Background:  Sexual transmission of ART drug resistance depends on shedding of genital virus, but the relationship between ART and drug resistance in plasma and genital secretions is undefined. Drug history was obtained and plasma, semen, and cervical virus were assayed for HIV RNA and genotype to compare sex and compartment-specific shedding and drug resistance.

Methods:  We assayed for HIV RNA, 144 plasma and genital specimens (64 semen and 80 cervical lavage / “Sno-strip” wicks). More than 400 copies/mL of HIV RNA were detected in genital secretions among 49 of 64 (77%) men and 29 of 80 (36%) women and RNA was sequenced by TrueGene, ViroSeq, or in-house assays. The HIVSeq program (<HIVDB.stanford.edu>) estimated resistance to nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI), and protease inhibitor (PI) drugs. Plasma and genital secretions, class-specific drug resistance, and genetic distances were compared within subjects, and between men and women.

Results:  Plasma and genital secretions were sequenced from 37 men and 28 women with a median use of 4.8 ART, 202 CD4 cells/mL and 4.9 log₁₀ HIV RNA copies/mL of plasma. Comparing genital secretions and plasma sequences identified similar nucleic acid concordance in 60% while 40% had genetic differences; these difference were often synonymous substitutions and when non-synonymous were often nucleic acid mixtures at drug resistance codons in 1 compartment. Plasma genotype of 57 subjects on drug within 90 days showed resistance to a similar number of drugs per class, trending toward more drug resistance among men compared to women to NRTI (18 of 28 [64%] men vs 14 of 29 [48%] women with resistance to at least 1 drug) and PI (12 of 28 [43%] men vs 9 of 29 [31%] women). However, men had less NNRTI drug resistance than women (11 of 28  [39%] men vs 16 of 29 [55%] women). When restricted to those on a drug within class within 90 days, these trends persisted (NRTI:  18 of 25 [62%] men vs 14 of 26 [54%] women; NNRTI:  7 of 11 [64%] men vs 10 of 13 [77%] women; PI:  12 of 19 [63%] men vs 9 of 16 [56%] women).

Conclusions:  Among highly ART-experienced subjects, there was markedly less detectable genital HIV shedding among women than men. More than half of men with any ART-resistant HIV in plasma shed resistant HIV in semen. Compared to the opposite sex, men had a higher frequency of PI drug resistance, while women had a higher frequency of NNRTI drug resistance in genital secretions. Plasma genotyping provides an excellent surrogate for genital secretions drug resistance and identifies risk of transmission of drug resistant virus.