By Ronald Baker, PhD

Widespread use of HIV protease inhibitors (PIs) has brought about dramatic improvements in the treatment and management of HIV/AIDS. Nonetheless, the seemingly inevitable development of antiretroviral drug resistance remains a barrier to effective long-term treatment of patients with HIV infection.

As the result of resistance and cross-resistance among the currently available anti-HIV drugs, there is a pressing need to discover or create new therapies that offer durable suppression of the virus in highly treatment-experienced patients.

The HIV PI darunavir (Prezista, aka TMC114), recently approved in the U.S. and even more recently in the European Union, has shown potent activity against both wild-type HIV and virus with multiple PI-resistant mutations in vitro. In addition, in combination with low-dose ritonavir, darunavir has demonstrated potent activity in treatment-experienced patients [1]. Darunavir/ritonavir 600/100 mg twice daily is the recommended (FDA-approved) dose for treatment-experienced HIV patients.

The POWER 1 and 2 studies (Performance Of TMC114/ritonavir When evaluated in treatment-Experienced patients with PI Resistance) were designed to assess the safety and effectiveness of darunavir/ritonavir compared with investigator-selected control or comparator PIs (CPIs) in treatment-experienced patients who have experienced virological failure. The primary analysis of the POWER 1 study appears in the February 19, 2007 issue of AIDS and is summarized below.

Power 1 Study

POWER 1 is a partially blinded, randomized 24-week dose-finding study that compares the safety and efficacy of 4 doses of darunavir plus low-dose ritonavir (darunavir/ritonavir) with investigator-selected control PIs.

Patients with 1 or more primary PI-resistance mutation and HIV RNA > 1000 copies/mL received optimized background therapy, plus darunavir/ritonavir 400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily, or 600/100 mg twice daily, or else CPI(s).

The primary endpoint (intent-to-treat) compared proportions of patients achieving viral load reduction >/= 1.0 log10 copies/mL from baseline.

Results

• In total, 318 patients were treated.

• Baseline mean viral load was 4.48 log10 copies/mL; median CD4 cell count was 179 cells/mm3.

• In the CPI arm, 62% of patients discontinued therapy (54% due to virological failure).

• 10% of darunavir/ritonavir patients discontinued therapy.

• More darunavir/ritonavir (69%-77%) than CPI patients (25%) reached the primary endpoint (P < 0.001).

• 43%-53% of darunavir/ritonavir patients and 18% of those in the CPI arm achieved viral loads < 50 copies/mL (P < 0.001).

• Darunavir/ritonavir was associated with greater mean CD4 cell count increases compared with CPI(s) (68-124 vs 20 cells/mm3; P < 0.05).

• Darunavir/ritonavir 600/100 mg twice daily demonstrated the highest virological and immunological responses.

• Adverse event (AE) incidence was similar between treatment arms.

• Headache and diarrhea were more common with CPI(s).

Safety

Overall AE incidences (all grades, regardless of causality), were comparable between patients receiving darunavir/ritonavir and CPI(s), despite treatment exposure differences (39.8 and 26.3 weeks, respectively).

No relationship between darunavir/ritonavir dose and AE incidence or discontinuation was observed, according to the authors. Excluding enfuvirtide-associated injection site reactions, the 2 most common treatment-emergent AEs (? 5% of darunavir/ritonavir patients) were headache (17%; 24% with CPIs) and diarrhea (16%; 29% with CPIs).

Overall, 36 darunavir/ritonavir patients and 9 CPI patients (14% each) reported one or more serious AE, most commonly pneumonia and headache. AEs led to discontinuation in 12 darunavir/ritonavir patients (5%) and 4 patients in the CPI arm.

In conclusion, the authors write, "TMC114/ritonavir [darunavir/ritonavir] demonstrated statistically higher 24-week virological response rates and CD4 cell count increases than CPI(s). TMC114/ritonavir 600/100 mg twice daily has received regulatory approval in treatment-experienced patients."

Discussion

The study authors note that following 24 weeks of treatment, darunavir/ritonavir brought about viral load reductions > 1.0 log10 copies/mL in a significantly higher proportion of treatment-experienced patients than CPI(s). Although this has classically been the efficacy benchmark in treatment-experienced patients, the therapeutic goal for this population has been redefined as achieving a viral load < 50 copies/m [2]. This goal is associated with greater durability of response [3], and likely represents the most stringent measure of virological efficacy, particularly in treatment-experienced patients.

