Two-threshold defined immune non-responders are associated with long-term morbidity in people with HIV: a prospective cohort study

A substantial proportion of people with HIV (PWH) fail to achieve full immune recovery despite long-term antiretroviral therapy (ART), potentially increasing their risk of serious comorbidities. This study investigated the association between immune non-responder (INR) and the incidence of AIDS-defining diseases (ADs) and non-AIDS-defining diseases (NADs) in a prospective cohort at the Third People's Hospital of Shenzhen, China. The low - and high-threshold cohorts included 7,874 and 8,077 individuals with baseline CD4⁺ T-cell counts < 350 and < 500cells/μL, respectively. INR was defined as failure to reach CD4⁺ T-cell thresholds (350 or 500 cells/μL) in two consecutive measurements during follow-up. Kaplan-Meier curves and Cox proportional hazards models were used to assess associations. Median follow-up after immune classification was 49.4 and 42.2 months in the low - and high-threshold cohorts, respectively. In the low-threshold cohort, INR was independently associated with significantly increased risks of ADs, including pneumocystis pneumonia (adjusted hazard ratio [aHR], 10.10; 95% confidence interval [CI]: 4.94-20.70), talaromycosis marneffei (aHR, 7.38; 95% CI: 3.51-15.50), and AIDs-defining cancers (aHR, 3.67; 95% CI: 1.20-11.20); and NADs, including end-stage liver disease (aHR, 15.00; 95% CI: 5.59-40.00), cardiovascular disease (aHR, 3.83; 95% CI: 2.14-6.87), chronic kidney disease (aHR, 1.78; 95% CI: 1.23-2.58), and non-AIDS-defining cancers (aHR, 4.75; 95% CI: 2.31-9.74). Similar associations were observed in the high-threshold cohort. INR is strongly associated with long-term morbidity in PWH. These findings highlight the need for improved risk assessment beyond CD4⁺ T-cell monitoring to reduce disease burden in PWH.