11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th:Abstract No. 36LB

S J Little¹, K K Koelsch¹, C C Ignacio¹, J K Wong^1,2, Y Lie³, S D W Frost¹, and D D Richman^1,2
1Univ. of California, San Diego, La Jolla, USA; ²San Diego VA Healthcare System, La Jolla, CA, USA; and ³ViroLogic, Inc., South San Francisco, CA, USA

BACKGROUND: We wanted to assess the persistence of transmitted drug resistant variants in the absence of antiretroviral drug (ARV) treatment among subjects with primary HIV infection.

METHODS: Baseline nucleotide sequence analysis of pol was used to identify major drug-resistance mutations among 11 subjects with primary HIV infection who deferred ARV. ARV drug susceptibility and replication capacity were measured using a single replication cycle assay (ViroLogic).

RESULTS: All 11 subjects (mean time from estimated date of infection: 65 days) had at least one major drug-resistance mutation identified at presentation with corresponding phenotypic resistance. The median baseline viral load was 5.3 log₁₀ copies/mL (range 2.5 to 7.4) and mean replication capacity was 84% of wild-type. Longitudinal samples were collected for a median of 225 days (range 82 to 1346 days) after infection and analyzed for persistence of transmitted drug resistant variants. Seven subjects were identified with NNRTI resistance (103N ± 181C), 2 with NRTI (70R, 74V/I, 184V, 215Y) and PI resistance (46I, 82A, 84V, 90M), 1 with NNRTI (188L) and PI resistance (30N), and 1 with 3-class drug resistance (103N, 215Y, 84V, 90M). The average time to reversion of 103N variants to mixed 103N/K populations was 196 days following the estimated date of infection (153 to 238 days, 95%CI). In the 4 patients with protease resistance mutations, no reversion was detected at 64, 191, 327, and 342 days after infection. Complete reversion of genotypic resistance was observed in only one patient at 1019 days after infection.

CONCLUSIONS: Transmitted drug resistance persisted for 9/11 subjects with reversion of a transmitted K103N variant in only 1 subject, nearly 3 years after infection. The persistence of transmitted drug resistant virus is consistent with the establishment of widespread infection with a pure population of resistant clone(s). Reversion of resistance is gradual and usually incomplete, resulting in the persistence of mixtures of wild type and resistant variants in plasma HIV RNA. No reversion of protease resistance was observed (n = 4), suggesting that the time to reversion is comparable to or even greater than that observed for K103N. The persistence of drug-resistant variants has significant implications for the treatment of ARV-naïve subjects and subsequent secondary transmission of drug resistant variants.

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