Background: Sexual transmission of drug resistance depends on viral shedding in genital secretions, but the relationship between drug resistance in plasma and genital secretions is not well defined. We compared compartmental shedding and drug resistance in viremic, multi-drug experienced subjects in AACTG 5077 prior to therapy change.

Methods: Matched plasma/genital secretion samples from 144 subjects (64 semen, 80 cervical lavage or Sno-strip wicks) were assayed for viral load. Plasma/GS pol was sequenced by 4 participating laboratories using TrueGene, ViroSeq, or independently validated assays. Genetic distance between plasma/genital secretion sequences from the same subject was determined by weighted Hamming distance to address mixtures. Drug susceptibility was estimated by Stanford's HIVDB (http://HIVDB.stanford.edu) for active drugs (AD) in previous year and future drug options (FDO) defined as drug classes to which the virus was susceptible (FDO1) and susceptible classes plus susceptible drugs (FDO2).

Results:  Viral load (>400 copies/mL) was detected in plasma of all 144 subjects and in genital secretions of 49 of 64 (77%) men and 29 of 80 (36%) women (p <0.0001). Sequences were obtained from plasma/genital secretion of 37 men and 28 women, median 5 prior antiretrovirals (ARV), 202 CD4 cells/µL and 4.9 log₁₀copies/mL plasma viral load. Nucleic acid concordance between plasma/genital secretion sequences within each subject was 71% while 29% were discordant. These differences were often synonymous substitutions, and when non-synonymous, were often nucleic acid mixtures at drug resistance codons in 1 compartment. All laboratories showed similar results between compartments:  median difference of 8.5 per 1000 nucleotides for men and 5.2 for women (p = 0.004). Resistance prediction by 3 methods (AD/FDO1/2) showed few differences between compartments:  34 of 37 (92%) men and 25 of 28 (89%) women for AD, 35 of 37 (95%) men and 28 of 28 (100%) women for FDO1, and 33 of 37 (89%) men and 26 of 28 (93%) women for FDO2.

Conclusions:  Among highly ARV drug-experienced subjects receiving ARV therapy, virus in genital secretions was more readily identified among men than women. Drug-resistance profiles were similar across compartments for men and women, with genotype differences mostly at drug-resistance codons as mixtures. Mixture-weighted differences showed greater genetic distance in men than women, but clinical measures of drug resistance (active drugs and future drug options) showed only modest differences between compartments with no differences between men and women. Plasma genotyping provides accurate surrogate information about drug resistance in genital secretions and identifies the potential risk for transmission of drug resistant virus.