In vitro and clinical studies have shown that subtype C viruses have a greater propensity to develop a K65R mutation due to polymorphisms at codons 64-66. This has potentially important public health implications given that subtype C infection accounts for around 50% of HIV infections worldwide and with the expanded use of tenofovir (TDF) as per WHO 2013 recommendations. We have exploited the wide diversity of viral subtypes within the UK to examine whether viral subtype influences the rate of virological failure (VF) on first-line TDF-containing regimens.
Patients were included if HIV care was received at a participating clinic in the UK CHIC study; their first-line regimen was TDF+(XTC)+(EFV, NVP, LPV/r, DRV/r or ATV/r); and ≥2 viral loads (VLs) measured after 6 months following ART initiation. Subtypes were defined according to Rega-3, based on resistance tests conducted pre-therapy or at treatment failure. Time to VF (2 consecutive VLs >200 copies/ml after 6 months of ART) was analysed using Cox models, adjusting for demographic factors, baseline CD4 and VL, ART regimen, and year of initiation. Follow-up was censored at last VL or discontinuation of TDF. Multiple imputation was used to include patients with missing subtypes, taking advantage of the strong association with demographic factors.
8746 patients were included and followed for a median of 3.3 years; 5465 (4123 observed, 1342 average of imputed) were subtype B, 1455 (823, 632) subtype C, and 1826 (1203, 623) non-B/non-C. Subtype B patients were mostly white (83%) and MSM (85%) while subtype C mostly black (70%) and heterosexual (79%). Subtype non-B/non-C patients were demographically more mixed (35% white, 53% black; 26% MSM, 63% heterosexual). Risk of VF for subtype non-B/non-C (173, 9.5%) was similar to subtype C (142, 9.8%) (aHR=1.1, 95% CI 0.8-1.4). In unadjusted analyses, patients with subtype B infection had a much lower risk of VF (309, 5.7%) than subtype C (HR=0.5, 95% CI 0.4-0.7). However this difference was markedly reduced in adjusted analyses (aHR=0.9, 95% CI 0.6-1.2, P=0.41), largely mediated by the effects of exposure group and ethnicity.
Patients infected with subtype C virus on a first-line TDF containing regimen appear not to experience a higher rate of VF with differences observed explained by demographic factors rather than a subtype effect. This is a reassuring finding for expanded use of TDF in southern Africa, India, and other areas where subtype C virus predominates.