Background:  The effect of transmitted drug resistance on CD4 cell decline remain unclear, and it is further unclear whether evolution of such resistant viruses, in the absence of therapy, influences the short-term natural history of infection.

Methods:  Sequence analysis of HIV-1 from 440 therapy-naďve individuals included within the CASCADE study, who seroconverted within 18 months of the last negative test, identified 65 persons infected with a strain carrying resistance-associated mutations.

Results:  Population based sequencing was performed for 20 of these individuals during the therapy-free follow-up period. The median time of follow-up was 15 months (interquartile range, 10 to 23 months). Of these persons, 12 showed subsequent evolution at the resistance positions, whereas the virus of 8 persons was stable during this period. In the reverse transcriptase gene, the drug-resistant 215Y or 215F codons evolved to alternative codons in all 6 cases, 70R reverted to the wild type 70K in 3 of the 4 persons, 67N evolved only in 1 of 4 patients to a wild type 67D, 215S evolved to wild type 215T in 1 of 3 patients, 219N evolved to 219K in 1 of 2 patients, and 1 patient with 184V reversed to the wild type 184M. The 181C variant evolved to the wild type 181Y in 1 of 2 persons. These codon changes were caused by single nucleotide mutations. No evolution was observed for other RT mutations:  41L, 69D, 69N, 190S, 210W, 215L, 215C, 215E, and 219Q. In the protease gene, resistance mutations 84V and 90M were stable in 2 persons. Comparing the CD4 cell count of the 12 evolving and 8 stable cases revealed no statistically significant difference at the date of the first sequence following seroconversion. Interestingly, a lower CD4 cell count was observed in the group without evolution at the second sequence time point (p = 0.043).

Conclusions:  Our results support the hypothesis that transmitted HIV-1—carrying either 215Y/F, 70R, or 184V—have decreased fitness and, possibly, pathogenicity, over the short term.