Two companies, Bristol Myers Squibb and GlaxoSmithKline, signalled new competition for the valuable first-line protease inhibitor market in presentations of resistance data at the Tenth Conference on Retroviruses and Opportunistic Infections today in Boston.
GlaxoSmithKline took isolates from the NEAT and SOLO studies of GW433908, a new formulation of amprenavir, to support the view that amprenavir should be used as the first protease inhibitor in HIV treatment.
The analysis compared isolates from amprenavir and nelfinavir-treated patients who had experienced virologic failure or failure to achieve virologic suppression in the NEAT and SOLO studies. Both studies compared the two drugs combined with a nucleoside analogue backbone of 3TC/abacavir, and in the NEAT study there was a 2:1 randomisation in favour of amprenavir. In the SOLO study, GW433908 was dosed once daily, boosted with 200mg of ritonavir, but in the NEAT study it was dosed without ritonavir twice daily.
In the NEAT study, 30 amprenavir-treated patients (18%) and 27 nelfinavir-treated patients (33%) experienced virologic failure. Eight amprenavir-treated patients developed primary or secondary protease mutations, and eight nelfinavir-treated patients developed these mutations, a non-significant difference.
However, in the SOLO study, no amprenavir-treated patients developed protease mutations despite 39 virologic failures. Twenty-seven of 62 nelfinavir-treated patients who experienced virologic failure developed protease mutations, a highly significant difference (p
The authors suggest that sub-optimal drug exposure in the unboosted amprenavir group explains the difference, and that use of GW-433908 with ritonavir could preserve future protease inhibitor options.
This view is likely to be contested by Bristol Myers Squibb, who presented details of genotypic and phenotypic analyses of 70 isolates from individuals who experienced failure of atazanavir-containing regimens in phase II and III studies.
This study found that in treatment-naïve individuals, atazanavir resistance was characterised by a unique mutation, I50L, that did not confer cross-resistance to other protease inhibitors, and indeed led to a slight improvement in susceptibility in most cases (>10-fold).
In contrast, PI-experienced individuals who switched to atazanavir, typically with at least three primary protease mutations at baseline, tended to suffer further loss of susceptibility to protease inhibitors with the accumulation of a varied pattern of mutations. No distinct pathway was evident.
Further information on this website
Resistance to protease inhibitors - overview of key findings
Colonno RJ et al. Emergence of Atazanavir Resistance and Maintenance of Susceptibility to Other PIs is Associated with an I50L Substitution in HIV Protease. Tenth Conference on Retroviruses and Opportunistic Infections, abstract 597, 2003.
MacManus S et al. GW433908 in ART-naïve subjects: absence of resistance at 48 weeks with boosted regimen and APV-like resistance profile with unboosted regimen. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 598, 2003.