Phase 3 Study Data on Once-daily Darunavir/ritonavir (Prezista/r) Versus Lopinavir/ritonavir (Kaletra) in Treatment-naïve HIV Patients: The ARTEMIS Trial

By Ronald Baker, PhD

Preliminary results of the Phase 3 ARTEMIS trial presented this week at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago (September 17-20, 2007) showed that 84% of treatment-naive patients receiving darunavir/ritonavir (Prezista, formerly TMC 114) with tenofovir/emtricitabine (Truvada) achieved an undetectable viral load (< 50 copies/m/L) at 48 weeks compared with 78% of patients receiving lopinavir/ritonavir (Kaletra) plus Truvada. The mean difference in response between the 2 groups was 5.3%.

Prezista is a second generation protease inhibitor (PI) that is highly active in vitro against both wild-type and PI-resistant HIV. ARTEMIS (Antiretroviral Therapy with TMC114 examined in naive subjects) is the first study of darunavir in HIV patients starting treatment for the first time.

This past June, the US Food and Drug Administration (FDA) granted "fast track" (accelerated) approval to darunavir for use in combination with other antiretroviral agents for the treatment of HIV infection in treatment-experienced adults, such as those infected with HIV strains resistant to more than 1 PI. The current recommended daily dose of darunavir is 600 mg (two 300 mg tablets) taken orally with 100 mg ritonavir twice daily with food.

The FDA has not approved the use of darunavir in treatment-naive patients, and use of the once-daily 800 mg dose used in the ARTEMIS study is experimental.

In the ARTEMIS study, researchers compared the efficacy and safety of darunavir/ritonavir with versus lopinavir/ritonavir in treatment-naive adult patients. In a pre-planned analysis, the study met the primary endpoint of non-inferiority. The 48-week primary analysis from ARTEMIS will be submitted to the FDA later this year as part of the post-marketing commitment for darunavir.

More about the ARTEMIS Study

ARTEMIS is an international ongoing, randomized, open-label Phase 3 trial that included 689 treatment-naive adults. Participants enrolled in the study had not previously received treatment with anti-HIV medications and had a viral load greater than 5000 copies. Overall, the study population had a mean baseline viral load of 4.85 log10 copies/mL and a median CD4 cell count of 225 cells/mm3.

Patients were randomized to receive darunavir/ritonavir 800/100 mg once daily or, based on approved dosing in each country, either lopinavir/ritonavir 800/200 mg once daily or 400/100 mg twice daily, plus a background regimen of Truvada once daily. Patient randomization was stratified based on viral load and CD4 cell count.

48-week Efficacy Results

In the per-protocol analysis of 689 patients randomized to the once-daily darunavir/ritonavir arm (n=343) versus the lopinavir/ritonavir arm (n=346), the 48-week analysis showed the following:

• 84% of patients in the darunavir/ritonavir arm achieved an undetectable viral load (< 50 copies/mL) versus 78% in the lopinavir/ritonavir arm.

• The median change in CD4 cell count from baseline was similar in the darunavir/ritonavir and lopinavir/ritonavir arms (137 vs 141 cells/mm3).

48-week Safety Findings

• In the 2 study arms, the adverse events of at least Grade 2 in severity included diarrhea, nausea, and rash.

• The rate of diarrhea was 4.1% in the darunavir/ritonavir arm vs 9.8% in the lopinavir/ritonavir arm.

• The rate of nausea was 1.7% in the darunavir/ritonavir arm vs 2.9% in the lopinavir/ritonavir arm.

• The rate of rash was 2.6% in the darunavir/ritonavir arm vs 1.2% in the lopinavir/ritonavir arm.

• The incidence of Grade 3-4 lipid-related adverse events reported in the darunavir/ritonavir arm was 1.7% vs 5.2% in the lopinavir/ritonavir arm.

• Both treatment arms had a low incidence of discontinuation.

• Discontinuations due to adverse events were 3.4% in the darunavir/ritonavir arm vs 6.9% in the lopinavir/ritonavir arm.

These efficacy and safety findings are summarized in the table below:

 DRV/r = darunavir/ritonavir
LPV/r = lopinavir/ritonavir
BL = baseline
VL = viral load
AE = adverse events
GI = gastrointestinal

"This is an important study because it provides information regarding the potential use of a once daily Prezista regimen for the treatment of adult patients who have never taken HIV medications before," said Edwin DeJesus, MD, Medical Director of the Orlando Immunology Center and the HUG-Me Program's adult clinic at Orlando Regional Medical Center.

The following points should be considered when initiating therapy with darunavir/ritonavir:

• Treatment history and, when available, genotypic or phenotypic resistance testing should guide the use of darunavir/ritonavir.

• The use of other active antiretroviral agents with darunavir/ritonavir is associated with a greater likelihood of treatment response.

• The risks and benefits of darunavir/ritonavir have not been established in treatment-naive adult or pediatric patients.

Important Safety Information for Prezista

PREZISTA does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

PREZISTA is contraindicated in patients with known hypersensitivity to any of its ingredients.

Coadministration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and have a narrow therapeutic index (e.g., astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, or triazolam) and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration is not recommended with carbamazepine, phenobarbital, phenytoin, rifampin, lopinavir/ritonavir, saquinavir, lovastatin, pravastatin, simvastatin, or products containing St. John's wort (Hypericum perforatum).

Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A in patients receiving PREZISTA/ritonavir. This list of potential drug interactions is not complete.

PREZISTA must be co-administered with 100 mg ritonavir and food to exert its therapeutic effect. Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentration of PREZISTA that will be insufficient to achieve the desired antiviral effect. Please refer to ritonavir prescribing information for additional information on precautionary measures.

Severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported in subjects receiving PREZISTA during the clinical development program. In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in seven percent of subjects treated with PREZISTA; discontinuation due to rash was 0.3 percent. Rashes were generally mild-to-moderate, self-limiting and maculopapular. REZISTA should be discontinued if severe rash develops.

PREZISTA should be used with caution in patients with known sulfonamide allergy.

New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.

PREZISTA should be used with caution in patients with hepatic impairment. There are no data regarding the use of PREZISTA in patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made.

Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.

Immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy.

The potential for HIV-cross-resistance among protease inhibitors has not been fully explored in PREZISTA/ritonavir treated patients.

PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. There are no adequate and well-controlled studies in pregnant women. The effects of PREZISTA on pregnant women or their unborn babies are not known.

In the pooled analysis of POWER 1 and 2 studies, the most frequently reported drug-related adverse events of at least moderate to severe intensity in patients receiving PREZISTA/ritonavir-containing regimen were headache (3.8%), diarrhea (2.3%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%).

Prezista Articles on HIV and Hepatitis.com

09/21/07

Sources

E Dejesus, R Ortiz, H Khanlou, and others. Efficacy and Safety of Darunavir/Ritonavir versus Lopinavir/Ritonavir in ARV Treatment-Naïve HIV-1-Infected Patients at Week 48: ARTEMIS. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, September 17-20, 2007. Abstract H-718b.

Prezista Prescribing Information

Tibotec Therapeutics. New Phase 3 Study in Treatment-naive Adults with HIV Evaluates Efficacy and Safety of Once-daily Prezista/ritonavir vs. Kaletra ad Part of HIV Combination Therapy. Press Release. September 18, 2007.