Pre-treatment integrase inhibitor resistance is uncommon in ART-naïve individuals with HIV-1 subtype A1 and D infections in Uganda
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Date
2020Author
Mccluskey, Suzanne M.
Kamelian, Kimia
Musinguzi, Nicholas
Kigozi, Simone
II, Yap Boum
Bwana, Mwebesa B.
Muzoora, Conrad
Brumme, Zabrina L.
Carrington, Mary
Carlson, Jonathan
Foley, Brian
Hunt, Peter W.
Martin, Jeffrey N.
Bangsberg, David R.
Harrigan, P. Richard
Siedner, Mark J.
Haberer, Jessica E.
Lee, Guinevere Q.
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Objective: Dolutegravir (DTG) is now a preferred component of first-line antiretroviral therapy (ART). However, prevalence data on natural resistance to integrase 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-naïve 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 2002–2010, 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. HLA typing was performed for all study participants.
Results: Plasma samples from 511 ART-naïve 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.
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