Pre-treatment integrase inhibitor resistance is uncommon in antiretroviral therapy-naive individuals with HIV-1 subtype A1 and D infections in Uganda

Suzanne M. McCluskey, Kimia Kamelian, Nicholas Musinguzi, Simone Kigozi, Yap Boum, Mwebesa B. Bwana, Conrad Muzoora, Zabrina L. Brumme, Mary Carrington, Jonathan Carlson, Brian Foley, Peter W. Hunt, Jeffrey N. Martin, David R. Bangsberg, P. Richard Harrigan, Mark J. Siedner, Jessica E. Haberer, Guinevere Q. Lee

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: Dolutegravir (DTG) is now a preferred component of first-line antiretroviral therapy (ART). However, prevalence data on natural resistance to integrase inhibitors [integrase strand transfer inhibitors (INSTIs)] in circulating non-subtype B HIV-1 in sub-Saharan Africa is scarce. Our objective is to report prevalence of pre-treatment integrase polymorphisms associated with resistance to INSTIs in an ART-naive cohort with diverse HIV-1 subtypes. DESIGN: We retrospectively examined HIV-1 integrase sequences from Uganda. METHODS: Plasma samples were derived from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, reflecting enrollment from 2002 to 2010, prior to initiation of ART. HIV-1 integrase was amplified using nested-PCR and Sanger-sequenced (HXB2 4230-5093). Stanford HIVdb v8.8 was used to infer clinically significant INSTI-associated mutations. Human leukocyte antigen (HLA) typing was performed for all study participants. RESULTS: Plasma samples from 511 ART-naive individuals (subtype: 48% A1, 39% D) yielded HIV-1 integrase genotyping results. Six out of 511 participants (1.2%) had any major INSTI-associated mutations. Of these, two had E138T (subtype A1), three had E138E/K (subtype D), and one had T66T/I (subtype D). No participants had mutations traditionally associated with high levels of INSTI resistance. HLA genotypes A∗02:01/05/14, B∗44:15, and C∗04:07 predicted the presence of L74I, a mutation recently observed in association with long-acting INSTI cabotegravir virologic failure. CONCLUSION: We detected no HIV-1 polymorphisms associated with high levels of DTG resistance in Uganda in the pre-DTG era. Our results support widespread implementation of DTG but careful monitoring of patients on INSTI with virologic failure is warranted to determine if unique mutations predict failure for non-B subtypes of HIV-1.

Original languageEnglish (US)
Pages (from-to)1083-1089
Number of pages7
JournalAIDS (London, England)
Volume35
Issue number7
DOIs
StatePublished - Jun 1 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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