Resistance Profile of the New Protease Inhibitor Darunavir (Prezista)

Prezista Tablet

The widespread use of protease inhibitors (PIs) in the treatment of HIV has resulted in the emergence of viral strains with extensive cross-resistance to the drugs. In turn, this has resulted in a decline in the effectiveness of the available PIs.

There is a need for new PIs that are safe, easy to use, tolerable, and effective against both resistant and wild-type HIV strains, and that can provide durable suppression in both treatment-naive and treatment-experienced HIV patients.

The recently approved PI darunavir (Prezista) has demonstrated greater resilience against the development of resistance and greater activity against resistant HIV strains than other PIs.

The U.S. Food and Drug Administration (FDA) approved darunavir, in combination with low-dose ritonavir (Norvir), as part of combination therapy for the treatment of HIV in treatment-experienced adults, such as those with HIV strains resistant to more than one other PI.

In the current study, published in March 1, 2008 issue of AIDS Research and Human Retroviruses, researchers explored the resistance profile of darunavir in treatment-experienced patients using pooled 24-week data from the POWER 1, 2, and 3 trials (N = 458) at the recommended dose of darunavir with low-dose ritonavir (600/100 mg twice daily).

As previously reported, pooled 48-week data from the POWER 1 and 2 showed that virological responses to darunavir/ritonavir were sustained through at least week 48.*

Following are the summary results of the present study:

• Baseline darunavir fold change in EC50 (50% effective concentration) was a strong predictor of virological response at week 24.

• Preliminary phenotypic clinical cut-offs of 10 and 40 were established.

• Virological response to darunavir/ritonavir was maintained in the presence at baseline of a high number of IAS-USA PI resistance-associated mutations (RAMS).

• A diminished response occurred with > 14 IAS-USA PI RAMs.

• 11 protease mutations associated with diminished darunavir/ritonavir virological response were identified: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V.

• These darunavir resistance-associated mutations (DRV RAMS) occurred in the presence of a high number of IAS-USA PI RAMS.

• Virological response was diminished with 3 or more DRV RAMS in the background of a high number of IAS-USA PI RAMS.

• Incremental numbers of DRV RAMS were more predictive of outcome than were IAS-USA PI RAMS.

• Mutations developing during darunavir/ritonavir virological failure (V32I, L33F, I47V, I54L, and L89V) were also included in the DRV RAMS list.

• Site-directed viral mutants carrying these 5 mutations, or any 1 of these mutations either alone or together with 1 or 2 IAS-USA PI RAMS, showed no reduced darunavir susceptibility.

• This suggests that a high number of additional background mutations is required for darunavir resistance.

These findings led the study authors to conclude, "In this population of treatment-experienced patients, darunavir/ritonavir demonstrated significantly greater efficacy than investigator-selected control PIs of trials POWER 1 and 2, regardless of baseline viral genotype or phenotype, while exhibiting a high genetic barrier to the development of resistance."

Discussion

The researchers found that in clinical practice, "only a small proportion of the treatment-experienced patient population is likely to harbor sufficient DRV RAMS to compromise the activity of darunavir."

They noted that the current understanding of the resistance profile for darunavir is based on data from studies in highly treatment-experienced patients. However, they emphasized, "Ongoing resistance studies will more clearly define the mutation profile for darunavir."

In particular, they pointed out that more data will become available from Phase 3 studies of the recently approved NNRTI etravirine (Intelence), in which patients also received darunavir/ritonavir. In addition, the authors wrote that new information will emerge from ongoing Phase 3 studies comparing darunavir/ritonavir 600/100 mg twice-daily and lopinavir/ritonavir in treatment-experienced (but lopinavir-naive) patients and darunavir/ritonavir 800/100 mg once-daily with lopinavir/ritonavir in treatment-naive patients.

04/15/08

References

S de Meyer, T Vangeneugden, B van Baelen, and others. Resistance Profile of Darunavir: Combined 24-Week Results from the POWER Trials. AIDS Research and Human Retroviruses 24(3): 379-388. March 1, 2008.

B Clotet, N Bellos, JM Molina, and others. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: A pooled subgroup analysis of data from two randomised trials. Lancet 369:1169-1178. 2007.

Other Sources

1. C Katlama, R Esposit, J Gatel, and others. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 21: 395-402. 2007.

2. S De Meyer, T Vangeneugden, E Lefebvre, and others. Phenotypic and genotypic determinants of resistance to TMC114: Pooled analysis of POWER 1, 2 and 3. 15th International Drug Resistance Workshop, Sitges, Spain, 13-17 June 2006. Abstract 73.

3. Tibotec Inc. Prezista (darunavir) Prescribing Information. October 2006. Available at www.prezista.com.

4. Prezista (darunavir) Summary of Product Characteristics. February 2007. Available at www.emea.eu/humandocs.