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Background Two-drug regimens (2-DRs) are increasingly used in people with HIV (PWH) with sustained virological suppression, demonstrating non-inferior efficacy compared with triple therapy (3-DRs). Since their long-term impact on the HIV-1 reservoir and its tissue distribution remain unclear, we evaluated longitudinal changes in blood reservoir markers after switching from 3-DR to 2-DR and explored their relationship with gut-associated lymphoid tissue (GALT).Materials and Methods Sixty-seven virosuppressed PWH were enrolled, 32 continued 3-DR and 35 switched to 2-DR. Peripheral blood was collected at baseline (T0) and after 18 months (T1). CD4+ T-cells were isolated and total HIV-1 DNA (CAD), intact proviral DNA (IP) and cell-associated HIV-1 RNA (CAR) were quantified by digital PCR. In a subset of people undergoing rectal biopsy, CAD (n=19) and IP (n=18) were measured in GALT at T0 and T1. Inter-group differences were assessed by Mann-Whitney U test, longitudinal changes by Wilcoxon signed-rank test, correlations by Spearman’s rank test, and predictors of reservoir dynamics by linear regression analysis.Results At T0, the two groups were comparable for sex, CD4+ count, zenith viral load and duration of ART, whereas the 2-DR group had lower age and higher nadir CD4+ ( table 1).In blood CD4+ T-cells, CAD, IP and CAR did not differ between groups at T0 (table 2) and only CAD and CAR were correlated in the whole dataset (Rho=0.653, p<0.001). Intra-group analyses over time showed decreased CAR in the 3-DR group (p=0.023), increased CAD (p=0.003) and decreased IP (p=0.039) in the 2-DR group. When comparing changes between groups, ΔIP (T1-T0) was the only marker with a significant difference (median [IQR] of 0.5 [9.0] in 3DR vs. -6.5 [14.3] in 2DR, p=0.035) (figure 1). In a model controlling for age, zenith VL, ART duration, nadir CD4+, baseline CD4+, and treatment group, T0 CAD predicted ΔCAD (B=0.499, p<0.001), baseline IP and CAR predicted ΔIP (B=-0.792, p<0.001; and B=2.821, p=0.011; respectively) and baseline CAR predicted ΔCAR (B=-0.418, p=0.001) (table 3), suggesting baseline-dependent reservoir kinetics.In GALT, CAD and IP values were not strongly correlated with the paired blood CD4+ T-cell values, and only a mild correlation of CD4+ T0 IP and GALT T0 CAD (Rho=0.608, p=0.012) emerged. CAD and IP did not change over time and were comparable between the 2DR and 3DR groups.Conclusions Treatment simplification was not associated with measurable expansion of the HIV-1 reservoir after 18 months, supporting the virological safety of 2-DR strategies. The lack of concordance between blood and GALT measurements suggests that peripheral blood may not fully recapitulate the reservoir dynamics and advises for expanding investigation of the lymphoid tissue.Abstract OC15 Table 1–3Abstract OC15 Figure 1Comparison of 2DR and 3DR for ACAD (A), AIP (B) and ACAR (C), defined as T1 - TO values, in the blood CD4+ T-cell compartment