Predictors of virological failure in <scp>HIV</scp>‐1‐infected patients switching to dolutegravir maintenance monotherapy

Wijting, Ingeborg E A; Rutsaert, Sofie; Rokx, Casper; Burger, David M.; Verbon, Annelies; Kampen, Jeroen J. A. van; Boucher, Charles A.; Rijnders, Bart J. A.; Vandekerckhove, Linos

doi:10.1111/hiv.12675

Cited by 23 publications

(22 citation statements)

References 18 publications

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“…The eight studies of persons receiving dolutegravir monotherapy for treatment simplification included three trials with 211 persons, three cohort studies with 92 persons, and two case reports 28–35 (Table 3). Overall, 16 persons developed VF and an INSTI resistance mutation.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of the genetic mechanisms of dolutegravir resistance

Rhee

Grant

Tzou

et al. 2019

Journal of Antimicrobial Chemotherapy

116

105

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Background Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy. Methods We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons. Results and conclusions We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir’s companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir’s companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.

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Section: Resultsmentioning

confidence: 99%

A systematic review of the genetic mechanisms of dolutegravir resistance

Rhee

Grant

Tzou

et al. 2019

Journal of Antimicrobial Chemotherapy

116

105

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“…Patients with a nadir CD4 count ≤ 200 cells/lL have been found to have a higher risk of virological failure on monotherapy [9]. In such patients, lower sCD14 levels and similar values of the other biomarkers studied were found in patients on dual therapy for 48 weeks compared with patients receiving ongoing triple therapy.…”

Section: Discussionmentioning

confidence: 90%

“…Hence, in the last few years, antiretroviral therapy (ART) simplification strategies have provided alternative treatments for the aging HIV‐1‐infected population with increasing rates of comorbidities . While several studies of dual therapy have suggested adequate long‐term efficacy and tolerability with fewer adverse events or have demonstrated noninferior efficacy compared with triple therapy , concerns about the possibility of increased residual viraemia, and increased systemic inflammatory activity and immune activation, are still present, as previously described for monotherapy strategies . This issue requires to be addressed urgently, in order to prevent possible suboptimal treatment in otherwise well‐treated, suppressed patients.…”

Section: Introductionmentioning

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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“…32 These results were in accordance with predictive factors of virological response in deintensification studies. 33,34 A recent trial of deintensification retained HIV DNA quantification as an inclusion criteria, with a threshold of <2.7 log 10 copies/10 6 PBMCs. 35 In our cohort, no impact on virological outcome was found of detection of new resistance on DNA GRT in patients virologically suppressed.…”

Section: Discussionmentioning

confidence: 99%

Virological Outcome After Choice of Antiretroviral Regimen Guided by Proviral HIV-1 DNA Genotyping in a Real-Life Cohort of HIV-Infected Patients

Meybeck

Alidjinou²,

Huleux

et al. 2020

AIDS Patient Care and STDs

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Issues have been raised concerning clinical relevance of HIV-1 proviral DNA genotypic resistance test (DNA GRT). To assess impact of DNA GRT on choice of antiretroviral therapy (ART) and subsequent virological outcome, we retrospectively reviewed decision-making and viral load (VL) evolution following DNA GRT performed in our center between January 2012 and December 2017, except those prescribed within the framework of a clinical trial. A total of 304 DNA GRTs were included, 185 (62%) performed in a context of virological success. Only 34% of tests were followed by ART change, more frequently in situation of virological success (39% vs. 26%, p = 0.02). In this situation, ART change guided by DNA GRT led to VL >20 copies/mL after 6 months in 5% of cases. In multivariate analysis, higher HIV DNA quantification (p = 0.01) was associated with occurrence of viremia. A higher nadir of CD4 count (p = 0.04) and a longer time with VL <20 copies/mL (p = 0.04) were independently associated with a lower risk of viremia. In situation of low-level viremia, ART change guided by DNA GRT led to VL <20 copies/mL after 6 months in 52% of cases, while decision to maintain the same treatment led to VL <20 copies/mL in 74% of cases. In multivariate analysis, longer time with VL >20 copies/mL (p = 0.02) was associated with persistence of virological replication. In conclusion, in situation of virological success, use of DNA GRT in addition to analysis of historical RNA GRT to guide ART optimization appears safe. Its prescription framework in situation of low-level viremia deserves to be better defined.

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Predictors of virological failure in HIV‐1‐infected patients switching to dolutegravir maintenance monotherapy

Cited by 23 publications

References 18 publications

A systematic review of the genetic mechanisms of dolutegravir resistance

A systematic review of the genetic mechanisms of dolutegravir resistance

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

Virological Outcome After Choice of Antiretroviral Regimen Guided by Proviral HIV-1 DNA Genotyping in a Real-Life Cohort of HIV-Infected Patients

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