Switching to dual/monotherapy determines an increase in CD8+ in HIV-infected individuals: an observational cohort study

Mussini, Cristina; Lorenzini, Patrizia; Cozzi‐Lepri, Alessandro; Marchetti, Giulia; Rusconi, Stefano; Gori, Andrea; Nozza, Silvia; Lichtner, Miriam; Antinori, Andrea; Cossarizza, Andrea; Monforte, Antonella d’Arminio

doi:10.1186/s12916-018-1046-2

Cited by 26 publications

(25 citation statements)

References 27 publications

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“…recently claimed that the restoration of this ratio was better achieved under multitherapy. This was due to a decrease in CD8 T cell count under three‐drug therapy contrasting with an increase in this count under double‐ART . In contrast, Belmonti et al .…”

Section: The Issue Of Inflammation and Immune Activationmentioning

confidence: 86%

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

et al. 2019

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Three‐drug combination antiretroviral therapy (ART) became available in 1996, dramatically improving the prognosis of people living with HIV. The clinical benefits of ART are due to the sustained viral load suppression and CD4 T cell gains. Major drawbacks of the first ART regimens were adverse events, and high pill burden, which led to the reduction of drug adherence resulting in frequent treatment discontinuations and the development of drug resistance. Due to increased viral potency of new antiretroviral drugs consideration of a two‐drug combination therapy repositioning occurred in an effort to reduce adverse events, drug‐drug interactions and cost, while maintaining a sustained antiviral effect. Various combinations of two‐drug regimens have been studied, and non‐inferiority compared to a three‐drug regimen has been shown only for some of them. In addition, a two‐drug combination regimen may not be suitable for every patient, especially those who are pregnant, those with tuberculosis or coexisting HBV infection. Furthermore no information has been generated concerning the secondary transmission of HIV from patients who have undetectable plasma viral load on two‐drug regimens. Additional studies of two‐drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation. While there is no urgent need to routinely switch patients to two‐drug combination therapy, due to the availability of drug combinations without significant toxicities, dual regimens represent a suitable option that deserve long‐term evaluation before being introduced to clinical practice.

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Section: The Issue Of Inflammation and Immune Activationmentioning

confidence: 86%

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

et al. 2019

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“…Despite the high genetic barrier of PIs to resistance development, the emergence of mutations at the active site of the protease leads to HIV-1 drug resistance and virological failure (VF). 6–9 The main pathways of drug resistance to PIs are well defined. They initiate with mutational changes in the active site of the viral protease, 10 followed by a step-wise accumulation of mutations surrounding the active site, 10–12 at cleavage sites 13–15 and at non-cleavage sites of the Gag-pol polyprotein, 15–17 which compensate for replication defects and increase phenotypic resistance.…”

Section: Introductionmentioning

confidence: 99%

“… 18 , 19 On the other hand, this rarely occurs in patients experiencing VF to cART based on the most recently developed boosted PIs as first-line regimens or in simplification strategies. 6 , 8 , 9 This observation raises questions about the mechanism leading to VF to boosted PIs. Although the answer remains elusive, increasing evidence points to the role played by the presence of mutations outside of the protease and other unexplored mechanisms of resistance.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Gag mutations alone are sufficient to reduce darunavir susceptibility during virological failure to boosted PI therapy

