Title

Subtype A1, D, and recombinant HIV-1 natural polymorphisms associated with lenacapavir drug resistance in Mbarara, Uganda

Presenter

Daniel Omoding

Authors

D. Omoding¹, N. Musinguzi¹, Y. Boum II², C. Muzoora¹, S. Kigozi¹, P.W. Hunt³, J.N. Martin³, D.R. Bangsberg⁴, J.E. Haberer^5,6, M.J. Siedner^1,5,6, S. McCluskey^1,5,6, G.Q. Lee⁷

Institutions

¹Mbarara University of Science and Technology, Mbarara, Uganda, ²Institut Pasteur de Bangui, Bangui, Central African Republic, ³University of California, San Francisco, San Francisco, United States, ⁴Oregon Health Sciences University, Portland, United States, ⁵Massachusetts General Hospital, Boston, United States, ⁶Harvard Medical School, Boston, United States, ⁷Weill Cornell Medicine, Department of Medicine, New York, United States

BACKGROUND: Lenacapavir (LEN) belongs to a new class of HIV drugs called capsid inhibitors, which target viral Gag p24. LEN is effective in combination with other antiretrovirals (ART) for subtype B HIV-1 infections. However, less data is available for its activity in non-subtype-B HIV-1, which could harbor natural polymorphisms that may reduce LEN susceptibility.
METHODS: The Uganda AIDS Rural Treatment Outcomes (UARTO) cohort enrolled ART-naïve adults in Mbarara, Uganda between 2002-2010 just prior to their initiation of ART. Participants were followed longitudinally until 2015. Archived plasma samples collected at any viremic time points pre- and post-ART-initiation were subjected to HIV-1 gag p24 Sanger sequencing, subtyped by RIP 3.0 and aligned using MUSCLE against reference sequence HXB2. Lenacapavir-associated resistance mutations were defined according to the 2022 IAS-USA drug resistance mutations list including L56I, M66I, Q67H, K70N/S/R, N74D/S, A105T and T107N. We also examined mutations reported in other studies including Q67K/N, K70H, N74H, A105S, and T107A/C.
RESULTS: We obtained 741 HIV-1 gag sequences from 546 participants; 73% were from pre-treatment specimens. The median age was 34 (IQR 29-39), and 69% of participants were female. Median pre-treatment viral load and CD4 count were 5.2 log10 copies/mL (IQR 3.7-5.7) and 127 cells/µL (IQR 64-196), respectively. All went on to initiate ART with an NNRTI-containing regimen. Cohort viral subtype distribution was 51% A1, 4% C, 30% D, 1% G and 14% intersubtype-recombinants. HIV-1 natural polymorphisms associated with LEN resistance were observed in 6/546 participants (1%; 95% CI 0.4-2.4%): One of these individuals (infected with C/D recombinant HIV-1) had K70R at 6-month post-therapy, and five individuals (three infected with A1 and two D HIV-1), had T107A pre-ART. In one individual, T107A persisted up to 3 years during post-therapy-initiation follow-up. Phylogenetic analysis revealed that p24 sequences containing T107A did not cluster into unique monophyletic groups, suggesting independent mutation events as opposed to transmission clusters.
CONCLUSIONS: Among individuals in western Uganda living with subtype A1, D, and intersubtype recombinant HIV-1, we observed a 1% prevalence of natural viral polymorphisms associated with lenacapavir resistance. Our findings provide preliminary evidence that LEN is likely to be active against circulating HIV-1 viruses in this region.

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