16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

SENSITIVE TESTING DEMONSTRATES A HIGH PREVALENCE OF TRANSMITTED DRUG RESISTANCE AMONG CONVENTIONALLY GENOTYPED WILDTYPE HIV-1 INFECTIONS

Antivir Ther. 2007; 12:S46 (abstract no. 39)

JA Johnson, J-F Li, X Wei, J Lipscomb, A Smith, and W Heneine
Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA

BACKGROUND: Highly-active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-1-infected individuals; however, drug-resistant viruses are a major hurdle to the success of HAART. Baseline testing of persons newly diagnosed with HIV is important for identifying transmitted drug resistance and for selecting fully active treatment regimens. We used sensitive real-time PCR testing to assess whether drug-naïve persons who were diagnosed with wild-type virus infections by conventional bulk genotyping had minority undiagnosed drug-resistance mutations.

METHODS: Using sensitive real-time PCR assays with detection cutoffs between 0.4–2.0% for clinical screening, we evaluated 205 persons documented to have wildtype virus infections. These samples represented 44% of the 471 total wildtype specimens in the cohort, and 89 (43%) were determined by antibody testing to be from recent infections (<6 months duration). Specimens were collected in Chicago and Los Angeles in 2003–2005. Twenty percent of all cohort participants had drug resistance mutations by standard bulk genotyping. We tested for the presence of low-frequency L90M protease mutations, and M41L, K70R, K103N, Y181C, M184V, T215F and T215Y reverse transcriptase-resistance mutations. Each assay had been validated against wild-type samples from the pre-antiretroviral drug era.

RESULTS: Real-time PCR analysis found that 33/205 (16%) wild-type virus samples had ≥1 of the resistance mutations tested. Each mutation was detected in at least two samples as low-frequency variants and the overall prevalence of mutations was 3.5% L90M, 4.5% M41L, 5% K70R, 4% K103N, 1.5% Y181C, 1.5% M184V, 1% T215Y and 2% T215F. Low-frequency mutations were equally found in recently-infected persons (17%) and persons with longer-duration infections (17%). One recent and three chronic infections (2% overall), respectively, had the following mutations to two drug-classes: L90M-M184V, L90M-Y181C, Y181C-T215F, and L90M-M41L-K70R.

CONCLUSION: The identification of resistance-associated mutations in drug-naïve persons previously diagnosed with wildtype virus infections increased the prevalence of transmitted drug resistance in this cohort from 20% to 33% (+65%). The considerable prevalence of low-frequency mutations and their equal occurrence in chronic infections demonstrate that a substantial proportion of transmitted drug-resistant variants decay and persist at low levels. These findings underscore the importance of sensitive baseline drug-resistance testing.

2007-06-12
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