Impact of intensification with raltegravir on HIV-1-infected individuals receiving monotherapy with boosted PIs

Abstract

BackgroundMonotherapy with ritonavir-boosted PIs (PI/r) has been used to simplify treatment of HIV-1-infected patients. In previous studies raltegravir intensification evidenced ongoing viral replication and reduced T cell activation, preferentially in subjects receiving PI-based triple ART. However, data about low-level viral replication and its consequences in patients receiving PI/r monotherapy are scarce.MethodsWe evaluated the impact of 24 weeks of intensification with raltegravir on markers of viral persistence, cellular immune activation and inflammation biomarkers in 33 patients receiving maintenance PI/r monotherapy with darunavir or lopinavir boosted with ritonavir. ClinicalTrials.gov identifier: NCT01480713.ResultsThe addition of raltegravir to PI/r monotherapy resulted in a transient increase in 2-LTR (long-terminal repeat) circles in a significant proportion of participants, along with decreases in CD8+ T cell activation levels and a temporary increase in the expression of the exhaustion marker CTLA-4 in peripheral T lymphocytes. Intensification with raltegravir also reduced the number of samples with intermediate levels of residual viraemia (10–60 HIV-1 RNA copies/mL) compared with samples taken during PI/r monotherapy. However, there were no changes in cell-associated HIV-1 DNA in peripheral CD4+ T cells or soluble inflammatory biomarkers (CD14, IP-10, IL-6, C-reactive protein and D-dimer).ConclusionsIntensification of PI/r monotherapy with raltegravir revealed persistent low-level viral replication and reduced residual viraemia in some patients during long-term PI/r monotherapy. The concomitant change in T cell phenotype suggests an association between active viral production and T cell activation. These results contribute to understanding the lower efficacy rates of PI/r monotherapies compared with triple therapies in clinical trials.

Differences in HIV Markers between Infected Individuals Treated with Different ART Regimens: Implications for the Persistence of Viral Reservoirs

“…Most intensification studies added an INSTI (raltegravir or dolutegravir) to the ART regimen. The impact of raltegravir intensification in individuals treated with ritonavir-boosted PI monotherapy has been documented by Puertas et al [101]. Raltegravir intensification in this specific context resulted in a transient increase in HIV episomal DNA levels in a significant proportion of participants, along with decreases in the CD8+ T-cell activation levels.…”

Cone-shaped HIV-1 capsids are transported through intact nuclear pores

“…For ddPCR (Hindson et al, 2011;Morón-López et al, 2017), set of primers/probe annealing to the gag open reading frame were used to detect late RT products (forward, 5'-CATGTTTTCAGCATTATCAGAAGGA-3'; reverse, 5'-TGCTTGATGTCCCCCCACT-3'; probe, 5'-FAM-CCACCCCACAAGATTTAAACACCATGCTAA-BHQ1-3' (Palmer et al, 2003)). 2-LTR circles were detected with another set of primers/probe (forward, 5'-CTAACTAGGGAACCCACTGCT-3'; reverse, 5'-GTAGTTCTGCCAATCAGGGAA-3'; probe, 5'-FAM-AGCCTCAATAAAGCTTGCCTTGAGTGC-BHQ1-3' (Puertas et al, 2018)).…”

A comparative analysis of unintegrated HIV-1 DNA measurement as a potential biomarker of the cellular reservoir in the blood of patients controlling and non-controlling viral replication

“…In fact, its relative scarcity might limit the ability of researchers to evaluate 2-LTR circle DNA, especially when the plasma viral load is very low. The 2-LTR species have been shown to be labile and are used as a surrogate marker of recent infection events [50][51][52] thus providing insight into reservoir dynamics. However, there is still some controversy around the use of 2-LTR species in this regard, with other reports showing that 2-LTR circles are stable in vitro and persist for a long time in infected cells [35,38,53].…”