Blanch-Lombarte

Santos

Peña

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background Virological failure (VF) to boosted PIs with a high genetic barrier is not usually linked to the development of resistance-associated mutations in the protease gene. Methods From a cohort of 520 HIV-infected subjects treated with lopinavir/ritonavir or darunavir/ritonavir monotherapy, we retrospectively identified nine patients with VF. We sequenced the HIV-1 Gag-protease region and generated clonal virus from plasma samples. We characterized phenotypically clonal variants in terms of replicative capacity and susceptibility to PIs. Also, we used VESPA to identify signature mutations and 3D molecular modelling information to detect conformational changes in the Gag region. Results All subjects analysed harboured Gag-associated polymorphisms in the absence of resistance mutations in the protease gene. Most Gag changes occurred outside Gag cleavage sites. VESPA analyses identified K95R and R286K (P < 0.01) as signature mutations in Gag present at VF. In one out of four patients with clonal analysis available, we identified clonal variants with high replicative capacity and 8- to 13-fold reduction in darunavir susceptibility. These clonal variants harboured K95R, R286K and additional mutations in Gag. Low susceptibility to darunavir was dependent on the Gag sequence context. All other clonal variants analysed preserved drug susceptibility and virus replicative capacity. Conclusions Gag mutations may reduce darunavir susceptibility in the absence of protease mutations while preserving viral fitness. This effect is Gag-sequence context dependent and may occur during boosted PI failure.

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“…Even in patients on successful triple therapy, there is evidence of persisting quantitative and qualitative defects in CD8 T cells [14][15][16], which are reflected in continuous immune activation which contributes to immunological exhaustion. Among patients switching to dual regimens, an increase of CD8 T-cell count has been reported [17], while a lower increase in CD4:CD8 ratio was found compared with patients on triple drug regimens [16]. In our TRILOBITHE pilot study, CD4 and CD8 counts in patients on dual regimens were similar to those in patients on triple therapy, while similar or decreased levels of some inflammation/activation markers were found, as expected, as inflammatory markers have been associated with residual viraemia and immune dysfunction [18].…”

Section: Discussionmentioning

confidence: 99%

Switching to dual antiretroviral regimens is associated with improvement or no changes in activation and inflammation markers in virologically suppressed HIV‐1‐infected patients: the TRILOBITHE pilot study

et al. 2019

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Objectives While the use of dual antiretroviral therapies could reduce the toxicity of antiretroviral treatment in treatment‐experienced HIV‐1‐infected patients, it is crucial to know if reducing the number of drugs could lead to an adverse increase in inflammation and activation markers. Methods This was a cross‐sectional pilot study conducted at the HIV‐1 Unit at the Tertiary University Hospital in Madrid, Spain, evaluating biomarkers of activation [interferon‐γ‐induced protein 10 (IP10), high‐sensitivity C‐reactive protein (hs‐CRP), soluble CD14 (sCD14) and sCD163], inflammation [interleukin‐6 (IL‐6)], blood coagulation (d‐dimer), and immune response [interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and IL‐4] in three groups of suppressed HIV‐1‐infected patients: patients continuing on triple therapy (26 patients), and patients who switched from triple to dual therapy, at 24 or 48 weeks after switching (13 and 36 patients, respectively). Results Demographic and immunovirological parameters were similar in the three groups of patients. IL‐6 and sCD14 levels were lower in patients at 48 weeks after switching to dual therapy compared with those found in patients who continued to receive triple therapy (P = 0.012 and P = 0.001, respectively), with no differences in the levels of the remaining biomarkers. Among patients with nadir CD4 count ≤ 200 cells/μL, sCD14 levels were lower in patients who had been on dual therapy for 48 weeks (14 patients) compared with those found in patients who received ongoing triple therapy (11 patients; P = 0.029), with no differences in the levels of the other biomarkers. Conclusions HIV‐1‐infected patients receiving dual regimens showed similar or even lower levels of inflammatory and activation markers compared with those found in patients who received ongoing triple therapy. Of note, similar data were obtained in patients with low nadir CD4 count.

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Switching to dual/monotherapy determines an increase in CD8+ in HIV-infected individuals: an observational cohort study

Cited by 26 publications

References 27 publications

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

HIV-1 Gag mutations alone are sufficient to reduce darunavir susceptibility during virological failure to boosted PI therapy

Switching to dual antiretroviral regimens is associated with improvement or no changes in activation and inflammation markers in virologically suppressed HIV‐1‐infected patients: the TRILOBITHE pilot study

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