Darunavir 206361-99-1

Darunavir is a second-generation protease inhibitor (PIs), designed specifically to overcome problems with the older agents in this class, such as indinavir. Early PIs often have severe side effects and drug toxicities, require a high therapeutic dose, are costly to manufacture, and show a disturbing susceptibility to drug resistant mutations. Such mutations can develop in as little as a year of use, and effectively render the drugs useless. Darunavir was designed to form robust interactions with the protease enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutations to PIs.

Darunavir received much attention at the time of its release, as it represents an important treatment option for patients with drug-resistant HIV. Patient advocacy groups pressured developer Tibotec not to follow the previous trend of releasing new drugs at prices higher than existing drugs in the same class. Darunavir was priced to match other common PIs already in use, such as kaletra. The drug costs around $9000 for a one year supply.

Efficacy

Prezista is an OARAC (DHHS) recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.

It was approved by the FDA for treatment-naive patients on October the 21st 2008.

Darunavir showed superiority to lopinavir/ritonavir and other protease inhibitors in the POWER trials. The POWER 1 and POWER 2 were designed for treatment-experienced patients, together with supportive data from the POWER 3 analysis . The patients eligible for these studies had experience with at least one protease inhibitor, one non-nucleoside reverse transcriptase inhibitor and two nucleoside reverse transcriptase inhibitors , and had one or more primary protease inhibitor mutations.

Darunavir also showed superior results to lopinavir in the TITAN trials (pre-planned, secondary endpoint, week 48), which was designed for patients with less advanced HIV disease compared to the POWER trials.

ARTEMIS trial

ARTEMIS includes 689 treatment-naive participants with a baseline viral load of at least 5000 copies/mL who were randomly assigned to receive 800/100 mg once-daily darunavir/ritonavir or 800/200 mg lopinavir/ritonavir given once- or twice-daily. At 96 weeks, darunavir/ritonavir remained non-inferior to lopinavir/ritonavir.

• In an intent-to-treat analysis, significantly more patients in the darunavir/ritonavir arm achieved HIV RNA < 50 copies/mL compared with the lopinavir/ritonavir arm (79% vs 71%; P = 0. 012).
• Response rates in the darunavir/ritonavir arm were statistically superior to those in the lopinavir/ritonavir arm for patients with high baseline viral load and low baseline CD4 count.
• Among patients with baseline viral load > 100,000 copies/mL, 76% of patients in the darunavir/ritonavir arm and 63% in the lopinavir/ritonavir arm achieved HIV RNA < 50 copies/mL (P = 0. 023).
• Once-daily darunavir/ritonavir was generally safe and well tolerated.
• Fewer patients in the darunavir/ritonavir arm discontinued treatment due to adverse events (4% vs 9%).
• Patients taking darunavir/ritonavir were less likely to have moderate to severe (grade 2-4) treatment-related diarrhea (4% vs 11%; P < 0. 001).
• Grade 2-4 treatment-related rash occurred infrequently in both arms (3% with darunavir/ritonavir vs 1% with lopinavir/ritonavir; P = 0. 273).
• Patients taking darunavir/ritonavir had smaller average increases in triglycerides (0. 1 vs 0. 8 mmol/L, or 12% vs 50%) and total cholesterol (0. 6 vs 0. 9 mmol/L, or 15% vs 23%) (both P < 0. 0001).

TITAN trial

Analysis of 595 treatment-experienced patients being lopinavir/r-naïve, HIV-1 infected adults with a viral load of >1000 HIV-1 RNA copies/mL. Pre-planned secondary endpoint findings include:

• 71 percent of patients in the darunavir/r arm reached an undetectable viral load (<50 copies/mL) vs. 60 percent of patients in the lopinavir/r arm, a statistically significant difference (p=0. 005)
• 77 percent of patients in the darunavir/r arm achieved at least a 1 log10 reduction in HIV RNA vs. 69 percent in the lopinavir/r arm, a statistically significant difference (p=0. 028)
• The median increase from baseline in CD4 cell count was similar between the darunavir/r and lopinavir/r arms (88 cells per cubic millimeter vs. 81 cells per cubic millimeter)

Development of resistance also was studied. Findings include:

• 10 percent of patients in the darunavir/r arm experienced virological failure vs. 22 percent of patients in the lopinavir/r arm
• Among patients experiencing virologic failure who had baseline and endpoint genotype data, 21 percent of patients in the darunavir/r arm developed primary PI resistance mutations vs. 36 percent of patients in the lopinavir/r arm, and 14 percent of patients in the darunavir/r arm developed primary NRTI resistance mutations vs. 27 percent of patients in the lopinavir/r arm

POWER 1 and POWER 2 trials

A pooled analysis of results from POWER 1 and POWER 2 demonstrated that after 24 weeks:

• Significantly more treatment-experienced patients achieved a reduction in viral load at the 24-week primary endpoint with darunavir, compared with the investigator-selected PI (70% vs 21%, respectively).
• Almost four times as many treatment-experienced patients (45%) have achieved an undetectable viral load with the darunavir containing regimen, compared with the investigator-selected PI arm (12%).
• In treatment-experienced patients, the darunavir containing regimen increases CD4 cell counts five times more than the investigator-selected PI arm (92 cells/mm3 vs 17 cells/mm3, respectively) (Johnson & Johnson Press Release, 2006; Lazzarin, 2005)

The efficacy results of POWER 1 and POWER 2 are confirmed by data from a large, non-randomized, open-label analysis known as POWER 3. After 24 weeks:

• 65 percent of patients achieved a reduction in viral load of 1 log10 or more, versus baseline.
• 40 percent of patients reached undetectable virus levels (<50 HIV RNA copies/mL). (Molina, 2005)

Pharmacoeconomic considerations

In the US and UK, healthcare costs were estimated to be lower with boosted darunavir than with investigator-selected control protease inhibitors in treatment-experienced patients.

Safety

The efficacy results of POWER 1 and POWER 2 are confirmed by data from a large, non-randomized, open-label analysis known as POWER 3. After 24 weeks: