{"doi":"10.1093/jac/dkab276","title":"High-level resistance to bictegravir and cabotegravir in subtype A- and D-infected HIV-1 patients failing raltegravir with multiple resistance mutations","abstract":"OBJECTIVES: The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs. PATIENTS AND METHODS: HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells. RESULTS: HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug. CONCLUSIONS: Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.","journal":"Journal of Antimicrobial Chemotherapy","year":2021,"id":179667,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9443,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":401454,"name":"Yue Li","orcid":"0000-0002-2353-4078","position":1,"is_corresponding":false},{"id":401455,"name":"Paul S Reyes","orcid":"0000-0002-3728-1593","position":2,"is_corresponding":false},{"id":401451,"name":"Mariano Avino","orcid":"0000-0002-6796-2453","position":3,"is_corresponding":false},{"id":401452,"name":"Abayomi S. Olabode","orcid":"0000-0002-6620-8694","position":4,"is_corresponding":false},{"id":388628,"name":"Cissy Kityo","orcid":"0000-0002-9286-7052","position":5,"is_corresponding":false},{"id":403129,"name":"Fred Kyeyune","orcid":null,"position":6,"is_corresponding":false},{"id":403130,"name":"Immaculate Nankya","orcid":null,"position":7,"is_corresponding":false},{"id":388795,"name":"Miguel E. Quiñones‐Mateu","orcid":"0000-0001-9170-5601","position":8,"is_corresponding":false},{"id":566368,"name":"Stephen D. Barr","orcid":"0000-0002-0028-7430","position":9,"is_corresponding":false},{"id":401456,"name":"Eric J. Arts","orcid":"0000-0002-4880-7968","position":10,"is_corresponding":false},{"id":401450,"name":"Emmanuel Ndashimye","orcid":"0000-0002-9112-9402","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-18T23:47:48.974996Z","pmid":"34453542","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}