Female sex is associated with continuous decline in intact HIV-1 proviruses during long-term antiretroviral therapy

Background: Understanding the factors associated with long-term intact HIV-1 proviral dynamics during suppressive ART is critical for developing HIV-1 cure strategies. In this study, we sought to evaluate the association between sex assigned at birth and HIV-1 reservoir dynamics in people with HIV (PWH) on long-term suppressive ART. Methods: Adult participants (17 men; 18 women) of the MACS/WIHS Combined Cohort Study with ≥10 years of suppressive ART and samples collected at 4–5-year intervals were included. We used the intact proviral DNA assay (IPDA) to measure intact and defective HIV-1 proviruses. Soluble inflammatory markers and, in women only, sex hormones were measured. Correlation was evaluated using Spearman's rank correlation test. Results: Among the 35 PWH, median follow-up was 12 years; 16 demonstrated continuous decreases in intact proviruses, while 19 had non-decrease patterns. Female sex and age at viral suppression were associated with a higher proportion of continuous intact HIV-1 DNA decreases, while age at ART initiation and nadir CD4 + cell count were not. By contrast, decrease in total and defective proviruses were not significantly different between the sexes. Higher estradiol levels in female PWH negatively correlated with interleukin 6 (IL-6, rho = −0.53, P = 0.001), and IL-6 negatively correlated with intact proviruses (rho = −0.38, P = 0.01). In male PWH, D-dimer rather than IL-6 negatively associated with intact proviruses (rho = −0.34, P = 0.02). These soluble markers and hormones were not associated with reservoir decay patterns. Conclusions: Among PWH with decade-long suppressive ART, less than half had sustained decline in intact proviral DNA. Female PWH more often exhibited continuous decline in intact HIV-1 DNA.