , Andersen K , Reekie J , Greenberg L , Bansi-Matharu L , Petoumenos K , Byonanebye D , Tusch E , Roen A , Bannister W , Mocroft A 
Published: December 2023

Abstract

Background
Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear.

Methods
We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality.

Results
CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10–6.19] and 2.03 [95% CI 1.24–3.33], respectively). CD4 cell counts below 350 cells/μL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies.

Conclusions
In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.