Archived HIV-1 DNA resistance mutations to rilpivirine and etravirine in successfully treated HIV-1-infected individuals pre-exposed to efavirenz or nevirapine

Gallien, Sébastien; Charreau, Isabelle; Néré, Marie-Laure; Mahjoub, Nadia; Simon, François; Castro, Nathalie De; Aboulker, J. P.; Molina, Jean‐Michel; Delaugerre, Constance

doi:10.1093/jac/dku395

Cited by 21 publications

(16 citation statements)

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“…The use of integrated proviral DNA rather than RNA isolated from circulating virus to monitor HIV drug resistance in patients failing treatment has been considered as an alternative method for drug resistance genotyping [ 28 ]. Sequencing of DNA is also an efficient method to study the archived and persistent viral reservoirs in patients with low or suppressed viral loads [ 29 ]. With the current focus on HIV persistence, it is important that studies investigating persisting viral populations during suppression are performed to better understand the viral dynamics and alternative future treatment options.…”

Section: Introductionmentioning

confidence: 99%

High level of HIV-1 drug resistance mutations in patients with unsuppressed viral loads in rural northern South Africa

Etta

Mavhandu

Manhaeve³

et al. 2017

AIDS Res Ther

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BackgroundCombination antiretroviral therapy (cART) has significantly reduced HIV morbidity and mortality in both developed and developing countries. However, the sustainability of cART may be compromised by the emergence of viral drug resistance mutations (DRM) and the cellular persistence of proviruses carrying these DRM. This is potentially a more serious problem in resource limited settings.MethodsDRM were evaluated in individuals with unsuppressed viral loads after first or multiple lines of cART at two sites in rural Limpopo, South Africa. Seventy-two patients with viral loads of >1000 copies/ml were recruited between March 2014 and December 2015. Complete protease (PR) and partial Reverse Transcriptase (RT) sequences were amplified from both plasma RNA and paired proviral DNA from 35 of these subjects. Amplicons were directly sequenced to determine subtype and DRM using the Stanford HIV Drug Resistance Interpretation algorithm.ResultsAmong the 72 samples, 69 could be PCR amplified from RNA and 35 from both RNA and DNA. Sixty-five (94.2%) viruses were subtype C, while one was subtype B (1.4%), one recombinant K/C, one recombinant C/B and one unclassified. Fifty-eight (84%) sequences carried at least one DRM, while 11 (15.9%) displayed no DRM. DRM prevalence according to drug class was: NRTI 60.8% NNRTI 65.2%, and PI 5.8%. The most common DRMs were; M184V (51.7%), K103N (50%), V106M (20.6%), D67N (13.3%), K65R (12%). The frequency of the DRM tracked well with the frequency of use of medications to which the mutations were predicted to confer resistance. Interestingly, a significant number of subjects showed predicted resistance to the newer NNRTIs, etravirine (33%) and rilpivirine (42%), both of which are not yet available in this setting. The proportion of DRM in RNA and DNA were mostly similar with the exception of the thymidine analogue mutations (TAMs) D67N, K70R, K219QE; and K103N which were slightly more prevalent in DNA than RNA. Subjects who had received cART for at least 5 years were more likely to harbour >2 DRM (p < 0.05) compared to those treated for a shorter period. DRM were more prevalent in this rural setting compared to a neighbouring urban setting.ConclusionWe found a very high prevalence of NRTI and NNRTI DRM in patients from rural Limpopo settings with different durations of treatment. The prevalence was significantly higher than those reported in urban settings in South Africa. The dominance of NNRTI based mutations late in treatment supports the use of PI based regimens for second line treatment in this setting. The slight dominance of TAMs in DNA from infected PBMCs compared to plasma virus requires further studies that should include cART subjects with suppressed virus. Such studies will improve our understanding of the pattern of drug resistance and dynamics of viral persistence in these rural settings.

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Section: Introductionmentioning

confidence: 99%

High level of HIV-1 drug resistance mutations in patients with unsuppressed viral loads in rural northern South Africa

Etta

Mavhandu

Manhaeve³

et al. 2017

AIDS Res Ther

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“…In phase 3 clinical trials in treatment-naive subjects, those who failed RPV-based ART had a greater risk of developing resistance than those failing EFV [ 26 – 28 ]. However, given the presence of M41L, which would be an unusual mutation to select de novo on RPV/FTC/TDF, we suspect that this participant may have had archived resistance before the switch, despite being virologically suppressed, as has been reported elsewhere [ 29 , 30 ]. Rilpivirine absorption is partially dependent on food and an acidic gastric environment.…”

Section: Discussionmentioning

confidence: 63%

A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans

Collins

Grant

Uwinkindi

et al. 2016

Open Forum Infectious Diseases

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“…16,17 Several studies have demonstrated the risk of archived resistance to rilpivirine especially in patients who had experienced previous virological failure while receiving non-nucleoside reverse transcriptase inhibitor (NNRTI). [18][19][20][21] Lambert-Niclot et al found good concordance between DNA and RNA GRT only in absence of prior virological failure. 11 DNA GRT could be useful in a virologically suppressed patient in the absence of prior RNA GRT, or in case of history of virological failure while receiving NNRTI and no RNA GRT at the time of failure.…”

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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Archived HIV-1 DNA resistance mutations to rilpivirine and etravirine in successfully treated HIV-1-infected individuals pre-exposed to efavirenz or nevirapine

Cited by 21 publications

References 16 publications

High level of HIV-1 drug resistance mutations in patients with unsuppressed viral loads in rural northern South Africa

High level of HIV-1 drug resistance mutations in patients with unsuppressed viral loads in rural northern South Africa

A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans

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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