Limited emergence of resistance to integrase strand transfer inhibitors (INSTIs) in ART-experienced participants failing dolutegravir-based antiretroviral therapy: a cross-sectional analysis of a Northeast Nigerian cohort

Abdullahi, Adam; Kida, Ibrahim Musa; Maina, Umar Abdullahi; Ibrahim, Amina Husaini; Mshelia, James; Wisso, Haruna; Adamu, Abdullahi; Onyemata, James Ezenwa; Edun, Martin; Yusuph, Haruna; Aliyu, Sani H; Charurat, Man; Abimiku, Alash’le; Abeler-Dorner, Lucie; Fraser, Christophe; Bonsall, David; ,; Abeler-Dörner, Lucie; Ayles, Helen; Bonsall, David; Bowden, Rory; Calvez, Vincent; Essex, Max; Fidler, Sarah; Fraser, Christophe; Grabowski, Kate; Golubchik, Tanya; Gupta, Ravindra; Hayes, Richard; Herbeck, Joshua; Kagaayi, Joseph; Kaleebu, Pontiano; Lingappa, Jairam; Moyo, Sikhulile; Novitsky, Vladimir; Ndung'u, Thumbi; Pillay, Deenan; Quinn, Thomas; Rambaut, Andrew; Ratmann, Oliver; Seeley, Janet; Ssemwanga, Deogratius; Tanser, Frank; Wawer, Maria; Cohen, Myron; D'Oliveira, Tulio; Dennis, Ann; Essex, Max; Fidler, Sarah; Frampton, Dan; Fraser, Christophe; Golubchik, Tanya; Hayes, Richard; Herbeck, Josh; Hoppe, Anne; Kaleebu, Pontiano; Kellam, Paul; Kityo, Cissy; Leigh-Brown, Andrew; Lingappa, Jairam; Novitsky, Vladimir; Paton, Nick; Pillay, Deenan; Quinn, Tom; Ratmann, Oliver; Ssemwanga, Deogratius; Tanser, Frank; Wawer, Maria; Kemp, Steven A; Gupta, Ravindra K

doi:10.1093/jac/dkad195

Cited by 12 publications

(13 citation statements)

References 53 publications

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“…In a study from Malawi, GRT was performed on 27 samples from more than 6400 individuals with VF [72]. In a study from Nigeria, GRT was performed on 33 samples from 281 individuals with VF [73]. In three studies from Tanzania, GRT was performed in nearly all of the 181 individuals with VF [74–76].…”

Section: Resultsmentioning

confidence: 99%

Risk of Emergent Dolutegravir Resistance Mutations In People Living With HIV: A Rapid Scoping Review

Chu,

Tao,

Kouamou

et al. 2024

Preprint

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BackgroundDolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of virological failure (VF) with emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART.MethodsWe performed a PubMed search using the term “Dolutegravir” last updated December 18, 2023, to estimate the prevalence of VF with emergent INSTI DRMs in clinical trials and cohorts of people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART.ResultsOf 2131 records identified by search, 43 clinical trials, 39 cohorts, and six cross-sectional studies provided data across six clinical scenarios based upon ART history, virological status, and ARVs co-administered with DTG: (1) ART-naïve PLWH receiving DTG plus two nucleoside reverse transcriptase inhibitors (NRTIs); (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on their previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.6% for scenario 3 and 2.9% for scenario 6. In the remaining four trial scenarios, prevalence of VF with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, while cross-sectional studies yielded prevalence data lacking denominator details.ConclusionsIn clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess the risk of VF with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.What is already known on this topicDolutegravir is known for its high resistance barrier, yet there remains a concern for virological failure and subsequent drug resistance in people living with HIV who begin first or second-line antiretroviral therapy with a dolutegravir-containing regimen.What this study addsThe prevalence of virological failure with the development of HIV mutations associated with reduced susceptibility to dolutegravir depends on a person’s virological response to previous antiretroviral therapy, the presence of HIV replication at dolutegravir initiation, and the antiretroviral drugs co-administered with dolutegravir.In clinical trial settings, the prevalence of virological failure with emergent dolutegravir resistance was rare among people initiating therapy with a dolutegravir-containing regimen and was 1.6% over a period of one to two years among those who had previously experienced virological failure on an earlier treatment regimen.In the subset of persons with virological failure on a first-line dolutegravir-containing regimen, the prevalence of emergent dolutegravir resistance was 0.7%, whereas in the subset of persons with virological failure on a second-line dolutegravir-containing regimen, the prevalence of emergent dolutegravir resistance was 20.4%.How this study might affect research, practice, or policyIn people living with HIV with virological failure on a first-line dolutegravir-containing regimen, enhancing medication adherence may prove more beneficial than transitioning to an alternative treatment regimen.In cases of virological failure on a second-line dolutegravir-containing regimen, the potential for dolutegravir resistance suggests a need to investigate the role of genotypic resistance testing to inform treatment changes.Population-level surveillance for acquired dolutegravir resistance should take into account the antiretroviral treatment history and level of HIV replication prior to the initiation of dolutegravir-containing therapy.

