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Impact of HIV viral diversity and baseline resistance on treatment outcomes and the emergence of resistance: the CASTLE study 48-week results
Journal of the International AIDS Society volume 11, Article number: P180 (2008)
HIV viral diversity and baseline (BL) substitutions have implications for response to antiretroviral therapy, the development of resistance and disease progression. Worldwide, approximately 90% of HIV infections are non-B subtypes. The CASTLE study is a randomized, open-label, prospective study comparing once-daily ATV/r with twice-daily LPV/r, both in combination with fixed-dose tenofovir/emtricitabine in 883 treatment-naive patients from 28 countries. The impact of HIV subtypes and BL resistance on efficacy and emergence of resistance is described.
HIV subtype was determined by comparison of genotypes with a consensus B sequence. Protease substitutions were classified as major or minor according to IAS-USA (2007) and the HIV Drug Resistance Database (HIVdb). Protease polymorphisms were defined as either: 1) IAS-USA minor substitutions assigned a score of 0 by the Stanford HIV database (HIVdb Genotype Resistance Interpretation); or 2) Non-IAS-USA PI substitutions (Clade B reference). Batched genotypes were performed on BL samples, and Genotype/PhenoSense (Monogram Biosciences, South San Francisco, CA, USA) on paired samples with virologic failure (HIV-RNA = 400 c/mL) through week 48 (i.e. rebound without resuppression; never confirmed VL<400 c/mL but remained on treatment at week 48; discontinued due to lack of efficacy before week 48).
Summary of results
18 HIV subtypes were represented: B (66%), C (16%), BF (8%), and AE (6%). Response rates overall and by subtype are presented in Table 1.
Response rates by baseline substitutions are presented in Table 2.
6% of subjects in each treatment group had virologic failure. PI substitutions emerged in 10/19 ATV/r and 8/20 LPV/r VFs; all were polymorphic except in two ATV/r subjects [1(N88S, M46I); 2 (L10F, V32I, M46I, K43T, A71I, G73S, L90M)]. The subject with N88S subsequently re-suppressed to undetectable levels on same regimen (ATV FC 3.71); M184V emerged in 5/19 and 4/20, and TAMs in 1/19 and 1/20, respectively. Virologic failure rates were consistent across the predominant subtypes represented in the study: ATV/r (B 5%, C 8%) and LPV/r (B 6%, C 8%).
Both regimens (ATV/r and LPV/r) achieved consistently high response rates regardless of HIV subtype or BL substitutions. Both regimens had infrequent emergence of non-polymorphic PI substitutions with virologic failure, and similar rates of selection of antiretroviral resistance mutations.
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Lataillade, M., Yang, R., Mancini, M. et al. Impact of HIV viral diversity and baseline resistance on treatment outcomes and the emergence of resistance: the CASTLE study 48-week results. JIAS 11, P180 (2008). https://doi.org/10.1186/1758-2652-11-S1-P180
- High Response Rate
- Resistance Mutation
- Virologic Failure
- Predominant Subtype
- Baseline Resistance