Background:  Genetic differences between HIV subtypes may be important in the management of ART in non-B-infected individuals, as well as in surveillance of resistance in regions with predominantly non-B subtypes. Our aims were to identify whether specific drug-resistant mutations in the protease (PR) gene of patients infected with non-B subtype are the same as those with subtype B infection; and whether novel mutations emerge in non-B subtype B viruses;

Methods:  Data consisted of PR sequences from all resistance tests in the UK HIV Drug Resistance Database, which collates nucleotide or amino acid resistance test results since 1996 from clinical centers in the United Kingdom. Subtypes were assigned to sequences using a position-specific scoring matrix (PSSM) based subtyping using the STAR algorithm. PR sequences for individuals who had been on a single first protease inhibitor (PI) for at least 28 days were compared with those from PI-naïve patients with the same subtype using c² tests to detect significant differences in the prevalence of amino acids at specific positions. Any significant differences (p <0.05) were considered potentially clinically relevant and compared with known IAS mutations

Results:  We successfully subtyped 15,624 genotypes, 11,692 of which were subtype B. The most frequent non-B subtypes were C (n = 2043), A (n = 815), D (n = 428), and AG (n = 322). After linkage with ART data, 2505 sequences were classified as from PI-naïve and 1155 from PI-exposed patients for ≥28 days. The analysis was based on patients exposed to saquinavir, nelfinavir, indinavir, ritonavir for subtypes A (98 naïve, 76 experienced), AG (58 naïve, 16 experienced), B (2024 naïve, 915 experienced), C (230 naïve, 94 experienced), and D (53 naïve, 42 experienced). In preliminary analyses, we found significant amino acid differences between PI-naïve and -experienced patients for B and most non-B subtypes at positions 14, 20, 46, 54, 74, 82, and 90, and novel associations at positions 83 and 89 for patients with subtype A, and 69 for subtype CRF02-AG/G.

Conclusions:  In this large database of patients with diverse HIV subtypes who underwent resistance testing, the majority of PR mutations in non-B subtype isolates also occurred in subtype B isolates. Novel non-B subtype-specific PR mutations were rare, and will require confirmation in other large resistance databases.