Abstract:
Introduction: Failure of protease-inhibitor (PI)-based second-line antiretroviral therapy (ART) with medication adherence but
no protease drug resistance mutations (DRMs) is not well understood. This study investigated the involvement of gp41 and
gag as alternative mechanisms, not captured by conventional resistance testing and particularly relevant in resource-limited
settings where third-line ART is limited.
Methods: We evaluated gp41 and gag for unique amino acids in seven subtype A infected Kenyans failing second-line therapy
with no PI resistance yet detectable lopinavir (query dataset), compared to seven similar-setting patients with PI resistance or
undetectable lopinavir and 69 publically available subtype A Kenyan whole-genomes sequences.
Results: Three gp41 (607T, 641L, 721I) and four gag (124S, 143V, 339P, 357S) amino acids were significantly more frequent
in the query dataset compared to the other datasets, with significantly high co-occurrence.
Conclusion: The genotypic analysis of a unique group of HIV-1 subtype A infected patients, identified seven amino acids that
could potentially contribute to a multi-gene mechanism of PI-based ART failure in the absence of PI DR mutations.
