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  18th HIV Drug Resistance Workshop
June 9-12 2009
Ft Myers Florida
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PI-Resistant Virus Seems More Prone to Emergence of Bevirimat Mutations
  Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
Naturally occurring gene shifts (polymorphisms) in HIV that make the virus less susceptible to the maturation inhibitor bevirimat probably mean people will have to be screened for such shifts before starting this antiretroviral, if it becomes licensed [1]. Two studies at the Resistance Workshop appear to raise the hurdle to clinical use of this novel agent by showing (1) accumulation of bevirimat mutations in subtype B isolates that already carry protease mutations, (2) a shift to a genetic motif favoring resistance to bevirimat in people with mutations conferring resistance to protease inhibitors (PIs), and (3) a high rate of bevirimat mutations in untreated people with HIV-1 subtypes other than B [2,3].
Bevirimat stymies HIV by blocking protease-directed cleavage at the junction between capsid (CA) and spacer peptide 1 (SP1) in HIV gag. Therefore evaluating the effect of protease mutations on bevirimat activity is essential to understanding the potential role of this investigational agent, which would probably be used in people with multidrug-resistant virus. Work published just before the Resistance Workshop found evidence that PI mutations had no impact on viral inhibition by bevirimat [4]. Most bevirimat and PI mutations had an additive effect in impairing viral replication. The exception was bevirimat mutation SP1-A1V, which permitted "robust replication" of HIV with or without PI mutations.
The investigators from the HIV Drug Resistance Program at the National Cancer Institute suggested their findings mean "resistance to bevirimat is less likely to emerge in patients who have failed PIs than in patients who are PI naive" [4]. The Resistance Workshop studies suggest the opposite [2,3].
In the first of these two studies, Monique Nijhuis and colleagues at the University Medical Center Utrecht sequenced the bevirimat-targeted gag region of 644 HIV isolates culled from three European sites [2]. The samples included 437 from antiretroviral-naive people, 270 of them with subtype B HIV-1 and 167 with non-B virus. Among 207 isolates from PI-experienced people with PI mutations, 166 were subtype B and 41 were non-B.
Nijhuis separated the non-B isolates into two groups, the first including subtypes AE, C, D, F, G, 04cpx, and 06cpx, and the second including subtypes A1, A2, AB, AG, H, K, and 11cpx. Almost 80% of group 1 isolates contained at least one bevirimat resistance mutation, as did more than half of group 2 isolates. Among the 270 subtype B isolates from antiretroviral-naive people, 30% had at least one mutation conferring resistance to bevirimat (including H358Y, L363M, Q369H, V370A/M/del, and T371del). Of the 166 subtype Bs from people with PI mutations, bevirimat mutations (including S368C, Q369H, V370A, and S373P) could be found in 45%, a significantly higher rate than in antiretroviral-naive people (P < 0.01). Bevirimat mutations proved significantly more likely in isolates with 3 or more PI mutations than in those with 2 or fewer PI mutations (53% versus 34%, P < 0.05).
The Utrecht team believes these findings "emphasize the [need for] screening for gag mutations before administration of bevirimat."
In second Utrecht study, Nijhuis and colleagues selected 8 recombinant viruses bearing PI resistance mutations in protease and/or the gag NC/p1 cleavage site [3]. After 5 complete passages of these viruses in cells exposed to increasing concentrations of bevirimat, the investigators sequenced the entire gag and protease genes. The rate at which resistance to bevirimat developed appeared to be unaffected by resistance mutations in protease. NC/p1 mutations delayed emergence of resistance to bevirimat.
Both wild-type virus and virus bearing NC/p1 gag cleavage site mutations almost exclusively selected the A364V bevirimat mutation. But the bevirimat mutation pattern in virus harboring mutations in protease proved "far more diverse" and favored selection of mutations in the QVT motif. Until this study, these QVT-motif substitutions were described as natural polymorphisms that render virus less susceptible to bevirimat. Nijhuis's group showed that QVT mutations can emerge under bevirimat pressure, especially in virus already bearing PI resistance mutations. These findings add to the evidence that people with virus resistant to PIs run a heightened risk of resistance to bevirimat.
1. Van Baelen K, Salzwedel K, Rondelez E, et al. Susceptibility of human immunodeficiency virus type 1 to the maturation inhibitor bevirimat is modulated by baseline polymorphisms in Gag spacer peptide 1. Antimicrob Agents Chemother. 2009;53:2185-2188.
2. Verheyen J, Verhofstede C, E Knops E, et al. High prevalence of bevirimat resistance mutations in non-B subtypes and in PI-resistant HIV isolates. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 127.
3. Fun A, van Maarseveen NM, Maas REM, Nijhuis M. Resistance mutations in the viral protease alter bevirimat resistance patterns in vitro. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 128.
4. Adamson CS, Waki K, Ablan SD, Salzwedel K, Freed EO. Impact of human immunodeficiency virus type 1 resistance to protease inhibitors on evolution of resistance to the maturation inhibitor bevirimat (PA-457). J Virol. 2009;83:4884-4894.