Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control.
Background
We analyzed humoral and cellular immune responses induced by SARS-CoV-2 mRNA vaccines in people living with HIV-1 (PLWH) with < 200 CD4+ T-cells.
Methods
Prospective cohort study including 58 PLWH with CD4+ T-cell counts <200 cells/mm3, 36 with CD4+ T-cell counts >500, and 33 HIV-1-negative controls. Antibodies against the SARS-CoV-2 Spike protein (anti-S IgG) and the receptor-binding domain (anti-RBD IgG) were quantified before and four weeks after the first and the second dose of BNT162b2 or mRNA-1273 (w8). Viral neutralization activity and T-cell responses were also determined.
Results
At w8, anti-S/anti-RBD IgG responses increased in all groups (P < 0.0001). Median (IQR) S-IgG and RBD-IgG at w8 were 153.6 (26.4; 654.9) and 171.9 (61.8; 425.8) in the HIV < 200 group compared to 245.6 (145; 824) and 555.8 (166.4; 1751) in the HIV > 500 group, and 274.7 (193.7; 680.4) and 281.6 (181; 831.8) BAU/mL in controls (P < 0.05). Neutralizing capacity and specific T-cell immune responses were absent or reduced in 33% of the HIV < 200 group, compared with 3.7% in the HIV > 500 (P = 0.0003).
Conclusion
One third of PLWH with CD4+ T-cell counts <200 cells/mm3 show low anti-S/anti-RBD IgG levels, reduced in vitro neutralization activity against SARS-CoV-2 and no vaccine-induced T-cells after receiving COVID-19 mRNA vaccines.
We present a method to fit a mixed effects Cox model with interval‐censored data. Our proposal is based on a multiple imputation approach that uses the truncated Weibull distribution to replace the interval‐censored data by imputed survival times and then uses established mixed effects Cox methods for right‐censored data. Interval‐censored data were encountered in a database corresponding to a recompilation of retrospective data from eight analytical treatment interruption (ATI) studies in 158 human immunodeficiency virus (HIV) positive combination antiretroviral treatment (cART) suppressed individuals. The main variable of interest is the time to viral rebound, which is defined as the increase of serum viral load (VL) to detectable levels in a patient with previously undetectable VL, as a consequence of the interruption of cART. Another aspect of interest of the analysis is to consider the fact that the data come from different studies based on different grounds and that we have several assessments on the same patient. In order to handle this extra variability, we frame the problem into a mixed effects Cox model that considers a random intercept per subject as well as correlated random intercept and slope for pre‐cART VL per study. Our procedure has been implemented in R using two packages: truncdist and coxme, and can be applied to any data set that presents both interval‐censored survival times and a grouped data structure that could be treated as a random effect in a regression model. The properties of the parameter estimators obtained with our proposed method are addressed through a simulation study.
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