Response to darunavir, tipranavir, or lopinavir after atazanavir failure
4 May 2007. Related: Conference reports, Drug resistance, European Resistance Workshop 5.
Mark Mascolini, for NATAP.org
Analysis of the Virco resistance database by workers at Tibotec (darunavirs maker) figured that most people stand a better chance of responding to darunavir/ritonavir than to boosted tipranavir or lopinavir after failure of atazanavir/ritonavir [1].
Marie-Pierre de Bethune and colleagues scrutinized 78,978 viral isolates sent to Virco from January 2004 through September 2006. They found 29,410 (37.2%) with reduced susceptibility to at least 1 protease inhibitor (PI), defined as a fold change in susceptibility above the lower clinical cutoff on the vircoTYPE assay. The Tibotec team divided the samples into five groups:
- Group 1: Susceptible to atazanavir/ritonavir (fold change < 2.7, Vircos lower clinical cutoff, n = 15,426
- Group 2: Reduced susceptibility to atazanavir/ritonavir (fold change 2.7 < 6.2, n = 3536)
- Group 3: Reduced susceptibility to atazanavir/ritonavir (fold change 6.2 < 14.3, n = 3155)
- Group 4: Reduced susceptibility to atazanavir/ritonavir (fold change 14.3 < 32.9, n = 2953)
- Group 5: Minimal susceptibility to atazanavir/ritonavir (fold change > 32.9, Vircos upper clinical cutoff, n = 4340).
The number of major IAS-USA-listed PI resistance mutations averaged 3.3 in group 1, 6.0 in group 2, 7.4 in group 3, 8.6 in group 4, and 9.9 in group 5. The median number (and range) of IAS-USA PI mutations per viral sample also rose in a stepwise manner across the atazanavir susceptibility groups–3 (0 to 12) for group 1, 6 (0 to 14) for group 2, 7 (2 to 14) for group 3, 9 (2 to 15) for group 4, and 10 (3 to 17) fr group 5.
According to upper and lower Virco clinical cutoffs for the PIs analysed, viral isolates had the highest predicted maximal response rate to darunavir/ritonavir, as well as the lowest predicted minimal response rate to those PIs (Table 1).
Table 1: Percent of isolates with predicted minimal and maximal response to 3 PIs after atazanavir/ritonavir failure
| PI | Group 1 | Group 1 | Group 3 | Group 4 | Group 5 |
|---|---|---|---|---|---|
| Minimal response | |||||
| DRV/r | 0.01% | 0.11% | 0.32% | 0.64% | 2.07% |
| LPV/r | 1.35% | 6.87% | 13.06% | 25.87% | 59.61% |
| TPV/r | 0.01% | 0.48% | 2.75% | 10.46% | 25.54% |
| Maximal response | |||||
| DRV/r | 98.32% | 91.54% | 82.31% | 70.06% | 46.11% |
| LPV/r | 95.86% | 68.67% | 42.09% | 16.46% | 5.28% |
| TPV/r | 93.93% | 66.12% | 29.35% | 34.20% | 21.08% |
DRV/r = darunavir/ritonavior; LPV/r = lopinavir/ritonavir; TPV/r = tipranavir/ritonavir
Reference:
- de Bethune MP, Bacheler L, De Meyer S, et al. Darunavir exhibits high levels of in vitro antiviral activity against clinical samples with different levels of susceptibility to atazanavir/ritonavir. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 47.