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Section: Resultsmentioning

confidence: 99%

Risk of Emergent Dolutegravir Resistance Mutations In People Living With HIV: A Rapid Scoping Review

Chu,

Tao,

Kouamou

et al. 2024

Preprint

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show abstract

“…In a study from Malawi, GRT was performed on 27 samples from more than 6400 individuals with VF [ 70 ]. In a study from Nigeria, GRT was performed on 33 samples from 281 individuals with VF [ 71 ]. In three studies from Tanzania, GRT was performed in nearly all of the 181 individuals with VF [ 72 , 73 , 74 ].…”

Section: Resultsmentioning

confidence: 99%

“…We described six such studies including one from Brazil of 113 PLWH with confirmed VF on a first-line regimen of DTG plus two NRTIs [ 42 ] and five from Sub-Saharan Africa. The studies from Sub-Saharan Africa included approximately 214 individuals, most of whom had prior ART experience before initiating DTG treatment [ 70 , 71 , 72 , 73 , 74 ]. The study from Brazil found that approximately six percent of the samples tested were found to have INSTI DRMs, whereas in the studies from Sub-Saharan Africa, approximately nine percent of the samples tested had INSTI DRMs.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Chu,

Tao,

Kouamou

et al. 2024

Viruses

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Background: Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART. Methods: We performed a PubMed search using the term “Dolutegravir”, last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART. Results: Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details. Conclusions: In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.

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“…At present, resistance to integrase inhibitors in treatment naïve individuals is very low, with some individuals selecting major INSTI mutations 10 , 46 ; however, ~10% of previously treatment-experienced individuals who go on to develop viremia whilst on an integrase inhibitor harbour INSTI mutations. Ongoing surveillance for INSTI resistance in the DTG treatment era is critical, given the highly promising results from CAB PreP studies 47 , 48 and emerging data showing that the use of LA CAB/RPV during acute HIV infection can result in the selection of major resistance mutations to INSTIs 49 .…”

Section: Discussionmentioning

confidence: 99%

HIV transmission dynamics and population-wide drug resistance in rural South Africa

Kemp,

Kamelian,

Cuadros

et al. 2024

Nat Commun

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Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission.

show abstract

Limited emergence of resistance to integrase strand transfer inhibitors (INSTIs) in ART-experienced participants failing dolutegravir-based antiretroviral therapy: a cross-sectional analysis of a Northeast Nigerian cohort

Cited by 12 publications

References 53 publications

Risk of Emergent Dolutegravir Resistance Mutations In People Living With HIV: A Rapid Scoping Review

Risk of Emergent Dolutegravir Resistance Mutations In People Living With HIV: A Rapid Scoping Review

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

HIV transmission dynamics and population-wide drug resistance in rural South Africa

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