"The effectiveness of TMC114/ritonavir," write the authors, "has been demonstrated by 53% of patients receiving TMC114/ritonavir 600/100 mg b.i.d. [twice daily] achieving viral loads < 50 copies/mL after 24 weeks, compared with 18% of patients receiving CPI(s)." Further, they note, "Patients receiving TMC114/ritonavir 600/100 mg b.i.d. also had the highest increase in CD4 cell count and increase in the proportion of patients with CD4 cell counts above 200 cells/mm3."

It should be noted that although darunavir/ritonavir demonstrated statistically higher virological and immunological responses compared with CPI(s) at 24 weeks, pair-wise comparisons of darunavir/ritonavir doses revealed no statistically significant differences for virological response. However, the authors state that "Numerically the greatest responses were observed with darunavir/ritonavir 600/100 mg b.i.d. which, combined with its safety and tolerability profile, supported its recent regulatory approval."

All patients receiving darunavir/r have been switched to this recommended dose for the ongoing open-label phase of the trial. The authors conclude, "Ongoing studies will define the efficacy and safety of TMC114/ritonavir in other patient populations."

Efficacy Results Presented, but Not Yet Published

Although the 24-week data from POWER 1 described above represent the only data from the series of POWER studies published to date in a peer-reviewed journal, preliminary data have been presented at recent scientific meetings on pooled 24-week efficacy data from POWER 1 and 2 and 24-week efficacy data from POWER 3. In addition, the Prezista product label includes supportive 48-week long term efficacy data from the pooled analysis of POWER 1 and 2 in treatment experienced patients who received darunavir/ritonavir 600mg/100mg twice daily.

POWER 1 and 2 Efficacy Results

In a pooled analysis of the POWER 1 and 2 studies, following 24 weeks of treatment [4]:

• 70% of 131 patients in the darunavir/ritonavir arm had a virological response compared with 21% of 124 patients in the control group; virological response was defined as a viral load decrease of at least 1.0 log10 (90% reduction) from baseline.

• 3 times as many patients in the darunavir/ritonavir arm (45%) achieved an undetectable viral load (< 50 copies/mL) compared with those in the investigator-selected control PI arm (12%).

• The mean increase in CD4 cell counts from baseline was 5 times higher in the darunavir/ritonavir group than in the control group (92 vs 17 cells/mm3, respectively).

POWER 3 Efficacy Results

The European Commission's recent conditional approval of darunavir was also based on supportive data from POWER 3, a non-randomized, open-label analysis of treatment-experienced patients similar to those in POWER 1 and POWER 2 and who received darunavir/ritonavir (600mg/100mg twice daily). Data from this large cohort (n = 327) showed that after 24 weeks [4]:

• 66% of patients achieved a reduction in viral load of 1.0 log10 or more from baseline.

• 43% attained undetectable virus levels (< than 50 copies/mL).

48-week Results

Additionally, the darunavir EU product label includes supportive 48-week long term efficacy data from the pooled analysis of POWER 1 and POWER 2 in treatment experienced patients who received darunavir/ritonavir 600mg/100mg twice daily. The 48-week analysis indicates that [5]:

• 61% of patients achieved a reduction in viral load of at least 1.0 log10 from baseline.

• 45% of patients attained undetectable virus levels (< 50 copies/mL).

02/20/07

Prescribing Information

Sources

C Katlama, R Esposito, J M Gatell, and others (for the POWER 1 study group). Efficacy and Safety of TMC114/ritonavir in Treatment-experienced HIV Patients: 24-week Results of POWER 1 [Fast Track Article]. AIDS 21(4): 395-402. February 19, 2007.

Prezista (darunavir). Summary of Product Characteristics, EU.

Tibotec Pharmaceuticals. Anti-HIV Medication Prezista Receives Conditional Marketing Authorization in the European Union. Press Release. February 16, 2007.

References

1. K Arastéh, N Clumeck, A Pozniak and others. TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial. AIDS 19: 943-947. 2005.

2. S M Hammer, M S Saag, M Schechter, and others. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 296: 827-843. 2006.

3. U.S. Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2005. Latest version available at: http://AIDSinfo.nih.gov

4. Prezista (darunavir). Summary of Product Characteristics, EU (page 15).

5. Prezista (darunavir). Summary of Product Characteristics, EU (page 16).