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First ART Response After Genotyping: T215 Revertants Signal Danger
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5th European HIV Drug Resistance Workshop
Cascais, Portugal
March 30, 2007
Mark Mascolini
People infected with resistant HIV responded as well to first-line antiretroviral therapy (ART) as people infected with wild-type (nonmutant) virus--as long as they had a resistance test before beginning treatment [1]. First-line failure rates were higher when genotyping detected T215 "revertants," AZT-related T215Y/F mutations reverting back to wild-type when genotyping was done.
This ongoing prospective German multicenter study includes 455 people genotyped for resistance mutations before starting ART. Forty of them (8.8%) had resistance-related mutations before treatment. An intent-to-treat analysis determined that 72.5% of people with primary resistance had a viral load under 50 copies after 48 weeks of treatment, compared with 75.9% of those without resistance mutations, a nonsignificant difference (P = 0.7). An on-treatment analysis also found statistically equivalent 48-week response rates in the primary resistance group (82.9%) and the group without pretreatment resistance (86.8%) (P = 0.6).
Among people in whom pre-ART genotyping spotted a T215 revertant (T215C, D, E, L, S, or V), 52.6% had a sub-50 viral load at week 48 compared with 76.6% of people without revertants in their baseline sample, a significant difference (P = 0.03). While 70.1% of people with AIDS when they began therapy had a week 48 load under 50 copies, 78.8% without AIDS had a sub-50 response at week 48, also a significant difference (P = 0.04).
Five of 24 people (21%) with revertants upon genotyping had a viral load above 50 copies at week 48, and 3 had loads above 400 copies. Everyone with revertants and a detectable 48-week load also had other resistance mutations--L90M in 3 people, K103N in 2, and V82A in 2. People in whom genotyping detected only a single mutation all had a sub-50-copy load at week 48.
Multivariate analysis determined that people with pretreatment T215 revertants had more than a 3 times higher risk of failure (viral load above 50 copies) at week 48 (odds ratio [OR] 3.44, 95% confidence interval [CI] 1.3 to 9.0, P = 0.01). People with AIDS before starting therapy had a 62% higher risk of failure (OR 1.62, 95% CI 1.1 to 2.6, P = 0.04). Men infected during sex with men had a 50% lower risk of 48-week failure than heterosexuals and injecting drug users (OR 0.5, 95% CI 0.3 to 0.8, P = 0.006). Factors that did not influence virologic response in this cohort were age, gender, nationality, ethnic origin, duration of HIV diagnosis, baseline CD4 count and viral load, primary drug resistance in general, drug class-specific resistance, multidrug resistance, HIV subtype, and number of treatment modifications.
Mark Oette (University Clinic of Duesseldorf) stressed the importance of genotyping before starting antiretrovirals--and then planning a regimen based on the results. Despite detection of T215 revertants, a few physicians prescribed first-line AZT or d4T, which probably explained some failures. Oette noted that clinicians sometimes prescribe a regimen on the same day they order a genotype, then forget to modify the combination when they get the results.
Reference
1. Oette M, Kaiser R, Daeumer M, et al. First-line HAART guided by genotypic resistance testing: beware of revertant variants. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 95.
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