HIV Treatment Bulletin - Vol. 7, No. 7/8, July/August 2006
Simon Collins, HIV i-Base

As the drug closest to approval and the subject of much hope based on preliminary studies, it was appropriate that there were more individual posters relating to darunavir (TMC-114) than for other individual drugs (and mainly, but not all, were from Tibotec). With limited data from people who have failed on darunavir, several of the analyses reported below are preliminary, but also important. Darunavir was approved by the FDA on 23 June 2006.

The first study from de Bethune and colleagues, showed the difficulty of selecting for darunavir resistance during in vitro passaging. Earlier studies showed PI mutations at R41T and K70E after 75 passages (260 days) which resulted in approximately 10-fold phenotypic resistance. This was extended to 327 passages (1155 days) in which further resistance developed at H69Q and V77I, plus an additional eight mutations in the gag gene (both inside and outside the cleavage site) and resulting in greater phenotypic fold-changes. However, when these mutations were reproduced in recombinant form, they remained phenotypically sensitive.

Key mutations at R41T, K70E or 41T and 70E combined only resulted in fold-change phenotype of 0.3, 0.7 and 0.2 to darunavir, and ranged from 0.2 to 1-fold FC to ritonavir, nelfinavir, saquinavir, amprenavir, lopinavir, atazanavir or tipranavir. Darunavir resistance also occurred more slowly than a similar in vitro experiment with these other six other PIs. The results indicated that resistance develops differently against wild-type virus compared to PI-resistant virus and will be important if darunavir is used in treatment naïve studies.

Picchio and colleagues from Virco predicted phenotypic sensitivity to darunavir using over 56,000 sample genotypes with different levels of PI resistance, from their database from 2004-5. [2] Clinical and/or biological cut-offs using upper and lower levels for each PI were used (3.4 and 99.6 for darunavir) to determine the relative sensitivity to darunavir, defined as maximal, reduced and minimal sensitivity. The complicated methodology is difficult to summarise, but both darunavir and tipranavir showed a low proportion of samples (<5%) with minimal and reduced responses. In a subgroup (n=371) with minimal and reduced response to all PIs except darunavir and tipranavir, ~70% had minimal or reduced response to both new PIs, ~20% had minimal or reduced response only to tipranavir with maximal response to darunavir; and 8% had minimal or reduced response to darunavir and maximal response to tipranavir.

They concluded that these data support a high genetic barrier to the development of resistance to darunavir and that isolates with high levels of PI resistance remain susceptible to this new PI.

Martin King from Abbott showed data from 18 treatment-experienced patients who demonstrated evolution of resistance to lopinavir/r. Median (IQR) FC susceptibility to LPV was 6.9 (4.4-18) at baseline and 63 (34-120) at virological rebound. Fold change for darunavir 1.4 (1.0-1.9) and 2.7 (1.2-9.2); and for tipranavir of 1.9 (1.1 – 3.2) and 1.8 (1.1-5.1) at the same timepoints respectively, suggested that phenotypic sensitivity to both darunavir and tipranavir was retained after high-level resistance to lopinavir/r. [3]

Important data on virological response to darunavir was presented by Tony Vangeneugden and colleagues who looked at phenotypic sensitivity score of background regimens from the three POWER studies, using vircoTYPE resistance assay. [4]

In combined analysis, shown in Table 1, they reported that PSS was predictive of virological responses to darunavir and control groups.

Table 1: Responses in POWER studies by baseline PSS score

Greater proportions of patients with a high PSS achieved viral load <50 copies/mL at weeks 24 and 48, although patients receiving darunavir had a consistently great response to treatment compared to control patients regardless of PSS score.

The numbers of PI mutations was not significant in the multivariate analysis (p=0.13). Most predictive were baseline CD4 and viral load, mean duration of HIV infection and baseline sensitivity to darunavir (p<0.0001) and baseline PSS score (p<0.0001).

Finally, Marie-Pierre de Béthune and colleagues presented an analysis of phenotypic and genotypic determinants of resistance related to virological response, summarised in Table 2. [5]

Table 2: Virological response and baseline sensitivity to darunavir

Darunavir fold-change increased with number of resistance mutations. While darunavir fold change was the strongest predictor of response, mutations associated with a diminished response included V11I, V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V and L89V, which were mostly present with a high number of other PI mutations. When 0, 1 and 2 of these key mutations were present, 64%, 50% and 42% of patients respectively achieved <50 copies/mL at week 24; with response rates of only 20% of patients with 3 and <10% or patients with 4 of these mutations were present.

This group was a better predictor than the IAS PI mutation list (where around 30-50% patients responded with up to 10 IAS mutations, and <20% responded with 11 or more mutations.

References:

Unless stated otherwise, all references to abstracts relate to the Programme and Abstracts from the XV International Drug Resistance Workshop, 13-17 June 2006, Sitges, Spain. The abstract book is published as a supplement to Antiviral Therapy 2006, Volume 11.

2006-07-10
IB060707-06

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