4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

ANTI-HIV ACTIVITY PROFILE OF TENOFOVIR (PMPA) AGAINST A PANEL OF NUCLEOSIDE-RESISTANT CLINICAL SAMPLES

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):4 (Abstract 4

MD Miller¹, NA Margot¹, K Hertogs², B Larder³ and V Miller^4
1Gilead Sciences, Foster City, USA; ²Virco, Mechelen, Belgium; ³Virco, Cambridge, UK; and ⁴JW Goethe University, Frankfurt, Germany

OBJECTIVES: To characterize the tenofovir susceptibility of clinical HIV samples expressing either lamivudine (M184V), high-level zidovudine (T215Y + others ± M184V), multinucleoside (Q151M and T69S insertions ± M184V) or zalcitabine (K65R ± M184V) resistance mutations in HIV-1 RT.

METHODS: Seventy-two outpatient HIV samples, 8–20 per mutation group, were chosen according to pre-defined resistance genotypes. Susceptibility to all licensed nucleoside analogues and tenofovir was assessed using the Antivirogram phenotypic resistance assay. In this assay, phenotypic classification is based upon IC₅₀ changes relative to the wild-type reference where sensitive is <four-fold, intermediate is four- to 10-fold, and resistant is >10-fold. The mean fold change for all samples in each genotypic group is presented.

RESULTS: HIV expressing M184V alone showed mild hyper-susceptibility to tenofovir (0.7-fold). High-level zidovudine-resistant HIV (>28-fold zidovudine-resistant; mean 3.5 zidovudine mutations) remained sensitive to tenofovir, demonstrating 3.1-fold reduced susceptibility, with only three of 20 samples having an intermediate phenotype. In the presence of M184V, the high-level zidovudine mutations were more sensitive to tenofovir and exhibited only a 2.4-fold change from wild-type. HIV with the currently rare multinucleoside- resistant T69S insertions were resistant to tenofovir (23-fold), but, in association with M184V, increased and intermediate susceptibility to tenofovir was observed (six-fold). In contrast, multinucleosideresistant HIV with Q151M showed full sensitivity to tenofovir (1.7-fold) regardless of M184V. HIV expressing K65R, a mutation associated with zalcitabine, didanosine and abacavir in vivo, and also selected by tenofovir in vitro, showed 3.4-fold reduced susceptibility to tenofovir but only 1.5-fold reduced susceptibility in the presence of M184V. This increase in tenofovir susceptibility due to M184V was confirmed by adding M184V through site-directed mutagenesis into three patient-derived recombinant viruses expressing K65R.

CONCLUSIONS: The presence of the M184V mutation increases tenofovir susceptibility in multiple HIV genotypes, resulting in wild-type susceptibility for HIV expressing the K65R RT mutation. Furthermore, tenofovir is uniquely active against multinucleosideresistant HIV expressing the Q151M complex, but shows some cross-resistance to the currently rare T69S insertions. These in vitro analyses also demonstrate the broad susceptibility and limited cross-resistance to tenofovir of HIV with common forms of zidovudine and lamivudine resistance and corroborate Phase II clinical trial results demonstrating the anti-HIV activity of tenofovir disoproxyl fumarate in heavily antiretroviral-experienced patients.

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2000-06-12
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